Larry C. Gilstrap

Antibodies From Preeclamptic Patients Stimulate Increased Intracellular Ca2+ Mobilization Through Angiotensin Receptor Activation

Background—Preeclampsia is a serious disorder of pregnancy characterized by hypertension, proteinuria, edema, and coagulation and vascular abnormalities. At the cellular level, abnormalities include increased calcium concentration in platelets, lymphocytes, and erythrocytes. Recent studies have shown that antibodies directed against angiotensin II type I (AT1) receptors are also highly associated with preeclampsia. Methods and Results—We tested the hypothesis that AT1 receptor–agonistic antibodies (AT1-AAs) could activate AT1 receptors, leading to an increased intracellular concentration of free calcium and to downstream activation of Ca2+ signaling pathways. Sera of 30 pregnant patients, 16 diagnosed with severe preeclampsia and 14 normotensive, were examined for the presence of IgG capable of stimulating intracellular Ca2+ mobilization. IgG from all preeclamptic patients activated AT1 receptors and increased intracellular free calcium. In contrast, none of the normotensive individuals had IgG capable of activating AT1 receptors. The specific mobilization of intracellular Ca2+ by AT1-AAs was blocked by losartan, an AT1 receptor antagonist, and by a 7-amino-acid peptide that corresponds to a portion of the second extracellular loop of the AT1 receptor. In addition, we have shown that AT1-AA–stimulated mobilization of intracellular Ca2+ results in the activation of the transcription factor, nuclear factor of activated T cells. Conclusions—These results suggest that maternal antibodies capable of activating AT1 receptors are likely to account for increased intracellular free Ca2+ concentrations and changes in gene expression associated with preeclampsia.

Intrapartum management of category II fetal heart rate tracings: towards standardization of care

There is currently no standard national approach to the management of category II fetal heart rate (FHR) patterns, yet such patterns occur in the majority of fetuses in labor. Under such circumstances, it would be difficult to demonstrate the clinical efficacy of FHR monitoring even if this technique had immense intrinsic value, since there has never been a standard hypothesis to test dealing with interpretation and management of these abnormal patterns. We present an algorithm for the management of category II FHR patterns that reflects a synthesis of available evidence and current scientific thought. Use of this algorithm represents one way for the clinician to comply with the standard of care, and may enhance our overall ability to define the benefits of intrapartum FHR monitoring.

Putting the “M” back in maternal–fetal medicine

Although maternal death remains rare in the United States, the rate has not decreased for 3 decades. The rate of severe maternal morbidity, a more prevalent problem, is also rising. Rise in maternal age, in rates of obesity, and in cesarean deliveries as well as more pregnant women with chronic medical conditions all contribute to maternal mortality and morbidity in the United States. We believe it is the responsibility of maternal-fetal medicine (MFM) subspecialists to lead a national effort to decrease maternal mortality and morbidity. In doing so, we hope to reestablish the vital role of MFM subspecialists to take the lead in the performance and coordination of care in complicated obstetrical cases. This article will summarize our initial recommendations to enhance MFM education and training, to establish national standards to improve maternal care and management, and to address critical research gaps in maternal medicine.

T Helper Cell Cytokine Profiles in Preterm Labor

Problem:  To compare concentrations of T‐helper cell cytokines in women with preterm labor (PTL) to normal pregnancies.

In vitro quantification of dexamethasone-induced surfactant protein B expression in human lung cells.

Objective: To determine whether the effect of a single 48-h exposure to dexamethasone in human lung cells is limited to 7–8 days.Study design: We used the NCI-H441 cell line, in which stability can be maintained beyond 7 days. The outcome was the stimulatory effect of dexamethasone on surfactant protein B (SP-B) gene transcription as expressed by SP-B mRNA accumulation. The experiment was conducted five times, in parallel with control. SP-B mRNA was determined at baseline, 48 h after dexamethasone exposure, and at 48-h intervals thereafter, up to 14 days, by quantitative reverse transcription polymerase chain reaction. Comparisons were made by the Mann-Whitney test.Results: In conditions of our experiment, the inductive profile of SP-B mRNA after exposure to dexamethasone demonstrated maximal stimulation at 48 h (13-fold over control). Subsequently, there was a decline in mRNA, with return to near control levels by day 8, suggesting reversibility of dexamethasone action.Conclusion: Our data support the view that the surfactant-inducing properties of corticosteroids are limited to 7–8 days.

Impact of progesterone on cytokine-stimulated nuclear factor-kappaB signaling in HeLa cells.

Objective. A key event in the pathways leading to preterm labor may be the activation of nuclear factor-kappaB (NF-κB) in the fetal membranes and the cervix. Anti-inflammatory agents, such as the corticosteroids, inhibit the activation of NF-κB. We proposed to investigate the effects of progesterone pretreatment on cytokine-stimulated activation of NF-κB in HeLa cells, a human cervical epithelial cell line. Methods. HeLa cells were pretreated with 10−7 M progesterone for 24 hours and exposed to 1 ng/mL interleukin-1β (IL-1β) for 1 hour. Nuclear and cytosolic extracts were subjected to Western blot analysis using anti-p65 and anti-inhibitory protein-κBα (anti-IκBα) antibodies. Densitometric data (n = 5) were compared using Kruskal–Wallis test. Results. Pretreatment with progesterone interfered with IL-1β-induced IκBα degradation. However, progesterone pretreatment resulted in a significant decrease in NF-κB protein subunit p65 in the cytoplasm. Pretreatment with progesterone did not reduce the amount of nuclear p65 and did not interfere with nuclear translocation of p65. Conclusion. Our observations suggest that any possible role played by progesterone in preterm labor prevention is not exerted through anti-inflammatory mechanisms of NF-κB down-regulation.

The effect of a clinical problem-solving curriculum on medical student examination performance

Abstract The objective of this study was to determine whether a clinical problem-solving curriculum during the third-year obstetrics/gynecology clerkship would affect National Board Medical Examiners (NBME) subject test performance. During the 1999–2000 academic year, 184 third-year medical students rotated through the obstetrics/gynecology clerkship. They were assigned to one of three clinical training sites. Thirty-six students were assigned to a community hospital, whereas the remaining 148 students were assigned to either a private university hospital or a county hospital. In July 1, 1999, the community hospital adopted a problem-solving curriculum designed to stimulate a better understanding of underlying mechanisms of disease rather than the memorization of facts. Each morning, an attending physician spent 20 minutes on interactive conferences. At the end of the clerkship, each student took the NBME subject test for obstetrics and gynecology. A test score of 80 was chosen as the honors level. Students who participated in the problem-solving curriculum scored significantly higher than did those taught by the traditional program, based on median NBME subject test scores, 79.0 (interquartile range, 74.0–82.0) versus 71.0 (interquartile range, 65.0–76.5), P

Antihypertensive medications in pregnant women with chronic hypertension

Abstract There is significant controversy regarding the role of medical therapy for mild chronic hypertension complicating pregnancy. 1 Difficult management dilemmas include identifying patients who would benefit from therapy, when therapy should be initiated, and deciding which agent to use.

Antithrombin III deficiency in pregnancy

Abstract Thromboembolism is one of the most significant and common medical problems occurring during pregnancy. Some pregnant women are at a higher risk of thromboembolism because of inheritable hypercoagulable states. Antithrombin III deficiency is one of the inheritable coagulable states that may lead to an increase in thromboembolism during pregnancy. It is inherited as an autosomal dominant condition and should be thought of when a patient gives a personal history or a strong family history of thromboembolism. Treatment consists of anticoagulation with Heparin throughout pregnancy until delivery at which time the patient can be managed with either Heparin or Antithrombin III concentrates. Women with Antithrombin III deficiency during pregnancy should be counseled regarding the risks of transmission to their offspring.

MITRAL VALVE DISEASE IN PREGNANCY

Abstract Mitral valve disease is most commonly of rheumatic origin. Mitral stenosis is the most common of these and the most serious. Ventricular filling time is critical in women with mitral stenosis, and tachycardia may significantly interfere with filling time. Pregnancy conditions associated with tachycardia include pain, infection, hypertension, anemia, and blood loss. The postpartum period is the most dangerous time for women with mitral stenosis because of all of the fluid changes. Women with severe disease may benefit from invasive hemodynamic monitoring to assure adequate preload and prevent failure. Women with mitral insufficiency generally tolerate pregnancy well. Cardiac decompensation may rarely occur, especially in women with severe, long-standing disease. Women with mitral valve disease may have atrial enlargement and atrial tachyarrhythmias, especially atrial fibrillation. Thus, they may be prone to thromboembolic phenomena. Such women should be treated with heparin. All women with mitral valve disease should receive subacute bacterial endocarditis prophylaxis. The majority of pregnant women with mitral valve disease can deliver vaginally, and cesarean section should be reserved for obstetric indications. Regional anesthesia is ideal for intrapartum pain relief, with the possible exception of women with severe mitral stenosis. Finally, these women should be managed by a multidisciplinary team approach to include obstetrician, perinatologist, cardiologist, and anesthesiologist.