Regulatory role of p27kip1 in the mouse and human testis.

p27kip1 is a cyclin-dependent kinase inhibitor that regulates the G1/S transition of the cell cycle. Immunohistochemical analysis showed that during mouse testicular development p27kip1 is induced when the fetal germ cells, gonocytes, become quiescent on day 16 postcoitum, suggesting that p27kip1 is an important factor for the G1/G0 arrest in gonocytes. In the adult mouse and human testis, in general, spermatogonia are proliferating actively, except for undifferentiated spermatogonia that also go through a long G1/G0 arrest. However, none of the different types of germ cells immunohistochemically stained for p27kip1. During development, Sertoli cells are proliferating actively and only occasionally were lightly p27kip1 stained Sertoli cells observed. In contrast, in the adult testis the terminally differentiated Sertoli cells heavily stain for p27kip1. Twenty to 30% of both fetal and adult type Leydig cells lightly stained for p27kip1, possibly indicating the proportion of terminally differentiated cells in the Leydig cell population. In p27kip1 knockout mice, aberrations in the spermatogenic process were observed. First, an increase in the numbers ofA spermatogonia was found, and second, abnormal (pre)leptotene spermatocytes were observed, some of which seemingly tried to enter a mitotic division instead of entering the meiotic prophase. These observations indicate that p27kip1 has a role in the regulation of spermatogonial proliferation, or apoptosis, and the onset of the meiotic prophase in preleptotene spermatocytes. However, as p27kip1 is only expressed in Sertoli cells, the role of p27kip1 in both spermatogonia and preleptotene spermatocytes must be indirect. Hence, part of the supportive and/or regulatory role of Sertoli cells in the spermatogenic process depends on the expression of p27kip1 in these cells. Finally, we show that the expression of p27kip1 transiently increases by a factor of 3 after x-irradiation in whole testicular lysates. Hence, p27kip1 seems to be involved in the cellular response after DNA damage.

Age of presentation in developmental disability.

It has not been determined whether severity of handicap or other associated factors are more important in determining the age of presentation for developmental disabilities. The relationship between age at presentation and referral source, presenting complaint, diagnosis, and associated factors (medical illness, motor signs, or behavioral disturbances) was examined in 738 consecutive children referred for developmental evaluation during 1982-1983. The nature of the complaint or diagnosis (motor, language, behavioral, or educational) was a far better predictor of age of presentation than the severity of the disorder. The degree of mental retardation did not affect age of presentation. Behavior problems did not affect the age of presentation for school failure or learning disability, but were associated with later presentation for motor delay, language delay, communication disorder, and within all IQ groups. The association of topography of handicap rather than severity with age of presentation should be considered when establishing or evaluating efforts at early identification of developmental disability.

Projections from the claustrum to the prelunate gyrus in the monkey.

In order to determine whether the cells in the monkey claustrum which project to visual area V4 are found in the same territory as cells projecting to other visual areas, we made injections of the retrograde fluorescent tracer diamidino yellow into area V4 in two monkeys. Injections of a second tracer, fast blue, were also made in area PM, an area just medial to area V4 on the prelunate gyrus, in one animal. Area V4 injections labeled cells in ventral claustrum over about 5-6 mm of its anterior-posterior extent. The more medial prelunate injection labeled cells in adjacent dorsal and more lateral claustrum. These results, together with data from other studies, suggest that in the monkey, as in the cat, there is a "visual" region of claustrum that is interconnected with multiple visual areas including V1, V2, V4, MT, FST, MST, TEO and TE. The data also suggest that dorsal and lateral to this region is another zone which is connected with different visual areas, including several in posterior parietal cortex.

Distribution of corticotectal cells in macaque.

We compared the cortical inputs to the superficial and deep compartments of the superior colliculus, asking if the corticotectal system, like the colliculus itself, consists of two functional divisions: visual and visuomotor. We made injections of retrograde tracer extending into both superficial and deep layers in three colliculi: the injection site involved mainly the upper quadrant representation in one case, the lower quadrant representation in a second case, and both quadrants in a third. In a fourth colliculus, the tracer injection was restricted to the lower quadrant representation of the superficial layers. After injections involving both superficial and deep layers, labeled cells were seen over V1, many prestriate visual areas, and in prefrontal and posterior parietal cortex. Both the density of labeled cells and the degree of visuotopic order as inferred from the distribution of labeled cells in cortex varied among areas. In visual areas comprising the lower levels of the cortical hierarchy, visuotopy was preserved, whereas in "higher" areas the distribution of labeled cells did not strongly reflect the visuotopic location of the injection. Despite the widespread distribution of labeled cells, there were several areas with few or no labeled cells: MSTd, 7a, VIP, MIP, and TE. In the case with an injection restricted to superficial layers, labeled cells were seen only in V1 and in striate-recipient areas V2, V3, and MT. The results are consistent with the idea that the corticotectal system consists of two largely nonoverlapping components: a visual component consisting of striate cortex and striate-recipient areas, which projects only to the superficial layers, and a visuomotor component consisting of many other prestriate visual areas as well as frontal and parietal visuomotor areas, which projects to the deep compartment of the colliculus.

Transurethral marsupialization of a medial prostatic cyst in patients with prostatitis-like symptoms.

PURPOSE: The results of transurethral marsupialization as treatment for medial prostatic cysts were assessed. MATERIALS AND METHODS: Between June 1992 and August 1994 we performed transrectal ultrasound on 704 patients with symptoms of bladder outlet obstruction or lower urinary tract symptoms and a medical prostatic cyst was found in 34 (5%). Transurethral marsupialization of the cyst via incision of the prostatic floor under transrectal ultrasound guidance was performed in 18 patients. Followup was 12 to 25 months (mean 18). RESULTS: Patients with a medial prostatic cyst complained of prostatitis-like symptoms (77%), scrotal pain (62%), impaired micturition (32%), small volume ejaculation (35%), painful ejaculation (24%), hemospermia (24%) and infertility (12%). After marsupialization of the cyst, symptoms resolved completely in 14 patients (78%), improved in 17 (94%) and did not improve in only 1 (6%). No complications of this procedure were noted. The 16 patients who did not undergo surgery still complain of prostatitis-like symptoms without evidence of bacterial prostatitis. CONCLUSIONS: We believe that a medial prostatic cyst can cause prostatitis-like symptoms and that marsupialization of the cyst can provide symptom relief in the majority of patients.

Tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist. Analysis of a multinational, multicentre, open-label study assessing the long-term efficacy and safety in patients with benign prostatic obstruction (symptomatic BPH). European Tamsulosin Study Group.

OBJECTIVE: This open-label extension study evaluated the efficacy and safety of tamsulosin (0.4 mg as a modified release formulation) once daily in patients with benign prostatic enlargement, lower urinary tract symptoms and benign prostatic obstruction (symptomatic BPH) for up to 60 weeks. METHODS: Patients were enrolled from two European, 12-week, placebo-controlled trials. This 60-week interim analysis includes the patients (n = 244) randomized to tamsulosin in the two placebo-controlled trials. RESULTS: The significant improvements in the primary efficacy parameters, maximum urinary flow rate (Qmax) and total Boyarsky symptom score, that were observed during the placebo-controlled trials, were sustained throughout the long-term extension study. Mean Qmax improved from baseline (before initiation of tamsulosin) to endpoint by 13.7% (p < 0.001) and remained between 11.5 and 12 ml/s during the entire follow-up period. Total Boyarsky symptom score improved by 36.2% from baseline to endpoint (p < 0.001). Similarly, the percentage of treatment responders, defined as an increase in Qmax of > or = 30% or a decrease in total symptom score of > or = 25%, remained constant throughout the 60-week period. At endpoint, 69% of patients demonstrated this clinically significant total Boyarsky symptom score response. During the 60-week study period, 51 patients (21%) experienced an adverse event considered to be possibly or probably related to study medication, the most common of which were dizziness and abnormal ejaculation, both occurring in 5% of patients. There were no clinically significant changes in blood pressure or pulse rate during the study. CONCLUSION: Long-term tamsulosin therapy is safe, well tolerated and improvements in urinary flow and symptoms are maintained for at least 60 weeks of treatment.

Tamsulosin: 3-year long-term efficacy and safety in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction: analysis of a European, multinational, multicenter, open-label study. European Tamsulosin Study Group.

OBJECTIVE: This open-label extension study evaluated the efficacy and safety of tamsulosin (0.4 mg as a modified release formulation) once daily in patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO) treated for up to 3 years. METHODS: Patients were enrolled from two European, 12-week, placebo-controlled trials. This analysis reports on 355 patients randomized originally to tamsulosin (n = 244) or placebo (n = 111) in the two placebo-controlled trials with follow-up data for up to 3 years. RESULTS: The significant improvements in the primary efficacy parameters, maximum urinary flow rate (Q(max)) and total Boyarsky symptom score that were observed during the placebo-controlled trials were sustained throughout the long-term extension study for up to 3 years in patients who remained on therapy. Mean Q(max) increased from baseline (range 0.7-1.8 ml/s; p < 0.05 vs. baseline) and remained between 11.5 and 12 ml/s during the entire follow-up period. Total Boyarsky symptom score also improved from baseline (range -3.7 to -4.1 (or -39 to -44%); p < 0.001 vs. baseline). Similarly, the percentage of treatment responders, defined as an increase in Q(max) of >/=30% or a decrease in total symptom score of >/=25%, remained constant throughout the 3-year period. The number of patients who had a clinically significant total Boyarsky symptom score response ranged between 69 and 80%. During the 3-year study period, 95 patients (27%) experienced an adverse event considered to be possibly or probably related to study medication, the most common of which (occurring in

Long-term use of tamsulosin to treat lower urinary tract symptoms/benign prostatic hyperplasia.

PURPOSE: The long-term efficacy and safety of 0.4 mg. tamsulosin once daily were assessed in patients with lower urinary tract symptoms/benign prostatic hyperplasia treated for up to 4 years. MATERIALS AND METHODS: A total of 516 patients were enrolled from 2 European open label studies that were extensions of 3 double-blind controlled studies. RESULTS: Significant improvement in maximum urine flow and total Boyarsky symptom score during the controlled trials was sustained throughout the extension study for up to 4 years in patients who remained on therapy. The increase in mean maximum urine flow from baseline was 1.2 to 2.2 ml. per second (p <0.001) and it remained 11.5 to 12 ml. per second during followup. Total Boyarsky symptom score was decreased from baseline by 4.1 to 4.7 points (p <0.001). The incidence of treatment responders, defined as a 25% or greater decrease in total symptom score, remained stable throughout the 4-year period. Increasing the dose of tamsulosin from 0.4 to 0.8 mg. seemed to have no substantial additional benefit. During the 4 years of treatment 26% of patients had side effects that were considered possibly or probably drug related. However, only 5% of patients discontinued treatment because of drug related side effects. No clinically significant changes in blood pressure or pulse rate occurred during the study. CONCLUSIONS: Long-term treatment with tamsulosin is safe and well tolerated in patients with lower urinary tract symptoms/benign prostatic hyperplasia. Improved efficacy was sustained during 4 years of followup.

Apoptosis regulation in the testis: involvement of Bcl-2 family members.

Using immunohistochemical techniques and Western blot analysis, the possible role of Bcl-2 family members Bax, Bcl-2, Bcl-x(s), and Bcl-x(l) in male germ cell density-related apoptosis and DNA damage induced apoptosis was studied. The apoptosis inducer Bax was localized in all mouse and human testicular cell types, but despite the fact that irradiation induces its transcriptional activator, p53 in the human, Bax expression did not change after irradiation. The apoptosis inhibitor Bcl-2 appeared to be present in late spermatocytes and spermatids and was up-regulated in these cells after a dose of 4 Gy of X-rays. Finally, Bcl-x was expressed in both the mouse and human testis. The apoptosis inhibiting long transcripts of Bcl-x, Bcl-x(l), were expressed in spermatogonia and spermatocytes and were up-regulated after X-irradiation. The apoptosis inducing shorter form of Bcl-x, Bcl-x(s), was found to be expressed only in somatic cells, like peritubular and Leydig cells. While Bax is important in germ cell density regulation, Bax expression did not change after DNA damage inflicted by X-radiation. Hence, spermatogonial apoptosis after X-irradiation may not be induced via the apoptosis inducer Bax. Furthermore, as Bcl-x(l), but not Bcl-2, is present in spermatogonia and spermatocytes, Bcl-x(l) may regulate germ cell density, possibly in cooperation with Bax. As Bcl-x(l) expression is enhanced after irradiation, this protein may also have a role in the response of spermatogonia and spermatocytes to irradiation.

Protein C inhibitor may modulate human sperm-oocyte interactions.

Protein C inhibitor (PCI) is a heparin-binding plasma serine protease inhibitor that was originally identified as an inhibitor of activated protein C. PCI has a broad protease specificity, inhibiting several proteases in hemostasis and fibrinolysis by acting as a suicide substrate. Recently it has been reported that proteases of the reproductive system, such as acrosin, prostate-specific antigen, and tissue kallikrein, can also be effectively inhibited by PCI. However, a direct relation between PCI and physiological events during fertilization has not yet been established. An attempt was made to monitor and localize the inhibition of the sperm protease acrosin by PCI. Localization experiments for PCI on epididymal spermatozoa showed that PCI is present on the acrosomal cap of human spermatozoa, which demonstrates the early presence of PCI in the male reproductive tract. Induction of the acrosome reaction in ejaculated human spermatozoa resulted in the disappearance of PCI from the plasma membrane overlying the acrosomal head and the appearance of a strict distribution at the equatorial segment of human spermatozoa. The activity of acrosin in sperm extracts could be effectively inhibited by PCI. Zona-binding assays showed that active PCI is able to block sperm-egg binding in a concentration-dependent manner. The combination of the potent inhibition of acrosin and sperm-egg binding by PCI and the localization studies suggested that PCI may protect spermatozoa against premature acrosome reaction and degradation, thereby modulating the acrosin activity so that it can coincide with binding to the oocyte.

Metastatic cancer of the prostate managed with buserelin versus buserelin plus cyproterone acetate.

We recruited 71 previously untreated patients with metastatic prostatic carcinoma to 2 separate consecutive prospective phase 2 studies done by the same group of investigators according to the same protocols in which only the treatment regimens differed. Of the patients 58 were treated with the luteinizing hormone-releasing hormone analogue buserelin alone (0.4 mg. 3 times daily intranasally) and 13 were treated with buserelin combined with cyproterone acetate, a potent antiandrogen (50 mg. 3 times daily orally). The objective of the study was to investigate the efficacy, safety and tolerability of the medication used during at least 12 months by studying adequate endocrine parameters, the rate and duration of response, as well as the rate of progression and possible side effects. All endocrine parameters were studied in 1 laboratory. Modified response criteria of the National Prostatic Cancer Project were used. The endocrine studies showed an effective suppression of plasma testosterone to castration levels by buserelin after an initial increase during the first 2 weeks. Luteinizing hormone and follicle-stimulating hormones were lowered significantly and could not be re-stimulated by the intravenous application of luteinizing hormone-releasing hormone. There was no correlation of plasma testosterone with response and progression. However, a significant correlation existed between higher basal cortisol levels at entry, and after 3 and 6 months, and progression. Response is reported for all patients at the 12-month interval and did not seem to differ among treatment groups. The rate of progression after all patients had been treated for 1 year was 37.9 per cent in the buserelin group and 41 per cent in the buserelin plus cyproterone acetate group. Three early deaths occurred in the buserelin group. Except for impotence, only mild side effects were noted. Our study shows that treatment of metastatic prostatic cancer by means of the luteinizing-hormone-releasing hormone analogue buserelin is safe and effective. The results obtained are compatible with those obtained by castration. In our study a superiority of total androgen withdrawal over testicular suppression alone could not be shown.

Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings.

OBJECTIVE: Methylphenidate (MPH), the most commonly prescribed drug for attention-deficit/hyperactivity disorder (ADHD), has a short half-life, which necessitates multiple daily doses. The need for multiple doses produces problems with medication administration during school and after-school hours, and therefore with compliance. Previous long-acting stimulants and preparations have shown effects equivalent to twice-daily dosing of MPH. This study tests the efficacy and duration of action, in natural and laboratory settings, of an extended-release MPH preparation designed to last 12 hours and therefore be equivalent to 3-times-daily dosing. METHODS: Sixty-eight children with ADHD, 6 to 12 years old, participated in a within-subject, double-blind comparison of placebo, immediate-release (IR) MPH 3 times a day (tid), and Concerta, a once-daily MPH formulation. Three dosing levels of medication were used: 5 mg IR MPH tid/18 mg Concerta once a day (qd); 10 mg IR MPH tid/36 mg Concerta qd; and 15 mg IR MPH tid/54 mg Concerta qd. All children were currently medicated with MPH at enrollment, and each child's dose level was based on that child's MPH dosing before the study. The doses of Concerta were selected to be comparable to the daily doses of MPH that each child received. To achieve the ascending rate of MPH delivery determined by initial investigations to provide the necessary continuous coverage, Concerta doses were 20% higher on a daily basis than a comparable tid regimen of IR MPH. Children received each medication condition for 7 days. The investigation was conducted in the context of a background clinical behavioral intervention in both the natural environment and the laboratory setting. Parents received behavioral parent training and teachers were taught to establish a school-home daily report card (DRC). A DRC is a list of individual target behaviors that represent a child's most salient areas of impairment. Teachers set daily goals for each child's impairment targets, and parents provided rewards at home for goal attainment. Each weekday, teachers completed the DRC, and it was used as a dependent measure of individualized medication response. Teachers and parents also completed weekly standardized ratings of behavior and treatment effectiveness. To evaluate the time course of medication effects, children spent 12 hours in a laboratory setting on Saturdays and medication effects were measured using procedures and methods adapted from our summer treatment program. Measures of classroom behavior and academic productivity/accuracy were taken in a laboratory classroom setting during which children completed independent math and reading worksheets. Measures of social behavior were taken in structured, small-group board game settings and unstructured recess settings. Measures included behavior frequency counts, academic problems completed and accuracy, independent observations, teacher and counselor ratings, and individualized behavioral target goals. Reports of adverse events, sleep quality, and appetite were collected. RESULTS: On virtually all measures in all settings, both drug conditions were significantly different from placebo, and the 2 drugs were not different from each other. In children's regular school settings, both medications improved behavior as measured by teacher ratings and individualized target behaviors (the DRC); these effects were seen into the evening as measured by parent ratings. In the laboratory setting, effects of Concerta were equivalent to tid MPH and lasted at least through 12 hours after dosing. Concerta was significantly superior to tid MPH on 2 parent rating scores, and when asked, more parents preferred Concerta than preferred tid IR MPH or placebo. Side effects on children's sleep and appetite were similar for the 2 preparations. In the lab setting, both medications improved productivity and accuracy on arithmetic seatwork assignments, disruptive and on-task behavior, and classroom rule following. Both medications improved children's rule following and negative behavior in small group board games, as well as in unstructured recess settings. Individual target behaviors also showed significant improvement with medication across domains in the laboratory setting. Children's behavior across settings deteriorated across the laboratory day, and the primary effect of medication was to prevent this deterioration as the day wore on. Results support the use of background behavioral treatment in clinical trials of stimulant medication, and illustrate the utility of a measure of individualized daily target goals (ie, the DRC) as an objective measure of medication response in both the laboratory and natural school settings. CONCLUSION: This investigation clearly supports the efficacy of the Concerta long-acting formulation of MPH for parents who desire to have medication benefits for their child throughout the day and early evening. (ABSTRACT TRUNCATED)