Tocolysis: Present and future treatment options.

In the United States, the generally accepted indication for tocolytic therapy centers on suppression of preterm labor. This may be in the form of preventative therapy with progesterone in women with prior spontaneous preterm birth or as an acute intervention to suppress established uterine contractions associated with cervical change occurring at less than 37 weeks gestation. This article seeks to apply this perspective to tocolytic therapy. Here, we provide a review of current tocolytic options and what the last decade of discovery has revealed about the regulation of myometrial excitability and quiescence. Moving forward, we must incorporate the emerging molecular data that is amassing in order to develop novel and effective tocolytic therapeutic options to prevent preterm labor and spontaneous preterm birth (sPTB).

Pulmonary Hypertension in Pregnancy: A Report of 49 Cases at Four Tertiary North American Sites.

OBJECTIVE: To identify whether pregnancy outcomes vary by etiology and severity of pulmonary hypertension and whether contemporary therapies influence outcomes. METHODS: A retrospective review of medical records at four academic institutions was conducted to identify pregnant women with pulmonary hypertension (2001-2015). International Classification of Diseases, 9th Revision codes for pulmonary hypertension and pregnancy were used to identify potential participants. Medical records were abstracted for demographics, management, and outcomes. Women were classified according to the 2013 World Health Organization (WHO) pulmonary hypertension classification groups 1-5. Mild pulmonary hypertension was defined as a mean pulmonary artery pressure 25-49 mm Hg and severe pulmonary hypertension as mean pulmonary artery pressure 50 mm Hg or greater or systolic pulmonary artery pressure 70 mm Hg or greater. Descriptive statistics were used to compare outcomes. RESULTS: Forty-nine women were identified. Mortality rate was 16% (n=8/49); all deaths occurred postpartum, and seven of eight deaths occurred in women with WHO group 1 pulmonary hypertension (mortality rate 23%, n=7/30). Of the women who had documented live births with known mode of delivery (n=41), mortality was 4 of 22 among women with severe pulmonary hypertension and 1 of 19 among women with mild pulmonary hypertension. Mortality among women who delivered by cesarean was 4 of 22 and was 1 of 19 among women who delivered vaginally. Neuraxial anesthesia was performed in 20 of 22 cesarean and 17 of 19 vaginal deliveries with no anesthesia-related adverse events. Women with severe pulmonary hypertension needed more advanced therapies such as inotropes, pulmonary vasodilators, and extracorporeal membrane oxygenation than did women with mild pulmonary hypertension, 19 of 26 compared with 7 of 22. Preterm delivery was more common in women with severe compared with mild pulmonary hypertension, 19 of 23 compared with 8 of 17. There was one 25-week intrauterine fetal demise, but no neonatal deaths. CONCLUSION: In this large series of pulmonary hypertension in pregnancy, mortality remained high despite advanced therapies. Maternal mortality was specific to WHO group 1 pulmonary hypertension and possibly associated with severe pulmonary hypertension. In selected patients with a favorable prognosis for vaginal birth, a trial of labor can be considered.

ß2-adrenergic receptor genotype and other variables that contribute to labor pain and progress.

BACKGROUND: ß2-Adrenergic receptor (ß2AR) activity influences labor. Its genotype affects the incidence of preterm delivery. We determined the effect of ß2AR genotype on term labor progress and maternal pain. METHODS: We prospectively enrolled 150 nulliparous parturients in the third trimester and obtained sensory thresholds, demographic information, and DNA. Cervical dilation, pain scores, and labor management data were extracted with associated times. The association of genetic and demographic factors with labor was tested using mixed effects models. RESULTS: Parturients who express Gln at the 27 position of the ß2AR had slower labor (P < 0.03). They progressed from 1-10 cm dilation in approximately 21 h compared with 14 h among other patients. Asian ethnicity, previously associated with slower labor, is highly associated with this polymorphism (P < 0.0001). Heavier and black patients had slower latent labor (P < 0.01, 0.01). Neuraxial analgesia was associated with slower labor progress (P < 0.0001). It could take up to 36 h for parturients who were black and/or more than median weight (165 lb) to transition from 1 cm cervical dilation to active labor. However, after this active phase began, labor rates among these patients were similar to that of other parturients. CONCLUSIONS: We detected a strong association between ß2AR genotype and slower labor. Asian ethnicity may be a proxy for ß2AR genotype. Black women and those of higher than average weight have slower latent labor. These results confirm many of the associations found when this mathematical model was applied to a large retrospective cohort, further validating this approach to description and analysis of labor progress.

Extracellular cAMP-dependent protein kinase (ECPKA) in melanoma.

Melanoma is one of the fastest rising malignancies in the United States. When detected early, primary melanomas are curable through surgery. However, despite significant improvements in diagnosis and surgical, local and systemic therapy, mortality rate in metastatic melanoma remains high. Furthermore, genetic alterations associated with the development and stepwise progression of melanoma, are still unclear. Previous reports show that the catalytic kinase subunit of the cAMP-dependent protein kinase is secreted by tumor cells and can be detected in the serum of cancer patients. We examine in this report the clinical significance of this secreted C subunit kinase termed extracellular protein kinase (ECPKA) in melanoma patients. Our results showed the presence of ECPKA activity in the serum of melanoma patients and correlate with the appearance and size of the tumor. Most importantly, surgical removal of melanoma causes a precipitous decrease in ECPKA activity in the sera of patients, suggesting that ECPKA may be a novel predictive marker in melanoma.

Reinventing the wheel of cyclic AMP: novel mechanisms of cAMP signaling.

Mechanisms of cAMP signal transduction have been thoroughly investigated for more than 40 years. From the binding of hormonal ligands to their receptors on the outer surface of the plasma membrane to the cytoplasmic activation of effectors, the ensuing cAMP signaling cascades and the nuclear gene regulatory functions, coupled with the structural elucidation of the cAMP-dependent protein kinase (PKA) and in vivo functional characterizations of each of the components of PKA by homologous recombination gene targeting, our understanding of cAMP-mediated signal transduction has reached its pinnacle. Despite this trove of knowledge, some recent findings have emerged that suggest hitherto novel and alternative mechanisms of cAMP action that could increase the signaling bandwidth of cAMP and PKA in cell growth and transcriptional regulation. This article attempts to review some of these novel and unconventional mechanisms of cAMP and PKA signaling, and to generate further enthusiasm in investigating and validating these new frontiers of the cAMP signal transduction pathway.