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D S Cunningham

Publications and source records attributed to D S Cunningham.

At least 19 recordsLinked to original sources
PubMed1998

Altered DNA repair and dysregulation of p53 in IRF-1 null hepatocytes.

The tumor suppressor proteins IRF-1 and p53 are involved in response pathways after DNA damage. In different cell types, IRF-1 and p53 can cooperate to produce cell cycle arrest (embryo fibroblasts) or can independently trigger apoptosis (lymphoid cells). p53 may also regulate DNA repair, but there is no information on IRF-1 and repair. The cell lineage dependency of these effects precludes extrapolation of findings to other tissues of relevance to human cancer. Here, we report the consequences of IRF-1 deficiency for apoptosis, cell cycle arrest, and DNA repair in primary hepatocytes after DNA damage and extend previous work on the role of p53 in hepatocytes. IRF-1-deficient hepatocytes showed reduced DNA repair activity compared with wild-type, as assessed by unscheduled DNA synthesis after UV irradiation (10J/m2) and by host reactivation of a UV-damaged reporter construct. p53-deficient hepatocytes also showed reduced unscheduled DNA synthesis after UV, but there was no impairment of specific repair in host reactivation assays. IRF-1 deficiency did not affect the p53-dependent G1/S arrest after UV irradiation. Hepatocyte apoptosis after UV treatment, previously reported to be independent of p53, was also independent of IRF-1. However, IRF-1 deficiency produced dysregulation of p53, manifested as increased transactivation of a p53-reporter plasmid in undamaged hepatocytes, and accelerated p53 stabilization after DNA damage. Hence, in hepatocytes, IRF-1 is not required for growth arrest or apoptosis after DNA damage, but the results suggest for the first time a role in DNA repair regulation.

Animals↗
PubMed1996

Single vs. multiple semen specimens in screening for male infertility factors. A comparison.

OBJECTIVE: To reevaluate the number of semen analyses necessary to establish whether further male infertility testing is necessary. STUDY DESIGN: The results of three consecutive semen analyses for infertility evaluations were retrospectively reviewed. A male factor was defined by an abnormal semen analysis if either the first specimen of three (single-sample screening) or two of the three specimens (multiple-sample screening) met World Health Organization criteria. Males considered abnormal by multiple-sample screening underwent sophisticated andrologic evaluation. RESULTS: A single-sample conventional semen analysis obtained from 209 males demonstrated a diagnostic accuracy of 10.4% false negatives and a sensitivity of 89.6% when compared to that of multiple-sample analysis. Andrologic evaluation of abnormal males by multiple-sample screening confirmed that 9 of the 11 men with normal first specimens were abnormal; all others were confirmed as abnormal. CONCLUSION: Analysis of multiple semen specimens provides a reliable screen in the evaluation of male factor infertility when the goal is to minimize the false negative rate of screening tests.

False Negative Reactions↗
PubMed1995

Decay-accelerating factor protects human trophoblast from complement-mediated attack.

Approximately one-fifth of first trimester losses can be characterized by the onset of hypocomplementemia prior to ultrasonographic loss of embryonic viability. Monoclonal antibodies to the membrane complement regulatory protein, decay-accelerating factor (DAF), were bound to the surface of trophoblastic tissues, with the estimated number of DAF molecules in tissues obtained from hypocomplementemic women less than those from normocomplementemic women (approximately 10%). While trophoblastic tissue obtained from normocomplementemic women did not decomplement normal human sera, pretreatment of this tissue with anti-DAF antibodies resulted in activation of the complement (C') system via the alternate C' pathway (ACP). If trophoblastic tissue from normocomplementemic women was pretreated with phospholipase C, decomplementation of human serum occurred. These data strongly suggest that trophoblasts evade the ACP with functional DAF, possibly through absorption of the molecule's lipophilic diacylglycerol membrane-anchored moiety into the outer lipid bilayer of the trophoblast and may be a rational means for the utilization of immunotherapy in recurrent spontaneous aborters.

Abortion, Habitual↗
PubMed1995

Effect of 1st-trimester loss on restoration of the hypothalamic-pituitary-ovarian axis.

This randomized prospective study was conducted to determine the length of time required for re-establishment of the reproductive axis following a 1st-trimester spontaneous abortion. The spontaneous gonadotropin secretion was significantly depressed during the first menstrual cycle after pregnancy loss, while the estradiol levels had normalized. Provocative testing revealed blunted gonadotropin release in the first menstrual cycle with return to normal during the first menstrual cycle after a spontaneous abortion. Endometrial biopsy specimens were also abnormal during the first menstrual cycle with normal histological characteristics by the second menstrual cycle. Therefore, restoration of the hypothalamic-pituitary- ovarian axis after a 1st-trimester loss is achieved within two menstrual cycles, as determined by return of normal pituitary function.

Abortion, Spontaneous↗
PubMed1995

Immune response characteristics in women with chlamydial genital tract infection.

Immune responses in women with chlamydial genital tract infection who achieved a bacteriologic cure were prospectively compared to those women who had an incomplete clinical response. Local anti-chlamydia IgA antibody responses were significantly diminished in the outpatient treatment group who had an incomplete response, while circulating IgG responses did not differ significantly between groups. This is in contrast to both specific and non-specific lymphoproliferative responses which were similar between uninfected controls and women with a chlamydial genital tract infection, regardless of treatment outcome. Thus, the kinetics of successful outpatient treatment of chlamydial genital tract infections may have an immunologic component which can be measured at the time of initial evaluation, and may be predictive of the clinical response to adjunctive antibiotics.

Adolescent↗
PubMed1995

Activation of complement in humans with a first-trimester pregnancy loss.

Serum complement (C') activity in recurrent spontaneous aborters and primiparous controls with successful and unsuccessful pregnancies was quantified so as to define the dynamics of C' activation in early pregnancy loss. C' hemolytic activity was shown to be stable throughout the first trimester of pregnancy and did not differ from preconception levels in all of the successful pregnancies of recurrent aborters and controls and in the majority of pregnancy losses. However, 30% of recurrent aborters and 20% of controls with a pregnancy loss demonstrated activation of C' by the alternate pathway as early as the 7th week with a progressive decline in C' activity until abortion was clinically completed. Circulating levels of C3 dropped from 1.34 to 0.53 mg/dl, and factor B levels declined from 0.34 to 0.14 mg/dl in these hypocomplementemic women. Pregnancy loss is therefore associated with C' activation in a subset of both recurrent and nonrecurrent aborters and this occurs largely before loss of fetal viability.

Abortion, Habitual↗
PubMed1995

Ultrasonographic characteristics of first-trimester gestations in recurrent spontaneous aborters.

OBJECTIVE: To compile, for the first time, serial ultrasonographic findings during the first trimester of pregnancy in women with a history of primary recurrent spontaneous abortion so as to define the dynamics of early normal and abnormal gestations in this category of gravidas. STUDY DESIGN: Transvaginal ultrasonograms were obtained weekly from 5 to 12 weeks' gestational age in 40 women, 10 each of four groups: recurrent spontaneous aborters and primiparas (controls), with both successful and failed gestations. RESULTS: Embryonic heart motion was detected in 40-50% of successful pregnancies during the fifth week of gestation and in the balance by the sixth week, while heart motion was detected in no more than 50% of pregnancies that later failed. Of the failed pregnancies, all were evident by the eighth week of gestation, including those with previously documented viability. The gestational sac size and crown-rump length were smaller than expected in both failed groups, with the sac size difference evident as early as week 5 and the crown-rump length difference apparent by week 7. CONCLUSION: Appropriate timing of the initial ultrasonogram in recurrent aborters (i.e., 8 weeks' gestational age) can identify, by means of heart motion and gestational sac features, all pregnancies that will ultimately fail.

Abortion, Habitual↗
PubMed1994

Spontaneous vulvar necrotizing fasciitis in Cushing's syndrome.

Necrotizing fasciitis is a potentially fatal condition, and the prognosis is worsened by immunosuppression. We describe what appears to be the first reported case of spontaneous vulvar necrotizing fasciitis occurring in a woman with uncontrolled hypercortisolism due to an ACTH-secreting thymic carcinoid tumor.

ACTH Syndrome, Ectopic↗
PubMed1994

Characterization of peripheral blood and peritoneal fluid mononuclear cell subsets in fertile and infertile women.

Mononuclear cell subpopulations from the peripheral blood (PB) and peritoneal fluid (PF) of fertile and infertile women were quantified by flow cytometry using a double-staining monoclonal antibody technique. No differences in the percentage distribution of mononuclear cells between fertile and infertile women were demonstrated when either the PB constituents or the PF components were compared to one another. When the mononuclear cell composition in the PB was compared with that in the PF however, the percentage of PF-activated T cells and monocytes was increased in both fertile and infertile women as opposed to that in the PB, while there was a decrease in T helper cells (fertile and infertile women) and natural killer cells (fertile women and infertile women with endometriosis). Even though shifts do exist in the immunocytes of PF from fertile and infertile women, evidence is lacking that the PF is an immunologic mediator of infertility.

Antibodies, Monoclonal↗
PubMed1993

Induction and measurement of antisperm antibody responses in vitro.

Using the Mishell and Dutton culture system an assay was developed for eliciting and quantifying sperm surface antigen (SSA)-specific immune responses in vitro. Peripheral blood mononuclear cells (PBMC) from sexually inexperienced and experienced women that were antisperm antibody (ASA) negative gave rise to a plaque-forming cell (PFC) response of similar magnitude (1,362 and 1,254 PFC/culture, respectively). PBMC from women that were ASA positive had lower PFC responses if cervical mucous antibodies were detected along with circulating antibodies (876 PFC/culture) than if they were not detected (1,512 PFC/culture). Limit dilution analysis was used to demonstrate that the level of the anticipated antibody response is regulated by T helper cell activity. The results of this investigation suggest that the antibody response to SSA is governed at least in part by both the secretory immune system and circulating T helper cells.

Adult↗
PubMed1993

Effect of the HELLP syndrome on maternal immune function.

The HELLP syndrome occurs in less than 1% of gravidas and is characterized by hemolysis, elevated liver enzymes and low platelet count. The status of immune function in these high-risk patients is not known but may be of great importance in better understanding the basis, if any, of immune dysfunction in pregnancy-associated hypertensive disorders and from the potential compounding effect of infection upon an already debilitated patient. We assessed maternal immune status in patients with the HELLP syndrome using conventional in vitro techniques. The results of these studies clearly show a depression of both T and B cell potential and impaired monocyte handling of intracellular pathogens (up to 33%, 11% and 17% of control values, respectively). The onset of this immunosuppression occurred before the clinical diagnosis of HELLP syndrome was made and persisted for at least 14 days after clinical resolution. Results of cell admixture studies suggest that these effects are mediated by accessory cells or their products and do not represent true lymphocyte dysfunction. The risk of opportunistic infections may therefore be increased in the patient with the HELLP syndrome because of this generalized immunosuppression and profound decrease in monocyte phagocytic and bactericidal activity.

Adult↗
PubMed1993

Suboptimal progesterone production in pathologic pregnancies.

Serum progesterone (P) levels were determined at the time of routine prenatal registration (227 patients) or upon presentation for evaluation of vaginal bleeding and/or abdominopelvic cramping/pain (135 patients). P associated with a normal intrauterine gestation was 24.63 +/- 4.19 (SD) ng/mL as compared with 6.29 +/- 2.43 ng/mL and 6.02 +/- 2.39 ng/mL for spontaneous abortions and ectopic gestations, respectively. Further, P differed between asymptomatic (11.92 +/- 9.61 ng/mL) and symptomatic patients (4.81 +/- 3.92 ng/mL) who were subsequently shown to have an abnormal gestation. By establishing a P cutoff point of < or = 14.2 ng/mL and < or = 10.5 ng/mL in asymptomatic and symptomatic patients, respectively, 100% screening sensitivity was reached, and therefore no abnormal gestations would escape detection in our study population. P was either in the normal or abnormal range as early as four weeks' estimated gestational age and persisted as such through the luteal-to-placental shift and up to the time of pregnancy loss or 12 weeks' estimated gestational age. Although there was no significant correlation between P and chorionic gonadotropin levels and pregnancy outcome, the binding constant for native chorionic gonadotropin was 15-52 times lower in 12 of 41 cases of spontaneous abortion but not ectopic gestation, suggesting a possible molecular basis for suboptimal P production. P is therefore an excellent adjunctive marker for prediction of early pregnancy outcome, and in some cases qualitative abnormalities in chorionic gonadotropin may dictate its production.

Analysis of Variance↗
PubMed1992

Peritoneal fluid from patients with endometriosis decreases sperm binding to the zona pellucida in the hemizona assay: a preliminary report.

OBJECTIVE: To evaluate the effect of peritoneal fluid (PF) from patients with endometriosis on gamete interaction under hemizona assay (HZA) conditions. DESIGN: The HZA was used to study the effect of PF from patients with endometriosis on sperm binding to the zona pellucida using media and normal PF as controls. SETTING: The patients were collected from a university hospital infertility clinic. PATIENTS: Peritoneal fluid from 16 women being evaluated for infertility or sterilization who were found to have endometriosis at surgery was used. Three normal patients, who were being sterilized, had PF that was used as a control. RESULTS: Results suggest that there is a significant reduction in the number of tightly bound sperm to the zona surface in endometriosis specimens as reflected in the hemizona index and that this effect is directly related to the stage of the disease. CONCLUSIONS: Although the sample is small, this methodology may help to elucidate one of the mechanisms responsible for endometriosis-associated infertility.

Ascitic Fluid↗
PubMed1992

Changes in T-cell regulation of responses to self antigens in women with pelvic endometriosis.

OBJECTIVE: To study autoimmune aspects of endometriosis. DESIGN: Lymphoblast transformation and hemolytic plaque formation were used to assess specific T- and B-cell activity against endometrial antigens. SETTING: Military teaching hospital. PATIENTS: Ninety-four healthy women of reproductive age undergoing diagnostic laparoscopy as part of an evaluation for infertility or chronic pelvalgia were accordingly grouped into those with normal pelvic peritoneum (20), mild endometriosis (50), and severe endometriosis (24). MAIN OUTCOME MEASURE: The study assessed the proliferative and humoral responses of lymphocytes from women with and without endometriosis to endometrial antigens and quantified the number of B-cell precursors, T-helper cells, and T-suppressor cells to these antigens. RESULTS: Unfractionated endometrial antigens were similarly blastogenic for lymphocytes from women with and without endometriosis. Despite equivalent numbers of B-cell precursors to these antigens, antiendometrial antibody responsiveness appears to have increased in women with mild endometriosis because of a decrease in T-suppressor cell activity and declined in women with severe endometriosis because of a further drop in T-suppressor cell activity and an increase in T-helper cell activity, as compared with women without endometriosis. CONCLUSIONS: Taken together, these experiments support the possibility that pelvic endometriosis may result from a break in specific T-cell tolerance rather than nonspecific polyclonal activation of responder lymphocytes.

Autoantibodies↗
PubMed1991

The effects of betamethasone on maternal cellular resistance to infection.

Antenatal administration of glucocorticoids is often used to facilitate fetal lung maturation in cases of prematurity; however, the effects of betamethasone on maternal immune function have not been established. Therefore maternal immune function was assessed with the use of in vitro techniques. Transient and incomplete suppression of the proliferative response to the T-cell mitogen phytohemagglutinin was demonstrated as early as 24 hours after administration of betamethasone. The magnitude and duration of suppression showed a corresponding increase with advancing gestational age, but these effects were not cumulative and were always short-lived (less than 72 hours). No such suppression of the B-cell mitogen lipopolysaccharide was detected. The nonspecific cellular resistance to infection of maternal monocytes was determined through coincubation with the facultative intracellular pathogen Listeria monocytogenes. Increased phagocytic activity with a normal bactericidal effect was measured in the cell preparations obtained from recipients versus nonrecipients of betamethasone. Taken together, these findings clearly show that both specific and nonspecific immune function are intact in the preterm gravid woman after administration of betamethasone and should allay concerns over its use for reasons of infection control alone.

Betamethasone↗
PubMed1991

Antisperm antibodies to sperm surface antigens in women with genital tract infection.

Antisperm antibodies to sperm surface antigens in nulligravid women with primary upper genital tract infections were measured by the sperm mixed agglutination reaction assay. As many as 56% of women with a primary episode of pelvic inflammatory disease had antisperm antibodies. In addition, 69% of those women with no history of genital tract infection but with laparoscopic evidence of past pelvic infection had significant levels of circulating antisperm antibodies. Electroimmunoblots of sperm preparations probed with the sera of women who had either known or presumed upper genital tract infection revealed a uniformly recognized 69 kd antigen. In contrast, women with circulating antisperm antibodies before primary upper genital tract infection recognized up to five distinct sperm antigen determinants of 27, 54, 131, 146, and 174 kd. It is a distinct possibility that genital tract infections may lead to immunopotentiation of antisperm antibodies that could affect fertility.

Adolescent↗