Biomedical subjects

F Khamsi

Publications and source records attributed to F Khamsi.

At least 19 recordsLinked to original sources

PubMed2001

Intracytoplasmic sperm injection increased fertilization and good-quality embryo formation in patients with non-male factor indications for in vitro fertilization: a prospective randomized study.

OBJECTIVE: To compare the fertilization rate and formation of good-quality embryos with conventional IVF and ICSI in patients with non-male factor infertility. DESIGN: Prospective controlled study. SETTING: Infertility clinic. PATIENT(S): Thirty-five patients with non-male factor infertility. INTERVENTION(S): Retrieved sibling oocytes were randomly assigned to conventional IVF or ICSI. Of sibling oocytes assigned to ICSI, only metaphase II oocytes were injected with sperm. MAIN OUTCOME MEASURE(S): Fertilization rate and formation of good-quality embryos per retrieved oocyte. RESULT(S): Per retrieved oocyte, ICSI resulted in better fertilization rate compared with conventional IVF (71.3% [134 of 188] vs. 57.2% [107 of 187]). Per retrieved oocyte, ICSI also resulted in better formation of good-quality embryos at 48 hours after retrieval compared with conventional IVF (64.4% [121 of 188] vs. 47.1% [88 of 187]). CONCLUSION(S): In IVF patients with non-male factor infertility, subjecting some sibling oocytes to ICSI increased the fertilization rate and formation of good-quality embryos per retrieved oocyte. It also avoided the problem of total fertilization failure in almost all cases.

Adult↗

PubMed2001

Differential effects of insulin-like growth factor-I and gonadotropins on the proliferative activity of two subgroups of granulosa cells: cumulus oophorus and mural granulosa cells.

OBJECTIVE: To evaluate the physiological role of insulin-like growth factor-I (IGFI) and its interaction with gonadotropins in cell replication of two types of granulosa cells (cumulus oophorus, CC) and mural granulosa cells (MGC). DESIGN: Controlled randomized study of the action and interaction of gonadotropins and IGFI on granulosa cell replication in the rat. SETTING: A university reproductive biology laboratory. INTERVENTION(S): The study examined the in vivo treatment with gonadotropins or an analogue of IGFI, long Arg3-insulin-like growth factor (LR3-IGFI), which does not bind to IGFI-binding proteins. MAIN OUTCOME MEASURE(S): Granulosa cell replication was evaluated by the use of 3H-thymidine incorporation. RESULT(S): It was noted that the CC replicate much faster than the MGC. These two types of granulosa cells have very different dose response curves to IGFI. Differential responses were seen in animal cells exposed to long Arg3-insulin-like growth factor in vivo and then exposed to FSH and LH in vitro. CONCLUSION(S): Although murine granulosa cells show proliferative activity when they are exposed to IGFI, the two types, CC and MGC, respond differently. IGFI is not the sole mediator of the action of FSH, and these two chemicals may act independently or in concert.

Animals↗

PubMed2001

Performing ICSI using an injection pipette with the smallest possible inner diameter and a long taper increases normal fertilization rate, decreases incidence of degeneration and tripronuclear zygotes, and enhances embryo development.

PURPOSE: To compare the efficacy of two types of injection pipette used for ICSI, one with a larger (5-7 microns) inner diameter and a shorter taper with that inner diameter, and another with the smallest (3-5 microns) possible inner diameter and a longer taper with that inner diameter. METHODS: Retrieved oocytes at metaphase II stage were injected using one of two types of injection pipette, in 33 and 94 cycles, respectively, in a total of 127 cycles in 108 patients. RESULTS: In comparison to the injection pipette with a larger (5-7 microns) inner diameter and a shorter taper with that inner diameter, the injection pipette with the smallest (3-5 microns) possible inner diameter and a longer taper with that inner diameter increased normal fertilization rate ((70 +/- 3.6)% vs. (86 +/- 2.2)%; P = .001; mean +/- SEM); decreased the incidence of degeneration ((14 +/- 2.4)% vs. (5 +/- 1.4)%; P = .001) and tripronuclear zygotes ((1.0 +/- 0.35)% vs. (0.1 +/- 0.21)%; P = .03); increased Day-2 diploid embryos ((69 +/- 3.7)% vs. (85 +/- 2.2)%; P = .001) and good-quality Day-2 diploid embryos ((67 +/- 4.0)% vs. (79 +/- 2.4)%; P = .03), all per injected oocyte; and increased the number of blastomeres per good-quality Day-2 diploid embryo ((3.0 +/- 0.21 vs. 3.8 +/- 0.12; P = .0003). CONCLUSIONS: Performing ICSI using an injection pipette with the smallest (3-5 microns) possible inner diameter and a longer taper with that inner diameter maximizes normal fertilization rate, minimizes the incidence of postinjection degeneration and tripronuclear zygotes, and enhances embryo development.

Adult↗

PubMed2001

Exposure of human oocytes to endometrioma fluid does not alter fertilization or early embryo development.

BACKGROUND: Extensive endometriosis causes a mechanical disturbance in the pelvis leading to obstructive-type infertility. However, minimal or mild endometriosis is suspected to cause infertility, possibly through a humoral agent. Previous studies reported the presence of a factor in the serum of patients with endometriosis which reduced fertilization and early embryo formation in a rat IVF model. METHODS: In the present article, we report a comparison of oocytes exposed to endometrioma fluid and oocytes not exposed (controls) in the context of a human IVF setting. We have been in the practice of aspirating oocytes into prewarmed 60-ml syringes containing culture medium. We have shown previously that this technique reduces the length of oocyte retrieval without compromising success. In 14 women undergoing oocyte retrieval, we inadvertently entered an endometrioma. This resulted in retrieved oocytes that were either exposed or not exposed to endometrioma fluid. RESULTS: In contrast to previous reports, we found no difference in fertilization or early embryo development between the two groups. The fertilization rate for oocytes exposed to an endometrioma was 60%, versus 56% for controls. The good-quality embryo formation rate for oocytes exposed to an endometrioma was 45%, versus 46% for controls.

Adult↗

PubMed2001

Novel demonstration of a physiologic/pharmacologic role of insulin-like growth factor-1 in ovulation in rats and action on cumulus oophorus.

Gonadotropins are well known to be the most important stimulus for ovarian follicular development. More recently, there is indirect evidence that insulin-like growth factor-1 (IGF-1) is also a very important autocrine/paracrine factor in folliculogenesis. We had access to an analog of IGF-1, LR3IGF-1, which binds very poorly to IGF-1 binding proteins and therefore was shown by previous investigators to have biologic effects. We studied rats that were superovulated with the use of gonadotropins. We showed that the addition of LR3IGF-1 by infusion further increased the ovulation rate (statistically significant) and increased the ovarian weight in two of three strains of rats. We demonstrated that infusion of LR3IGF-1 or injection of equine chorionic gonadotropin or a combination of these two were associated with oocytes with reduced number of cumulus cells (statistically significant). We conducted an experiment to determine whether in vitro culturing with varying dosage of IGF-1 may stimulate cumulus cell replication to improve the quality of oocyte cumulus complex. IGF-1 did not show any change in this respect. Through these physiologic (pharmacologic) studies, we have shown that IGF-1 (analog) can further increase the ovulation rate induced by gonadotropins.

Animals↗

PubMed2001

Recent discoveries in physiology of insulin-like growth factor-1 and its interaction with gonadotropins in folliculogenesis.

Ovarian follicular development is under the influence of gonadotrophins. The manner by which gonadotrophins achieve their role in cell replication and hormone production is through other specialized molecules. Insulin-like growth factor-1 (IGF-1) is considered to be one of the most important of these molecules. IGF-1 is present in relatively large amounts in the ovary and the IGF-1 gene is expressed in the graafian follicle. IGF-1 binding proteins modulate the action of IGF-1 and are influenced by gonadotrophins. Null mutations of genes encoding IGF-1 and type-1 IGF receptor have demonstrated the obligatory role of IGF-1 in folliculogenesis. It was proposed that IGF-1 may be an obligatory mediator of gonadotrophin-induced folliculogenesis and that the interaction is synergistic. From this point, one group embarked on a series of physiological studies to further elucidate the interaction of these molecules. We discovered that, according to circumstances, follicle stimulating hormone (FSH) may act with IGF-1 synergistically (as was postulated before), additively, independently, or even antagonistically. We discovered that granulosa cells must first be exposed to FSH and then they respond well to IGF-1. All previous studies of granulosa cells were done on mural granulosa cells. We subsequently showed that cumulus type of granulosa cells (adjacent to the oocyte) behave differently in their responses to gonadotrophins and IGF-1.

Animals↗

PubMed2001

Granulosa cells of the cumulus oophorus are different from mural granulosa cells in their response to gonadotrophins and IGF-I.

There are two types of granulosa cells: those which surround the oocyte are cumulus cells (CC) and those which surround the antrum are mural granulosa cells (MGC). These cells are under the influence of several hormones and growth factors, the most important of which are gonadotrophins and IGF-I. In this article, we report novel observations on the differences between these two types of granulosa cells and their interaction with gonadotrophins and IGF-I. We were able to conduct physiological studies on the role of IGF-I by using an analogue of IGF-I which does not bind to IGF-I-binding proteins (LR3-IGF-I). Immature rats received saline, equine chorionic gonadotrophin (eCG), LR3-IGF-I or eCG plus LR3-IGF-I by infusion using a pump from 24-29 days of age. The rats were killed and the ovaries removed. Surface follicles were punctured and MGC and oocyte cumulus complexes were removed. These were cultured in saline (control) and in three different doses of FSH. Cell replication was assessed by 3H-thymidine incorporation and differentiation was evaluated by the measurement of progesterone secretion. It was noted that CC replicated ten times more than MGC. Similarly, progesterone secretion by CC was six times more than by MGC. In vivo exposure to gonadotrophins (eCG) positively influenced in vitro treatment with FSH in both cell types. This phenomenon was observed in both cell replication and progesterone secretion. The IGF-I analogue had a positive effect on cell replication of MGC but a negative effect on the cell replication of CC. With respect to progesterone secretion, the IGF-I analogue had a negative effect on CC but a positive effect on MGC. In conclusion, CC behaved differently from MGC in response to gonadotrophins and the IGF-I analogue. IGF-I and FSH acted additively, synergistically or antagonistically in different circumstances.

Analysis of Variance↗

PubMed2000

The status of controlled prospective clinical trials for efficacy of intracytoplasmic sperm injection in in vitro fertilization for non-male factor infertility.

PURPOSE: Intracytoplasmic sperm injection (ICSI) of some sibling oocytes may have a beneficial effect in couples going through in vitro fertilization for causes of infertility not related to the male factor. Our purpose was to critically appraise the randomized controlled studies done in this area and arrive at some recommendations. METHODS: The four controlled trials done so far have utilized similar methodology, i.e., they randomly allotted sibling oocytes to ICSI versus standard insemination in patients going through in vitro fertilization and embryo transfer. RESULTS: In the first trial reported in 1995 there was no difference in fertilization rate, whereas the later trials reported in 1997, 1999, and 2000 showed improvement with ICSI that reached statistically significant level in the last two studies. CONCLUSIONS: Total fertilization failure of an in vitro fertilization cycle can be prevented and fertilization can be improved if half of sibling oocytes are subjected to ICSI.

Controlled Clinical Trials as Topic↗

PubMed2000

Novel studies on influence of gonadotropins and insulin-like growth factor-I on growth of cumulus oophorus in the rat.

In the final developmental stage of a Graafian follicle, there are two functionally distinct types of granulosa cells: the cumulus cells (CCs) and the mural granulosa cells (MGCs). Previous studies focused on follicle-stimulating hormone (FSH) and insulin-like growth factor I (IGF-I) interactions in MGCs. Our goal was to study these interactions in CC proliferation. Immature rats received in vivo treatments of either saline, equine chorionic gonadotropin (eCG) with high FSH activity, an IGF-I analog (LR3-IGF-I) with poor binding to IGF-I binding proteins, or a combination of both hormones. CCs from each in vivo treatment were then cultured and treated in vitro with either saline, FSH, or IGF-I. CCs proliferation were assessed by measurement of 3H-thymidine incorporation. Prior in vivo treatment with eCG resulted in the highest proliferative activity of CCs when combined with FSH in vitro treatment. In vivo treatment with LR3-IGF-I had no effect on CC replication. CC replication was higher in FSH in vitro treatment than of IGF-I. The combination of eCG and LR3-IGF-I was the only in vivo treatment to stimulate higher CC proliferation with IGF-I in vitro treatment. This study suggests that FSH does not act through IGF-I, a mechanism previously proposed.

Animals↗

PubMed1999

Effects of granulosa cells, cumulus cells, and oocyte density on in vitro fertilization in women.

The objective of this study was to determine if in vitro fertilization (IVF) rate is affected by the diameter of oocyte-cumulus complex (OCC), by coculturing oocytes with autologous granulosa cells, or by increasing the oocyte density in culture medium. Women with previous fertility problems underwent the IVF program. In study 1, the diameter of OCC was graded on retrieval on a scale of 0-3: grade 0 = no cumulus at all; grade 1 = diameter of 75-100 microm; grade 2 = diameter of 125-150 microm; and grade 3 = diameter of 200-225 microm. In study 2, oocytes were cocultured with autologous granulosa cells. In study 3, oocytes were cocultured in groups of one, two, or four. OCCs with a grade > 1.5/3 resulted in a greater (P = 0.04) proportion of embryo/oocyte than did OCCs with a grade < 1.5/3 (0.91 +/- 0.05 vs 0.68 +/- 0.10; mean +/- SEM). Coculturing oocytes with autologous granulosa cells did not affect (P = 0.42) the proportion of embryo/oocyte (0.63 +/- 0.11 vs 0.74 +/- 0.07 in controls). Coculturing oocytes in groups of two or four in culture drop did not affect (P = 0.37 and P = 0.38, respectively) the proportion of embryo/oocyte (0.63 +/- 0.07 vs 0.73 +/- 0.08 in controls, and 0.73 +/- 0.08 vs 0.63 +/- 0.08 in controls, respectively). In conclusion, coculturing oocytes with autologous granulosa cells or increasing the oocyte density from 1 to 2 or 4 oocytes/culture drop, in the context of our study, did not affect rate of IVF and embryo formation. The diameter of OCC at retrieval may give some indication regarding its future fertilization and development. This diameter varies with the type of ovarian stimulation and the patient's age. This variation in diameter does not correlate with oocyte maturity.

Cell Communication↗

PubMed1998

Recent advances in assisted reproductive technologies.

Assisted reproductive technologies (ART) have received considerable attention, both clinically and empirically. Drs. Steptoe and Edwards removed one oocyte surgically from a woman with infertility related to tubal disease. They fertilized this oocyte in vitro and transferred the formed embryo to the woman's uterus and achieved pregnancy and delivery. The technique of in vitro fertilization (IVF) and embryo transfer (ET) quickly became widely utilized for other causes of infertility as well as for tubal disease. In the last 5 years there has been a number of new developments that are reviewed in this article. The most important and now widely practiced technology has been direct intracytoplasmic injection (ICSI) of the husband's sperm into the wife's oocyte. This was developed for treatment of infertility related to low sperm count. Subsequently it was shown that sperm can be aspirated from epididymis or found in testicular biopsy in obstructive azoospermia. Another promising development is in vitro maturation (IVM) of immature oocytes. This has the potential of avoiding ovarian hyperstimulation, which can be uncomfortable and occasionally dangerous. Some oocytes are unable to fertilize and/or develop into normal embryos. It may be possible that the problem is with the machinery of cytoplasm of the oocyte. Therefore cytoplasmic transfer from a normal oocyte to an abnormal oocyte may overcome the problem. Infertile couples may be faced with many psychological problems that become even more complex with various treatments. Whereas donation of oocytes or embryos can be technically quite simple, there are many psychological issues involved. As can be gathered from aforementioned discussions, the treatments developed for infertility appear to be somewhat illogical and in the style of "shot gun therapy." In the field of infertility, as in other areas of medicine, it is of paramount importance to know the details of disease mechanisms. This in turn will allow specific and logical treatments to be developed.

Animals↗

PubMed1997

Some psychological aspects of oocyte donation from known donors on altruistic basis.

OBJECTIVE: To survey a sample of couples along with their chosen oocyte donors regarding psychological variables. DESIGN: Patients in an infertility clinic were interviewed by a counselor using a semistructured interview format designed to gather systematic data. SETTING: Infertility clinic. PATIENT(S): Ten recipient couples along with their donors were seen. RESULT(S): Oocyte recipients ranged in age from 30 to 49 years with a mean age of 40 years. Oocyte donors ranged in age from 21-34 years with a mean age of 29 years. Eighty percent of donors were married or involved in a serious relationship; 90% of donors had at least one child. The major reason for acting as a donor was altruism. Anonymity was a primary concern for recipients and donors: 80% of the sample had not confided in anyone at the present time. 70% did not intend to disclose any information at any time; 80% did not plan to inform the child, while 20% were undecided at the present time; and 90% indicated good to excellent support systems. CONCLUSION(S): The present study provides significant information regarding Canadian couples undergoing the oocyte donation program with known donors.

Adult↗

PubMed1997

Interactions between follicle-stimulating hormone and growth factors in regulation of deoxyribonucleic acid synthesis in bovine granulosa cells.

Follicle growth is regulated by the combined actions and interactions of pituitary gonadotropic hormones and local intraovarian paracrine and/or autocrine agents, including the peptide growth factors, insulin-like growth factor-I (IGF-I), and epidermal growth factor (EGF). The present study was undertaken to determine a) whether the previously demonstrated inhibitory effect of FSH on DNA synthesis was related to its ability to cause cumulus mucification as a differentiated response incompatible with continued proliferation, and b) whether increased IGF-binding proteins (IGFBP) secreted in response to FSH competed with IGF receptors, thereby inhibiting response to exogenous IGF-I. To determine the effects of cumulus mucification in modulating the mitogenic response to IGF-I, two other agents that induce cumulus mucification by different mechanisms, EGF and dibutyryl cAMP (dbcAMP), were compared with FSH. To determine the possible role of IGFBP in modulating the mitogenic response to IGF-I, an IGF-I analogue that does not bind to IGFBP, long arg3-IGF-I (LR3-IGF-I), was compared with native IGF-I for efficacy in stimulating DNA synthesis in the absence and presence of each of the above agonists. Both IGF-I and LR3-IGF-I stimulated [3H]thymidine incorporation in cumulus cells to a much greater extent than in mural granulosa cells. Incorporation in mural cells was increased by each of FSH, EGF, and dbcAMP acting by itself, and in most instances was considerably enhanced by the combined action of these agents with each of the IGF-I forms. In contrast, the considerably greater stimulatory effect of both IGF-I and LR3-IGF-I on cumulus cells was markedly decreased by each of FSH, EGF, and dbcAMP. These findings suggest that the inhibition of IGF-I-stimulated DNA synthesis in cumulus cells is a consequence of induction of cumulus cell differentiation (mucification) by FSH and EGF rather than through competition between IGF-I receptor and IGFBP secretion induced by these agents.

Animals↗

PubMed1996

Role of germinal vesicle on protein synthesis in rat oocyte during in vitro maturation.

To investigate the role of the germinal vesicle (GV) on in vitro maturation (IVM) of rat oocytes, we examined protein synthesis during IVM by comparing polypeptide patterns in control and enucleated oocytes using one and two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Separation of polypeptides extracted from the cytoplasm of GV by one-dimensional SDS-PAGE revealed that a 55 kDa polypeptide was present only in the GVs of rat oocytes. At 0, 12, 24, 36, and 44 hr after PMSG injection, prior to the initiation of maturation, enucleated oocytes synthesized the same major polypeptides as cumulus intact (CI) oocytes. During meiotic maturation, no major changes were detected in protein synthesis from prophase (GV stage) to prometaphase I (0-6 hr IVM). However, after entry into prometaphase I (7 hr IVM), striking changes were seen; a 24 kDa polypeptide disappeared and expression of a 34 kDa polypeptide became stronger. This pattern lasted until metaphase II. We detected no major differences in the pattern of protein synthesis between CI and enucleated oocytes using two-dimensional PAGE. These results indicate that protein synthesis in the maturing rat oocyte is controlled by cytoplasmic regulators rather than intrinsic nuclear components.

Animals↗

PubMed1996

Expression of urokinase-type plasminogen activator in human preimplantation embryos.

During embryo implantation in the human trophoblast cells invade the endometrium and plasminogen activators (PA) are implicated in this tissue invasion process. Our studies on surplus embryos from patients undergoing in-vitro fertilization (IVF) treatments showed that PA activity was present in secretions of blastocysts but not embryos at the 2-4-cell stage. The secretion of this PA activity by blastocysts was increased by the addition of epidermal growth factor (EGF) to the embryo cultures. This PA activity had a molecular weight similar to that of urokinase-type PA (uPA). The mRNA for uPA was present in blastocysts, as determined by the reverse-transcription and polymerase chain reaction (RT-PCR) technique. These data indicate that uPA is produced by human preimplantation embryos and may play a role in early human development and embryo implantation.

Blastocyst↗

PubMed1996

Differential effects of insulin-like growth factor-I and follicle-stimulating hormone on proliferation and differentiation of bovine cumulus cells and granulosa cells.

Effects of gonadotropins and peptide growth factors on 3H-thymidine incorporation, as an indicator of proliferation of granulosa cells and cumulus cells from bovine ovarian follicles during in vitro culture, were determined. Incorporation of 3H-thymidine in cumulus cells during 24-h culture in protein-free medium was about 100-fold greater than in granulosa cells from small follicles. Small but significant (p < 0.05) increases in incorporation of 3H-thymidine in cumulus cells (2.5-fold), but not in granulosa cells, resulted from addition of FSH, LH, or epidermal growth factor to culture media. Much larger, highly significant (p < 0.01) increases in 3H-thymidine incorporation resulted from exposure of both cumulus cells (18-fold) and granulosa cells (6-fold) to insulin-like growth factor-I (IGF-I). Addition of IGF-I together with FSH resulted in additive increases in 3H-thymidine incorporation in granulosa cells over a wide range of each agonist. In contrast, addition of FSH markedly decreased the stimulatory effect of a maximally effective concentration of IGF-I on incorporation in cumulus cells. Addition of estradiol, either alone or with IGF-I, had no consistent effect on 3H-thymidine incorporation in either cumulus cells or granulosa cells. Differentiated functions of cumulus and granulosa cells, including cumulus expansion (an indicator of hyaluronic acid secretion) and progesterone secretion, were investigated under the same culture conditions. FSH was highly effective in stimulation of cumulus cell expansion, with maximal expansion occurring at the lowest concentration tested (0.04 micrograms/ml). LH was effective only at considerably higher concentrations consistent with degree of contamination with FSH. IGF-I was ineffective in inducing cumulus expansion, either alone or together with FSH. FSH and IGF-I by themselves each stimulated progesterone secretion by both cumulus and granulosa cells, with further additive stimulatory effects by the two agents in combination. On a per cell basis, cumulus cells produced considerably more progesterone than granulosa cells under both basal and hormone-stimulated conditions. The results suggest that IGF-I has a dual role in follicle regulation--that it acts additively with FSH as an autocrine regulator of granulosa cell growth and, in the absence of FSH, as a paracrine regulator of cumulus cell proliferation in small antral follicles. The effect of FSH, by inducing cumulus expansion, may terminate further cumulus cell proliferation before ovulation.

Animals↗

PubMed1995

Ketoconazole in the management of paraneoplastic Cushing's syndrome secondary to ectopic adrenocorticotropin production.

PURPOSE: To evaluate the safety and efficacy of ketoconazole treatment in the management of patients with paraneoplastic Cushing's syndrome (CS) secondary to ectopic adrenocorticotropin (ACTH) production by malignant neoplasms (ECS). PATIENTS AND METHODS: A retrospective chart review was undertaken for 15 consecutive patients with ECS treated with ketoconazole. Strict criteria were defined for diagnosis of ECS and for clinical, biochemical, and hormonal responses. RESULTS: There were four women and 11 men with a median age of 59 years (range, 44 to 84). Eleven patients had primary lung cancer (nine small-cell [SCLC], one mixed SCLC/non-SCLC, and one non-SCLC); two had carcinoid tumors (one bronchial, one pancreatic); one had hepatocellular carcinoma; and one had medullary carcinoma of the thyroid. Eight patients had ECS diagnosed at tumor presentation. Clinical findings included proximal muscle weakness (n = 10), peripheral edema (n = 8), and hypertension (n = 8). Biochemical abnormalities included hypokalemia (n = 14), metabolic alkalosis (n = 13), and new or worsened diabetes mellitus (n = 10). Patients received ketoconazole in dosages of 400 to 1,200 mg/d titrated by changes in urinary free-cortisol (UFC) levels for a median duration of 26 days (range, 3 to 1,059), and nine also received chemotherapy with ketoconazole. Hypokalemia, metabolic alkalosis, diabetes mellitus, and hypertension improved in the majority of patients. Ten patients had a hormonal response, with seven complete responses (median duration, 25 days; range, 6 to 989). The occurrence of symptomatic hypoadrenalism was definite in three patients and probable in one. Most patients died of progressive malignant disease accompanied by escape from hormonal control by ketoconazole. The median survival duration of the group was 19 weeks (range, 1 to 154). CONCLUSION: Ketoconazole results in biochemical and hormonal improvement for most patients with ECS. It has few adverse effects, but may impair the cortisol response to stress. For that reason, replacement corticosteroids should be considered for patients with hormonal response, and moderate- to high-dose corticosteroids should be given for any potential stress situations. The ultimate control of the syndrome is dependent on successful treatment of the underlying tumor.

ACTH Syndrome, Ectopic↗

PubMed1994

Expression of plasminogen activator genes and enzymatic activities in rat preimplantation embryos.

Plasminogen activator has been implicated in tissue invasion and remodelling because of its role in the degradation of the extracellular matrix. Its activity can be detected in mouse embryos as early as day 6 of pregnancy, suggesting that plasminogen activator is involved in the process of implantation. The present study determined the time course of expression of the genes encoding tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) during the preimplantation period in rats by the sensitive mRNA phenotyping procedure of reverse transcription-PCR. The tPA mRNA was present in rat oocytes and two-cell embryos, but was not detected between the four-cell and blastocyst stages. The uPA mRNA was first detected in two-cell rat embryos, and was present through to the blastocyst stage. In chromogenic assays, plasminogen activator activity was detected in oocytes and embryos between two-cell and blastocyst stages. Most plasminogen activator activity present in preimplantation embryos appeared to be uPA, as it could be inhibited by anti-uPA antibody and a specific uPA inhibitor, amiloride, but not by anti-tPA antibody. The present data demonstrate the expression of uPA gene and uPA activity in preimplantation rat embryos, suggesting that embryonic uPA may be involved in early embryo development and implantation.

Amino Acid Sequence↗