Pharmacokinetics of raloxifene and its clinical application.

Hormone replacement therapy (HRT) administered to postmenopausal women relieves climacteric symptoms, prevents loss of bone mass, and counteracts the development of coronary artery disease. However, whereas all the benefits associated with HRT are achieved only following long-term therapy, the long-term compliance to the regimen is poor. The most common reasons for discontinuance are uterine bleeding, breast pains, and a fear of breast cancer. Long-term HRT may be associated with an increased risk of breast cancer. Consequently, there is a need for an "ideal estrogen", designed to pinpoint desired target tissues for estrogen, such as the bone and liver, while acting as an antiestrogen in uterus and breast tissues. Raloxifene belongs to a new class of compounds, selective estrogen receptor modulators (SERMs). It binds to and interacts with estrogen receptors, acting as an estrogen agonist in bone and liver, but as an estrogen antagonist in breast and uterus. Therefore, raloxifene represents a potentially important alternative to HRT in postmenopausal women for the prevention and treatment of osteoporosis and cardiovascular disease. Clinical studies regarding the drug's long term benefits are still required.     

The dehydroepiandrosterone loading test. IV. Evaluation of clinical utility

This report complements the previously described preliminary clinical evaluation of the dehydroepiandrosterone (DHEA) loading test (DLT) by presenting the results of 65 DLTs in 59 patients. In patients whose fetuses were suspected of being intrauterine growth retarded, a DHEA to estrogen conversion rate constant less than or equal to 3.0 x 10(-3) min(-1) was associated with a birth weight below the tenth percentile in 60% of the pregnancies, whereas a conversion rate constant above this threshold was not associated with the same degree of growth retardation. The DLT continues to qualify as an accurate predictor of pregnancy outcome as judged by birth weight. Although it seems to be too cumbersome to serve as a screening technique, the DLT will permit evaluation of the efficacy of various pregnancy interventions directed toward improvement of the intrauterine environment, such as bed rest, tocolysis, or antihypertensive medication.     

Correlation of acrosomal status and sperm performance in the sperm penetration assay

The sperm of some infertile men are unable to penetrate zona pellucida-free hamster oocytes but gain that ability after treatment with human follicular fluid (hFF). We asked whether altered incidences of acrosome reacted sperm explained these observations. Patient sperm failing to penetrate oocytes had fewer acrosome reactions than did healthy males, but the percentage reacted was not correlated with oocyte penetration. Sperm incubated 3 hours, then exposed to hFF, exhibited increased penetrations for 7 of 10 males, without an increase in percentage reacted sperm. Sperm incubated 22 hours before hFF treatment had penetrating ability enhanced 250- to 1000-fold, but the percentage reacted increased only sixfold. We conclude that factors other than the percentage reacted sperm are the major determinants of penetration capacity.     

远程胎心监护临床应用价值评估

远程胎心监护技术是一种开放式分布的监护系统，是院内胎心监护的补充，围产期保健的院外延伸；丰富了家庭自我监护的内涵，是胎儿安全的有力保障；为高危妊娠和伴有脐带因素胎儿的孕期管理开辟了一条有效、实用、可行的新途径。科学管理，加强质控乃是远程胎心监护开展与推广的前提。     

Two-color fluorescence staining of lectin and anti-CD46 antibody to assess acrosomal status

OBJECTIVE: To examine potential methods for distinguishing between the acrosome reaction and acrosomal loss. DESIGN: Prospective randomized study. SETTING: Department of Obstetrics and Gynecology, Osaka University Hospital, Suita, Japan. PATIENT(S): Five healthy volunteers and 34 patients with normozoospermia who were participating in an IVF program. INTERVENTION(S): Semen samples were collected from the volunteers before the hamster egg penetration assay and from the patients at the time of IVF. MAIN OUTCOME MEASURE(S): The numbers of oocytes penetrated and spermatozoa bound were determined with the hamster egg penetration assay. Acrosomal status was assessed with two-color fluorescence staining using fluorescein isothiocyanate-conjugated Pisum sativum agglutinin (FITC-PSA) and MH61 (anti-CD46 monoclonal antibody) with Texas red-conjugated antimouse immunoglobulin G antiserum. RESULT(S): The MH61 monoclonal antibody inhibited the penetration of human spermatozoa into hamster oocytes but did not reduce the number of spermatozoa bound to the zona-free hamster oocytes. Two-color fluorescence staining revealed four staining patterns of the acrosomal region. The percentage of PSA-negative/CD46-positive spermatozoa increased to a greater extent than that of PSA-negative/CD46-negative spermatozoa with an increase in the incubation time. CONCLUSION(S): Two-color fluorescence staining with FITC-PSA and the anti-CD46 monoclonal antibody may be useful for distinguishing between the acrosome reaction and acrosomal loss.     

Decision analysis and its application in clinical medicine

Decision analysis is increasingly used to address difficult medical problems. Case-by-case models designed for individual patients facing complex trade-offs in their medical care often help individual clinical decision making, but are expensive and time consuming. On the other hand, generic models addressing broad clinical questions that can be adapted from one patient to another, can often make valid projections about specific outcomes, such as life expectancy, quality-adjusted life expectancy, and cost-effectiveness issues, and represent a useful approach to clinical decision making.     

Assay of amniotic phosphatidylglycerol and its prospective clinical application

From January 1985 to August 1987, 184 amniotic fluid specimens were collected from 150 cases of normal and high-risk pregnancies. Using L/S ratio as control, amniotic phosphatidylglycerol (PG) was assayed by modified method of one dimensional, twice run, thin-layer chromatography (TLC). The results were applied prospectively to clinical work. The distance of run for amniotic phospholipids was very consistent. The clinical correspondent rate was 98.67% and was not influenced by either blood or meconium staining. The false negative rate for PG was 1.33%, significantly lower than that of L/S ratio (22.62%). There was no false positive case. All reagents used except standard PG are made in China, but the amount of PG required for each test is minimal. Necessary equipment are simple and local-made. The method is simple and rapid. Therefore, it can be used in any clinical laboratory. So far such method has not been applied clinically in China for prospective study.     

Evaluation of vasculogenic impotence using dynamic penile washout test

Two control volunteers and 8 impotent patients entered this study for evaluation of arterial function and venous competence of the corpus cavernosum. The skin and corporeal xenon-133 (Xe-133) penile washout tests were conducted on each person before and 5 and 60 minutes after an intracavernous injection of prostaglandin E1. The half-time clearance (T 1/2) and blood flow (Q) were used for evaluation. The parameters of the skin washout test obtained from impotent patients changed from T 1/2 = 14.3 +/- 6.2 minutes, Q = 3.75 +/- 2.56 ml/100g tissue/minute preinjection to T 1/2 = 5.23 +/- 1.78, Q = 9.96 +/- 2.69 at 5 minutes post-injection and T 1/2 = 3.89 +/- 0.86, Q = 12.9 +/- 3.0 at 60 minutes post-injection, p less than 0.01; while the corporeal washout test changed from T 1/2 = 84.6 +/- 107.1 minutes, Q = 2.91 +/- 3.17 ml/100g tissue/minute to T 1/2 = 41.2 +/- 99.6, Q = 10.6 +/- 9.7 and T 1/2 = 13.9 +/- 16.2, Q = 7.78 +/- 6.35, p less than 0.05, respectively. The flow ratio (post-injection/pre-injection) was 1.01-6.04 at 5 minutes and 1.39-8.01 at 60 minutes later in the skin washout test, and 1.07-72.2 at 5 minutes and 0.60-45.7 at 60 minutes in the corporeal washout test. However, the individual variations were considerable. This study suggests that the Xe-133 penile washout test after an intracavernous injection may help in demonstrating the hemodynamics of the cavernosal arteries and dorsal arteries, and in evaluating the severity of penile vascular impairment. Moreover, the flow ratio may reflect vascular compliance; the higher the ratio, the better the compliance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role and regulation of intracellular calcium in acrosomal exocytosis.

Calcium influx is required for the mammalian sperm acrosome reaction, an exocytotic event occurring in the sperm head after binding to the egg. Prior to this binding, the spermatozoon undergo, in the female reproductive tract, a series of biochemical transformations, collectively called capacitation. The first event in capacitation is the elevation of intracellular calcium, bicarbonate and hydrogen peroxide, which collectively activate adenylyl cyclase to produce cyclic-AMP, which activates protein kinase A. During capacitation, there is an increase in the membrane-bound phospholipase C, and this binding is highly stimulated by adding epidermal growth factor to the cells. We suggest that zona-pellucida binds to at least two different receptors in the sperm head plasma membrane. One is a G(i)-coupled receptor that can activate phospholipase Cbeta(1) and might regulate adenylyl cyclase to further enhance cyclic-AMP levels. The cyclic AMP activates protein kinase A to open a calcium channel in the outer acrosomal membrane, resulting in a relatively small rise in cytosolic calcium. This rise in Ca(2+) leads to activation of phospholipase Cgamma, which is coupled to the second tyrosine kinase receptor. The products of phospholipase C activity, diacylglycerol and inositol-trisphosphate (IP(3)), will lead to activation of protein kinase C (PKC) and IP(3)-receptor. PKC will open a calcium channel in the plasma membrane and IP(3) will activate the calcium channel in the outer acrosomal membrane, leading to a higher increase in cytosolic calcium. In addition, the depletion of calcium in the acrosome will activate a store-operated Ca(2+) channel, resulting in a very fast increase in cytosolic calcium (300-500 nM), leading to membrane fusion and completing the acrosome reaction.     

Studies on RIA of 16 alpha-hydroxyestrone and its clinical application

16 alpha-hydroxyestrone (16 alpha-OH-E1) is an important intermediary metabolite in the biosynthetic pathway leading to estriol. No established routine method has been published to measure this steroid in the organism. A new RIA 16 alpha-OH-E1 method was developed and by using this method some interesting clinical data were obtained. Method: Rabbits were immunized with 16 alpha-OH-E1-3-CME-BSA to produce its antiserum. 16 alpha-OH-E1-3H was synthesized by incubating estrone-3H with the human fetal liver preparation and NADPH. As samples, peripheral blood of pregnant women, umbilical artery blood (UA), umbilical vein blood (UV) and amniotic fluid were collected. To each sample, 1000 dpm of 16 alpha-OH-E1-3H was added as a tracer, extracted with ether, and the extract was separated on TLC and LH-20. The 16 alpha-OH-E1 fraction was collected and used for RIA. Results: The 16 alpha-OH-E1 levels (ng/ml) in peripheral maternal blood of normal gestation before 11 weeks, 12-23 weeks, 24-36 weeks and after 37 weeks were 0.98 +/- 0.07 (mean +/- S.E.), 2.42 +/- 0.30, 4.76 +/- 0.42 and 5.49 +/- 0.98, respectively. A significant increase in the steroid titer was observed as gestational weeks advanced.(ABSTRACT TRUNCATED AT 250 WORDS)     

Significance of testicular size measurement in andrology. I. A new orchiometer and its clinical application

When performing a physical examination in the andrology clinic, accurate measurement of testicular size is important. Two methods for measuring testicular size have been developed using calipers for measurement and comparison with plastic testicular models. We have developed a new orchiometer, which consists of a graded series of punched-out elliptical rings with the volume of the ellipsoids indicated on each ring. Testicular sizes measured by our orchiometer had a better correlation with real testicular size determined by water displacement of testes after castration when compared with those data obtained by using calipers. By the use of this orchiometer, the normal range of the adult testicular size was greater than 14 ml in Japan and greater than 17 ml in the United States. This orchiometer is valuable for the rapid and accurate assessment of sexual maturation in children and men.     

Inhibitors of acrosomal proteinase as antifertility agents. A problem of acrosomal membrane permeability (author's transl)

In vitro studies were performed to investigate the accessibility of acrosin to various proteinase inhibitors inside the intact acrosome of testicular, ejaculated, and uterine human spermatozoa. As test system, the gelatin plate assay was used. For this assay, it was shown formerly that a correlation exists between the size of the digested lysis areas (halo formation) and acrosin activity estimated with synthetic substrates. In addition, saturation of the gelatin substrate membranes with acrosin inhibitors including highly specific ones before application of spermatozoa completely prevented halo formation indicating that the gelatinolytic activity of human spermatozoa is caused exclusively by acrosin. When human spermatozoa were incubated with various acrosin inhibitors (concentration: 1 mmol/1) prior to application to the gelatine membrane, reduction of halo formation could not be observed, however. This result indicates that most of the tested acrosin inhibitors (9 naturally occurring protein inhibitors, 2 microbial peptide inhibitors, 19 synthetic inhibitors) were unable to penetrate the acrosomal membranes of testicular, ejaculated, and uterine human spermatozoa. Only 2 inhibitors caused moderate to complete inhibition of the gelatinolytic activity of the spermatozoa if applied in concentrations between 1-10 mmol/l: the proteinase inhibitor aprotinin and the synthetic inhibitor NPGB (4-nitrophenyl 4-guanidinobenzoate). Obviously, human acrosomal membranes seem to be especially impenetrable to proteins, polypeptides, and synthetic agents. Those acrosin inhibitors penetrating the human sperm head membranes are either too toxic or the local concentration necessary for effective acrosin inhibition in vivo cannot be achieved within the male or female genital tract secretions. Therefore, acrosin inhitibors cannot be used for human contraception at present. Thus, it is mandatory to continue the search for suitable acrosin inhibitors with low toxicity easily penetrating into the intact sperm acrosome.     

The development of a new flexible hysterofiberscope and its clinical application

Hysteroscopy is a diagnostic method for intrauterine lesion. Most kinds of hysteroscope are rigid in type. Cervical dilatation and insertion of the trocar are necessary for hysteroscopy. These procedures can be very painful to the patient. Also subsequent blood clotting and injury to the endometrium may interfere with the diagnosis. With the help of Fuji Photo Optical Company, a new flexible hysterofiberscope (3.7 mm in diameter) was developed. The scope is divided into three portions; a front flexible part, a rigid middle part and a soft rear part. Cervical dilatation and anesthesia were not required even in a primiparous woman. The operator can observe the cervical canal, the uterine cavity and the tubal ostium very easily in a comfortable position. From Nov. 85 to Sep. 86 we carried out hysteroscopy in 411 patients with this new scope. The fluid medium which we used was a solution of 10% dextrose in water. The indications for hysteroscopy were abnormal uterine bleeding (187 cases), uterine myoma (80 cases), sterility (52 cases), post-transcervical surgery (22 cases) and others (70 cases). No complications were encountered during or after the procedure. The results were satisfactory. This new flexible hysterofiberscope has been proved an efficient tool for intrauterine diagnosis.