Hypertensive Disorders of Pregnancy.

Hypertensive disorders in pregnancy are a leading cause of global maternal and fetal morbidity. The four hypertensive disorders of pregnancy include chronic hypertension, gestational hypertension, preeclampsia-eclampsia, and chronic hypertension with superimposed preeclampsia. A careful history, review of systems, physical examination, and laboratory analysis can help differentiate these disorders and quantify the severity of the disease, which holds important implications for disease management. This article reviews the different types of disorders of hypertension in pregnancy and how to diagnose and manage these patients, with special attention paid to any recent changes made to this management algorithm.

Adaptive leadership curriculum for Indian paramedic trainees.

BACKGROUND: Paramedic trainees in developing countries face complex and chaotic clinical environments that demand effective leadership, communication, and teamwork. Providers must rely on non-technical skills (NTS) to manage bystanders and attendees, collaborate with other emergency professionals, and safely and appropriately treat patients. The authors designed a NTS curriculum for paramedic trainees focused on adaptive leadership, teamwork, and communication skills critical to the Indian prehospital environment. METHODS: Forty paramedic trainees in the first academic year of the 2-year Advanced Post-Graduate Degree in Emergency Care (EMT-paramedic equivalent) program at the GVK-Emergency Management and Research Institute campus in Hyderabad, India, participated in the 6-day leadership course. Trainees completed self-assessments and delivered two brief video-recorded presentations before and after completion of the curriculum. RESULTS: Independent blinded observers scored the pre- and post-intervention presentations delivered by 10 randomly selected paramedic trainees. The third-party judges reported significant improvement in both confidence (25 %, p < 0.01) and body language of paramedic trainees (13 %, p < 0.04). Self-reported competency surveys indicated significant increases in leadership (2.6 vs. 4.6, p < 0.001, d = 1.8), public speaking (2.9 vs. 4.6, p < 0.001, d = 1.4), self-reflection (2.7 vs. 4.6, p < 0.001, d = 1.6), and self-confidence (3.0 vs. 4.8, p < 0.001, d = 1.5). CONCLUSIONS: Participants in a 1-week leadership curriculum for prehospital providers demonstrated significant improvement in self-reported NTS commonly required of paramedics in the field. The authors recommend integrating focused NTS development curriculum into Indian paramedic education and further evaluation of the long term impacts of this adaptive leadership training.

CXCR7 controls competition for recruitment of ß-arrestin 2 in cells expressing both CXCR4 and CXCR7.

Chemokine CXCL12 promotes growth and metastasis of more than 20 different human cancers, as well as pathogenesis of other common diseases. CXCL12 binds two different receptors, CXCR4 and CXCR7, both of which recruit and signal through the cytosolic adapter protein ß-arrestin 2. Differences in CXCL12-dependent recruitment of ß-arrestin 2 in cells expressing one or both receptors remain poorly defined. To quantitatively investigate parameters controlling association of ß-arrestin 2 with CXCR4 or CXCR7 in cells co-expressing both receptors, we used a systems biology approach combining real-time, multi-spectral luciferase complementation imaging with computational modeling. Cells expressing only CXCR4 maintain low basal association with ß-arrestin 2, and CXCL12 induces a rapid, transient increase in this interaction. In contrast, cells expressing only CXCR7 have higher basal association with ß-arrestin 2 and exhibit more gradual, prolonged recruitment of ß-arrestin 2 in response to CXCL12. We developed and fit a data-driven computational model for association of either CXCR4 or CXCR7 with ß-arrestin 2 in cells expressing only one type of receptor. We then experimentally validated model predictions that co-expression of CXCR4 and CXCR7 on the same cell substantially decreases both the magnitude and duration of CXCL12-regulated recruitment of ß-arrestin 2 to CXCR4. Co-expression of both receptors on the same cell only minimally alters recruitment of ß-arrestin 2 to CXCR7. In silico experiments also identified ß-arrestin 2 as a limiting factor in cells expressing both receptors, establishing that CXCR7 wins the "competition" with CXCR4 for CXCL12 and recruitment of ß-arrestin 2. These results reveal how competition for ß-arrestin 2 controls integrated responses to CXCL12 in cells expressing both CXCR4 and CXCR7. These results advance understanding of normal and pathologic functions of CXCL12, which is critical for developing effective strategies to target these pathways therapeutically.

Carboxy-terminus of CXCR7 regulates receptor localization and function.

Chemokine receptor CXCR7 is essential for normal development, and this receptor promotes initiation and progression of diseases including cancer and autoimmunity. To understand normal and pathologic functions of CXCR7 and advance development of therapeutic agents, there is a need to define structural domains that regulate this receptor. We generated mutants of CXCR7 with deletion of different lengths of the predicted intracellular tail and analyzed effects on CXCR7 signaling and function in cell-based assays. While wild-type CXCR7 predominantly localized to intracellular vesicles, progressive deletion of the carboxy terminus redistributed the receptor to the plasma membrane. Truncating the intracellular tail of CXCR7 did not alter binding to CXCL12, but mutant receptors had reduced scavenging of this chemokine. Using a firefly luciferase complementation system, we established that deletions of the carboxy terminus decreased basal interactions and eliminated ligand-dependent recruitment of the scaffolding protein ß-arrestin-2 to receptors. Deleting the carboxy terminus of CXCR7 impaired constitutive internalization of the receptor and reduced activation of ERK1/2 by CXCL12-CXCR7. Inhibiting dynamin, a molecule required for internalization of CXCR7, increased ligand-dependent association of the receptor with ß-arrestin-2 and enhanced activation of ERK1/2. These studies establish mechanisms of action for CXCR7 and establish the intracellular tail of CXCR7 as a critical determinant of receptor trafficking, chemokine scavenging, and signaling.