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The human asialoglycoprotein receptor (ASGPR), also called hepatic lectin, is an integral membrane protein and is responsible for the clearance of desialylated, galactose-terminal glycoproteins from the circulation by receptor-mediated endocytosis. It can be subdivided into four functional domains: the cytosolic domain, the transmembrane domain, the stalk and the carbohydrate recognition domain (CRD). The galactose-binding domains belong to the superfamily of C-type (calcium-dependent) lectins, in particular to the long-form subfamily with three conserved intramolecular disulphide bonds. It is able to bind terminal non-reducing galactose residues and N-acetyl-galactosamine residues of desialated tri or tetra-antennary N-linked glycans. The ASGPR is a potential liver-specific receptor for hepatitis B virus and Marburg virus and has been used to target exogenous molecules specifically to hepatocytes for diagnostic and therapeutic purposes.Here, we present the X-ray crystal structure of the carbohydrate recognition domain of the major subunit H1 at 2.3 A resolution. While the overall fold of this and other known C-type lectin structures are well conserved, the positions of the bound calcium ions are not, indicating that the fold is stabilised by alternative mechanisms in different branches of the C-type lectin family. It is the first CRD structure where three calcium ions form an intergral part of the structure. In addition, the structure provides direct confirmation for the conversion of the ligand-binding site of the mannose-binding protein to an asialoglycoprotein receptor-like specificity suggested by Drickamer and colleagues. In agreement with the prediction that the coiled-coil domain of the ASGPR is separated from the CRD and its N-terminal disulphide bridge by several residues, these residues are indeed not alpha-helical, while in tetranectin they form an alpha-helical coiled-coil.

Autosomal dominant neurohypophyseal diabetes insipidus is caused by mutations in the gene encoding the vasopressin precursor protein, prepro-vasopressin-neurophysin II. We analyzed the molecular consequences of a mutation (DeltaG227) recently identified in a Swiss kindred that destroys the translation initiation codon. In COS-7 cells transfected with the mutant cDNA, translation was found to initiate at an alternative ATG, producing a truncated signal sequence that was functional for targeting and translocation but was not cleaved by signal peptidase. The mutant precursor was completely retained within the endoplasmic reticulum. The uncleaved signal did not affect folding of the neurophysin portion of the precursor, as determined by its protease resistance. However, formation of disulfide-linked aggregates indicated that it interfered with the formation of the disulfide bond in vasopressin, most likely by blocking its insertion into the hormone binding site of neurophysin. Preventing disulfide formation in the vasopressin nonapeptide by mutation of cysteine 6 to serine was shown to be sufficient to cause aggregation and retention. These results indicate that the DeltaG227 mutation induces translation of a truncated signal sequence that cannot be cleaved but prevents correct folding and oxidation of vasopressin, thereby causing precursor aggregation and retention in the endoplasmic reticulum.

The hepatic asialoglycoprotein receptor is a hetero-oligomer composed of two homologous subunits. The specificity and affinity of ligand binding depends on the number and spatial arrangement of several galactose-binding sites within the receptor complex. Previous studies indicated that both subunits are required for high-affinity ligand binding, i.e. for the simultaneous interaction with three galactose residues within an N-linked glycan. However, we found that asialoorosomucoid (ASOR) and asialofetuin (ASF) bind to transfected COS-7 cells expressing subunit H1 in the absence of the second subunit H2. ASOR binding occurred with a dissociation constant of approximately 40 nM, approximately four-times higher than the Kd of ASOR binding to the hetero-oligomeric receptor. Normalized to the amount of H1 expressed, approximately 10-times fewer binding sites were produced by H1 alone. A glycopeptide with a single tri-antennary N-linked glycan purified from ASF bound to the hetero-oligomeric receptor, but did not bind detectably to H1-expressing COS-7 cells. H1 is thus unable to simultaneously recognize all three galactose residues in a glycan. From this, we conclude that, at a sufficiently high density of H1 on the cell surface, high-affinity binding of ASOR and ASF is the result of two or more glycans interacting with H1 oligomers with low affinity in a bivalent manner.

The introduction of intracytoplasmic sperm injection and the use of spermatozoa extracted from the testicles have changed the option for conception for azoospermic patients. The purpose of the present study was to evaluate the IVF outcome after using cryopreserved testicular sperm samples in comparison with fresh ones. A total of 667 in vitro fertilisation cycles with fresh or cryopreserved testicular sperm obtained by an open biopsy and testicular needle aspiration were evaluated. Sperm motility was present in 70.9% of the cycles in Group-I, 77.8% cycles in Group-II and in 83.3% In Group-III (NS). The fertilisation rates were similar in the three study groups (50%, 48.6% and 54.8% respectively). The pregnancy rates were 26.7%, 22.2% and 16.3% respectively (NS). The delivery rate, however, was significantly lower in Group-III (4.1%) than in Group-I and -II (18.4% and 15.9%, respectively, P0.05). The IVF results after use of cryopreserved testicular sperm are comparable with those obtained with the fresh specimens. Lack of sperm motility before cryopreservation does not exclude favourable outcome and therefore testicular sperm freezing is feasible whenever there are enough sperm cells in the extracted testicular tissue.

To determine whether complete failure of fertilization of oocytes in couples with unexplained infertility persists during subsequent in vitro fertilization (IVF) cycles.A retrospective study of 120 cycles of IVF in 44 couples with unexplained infertility and complete failure of fertilization during their first IVF trial.In vitro fertilization unit of the Sheba Medical Center.Forty-four couples undergoing IVF for unexplained infertility.Fertilization rate of retrieved oocytes and pregnancy rate.Of the initial 44 couples, 37 underwent additional IVF cycles and 30 (81.1%) achieved fertilization. Seven patients conceived during the study period as a result of IVF and two conceived spontaneously.Complete failure of fertilization does not necessarily persist during subsequent IVF cycles. Therefore, at least two more IVF cycles should be attempted before reverting to other therapeutic options. However, although fertilization can be achieved in most couples, the mean oocyte fertilization rate during subsequent cycles in this group is low. This suggests an underlying undiagnosed pathology of oocyte/sperm interaction in some of these patients.

This prospective study was designed to examine the feasibility of natural cycle in vitro fertilization (IVF) in poor responders, and the clinical factors that may predict successful outcome. Twenty-two poor responders underwent IVF treatment with 44 unstimulated cycles. The results of the natural cycles were compared with those of the 55 low-response stimulated cycles of these patients during the 12 months prior to the study. Eighteen (82%) patients had at least one oocyte retrieved, while nine (41%) had at least one cycle with embryo transfer. Two (9%) patients each gave birth to a healthy term baby. These results are comparable with those of the stimulated cycles. Serum early follicular follicle stimulating hormone (FSH) level was found to be the only reliable predictor of oocyte recovery and overall outcome in each specific natural cycle. However, because of great variability in basal FSH levels among different cycles of the same patient, this is not a reliable predictor of outcome in future cycles. We conclude that poor responders are a unique group of patients who may benefit from natural-cycle IVF treatment.

This study was conducted to determine whether glucocorticoid supplementation for patients with polycystic ovarian disease during ovulation induction with gonadotropins for in vitro fertilization (IVF) therapy is beneficial.Seventy-one cycles of patients undergoing first attempts at IVF, with classical polycystic ovarian disease and hyperandrogenemia, who enrolled in the IVF-embryo transfer program, were evaluated retrospectively. In 20 cycles (20 patients) glucocorticoid supplementation was noted and compared to 51 cycles (51 patients) without glucocorticoid as adrenal androgen suppression. Ovaries were stimulated by gonadotropin releasing hormone agonist, human menopausal gonadotropin, and dexamethasone. Ovarian responsiveness and IVF-embryo transfer outcome were analyzed and included the number of follicles17 mm in diameter, serum estradiol concentration on the day of human chorionic gonadotropin administration, number of human chorionic gonadotropin ampoules administered, number of oocytes retrieved, percentage of oocytes fertilized, number of embryos transferred, implantation rate, and number of clinical pregnancies and their outcome.The results showed that the pregnancy rate in patients who received glucocorticoid was 22.1%, compared to 26% in the controls (statistically insignificant). The IVF cycle variables studied revealed no statistically significant differences.Our observations did not support the notion that adrenal androgen suppression by glucocorticoid, or as an adjuvant therapy, is beneficial to patients with polycystic ovarian disease who enrolled in an IVF-embryo transfer program.

Our purpose was to assess the incidence of multiple pregnancies and their obstetric outcome after intracytoplasmic sperm injection.The study group comprised women who delivered twins or triplets after intracytoplasmic sperm injection and standard in vitro fertilization. The incidence and main perinatal outcome of 140 multiple pregnancies resulting from intracytoplasmic sperm injection or standard in vitro fertilization treatment were analyzed.A total of 60 multiple pregnancies was obtained after intracytoplasmic sperm injection (3.4 +/- 1.1 embryos/cycle) and 80 after standard in vitro fertilization (3.3 +/- 2.0 embryos/cycle). The incidence of multiple pregnancy, i.e., 22.6 compared to 20.7%, respectively, was calculated. The obstetric outcome of 47 multiple pregnancies after intracytoplasmic sperm injection was 39 twin deliveries at between 27 and 37 weeks of gestation (mean, 36 +/- 3.3) and 8 successful triplet deliveries between 26 and 36 weeks of gestation (mean 32.6 +/- 2.4). The outcome after regular in vitro fertilization was similar. No major malformations were observed.The results of this study showed that the incidence of multiple pregnancies after intracytoplasmic sperm injection was similar to that after standard, conventional in vitro fertilization. The perinatal outcome did not differ between both groups.

To evaluate the fertility potential after primary cesarean section (CS) in anovulatory patients treated for ovulation induction with gonadotropins.A controlled, prospective study was conducted on 97 anovulatory patients who delivered a neonate either abdominally or vaginally after ovulation induction with human menopausal gonadotropin/human chorionic gonadotropin (hMG/hCG). After four cycles of hMG/hCG therapy, cumulative pregnancy rates and abortions were observed. In both groups, patients who did not conceive underwent hysterosalpingography to evaluate uterine and tubal patency.The cumulative pregnancy rate in the anovulatory, post-cesarean section patients treated with hMG/hCG was 61.9%, as compared to 59.6% in the control group (statistically nonsignificant). The abortion rate was similar in both groups.The risk of uterine or tubal infertility is probably not substantially increased in patients on whom uncomplicated cesarean sections have been performed. Anovulatory patients who conceive after treatment with gonadotropins and deliver abdominally should be referred for medical treatment before evaluation of any uterine or tubal infertility.

Our purpose was to assess whether one or more sperm parameters have predictive value for the outcome of intrauterine insemination treatment.Infertile couples whose normoovulatory and normomechanical female partners underwent superovulation and intrauterine insemination were investigated. The semen profile of the male partner was discounted. In 160 couples, 544 cycles were obtained, resulting in 59 ongoing pregnancies (10.84%/cycle, 36.87%/patient).The only parameter found to be significantly correlated with a positive outcome was the degree of sperm motility following preparation for intrauterine insemination. Close to half (47.5%) of the couples with a very good or an excellent degree of sperm motility conceived, whereas only 8.3% of those patients who had poor or fair sperm motility conceived. None of the semen characteristics, such as volume, count, percentage motility, or percentage normal morphology, were found to correlate with cycle outcome. Although there was a progressive increase in the pregnancy rate with an increase in the total number of motile sperm inseminated, it did not reach significance. Seventy percent of the pregnancies were achieved within a maximum of three treatment cycles. The spermatogram is not accurate enough as a prognostic factor for treatment outcome.The degree of sperm motility, after appropriate preparation for intrauterine insemination, is the only parameter to be correlated with treatment outcome. For couples with a normal female partner, we suggest a maximum of three treatment cycles of induction of ovulation and intrauterine insemination, whenever good progressive motile sperm is obtained after suitable preparation. For cases with poor sperm progression, we suggest appropriate couple counseling and that an alternative assisted reproduction procedure be taken into consideration.

The human hepatic asialoglycoprotein receptor is a noncovalent hetero-oligomer composed of two homologous subunits, H1 and H2, with an as yet unknown stoichiometry. Ligand specificity and binding affinity depend on the arrangement of the subunits in the complex. An 80-amino acid segment connecting the transmembrane and the carbohydrate binding domains contains heptad repeats characteristic of alpha-helical coiled coil structure. We expressed and purified corresponding peptides, H1S and H2S, and confirmed by circular dichroism spectroscopy that they can assume alpha-helical conformation. Oxidative cross-linking of amino-terminal cysteines generated specific covalent oligomers, indicating that separately H1S forms trimers and H2S tetramers. Upon mixing, covalent heterotetramers were formed with a preferred stoichiometry of 2 H1S and 2 H2S peptides. These results suggest that the stalk segments of the receptor subunits oligomerize to constitute an alpha-helical coiled coil stalk on top of which the carbohydrate binding domains are exposed for ligand binding. We propose that the functional asialoglycoprotein receptor is a 2:2 heterotetramer.

A group of 78 infertile women, diagnosed as having tubal factor infertility only, was enrolled in a prospective, randomized study conducted to determine whether the addition of different doses of glucocorticoids to the protocol of ovulation induction for in-vitro fertilization (IVF) would be beneficial. Oocyte numbers, percentage of fertilization, oestradiol, luteinizing hormone and follicle stimulating hormone serum concentrations, number of embryo transfers and pregnancy rate were evaluated. Compared to control cycles (group A; n = 24), the addition of 0.5 mg (group B; n = 27) of 1 mg dexamethasone (group C; n = 27), combined with the protocol of programmed oocyte retrieval for IVF patients in the study, demonstrated equivalent results. The mean numbers of oocytes retrieved were 10.8 +/- 3.9 in the control group, compared to 11.2 +/- 4.0 in group B and 10.5 +/- 3.6 in group C. The fertilization rates were 69 +/- 21, 66 +/- 18 and 70 +/- 15% respectively. The pregnancy rates were 20, 16 and 20.8% respectively. The addition of up to 1 mg dexamethasone daily to the protocol of ovulation induction for oocyte retrieval did not improve the overall IVF-embryo transfer outcome in patients with tubal factor infertility.

To compare hysteroscopic endometrial resection with transabdominal hysterectomy in women with menorrhagia who failed to respond to conservative treatment.In order to attain correlated samples, only patients with a normal-sized or moderately enlarged uterus were included in the study.The operating time, hospital stay and number of women requiring postoperative blood transfusion was significantly lower in the hysteroscopy group. Following hysteroscopy, uterine perforation occurred in three patients, fluid overload in two and dilutional hyponatremia in one. Laparotomy was performed for suspected bowel injury in two cases. The main complication in women undergoing hysterectomy was postoperative fever (36.5%). One case of vesicovaginal fistula was diagnosed seven days postoperatively.The results indicate that endometrial resection, with its low cost and prompt recovery, offers a promising alternative treatment for women with abnormal uterine bleeding.

To assess the use of transvaginal ultrasound guidance during operative laparoscopy.Five of 98 consecutive cases of operative laparoscopy for benign-appearing ovarian cysts were complicated by extensive intrapelvic adhesions and a distorted anatomy. Following prolonged dissection, simultaneous transvaginal ultrasonography was used in these cases.In all cases we were able to ultrasonographically image and locate the ovarian cyst during the laparoscopic procedure. In four cases this was a significant aid in expediting the procedure and avoiding damage to adjacent pelvic structures. In one case, identification of the ovarian cyst facilitated the decision to resort to laparotomy.In selected cases, laparoscopic surgeons should be aware of the feasibility and possible benefits of the use of simultaneous intraoperative transvaginal ultrasonography.

The hepatic asialoglycoprotein receptor is a hetero-oligomer composed of two homologous subunits. The specificity and affinity of ligand binding depends on the number and spatial arrangement of several galactose-binding sites within the receptor complex. Previous studies indicated that both subunits are required for high-affinity ligand binding, i.e. for the simultaneous interaction with three galactose residues within an N-linked glycan. However, we found that asialoorosomucoid (ASOR) and asialofetuin (ASF) bind to transfected COS-7 cells expressing subunit H1 in the absence of the second subunit H2. ASOR binding occurred with a dissociation constant of approximately 40 nM, approximately four-times higher than the Kd of ASOR binding to the hetero-oligomeric receptor. Normalized to the amount of H1 expressed, approximately 10-times fewer binding sites were produced by H1 alone. A glycopeptide with a single tri-antennary N-linked glycan purified from ASF bound to the hetero-oligomeric receptor, but did not bind detectably to H1-expressing COS-7 cells. H1 is thus unable to simultaneously recognize all three galactose residues in a glycan. From this, we conclude that, at a sufficiently high density of H1 on the cell surface, high-affinity binding of ASOR and ASF is the result of two or more glycans interacting with H1 oligomers with low affinity in a bivalent manner.

We present a rare case in which therapy of primary ovarian pregnancy, using laparoscopic laser surgery (videolaseroscopy), was successfully performed without the need of laparotomy. Because operative laparoscopy has the benefits of reduced morbidity, reduced hospitalization and rapid recovery, and because it has the advantage of reducing postoperative adhesions as compared to laparotomy, it is the preferable technique for treatment of ovarian gestation after a laparoscopic diagnosis, especially for a woman who desires to preserve her fertility potential.

The outcome after fluid aspiration from 41 sonographically benign-appearing ovarian cysts was assessed. The considerable probability of recurrence was significantly higher after ultrasound-guided aspiration than following aspiration via laparoscopy (54% versus 30%, respectively, at 36 months). Although all the recurring cysts were benign, the concern with malignancy and the high recurrence rate seem to indicate that fluid aspiration from sonographically benign-appearing cysts by either method is not the management of choice.

The effect of an intraumbilical prostaglandin (PG) F2 alpha injection on the third stage of normal labor was studied in 54 normal, laboring women at term. Either 1 mg of PGF2 alpha diluted to 20 mL in normal saline (27 women) or 20 mL of normal saline alone (27 women) was injected into the umbilical vein immediately after delivery using a randomized, double-blind protocol. The mean (+/- SD) duration of the third stage was 7.31 +/- 6.37 minutes in the PGF2 alpha patients and 8.94 +/- 7.10 in the normal saline patients. Intraumbilical PGF2 alpha did not influence the third stage of normal labor.

The role of cervical cerclage was evaluated in 54 pregnant women with anomalous uteri. Forty-six of them delivered live neonates, and eight aborted. The success rate was 85.2% as compared to 22% in previous pregnancies. The mean gestational age was 38 weeks (range, 32-42). The average birth weight was 3,150 g. Complications from the cerclage procedures were minor. Our results support the trend toward the use of cervical cerclage in pregnant women with anomalous uteri.

Ovulation induction with various drugs can achieve successful pregnancy in the anovulatory patient. The overall pregnancy rate achieved approaches that found in the normal population. Several epidemiologic reports have shown that the expectancy of establishing a clinically detectable pregnancy during one menstrual cycle among normal healthy women was approximately 25% [1, 2]. Out of these, approximately 15% would abort [3]. Pregnancies which aborted early or preclinically were not considered in the overall pregnancy rate. Leridon [4] reported a clinical pregnancy rate of 42% per cycle of exposure and a 26% clinical abortion rate in a normal population. Higher pregnancy rates in normal conceptional cycles were reported by others [5, 6]. Edmonds et al. [6] found a positive assay of urinary human chorionic gonadotropin (hCG) in 60% of exposed ovulatory cycles, of which 62% aborted with the majority of these losses occurring subclinically.

A patient who suffered from polycystic ovarian disease and anovulation, was treated with pure follicle stimulating hormone for induction of ovulation. The treatment was stopped and human chorionic gonadotrophin was not administered because of high serum oestradiol levels and multiple follicular development. Ovulation occurred 11 days after pure follicle stimulating hormone was discontinued, the patient developed third-degree ovarian hyperstimulation syndrome and conceived with a quintuplet pregnancy.

The effect of cervical cerclage on the survival rate of the fetus was studied in 86 pregnancies of women with congenital uterine anomalies and a random group of 106 pregnancies in women with normal shaped uteri. The uterine morphologic factors were determined in all by hysterosalpingography, and when necessary, hysteroscopy and laparoscopy were combined. The incidence of hysterosalpingography-proved cervical incompetence (23 per cent) was similar in both groups. Sixty-seven and 29 pregnancies were managed with cervical cerclage in each group, respectively. The fetal outcome was stratified by cervical incompetence and obstetric history. The percentage of viable newborns was significantly higher in women with malformed uteri who underwent cerclage (88 per cent) compared with those without cerclage (47 per cent). No statistically significant beneficial effect of cerclage was found for normal uteri, even when only those with a history of recurrent fetal loss were considered.

A case of bilateral adnexal torsion after clomiphene citrate therapy is reported. Although this is rare, there is an increased risk after ovulation induction. Laparoscopic aspiration was successfully performed.

The obstetric risk associated with congenital uterine malformations was studied in a group of 67 women who had undergone hysterosalpingography (HSG) during an eight-year period. HSG was performed to investigate primary (21% of the cases) and secondary (19%) infertility (group 1) or recurrent early fetal loss (60%) (group 2). The study group was compared with a random control group of 130 patients with HSG-proven normal uteri, matched for the presenting symptom. Prematurity and intrauterine fetal death were found to be significantly more common (P less than .05) for women in group 1 with uterine anomalies. The mean birth weight for preterm infants (less than 37 weeks) was significantly lower (P less than .01) for women with malformed uteri. The incidence of antepartum bleeding during pregnancy (P less than .01), breech presentation and cesarean section (P less than .001) was significantly higher for the study group. Premature rupture of the membranes was diagnosed more frequently (P less than .05) only in group 1. Patients with congenital uterine anomalies are a high-risk obstetric group. Primary infertility may be a more common presenting complaint in women with uterine anomalies than previously recognized.

(1990). Systemic adverse reaction to an oxytocin preparation. Journal of Obstetrics and Gynaecology: Vol. 10, No. 3, pp. 224-225.

The hepatic asialoglycoprotein receptor, a non-covalent hetero-oligomer of two subunits, is a constitutively cycling endocytic receptor. However, the ligand asialoorosomucoid caused downregulation of up to 40% of surface binding sites and a twofold increase in internalization rate. This was not the result of receptor crosslinking, since monovalent ligands had the same effect. Ligand binding thus appears to transmit a signal to the cytosolic portion of the receptor not unlike in signaling receptors. The two subunits were endocytosed at different average rates lower than that of ligand, indicating heterogeneity in oligomer formation and potentially in ligand specificity.

The effects of various parameters on age at menopause have been investigated in five ethnic groups in Israel comprising East European, West European, North African, Israeli and other Middle Eastern (Mediterranean) women, respectively. The data were acquired by means of anonymous questionnaires and were programmed for 1770 women. Correlation coefficients between various variables and age at menopause revealed three variables which have a straight correlation, vis. obesity index, number of children, and years of amenorrhoea (during the reproductive years). The years-of-smoking variable has an inverse correlation with age at menopause. East Europeans have the highest age at menarche. Two-way analysis of variance has shown that the obesity index, years of amenorrhoea, number of children and years-of-smoking parameters are individually more important than ethnic origin. The finding that the age at menopause is highest in the North African group is explained by the higher incidence in this group of high parity, a greater number of amenorrhoea, obesity, and low cigarette consumption. Since many habits (such as smoking, diet, use of contraceptive pills, multiple partners and marital obligations) are subject to frequent change in the modern world, it is of the utmost importance to repeat such a study every few years.

Fifty-seven patients with large recurrent inguinal hernia had undergone repair using Marlex mesh. Fifty-six patients had excellent results, one patient suffered a recurrence. There were two wound infections and no deaths. Polypropylene is an excellent prosthetic material for replacement of attenuated or destroyed posterior wall of the inguinal canal. It is biologically inert and resistant to infection.