Biomedical subjects
Publications and source records attributed to C A Long.
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PURPOSE: To compare pregnancy rates per treatment cycle of artificial inseminations with donor sperm in patients receiving one versus two inseminations. METHODS: Retrospective cross-sectioned analysis of 167 patients who underwent 869 cycles receiving one or two donor inseminations were reviewed from 1987 through 1993 at our institution. RESULTS: A total of 256 cycles with one donor insemination per cycle resulted in 21 pregnancies and a cycle of fecundity of 8.2%, and 613 cycles with two donor inseminations resulted in 35 pregnancies and a cycle fecundity of 5.7%. Life table and logistic cumulative probability analysis of pregnancy occurrence showed no difference between treatment groups. CONCLUSIONS: These data suggest there are no important clinical differences of cycle fecundity or cure rate in one versus two inseminations with donor sperm. Economic costs of two inseminations may not be justified.
OBJECTIVE: Measurements of serum progesterone to predict early gestational normalcy have been found to be as predictive as serial hCG titers. Since ultrasound would be the diagnostic tool of choice if hCG was > 2000 mIU/ml, the purpose of the present study was to determine the best predictive value of a single progesterone measurement when hCG levels were < 2000 mIU/ml. DESIGN: Relative operating characteristic analysis of progesterone level as a predictor of early gestational normalcy when hCG is < 2000 mIU/ml. MATERIALS AND METHODS: Ninety-three pregnant patients that conceived spontaneously were evaluated with progesterone measurements when the patient's hCG was < 2000 mIU/ml. Two-by-two contingency tables were constructed that compared pregnancy outcome with multiple discriminatory serum progesterone concentrations between 0 and 38 ng/mL. From these tables, a relative operating characteristic (ROC) curve was generated to compare the sensitivity and false-positive rates. RESULTS: Of a total of 93 pregnancies, 27 had a normal outcome and 66 had an abnormal outcome. The ROC curve indicated that a serum progesterone concentration of 12 ng/ml had the highest sensitivity associated with the lowest false-positive rate. The area under the curve was equal to 0.941 +/- 0.024. This observation was compared to our previously reported data of progesterone levels that included hCG levels > 2000 mIU/ml, yielding an area under the curve of 0.772 +/- 0.053. Calculation of the critical ratio z revealed that there is a significant improvement in the predictive value of progesterone when hCG is < 2000 mIU/ml (P < 0.005). CONCLUSION: A single serum progesterone level has a better predictive value of pregnancy normalcy when hCG measurements are < 2000 mIU/ml.
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Recent results with primate plasmodia and rodent models of infection have focused attention on the C-terminal region of the merozoite surface protein-1 (MSP-1) as one of the leading candidates for vaccination against the erythrocytic stages of malaria. However, sequence heterogeneity of this region may compromise its use as a vaccine candidate. While the C-terminal region of MSP-1 from the two prototypic alleles of P. falciparum has been shown to be relatively conserved in laboratory-maintained strains, little data exist on sequence heterogeneity of this region in field isolates from diverse geographic areas. To address this question, DNA encoding the C-terminal, Cys-rich region of P. falciparum MSP-1 from field samples was analyzed by a polymerase chain reaction (PCR)-direct sequencing method. Sequence data were consistent with those obtained from laboratory-maintained strains. In 15 isolates from Africa, Asia and Latin America, only a few nucleotide changes were found leading to amino-acid alterations at four positions out of 102 residues. All the variations corresponded to the predicted amino-acid sequence of the other prototype, suggesting that these changes were possibly due to allelic recombinations. The four changes were E-->Q at position 1644 and TSR-->KNG, or KNG-->TSR at positions 1691, 1700 and 1701. Thus, only three patterns of the C-terminal, Cys-rich region of MSP-1, E-TSR, Q-KNG and Q-TSR, were detected. All the Cys residues were conserved. These results support the potential utility of the C-terminal region of MSP-1 as a vaccine candidate.
OBJECTIVE: To determine if elevated LH at the time of hCG administration occurs and adversely affects success in a low-dose gonadotropin-releasing hormone analogue (GnRH-a) flare-up protocol in hMG-stimulated IVF cycles. DESIGN: Pearson correlation matrix analysis of hormonal, gamete, and clinical data derived from 203 consecutive IVF cycles was performed. All patients were treated with low-dose GnRH-a (250 micrograms SC leuprolide acetate) and hMG. In 203 consecutive IVF cases, serum was obtained on the day of hCG administration and assayed for E2, LH, and P. These data were correlated with peak E2, number of follicles, oocytes, embryos, and conceptions. Additionally, patients with elevated LH were compared with the nonelevated LH group. RESULTS: Twenty six women had LH > 35 mIU/mL (mean +/- SEM; 51.1 +/- 1.9) and five pregnancies (cycle fecundity 19.2% per retrieval). One hundred seventy-seven patients had LH < 35 mIU/mL (16.3 +/- 0.5) and 25 pregnancies (cycle fecundity 14.1%). There were no differences in the mean P (1.0 +/- 0.1 ng/mL, conversion factor to SI unit, 3.81) and E2 (1,672 +/- 144 pg/mL, conversion factor to SI unit, 3.671) of the former group compared with the P (1.1 +/- 0.07 ng/mL) and E2 (1,456 +/- 69 pg/mL) of the latter group. There was no correlation with the number of follicles, oocytes, embryos, pregnancies, E2, or P to LH concentration (rmax = 0.132). CONCLUSION: In a low-dose, GnRH-suppression, IVF induction protocol, elevated LH occurs in a small subset (13%) of women at the time of hCG administration. This event does not appear to alter cycle fecundity nor induce premature luteinization.
OBJECTIVE: To determine the follicular and luteal phase impact of low-dose GnRH agonist (GnRH-a) treatment during follicular stimulation for IVF. DESIGN: A randomized prospective study compared patients receiving low-dose GnRH-a and hMG therapy to clomiphene citrate (CC) and hMG cycles. SETTING: Patients were treated through a university-based IVF-ET program. PATIENTS: Thirty-six patients underwent follicular stimulation with low-dose GnRH-a and hMG and were compared with 34 patients undergoing ovulation induction with CC and hMG. RESULTS: Significantly shorter luteal phase length occurred with GnRH-a and hMG therapy; however, there was no statistically significant difference in luteal P levels. Follicular parameters were the same (peak E2, number of follicles, and number of oocytes), suggesting that folliculogenesis was not altered. There were no statistical differences in pregnancy rates. CONCLUSIONS: Sustained low-dose GnRH-a therapy during follicular stimulation does not have a clinical effect on luteal function.
PROBLEM: Immunosuppressive factor(s) of trophoblast origin may contribute to the immunological privilege afforded the fetal allograft. Characterization of these immunoregulators in humans has been impeded by a lack of sufficient quantities of early gestational trophoblast for experimentation. METHOD: In this study, a cloned choriocarcinoma cell line (BeWo) was evaluated as an experimental model of trophoblast-derived immunoregulation. BeWo cells were cultured in both serum-supplemented (15% fetal bovine serum; FCS-CM) and serum-free (10% bovine serum albumin, BSA-CM; 0.01% gelatin, Gel-CM) media. Immunosuppressive activity was determined through the use of interleukin-2-dependent (CTLL-2) and -independent (LBRM) cell lines. Human chorionic gonadotropin (hCG) levels were determined by an immunoradiometric assay, and cellular morphology was assessed by light microscopy. RESULTS: In the serum-supplemented cultures, a portion of cells underwent transformation from single nucleated cytotrophoblast to multinucleated syncytiotrophoblast during days 1 to 5 of culture and was accompanied by a rise in hCG. Serum-free cultures were characterized as islands of cytotrophoblast and did not exhibit differentiation. FCS-CM suppressed CTLL-2 and LBRM proliferation with estimated EC50 values of 415 and 280 micrograms protein/mL, respectively. Gel-CM suppressed CTLL-2 and LBRM proliferation with EC50 values of 12 and 7 micrograms protein/mL, respectively. BSA-CM suppressed CTLL-2 proliferation with an EC50 of 132 micrograms protein/mL, but failed to suppress LBRM proliferation below 50% of control. CONCLUSION: These results suggest that the BeWo cell line is a promising model for the study of trophoblast-derived suppressive factors and that these factors can be generated in serum-free medium.
The purpose of this study was to correlate surgical experience with operating efficiency. A retrospective review of 303 operative laparoscopic procedures was performed during a 48-month interval and during the acquisition of surgical skills by one faculty member. Population demographics and surgery time were evaluated in 41 cases (13.5%) of ovarian cystectomy. Patients were categorized into fertility-related or gynecologic indications for surgery. Surgical time for successful laparoscopically directed resection of benign ovarian cysts was significantly reduced over the study interval (P = .008). Endometrioma was the most common pathologic finding in women with impaired fertility, and benign epithelial tumors were the lesion encountered most commonly in gynecologic patients. Benign teratoma occurred infrequently in both groups. No malignancy was observed in this group of premenopausal women, who had unilocular cysts less than 8 cm in diameter. Reduction in surgical time for laparoscopically directed ovarian cystectomy occurs after experience is gained by repeated application of the technique.
The nucleotide (nt) sequence of the 5' portion of the gene encoding the Plasmodium yoelii yoelii (Pyy) 17XL merozite surface protein-1 (MSP-1) was determined by direct sequencing of both strands of the polymerase chain reaction (PCR) product. This report completes the entire coding region of the Pyy 17XL MSP-1 gene which we have found to be identical to the nt sequence of the Pyy YM MSP-1 [Lewis, Mol. Biochem. Parasitol. 36 (1989) 271-282], despite independent selection of parasite clones, passages and replications in mice over many years.
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OBJECTIVE: To determine if a "discriminatory" P concentration could be established that predicted abnormal early pregnancies in clomiphene citrate (CC)-conceived cycles. DESIGN: Progesterone concentrations of gestations between 28 and 49 days from last menstrual period in both spontaneously conceived and CC-stimulated cycles were analyzed using a relative-operating characteristic (ROC) curve. INTERVENTIONS: Serum P concentrations were measured in 222 pregnant patients from the first 49 days of gestation. One hundred sixteen patients conceived in a spontaneous cycle and 106 patients conceived in CC-treated cycles. Two by two contingency tables were used to calculate the true-positive (sensitivity) and false-positive rates at 20 specific P at 20 specific P concentrations. A ROC curve was then generated by plotting the sensitivity of the test against the percent of normal patients incorrectly classified (false positive) at each P level. The best discriminatory value was estimated in each curve at a point of high sensitivity associated with a minimal false-positive value. The areas under the curve and SE were calculated for each group and compared by the critical ratio z-test. RESULTS: The best discriminatory P concentration was 10 ng/mL (32 nmol/L) for spontaneously conceived pregnancies and 30 ng/mL (95 nmol/L) for CC-treated pregnancies. The area under each ROC curve was significantly predictive. Comparison of the two curves indicated that the ability of P measurements to predict gestational complications was independent of follicular stimulation. CONCLUSIONS: Follicular stimulation with CC increases the discriminatory P value that predicts gestational normalcy but does not alter the clinical utility of the test.
OBJECTIVE: To determine the regulatory role of hCG on P secretion in normal and abnormal (abortive and ectopic) first trimester pregnancies. STUDY DESIGN: The number of doublings of hCG per day (1/DT; reciprocal of hCG doubling time) was correlated with serum P using linear and nonlinear models in normal intrauterine pregnancies, spontaneous abortions, and ectopic pregnancies (EPs) conceived spontaneously or after clomiphene citrate (CC). RESULTS: Linear correlations between P and 1/DTs of hCG were poor. In contrast, nonlinear modeling with a hyperbolic curve fit the data well and allowed all of the data to be included for analysis regardless of the pregnancy type. Furthermore, this model could be used to explain the differential P concentrations seen in normal and abnormal first trimester pregnancies. The nonlinear hyperbolic model demonstrated that follicular events determine the maximal P production during early gestation. Human chorionic gonadotropin 1/DTs approximately equal to 0.5 sustain maximal P production. Progesterone production is then sustained by the rate of change of hCG. CONCLUSION: Nonlinear correlation analysis suggests that P production in early gestations is regulated by prior follicular events and the rate of hCG production.
PROBLEM: In sheep and cattle, trophoblast-derived interferons serve as signals for the maternal recognition of pregnancy and may regulate the immunologic relationship between the fetus and mother. METHOD: In this study, soluble extracts prepared from human hydatidiform mole decidua (DE) and trophoblast (HME) were screened for immunosuppressive activity using an interleukin (IL)-2-dependent T-cell line (CTLL2). Antibody neutralization studies were performed with monoclonal antibodies to alpha- and beta-interferon (IFN). RESULTS: HME suppressed (P < 0.05) IL-2-stimulated (2 IU/well) CTLL2 proliferation at doses ranging from 500 (52 +/- 2% of control) to 100 (74 +/- 5%) micrograms/ml concentrations. DE also suppressed (P < or = 0.05) CTLL2 proliferation in a dose-related fashion from 500 (20 +/- 6% of control) to 100 (71 +/- 8%) micrograms/ml doses. Preincubation with the alpha- and beta-IFN antibody preparations had no effect on CTLL2 suppression by the DE sample. In contrast, the beta-IFN antibody partially neutralized the suppressive activity of HME at each of the dilutions tested. The monoclonal antibody to alpha-IFN failed to neutralize HME suppression at any of the doses tested. CONCLUSIONS: These results suggest that hydatidiform mole trophoblast produces a beta-IFN-like macromolecule that may abrogate maternal rejection responses that are harmful to the developing fetal allograft.
PROBLEM: Soluble trophoblast extracts (HME) from some human hydatidiform mole pregnancies suppress IL-2-dependent T-cell proliferation, while others express no immunosuppressive bioactivity. This study was designed to determine if suppression by HME was correlated with gestational age, uterine size, or hCG secretion. METHOD: Soluble extracts were prepared from nine hydatidiform mole trophoblast samples and screened for immunosuppressive activity using a murine cytotoxic T-cell proliferation assay (CTLL-2). Gestational ages were determined from last menstrual cycle and uterine size was estimated at the time of surgery. Serum samples were collected prior to uterine evacuation and were assayed for human chorionic gonadotropin (hCG). RESULTS: Four of nine HME samples significantly (P < 0.05) suppressed CTLL2 proliferation, while five exhibited no suppressive activity. A strong positive correlation (r = 0.639) was noted for the relationship between gestational age of the molar pregnancies and interleukin-2 (IL-2)-stimulated CTLL2 proliferation (expressed as % of control) in the presence of HME (500 micrograms/mL). This indicates that HME suppression of CTLL2 proliferation is highest in early gestation and then declines with increasing gestational age. A similar correlation was observed between estimated uterine size at surgery and CTLL2 proliferation with added HME, although the association was not as strong (r = 0.359). No association was noted between hCG levels and CTLL2 proliferative responses (r = -0.091). CONCLUSIONS: The results of this study suggest that production of immunosuppressive factors by hydatidiform mole trophoblast is developmentally regulated, and decreases with advancing gestation.
Taxol, a natural product used to treat a variety of human cancers, is shown here to be extremely effective against chloroquine- and pyrimethamine-resistant malaria parasites. Addition of Taxol (1.0 microM) for one cycle to cultures of human erythrocytes infected with Plasmodium falciparum prevents the establishment of new infections. Blood parasitemia is eliminated in mice infected with Plasmodium chabaudi adami when they are given a single intraperitoneal injection of Taxol at 150 mg/m2. The majority of the animals treated immediately preceding parasite schizogony remain free of infection after eight replication cycles. The impressive antimalarial activity of Taxol, at a dosage that has been tolerated in humans, establishes its potential utility for treatment of severe, drug-resistant human malaria.
In those individuals who live in endemic areas, immunity to malaria is slow to develop and stage-specific. The nature and antigenic specificity of this response, which may involve components of both cell-mediated and humoral immunity, is not well understood. Rodent models provide useful systems to explore the spectrum of host responses that may contribute to resolution of erythrocytic-stage infection or possibly to pathogenesis. Moreover, these models allow identification of plasmodial molecules that can induce different types of host responses. Two different mouse model systems, Plasmodium yoelii yoelii and P. chabaudi adami are presented. These have been selected because resolution of infection by P. yoelii yoelii has been shown to require B cell-dependent mechanisms, while control of acute P. chabaudi adami infection can be achieved by T cell-dependent mechanisms. A monoclonal antibody that provides passive protection to P. yoelii challenge infection has been shown to recognize the cysteine-rich, carboxyl-terminal region of the merozoite surface protein-1. This region, obtained in an appropriate configuration from recombinant Escherichia coli, can induce significant protective immune responses in naive mice. In contrast, cell-mediated immune mechanisms make a major contribution to resolution of asexual-stage P. chabaudi adami infection. An empirical approach using continuous flow electrophoresis has identified several low molecular weight plasmodial proteins that can induce partial protective responses in susceptible hosts. These observations are briefly discussed with respect to human malaria.
The novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor CP-113,818 has been characterized in vitro against ACAT isolated from liver and intestine from a variety of species including human subjects, and in vivo in cholesterol-fed rats, hamsters, rabbits, and two species of nonhuman primates. CP-113,818 is a potent and specific inhibitor of liver and intestinal ACAT with IC50s ranging from 17 to 75 nM. This ACAT inhibitor also prevented the absorption of exogenous radiolabeled cholesterol in hamsters (ED50 = 6 micrograms/kg), rabbits (ED50 1/2 10 micrograms/kg), and cynomolgus and African green monkeys (40 and 26% inhibition at 10 mg/kg, respectively). CP-113,818 effectively prevented the increase in liver cholesterol levels in cholesterol-fed rats, hamsters, and rabbits. In lipoprotein characterization studies in rabbits, CP-113,818 selectively decreased apoB-containing lipoproteins (beta-VLDL, IDL, and LDL) and shifted the distribution of cholesterol from beta-VLDL, IDL, and LDL (96% before treatment to 81% after treatment) to HDL (4% before treatment to 19% after treatment). Finally, in monkeys, CP-113,818 significantly decreased LDL cholesterol by approximately 30% while either increasing HDL cholesterol (cynomolgus monkeys) or not affecting HDL cholesterol (African green monkeys), thereby improving the total plasma cholesterol/HDL ratios. In summary, CP-113,818 significantly inhibited cholesterol absorption, prevented the increase in liver cholesterol, and improved the lipoprotein profiles by selectively decreasing the cholesterol concentrations of the atherogenic lipoproteins (VLDL, IDL, and LDL) in a variety of cholesterol-fed animals. These data suggest that ACAT inhibition may be a useful therapeutic approach for lowering LDL cholesterol and thereby reducing the risk of developing coronary heart disease.