Mouse Cytomegalovirus: Necrosis of Infected and Morphologically Normal Submaxillary Gland Acinar Cells During Termination of Chronic Infection

The ultrastructural lesions in the submaxillary glands of C₃H mice chronically infected with the murine cytomegalovirus are reported. Virus was synthesized in the nucleus of acinar glandular cells. After passage into the cytoplasm, virus was located in large vesicles which were derived from the Golgi apparatus. These vesicles, which were periodic acid-Schiff positive, migrated to the apex of the cell and released virus into the acinar lumen or canaliculi. Eventually, lymphocytes infiltrated the interstitium and surrounded the basal lamina of acini which contained infected cells. In acini encompassed by lymphocytes, both infected cells and morphologically normal acinar cells simultaneously degenerated, producing a small focus of necrosis. Physical contact between lymphocytes and necrotic cells did not occur for an intact basal lamina was always found interposed between them. Degeneration of infected cells coincided with a decrease in virus titer in the salivary glands. Degeneration of infected and normal acinar cells also occurred in DBA 2 mice which lack the fifth component of complement. In mice conditioned with cortisone to suppress inflammation, neither infected nor normal acinar cells degenerated. We concluded from the electron microscope observations that lymphocytes terminate chronic MCMV infection, that MCMV infection of acinar epithelium is not cytolytic and that normal cells also undergo necrosis during termination of chronic MCMV infection. It is postulated that lymphocytes in responding to infection release a cytotoxic substance which diffuses into the acini and causes indiscriminate necrosis of acinar cells.     

Light-microscopic stereology for the study of the ventral and dorsal prostates of the syrian hamster: Strategy,techniques, and applications

A stereological approach to studying the architecture of the ventral and dorsal prostates of the Syrian hamster is described. In this approach, the prostate is considered to consist of acinar and interacinar compartments. The acinar compartment is divided into luminal, epithelial, lamina proprial, and muscular stromal compartments. Volume fractions of acini and interacinar tissue are calculated with reference to the volume of the gland; those of the acinar components are calculated with reference to the acinar volume. Volume fractions are determined from point counts. The surface fraction of the secretory epithelium is determined from intercept counts, with reference to the volume of the epithelium. By assuming that the acini are cylindrical, the acinar length fraction is calculated with reference to the volume of the gland. Absolute values for the volumes of different components, epithelial surface area, and acinar length can be determined from the weight of the gland, its specific gravity, and the volume fraction of that component, or epithelial surface fraction, or acinar length fraction, respectively. Finally, from these values and assuming a cylindrical shape for acini, characteristics of the typical acinus, including its radius, the thicknesses of its epithelium, lamina propria, and muscular stroma, and the amount of mucosal folding can be calculated from simple geometrical formulae. This approach is illustrated from a consideration of the ventral and dorsal prostates of 20-week-old Syrian hamsters.     

Phyllodes tumor of the prostate with exuberant glandular hyperplasia

Reported herein is an unusual case of prostatic phyllodes tumor with exuberant glandular hyperplasia that led to misdiagnosis of adenocarcinoma. The tumor was detected in a 52-year-old man who had a 1 year history of dysuria. Adenocarcinoma of the prostate was diagnosed from a needle biopsy specimen. The patient received hormonal therapy for 6 months and underwent radical prostatectomy. Histologically, the tumor had an atypical stromal cell proliferation and elongated slit-like glands characteristic of a phyllodes tumor. The tumor was also accompanied by a florid proliferation of small acini, most of which lacked basal cells, a common manifestation of adenocarcinoma in the overall tumor area. The following features of the resected tumor were helpful for concluding that these acini were benign: lack of cytological anaplasia in spite of structural atypia, presence of scattered basal cells confirmed by immunohistochemistry (high-molecular-weight cytokeratin), and histological transition from these acini to apparently benign slit-like glands. The final diagnosis was then made as 'phyllodes tumor of the prostate with exuberant glandular hyperplasia'. Atypical stromal cells might provide a clue for the recognition of this rare tumor at initial diagnosis by needle biopsy.     

Down-regulation of CEACAM1 in human prostate cancer: correlation with loss of cell polarity, increased proliferation rate, and Gleason grade 3 to 4 transition

Many cancers have altered expression of various cell adhesion molecules. One of these is CEACAM1, which has been found to be downregulated in several carcinomas, including prostate cancer. We explored its immunohistochemical expression in a set of 64 total prostatectomy specimens and compared it with that of the epithelial cell adhesion molecule E-cadherin and occludin, a tight junction-associated molecule. The luminal surface of the epithelial cells of normal prostate glands and ducts showed a dense expression of CEACAM1. This pattern prevailed in prostate cancer of Gleason grades 1 to 3 as long as the cells maintained their polarity and formed individual glands. With "fusion" of glands (ie, in the transition to Gleason grade 4), the expression of CEACAM1 was lost in polygonal nonpolar cells and was lost or focally very weak in cells lining a lumen in the cribriform complexes. E-cadherin, which outlined the basolateral cell membranes of contacting neighboring epithelial cells was also downregulated in prostate carcinomas. However, the loss of E-cadherin expression in higher grades was gradual and not related to the Gleason 3 to >4 transition. Occludin was also lost in polygonal (ie, unpolarized) cells of Gleason grades 4 and 5, but remained expressed in all cells facing a lumen in all grades of cancer, which CEACAM1 was not. In conclusion, downregulation of CEACAM1 as well as that of occludin in prostate cancer is associated with loss of cell polarity. It coincides with the formation of the complex glandular architecture of Gleason grade 4 pattern or complete loss thereof in Gleason grade 5 patterns. The proliferative activity, measured as Ki67 labeling index, showed a fourfold increase in the carcinoma cells with lost CEACAM1 expression, supporting previous observations that CEACAM1 regulates cell proliferation. Immunohistochemical analysis of CEACAM1 expression patterns may be useful in assessment of the malignant potential of prostate carcinoma.     

Expression of cyclin D1 in normal, metaplastic, hyperplastic endometrium and endometrioid carcinoma suggests a role in endometrial carcinogenesis

CONTEXT: Endometrioid carcinoma is often preceded by characteristic histopathologic lesions known as endometrial hyperplasia. Estrogen appears to be involved in the development of endometrioid carcinoma. Other mechanisms of endometrial carcinogenesis include mutations in p53 and PTEN tumor suppressor genes and overexpression of cyclin D1. However, the pattern of cyclin D1 expression is not well defined in normal, hyperplastic, neoplastic, and metaplastic endometrium. DESIGN: Cyclin D1 immunohistochemical analysis was used to evaluate 108 fixed, paraffin-embedded endometrial biopsy specimens and uterine resections obtained from 108 patients. Specimens included proliferative and secretory endometria, simple and complex hyperplastic lesions, and endometrioid adenocarcinoma. Normal and metaplastic surface epithelia were also evaluated independently of glandular morphologic features. RESULTS: Cyclin D1 was significantly overexpressed in glands with complex hyperplasia and endometrioid adenocarcinoma compared with proliferative or secretory endometrium and simple hyperplasia. Significant overexpression was also noted in papillary, syncytial, and squamous metaplasias compared with normal surface epithelium or epithelium with tubal metaplasia. CONCLUSION: Overexpression of cyclin D1 increases from normal endometrium to hyperplasia and carcinoma, suggesting that it may play a role in endometrial carcinogenesis. Overexpression of cyclin D1 in endometrial glands was independent from overexpression of cyclin D1 in surface metaplastic epithelium.     

Effects of short-day photoperiods and of castration on the structural integrity of the ventral and dorsal prostates of the Syrian hamster (Mesocricetus auratus)

Short-day photoperiods and castration both cause reductions in the weights of male accessory sex glands. In the Syrian hamster, we have found that the ventral prostate loses less weight following these treatments than does the dorsal prostate. In this paper, we report on the effects of the pineal and of castration on the structural integrity of these glands, as assessed by stereological techniques. Short days result in little alteration to the ventral prostate or its acinar composition. The typical acinus is narrower following 10 weeks in short days. The ventral prostate also responds to castration with a narrower acinus, and, in addition, it shows a decrease in the epithelial volume fraction and increases in those of the lumen and muscular stroma. In neither case is there a change in the proportion of the gland consisting of acinar or interacinar components. Short-day photoperiods and castration generally show similar effects in the dorsal prostate. In both cases, there are increases in the proportion of the gland made up of interacinar tissue. Within the acini, there are decreases in the volume fractions of lumen and large increases in those of lamina propria and muscular stroma. Following both treatments, typical acini are narrower and show reduction in the thickness of the epithelium and increases in the thickness of the lamina propria and muscular stroma. Thus, in the ventral prostate, both short days and castration lead to subtle changes which are different with each treatment and which differ from those that occur in the dorsal prostate. In the dorsal prostate, there are relative increases in the proportions of nonepithelial elements following both of these treatments. These results are discussed in relation to the mode of action of the pineal in causing accessory sex gland regression.     

Morphological and immunohistochemical characteristics of the heterogeneous prostate-like glands (paraurethral gland) seen in female Brown-Norway rats.

Morphological and immunohistochemical characteristics of the prostate-like glands (paraurethral gland) seen spontaneously in female Brown-Norway (BN) rats were investigated by gross, and light and electron microscopic examination. At 9- to 10-weeks-old, the paraurethral gland was detected in 50 out of 52 female animals examined (96.2%), and it was observed as single or paired structures located ventrolaterally in the urethra just caudal to neck of the urinary bladder. Microscopically, the glandular acini consisted of flat to cuboidal secretory epithelium surrounded by the smooth muscle. The glands displayed modest secreting activity, and a few secreting materials were observed in the acinar lumens. The main peripheral ducts were located in the urethral wall, and drained into the urethra on both sides. Ultrastructurally, abundant rough endoplasmic reticulum (RER), numerous mitochondria and lysosomes, and secretory granules in the apical portion of the epithelial cells were noted, and basal cells were also observed. These gland epithelial cells showed positive reactions when stained for androgen receptor (AR), prostate specific antigen (PSA), or prostate specific acid phosphatase (PSAP). The nature of this paraurethral gland resembled that of the prostate gland in male rats. Thus, the paraurethral glands seen in the females were considered homologous to the prostate gland in males.     

Histochemical studies of epithelial cell glycoconjugates in atrophic, metaplastic, hyperplastic, and neoplastic canine prostate

The nature and distribution of lectin receptors were studied in normal, atrophic, metaplastic, hyperplastic, and neoplastic epithelium of canine prostate. Results were compared with prostatic epithelium of castrated dogs treated for 2 weeks with estradiol-17 beta 17-cyclopentylpropionate, 5 alpha-adrostane-3 alpha,17 beta-diol dipropionate, or 5 alpha-dihydrotestosterone. Eight biotinylated lectins were used as histochemical probes and avidin-biotin-peroxidase complex served as the visualant. Receptors for Ulex europaeus agglutinin-I were present in atrophic prostatic epithelium. Receptors for U. europaeus agglutinin-I, wheat, germ agglutinin, Dolichos biflorus agglutinin, and soybean agglutinin were present in epithelium that had undergone squamous metaplasia. Binding of peanut agglutinin receptors was present, to a limited extent, in squamous epithelium and was increased after they were unmasked (sialic acid residues cleaved with neuraminidase). In glandular cells of normal canine prostate and in benign prostatic hyperplasia, receptor sites were stained with Ricinus communis agglutinin-I, Concanavalia ensiformis agglutinin wheat germ agglutinin, and U. europaeus agglutinin-I. The basal cells in these tissues did not bind lectins. Prostatic carcinoma cells demonstrated receptors for wheat germ agglutinin and U. europaeus agglutinin-I. Responding and atrophic acini were present in prostates of castrated dogs treated with estradiol-17 beta 17-cyclopentylpropionate. Glandular cells of atrophic acini exhibited lectin receptor profiles similar to counterparts in castrated-untreated dogs. However, glandular cells responding to estrogen exhibited staining of free and cryptic peanut agglutinin receptor sites. Glandular cells of castrated dogs treated with 5 alpha-androstane 3 alpha,17 beta-diol dipropionate and 5 alpha-dihydrotestosterone have a pattern of lectin receptors similar to that found in normal and hyperplastic epithelium. Our studies show significant differences in lectin-binding patterns in the epithelium of atrophic, metaplastic, hyperplastic, and neoplastic canine prostate. They also demonstrate that the species of carbohydrate residues present in the glandular cells can be modified with sex hormones.     

Morphological Characterization of Acinar Cluster in Mouse Lung Using a Multiscale‐based Segmentation Algorithm on Synchrotron Micro‐CT Images

Understanding the three‐dimensional morphology of pulmonary acini is essential when exploring the biomechanics of respiratory function. In this study, we characterized the morphology of individual acini and a cluster of acini stemming from the same terminal conducting airway using a quantitative approach based on the semi‐automatic segmentation of synchrotron micro‐CT images of mouse lung. The volume and surface area of five clusters of mouse acini including 50 individual acini were estimated based on the voxel and surface mesh of segmented acini at FRC. The pathway length and width were estimated for one cluster including 15 acini based on the skeleton of segmented acini. The acinar volume was 0.09 ± 0.07 mm³ (mean ± SD), and the surface area was 6.82 ± 4.49 mm², in agreement with previous studies. The volume of the acinar clusters was 0.89 ± 0.34 mm³, and the surface area was 68.18 ± 17.66 mm². The largest volume acinus per cluster was found in the distal region of the terminal conducting airway, and apparent respiratory bronchioles were observed only in large‐volume acini. The generation number of pathways per acinus was 8 ± 2 (range: 6–12). The pathway length at lower generations (generations 2–6) increased with the generation number in a single cluster, while did not significantly change at lower generations in some acinar groups. The pathway width increased with increasing generation numbers. Our approach characterized the quantitative morphology of pulmonary acinar clusters in mouse lung, and the results can be used in further biomechanical simulation studies. Anat Rec, 299:1424–1434, 2016. © 2016 Wiley Periodicals, Inc.     

Neuroendocrine cells in the vestibular glands of the genital tract of cows and pigs

The presence of neuroendocrine (NE) cells producing biogenic amines and hormonal peptides has been investigated in the vestibular glands of the genital tracts of cows and pigs using immunohistochemistry. NE cells containing chromogranin A-, serotonin-, cholecystokinin- and somatostatin-immunoreactive material were found in both major and minor vestibular glands. Such cells were numerous, scattered in the acini and excretory duct epithelium, small in size and rounded, triangular or bipolar in shape. The function of the NE vestibular cells has been related to the secretory activity of the glands and to a sexual climax induction mechanism involving the stimulation of 5HT(3) receptors of vestibular nociceptor nerve fibers. The role of NE cells in small cell carcinomas of the vestibular glands is a topic for further investigation owing to possible parallelism between this type of tumor and the small cell carcinoma of the human prostate.     

The streaming submandibular gland

Twenty female young adult rats were injected with tritiated thymidine (3HTdR). The animals were then killed in groups of five, at the following times: 1 hour, and 4, 16, and 23 days. Autoradiograms of sections through the submandibular gland were prepared, and the location of labelled cells in relationship to tubuli and acini was recorded. The different tubular and acinar cross sections could be distinguished by their cell number. Narrow tubuli had fewer nuclei than the wider ones. The nuclear number of a cross section was defined as its class and the location of a labelled epithelial cell was expressed in relationship to the class where it was found. The location of a labelled stromal cell was determined by the class of its neighboring tubular or acinar cross sections. The mean cell numbers of intercalated, granular, and striated duct cross sections were, respectively, 4.7, 10.5, and 10.2, while the average cell content of acini was 4.7 cells. One hour after labelling most labelled tubular epithelial and stromal cells were found in tubular cross sections (or low tubular classes), while in the acini, labelled epithelial and stromal cells were found mainly in wider cross sections (or higher acinar classes). Within the next 23 days labelled tubular cells and stroma proceeded into higher classes, while labelled acinar epithelium and stroma cells were displaced into narrower cross sections (or lower classes). The displaced tubular epithelium and stroma covered daily 0.26 classes. At this velocity the cell will reach the highest tubular class in 62 days and the estimated maximal tubular cell life span is 62 days.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose effects of acetylcholine on the cell volume of rat mandibular salivary acini.

The effects of acetylcholine (ACh) on the cell volume of the isolated rat mandibular acini were studied stereologically using video-enhanced contrast optical microscopy. The lengths of major and minor axes of the acini were measured in the successive video images, from which the relative volume change was estimated. ACh induced a rapid shrinkage of the acinar cell to reach minimum volume within 1 min. Simultaneously, the acinus and acinar clump shrunk in the same proportion as the acinar cell. The initial volume decrease induced by ACh was dose dependent: 0.92 at 10(-8) M, 0.91 at 10(-6) M, 0.77 at 10(-5) M, 0.78 at 10(-4) M, and 0.75 at 10(-3) M (the relative volume compared with the resting control). During sustained stimulation by ACh for 3 min, the volume of acinar cell remained at the plateau level at concentrations lower than 10(-5) M ACh, whereas the volume increased by 0.1-0.15 at concentrations higher than 10(-4) M ACh. The dose-dependent manner of the cell volume coincided with the fluid secretion measured in the isolated perfused gland. The findings on the dose effects of ACh are discussed in connection with the intercellular communication and the movement of electrolytes.     

Three-dimensional microscopic image reconstruction of prostatic adenocarcinoma

CONTEXT: Routine microscopy provides only a 2-dimensional view of the complex 3-dimensional structure that makes up human tissue. Three-dimensional microscopic image reconstruction has not been described previously for prostate cancer. OBJECTIVES: To develop a simple method of computerized 3-dimensional image reconstruction and to demonstrate its applicability to the study of prostatic adenocarcinoma. METHODS: Serial sections were cut from archival paraffin-embedded prostate specimens, immunostained using antikeratin CAM5.2, and digitally imaged. Computer image-rendering software was used to produce 3-dimensional image reconstructions of prostate cancer of varying Gleason grades, normal prostate, and prostatic intraepithelial neoplasia. RESULTS: The rendering system proved easy to use and provided good-quality 3-dimensional images of most specimens. Normal prostate glands formed irregular fusiform structures branching off central tubular ducts. Prostatic intraepithelial neoplasia showed external contours similar to those of normal glands, but with a markedly complex internal arrangement of branching lumens. Gleason grade 3 carcinoma was found to consist of a complex array of interconnecting tubules rather than the apparently separate glands seen in 2 dimensions on routine light microscopy. Gleason grade 4 carcinoma demonstrated a characteristic form of glandular fusion that was readily visualized by optically sectioning and rotating the reconstructed images. CONCLUSIONS: Computerized 3-dimensional microscopic imaging holds great promise as an investigational tool. By revealing the structural relationships of the various Gleason grades of prostate cancer, this method could be used to refine diagnostic and grading criteria for this common tumor.     

The relationship of basement membrane to histologic grade of human prostatic carcinoma

The presence or absence of basement membrane (BM) was examined in normal and neoplastic adult prostatic tissue as well as prostate cell lines using immunohistochemistry and electron microscopy. Immunohistochemical studies using antibodies directed against laminin and type IV collagen were done on 55 samples of human prostate representing various grades of prostate carcinoma. The percentage of glandular structures surrounded by BM was determined. Benign prostates (n = 15) had BM around 99% of the acini. Gleason Grade II adenocarcinoma (n = 9) had 65%, Grade III (n = 5) had 23%, Grade IV (n = 12) had 15%, and Grade V (n = 7) had 0% BM around glandular structures, respectively. None of the metastases (n = 7) had visible BM. By transmission electron microscopy, 32 prostates were examined for the glandular profile of BM. One hundred percent of the acini in the benign prostates (n = 17) had BM. Of the low grade carcinomas, Gleason I and II (n = 4), 44% of the acini had BM, and of the high grade carcinomas, Gleason IV and V (n = 7), 34% had BM. None of the metastases (n = 4) had BM by electron microscopy. We conclude that, in prostatic carcinoma, there is a progressive loss of BM with decreasing differentiation, and that in prostate carcinoma metastases there is a complete loss of epithelial BM.     

Ultrastructural aspects of calf submandibular glands

Submandibular gland biopsies from four calves were examined by electron microscopy. Most of the parenchyma consists of mucous acini capped by seromucous demilunes. Secretory product of the demilunes reaches the acinar lumen via intercellular canaliculi located between adjacent demilunar cells or by narrow apical extensions of demilunar cells bordering the lumen in common with acinar cells. Intercellular canaliculi are absent between mucous acinar cells, but intercellular space is present at junctions of demilunar cells, acinar cells, and intercalated duct cells. Intercalated ducts are short and connect mucous acini with striated ducts. Striated ducts show more basal infoldings and mitochondria than those of bovine parotid glands. Nuclear bodies are present in most epithelial cell types of the gland but are larger and more easily recognized in nuclei of striated duct cells. Attempts are made to correlate the structure of bovine submandibular glands with its secretion of small amounts of hypotonic saliva relative to the larger volume of isotonic saliva secreted by parotid glands of the same animal.     

Cell deletion by apoptosis during regression of rat parotid sialadenosis

Enlargement of the rat parotid salivary glands was induced by repeated administration of isoproterenol. Mean wet weights of the treated glands increased steadily to 240% of control values. Following withdrawal of the drug, quantitative histological techniques were used to investigate the balance between hypertrophy, hyperplasia and apoptosis. The volume occupied by acinar cells relative to the total gland volume together with cytoplasmic|:|nuclear area ratios as measures of hypertrophy increased during the early experimental period. Similarly, serous acinar cell mitotic counts increased, indicating that hyperplasia had occurred. Apoptosis was demonstrated at light microscopical level to be the main mechanism for cell deletion as the glands returned to normal size and weight. The results indicate that hypertrophy and hyperplasia of serous acinar cells contribute to isoproterenol-induced sialadenosis. The experimental animal model demonstrates that these proliferative changes are completed by 48 h and thereafter are balanced by apoptosis as the glands recover their normal size and weight.     

假增生型前列腺癌的病理学特征

目的探讨假增生型前列腺癌（PHPA）的临床病理特征及其发生率和生物学行为。方法复查上海交通大学附属第六人民医院2005年1月1日-2006年12月31日860例直肠B超引导下前列腺穿刺活检和46例前列腺癌根治手术切片,对疑有PHPA组织作34βE12（或CK5／6）、p63和AMACR单项免疫组织化学标记（EnVision法）和34βE12／p63／AMACR鸡尾酒抗体双重免疫组织化学标记,将在1个组织块中PHPA占该组织块中癌总量的面积百分比〉60％的病例归入本组,并作病理学分析。结果PHPA在穿刺活检和前列腺癌根治标本中的发生率分别为7．0％和15．2％。66．7％的PHPA与普通型前列腺癌直接移行,76．7％在其他组织块中有普通型癌。PHPA占穿刺活检中癌总量的比例为5％～100％,占根治标本中癌总量的比例为1％～30％。PHPA以大中腺泡增生为主,癌细胞分化较好,排列有极性,腔内常有残存淀粉样小体,低倍镜下类似良性前列腺增生。但腺泡排列紧密,腔内有嗜酸性结晶体和颗粒状无定形物质,核增大,有大核仁,免疫标记AMACR阳性,基底细胞标记阴性,在20项提示恶性的形态学指标中10项出现几率966．7％。PHPA虽然分化较好,但66．7％的PHPA有间质浸润,6．7％有神经浸润,3．3％有腺外浸润,3．3％发生骨转移,肿瘤分布部位周围带多于移行带。结论PHPA的实际发生率不低,绝大多数与普通型癌并存,由于形态学类似良性,肿瘤细胞量又不占多数,因此在诊断中容易被忽视,PHPA高分化前列腺癌不同,应属于Gleason3级的中分化腺癌。     

Correlation of early cytodifferentiation of the human fetal prostate and leydig cells

The ultrastructural differentiation of the human prostatic epithelium and mesenchyme was studied in early developing glands and correlated with the differentiation of the Leydig cells of the same individuals during the tenth to sixteenth weeks. After initial folding of the basal lamina, the epithelial cells began to migrate into the differentiated, condensed mesenchyme at the end of the 10th week, and in the 11th week some of the prostatic outgrowths acquired a lumen. The acinar and tubular epithelium in the fetal prostate remained stratified, and adult type simple epithelium was not seen during the period between the 10th and 16th weeks. As a sign of incipient secretory activity, a few epithelial cells became polarized, and secretion granules with flocculent or dense content appeared in the Golgi area and in the apical parts of the cells in the 13th week. Occasional direct epitheliomesenchymal cell contacts were visible in association with the appearance of the secretory activity. Two cell types, not seen in the normal adult prostate, appeared in the epithelium of the primitive glands. Their nature and role in the glandular morphogenesis are not clear. During this time, the ultrastructural differentiation of the Leydig cells continued and their size and number increased. They occupied almost the whole in terstitium by the time secretion granules appeared in the prostatic cells. These findings support the current notion that androgens secreted by Leydig cells are the major regulators of prostatic development in man.