Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses

On the basis of results of studies using high doses of estrogens, exposure to estrogen during fetal life is known to inhibit prostate development. However, it is recognized in endocrinology that low concentrations of a hormone can stimulate a tissue, while high concentrations can have the opposite effect. We report here that a 50% increase in free-serum estradiol in male mouse fetuses (released by a maternal Silastic estradiol implant) induced a 40% increase in the number of developing prostatic glands during fetal life; subsequently, in adulthood, the number of prostatic androgen receptors per cell was permanently increased by 2-fold, and the prostate was enlarged by 30% (due to hyperplasia) relative to untreated males. However, as the free serum estradiol concentration in male fetuses was increased from 2- to 8-fold, adult prostate weight decreased relative to males exposed to the 50% increase in estradiol. As a model for fetal exposure to man-made estrogens, pregnant mice were fed diethylstilbestrol (DES) from gestation days 11 to 17. Relative to controls, DES doses of 0.02, 0.2, and 2.0 ng per g of body weight per day increased adult prostate weight, whereas a 200-ng-per-g dose decreased adult prostate weight in male offspring. Our findings suggest that a small increase in estrogen may modulate the action of androgen in regulating prostate differentiation, resulting in a permanent increase in prostatic androgen receptors and prostate size. For both estradiol and DES, prostate weight first increased then decreased with dose, resulting in an inverted-U dose-response relationship.     

5-Azacytidine induces toxicity in PC12 cells by apoptosis

5-Azacytidine (5 Az)is a potent inhibitor of DNA methylation, and it may allow inactive genes to become expressed. In a previous study, we demonstrated that 5 Az administered to the dam induced apoptosis in the brains of fetal mice. In this study, the 5 Az-induced apoptosis was further characterized in differentiated PC 12 cells as a model for neuronal apoptosis. Cell death, determined by the activity of released lactate dehydrogenase (LDH) into the medium, occurred from 24 to 48 hrs after 5 Az treatment. Toxicity for differentiated PC 12 cells was observed on treatment with more than 10(-1) micrograms/ml of 5 Az, and it reached the maximal level at 10 micrograms/ml. Cycloheximide, an inhibitor of protein synthesis, prevented 5 Az toxicity, suggesting that this cell death required protein synthesis which could be related to the activation of a dormant gene(s). Electrophoresis of DNA from 5 Az-treated cells evoked ladder formation, indicating the cleavage of DNA into nucleosomes. Scanning electron microscopy demonstrated bleb formation, the so-called apoptotic bodies on the cell surface. The biochemical and morphological findings indicated that 5 Az-induced cell death occurred in the form of apoptosis. 5 Az-induced cell death was prevented by treatment with cAMP but not by treatment with high K+ or deoxycytidine. These results suggest that a cAMP-sensitive mechanism is involved in 5 Az-induced cell death. PC 12 cells should be of value in elucidating the molecular mechanism of 5 Az-induced neuronal apoptosis.     

Is "involuntary childlessness" within the realm of family medicine responsibility of the general practitioner?

The aim of the study was to assess whether or not management of infertility is within the domain of the general practitioner in his capacity as a family physician. All accredited family physicians in the wider area of Goettingen were invited to take part in our survey. A total of 57 doctors (84%) participated. In personal interviews the family physicians were encouraged to frankly discuss the following main topics: the frequency of infertility in their own practice as well as their care for and attitudes towards infertile patients. Many family physicians interviewed were reluctant to address involuntary childlessness and underestimated its frequency. According to their patients' needs and demands, however, family doctors--above all in rural practices--have been participating in the screening and counseling of, and providing emotional support for, involuntarily childless patients. A qualitative analysis of the interview data revealed that many family physicians regarded infertility as the patients' private matter and placed it within the domain of specialists. About one-third of the physicians expressed negative attitudes towards infertile patients. Moreover, assisted reproduction techniques were sometimes rejected as "unnatural" methods. If a family-oriented approach should be amplified in family practice by offering supportive counseling for infertile patients, continuing medical education will have to take these attitudes into account.     

Pancreaticoduodenectomy for selected periampullary neuroendocrine tumors: fifty patients

BACKGROUND: Most resectable pancreatic or peripancreatic neuroendocrine tumors are treated by enucleation or distal pancreatectomy. A minority of tumors may require pancreaticoduodenectomy for complete tumor excision because of their large size, location, or lymph node involvement. METHODS: This study reviews the management of 50 patients treated by pancreaticoduodenectomy for periampullary neuroendocrine tumors between 1962 and 1996 at a single institution. RESULTS: There were 30 men and 20 women with a mean age of 52 +/- 2 years. Functional tumors were resected in 17 patients: insulinoma, seven tumors; gastrinoma, eight tumors; vipoma, one tumor; and glucagonoma, one tumor. Tumors were classified as malignant in 29 patients and benign in 21. The median intraoperative blood loss was 800 ml, and the median number of units of blood transfused was zero. The postoperative length of stay was 20 +/- 2 days. Postoperative morbidity included 11 patients (24%) with a pancreatic fistula and four patients (8%) with a biliary fistula. There was one in-hospital death (2%), in 1967. The actuarial survival rates at 2, 5, and 7 years are 81%, 73%, and 65%, respectively. Patients with benign tumors had a significantly improved 5-year survival rate (94%) compared with those with malignant tumors (61%; p = 0.03). CONCLUSIONS: Selected patients with periampullary neuroendocrine tumors can be managed successfully by pancreaticoduodenectomy, with low mortality and acceptable morbidity rates.     

Activation of protein-tyrosine kinase Pyk2 is downstream of Syk in FcepsilonRI signaling

Aggregation of the FcepsilonRI, a member of the immune receptor family, induces the activation of proteintyrosine kinases and results in tyrosine phosphorylation of proteins that are involved in downstream signaling pathways. Here we report that Pyk2, another member of the focal adhesion kinase family, was present in the RBL-2H3 mast cell line and was rapidly tyrosine-phosphorylated and activated after FcepsilonRI aggregation. Tyrosine phosphorylation of Pyk2 was also induced by the calcium ionophore A23187, by phorbol myristate acetate, or by stimulation of G-protein-coupled receptors. Adherence of cells to fibronectin dramatically enhanced the induced tyrosine phosphorylation of Pyk2. Although Src family kinases are activated by FcepsilonRI stimulation and tyrosine-phosphorylate the receptor subunits, the activation and tyrosine phosphorylation of Pyk2 were downstream of Syk. In contrast, tyrosine phosphorylation of Pyk2 by stimulation of G-protein-coupled receptors was independent of Syk. Therefore, the FcepsilonRI-induced tyrosine phosphorylation of Pyk2 is downstream of Syk and may play a role in cell secretion.     

The incidence of low-pressure urethra as a function of prolapse-reducing technique in patients with massive pelvic organ prolapse (maximum descent at all vaginal sites)

OBJECTIVE: Our aims were to compare several prolapse-reducing techniques during urodynamic evaluation and prospectively evaluate their usefulness in identifying the incidence of low urethral closure pressure in continent patients with massive prolapse. STUDY DESIGN: This preoperative, prospective, repeated-measures urodynamic study evaluated the maximum urethral closure pressure with the use of four different techniques in 30 consecutive continent patients with grade 4 prolapse at all vaginal sites. Twenty patients with grade 0 prolapse served as the control group. All patients from the prolapse group underwent surgical treatment and were followed up clinically for a minimum of 1 year. RESULTS: Use of the Scopette (Birchwood Laboratories, Eden Prairie, Minn.) reduction technique to reduce the prolapse in a linear orientation during multichannel urodynamics revealed a 56% incidence of low-pressure urethra and an overall genuine stress urinary incontinence of 83% in patients with massive pelvic organ prolapse but without clinical urinary incontinence. CONCLUSIONS: There may be an increased indication for sling urethropexy in patients with massive prolapse.