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Background and objective Severe preeclampsia may be managed expectantly before 34 weeks gestation with close surveillance. Utilized in fetal growth restriction (FGR), evidence supports umbilical artery (UA) Doppler preventing neonatal morbidity from hypertensive disease and predicting adverse outcomes in preeclampsia. We evaluated the association of abnormal UA Doppler waveforms with early delivery (before 34 weeks gestation) and adverse maternal-fetal outcomes in patients with early severe preeclampsia without FGR. Methodology This is a retrospective cohort study of singleton pregnancies with International Classification of Diseases (ICD) Ninth or Tenth Revision, defined severe preeclampsia diagnosed before 34 weeks gestation without FGR from January 1, 2018, through January 27, 2023, at a large tertiary care center where S/D ratios were calculated from UA Doppler interrogation of a free loop of cord at least once weekly. This study was approved by the IRB (ID:00002216) and granted a full Health Insurance Portability and Accountability Act (HIPAA) waiver of consent. Exclusion criteria were major congenital anomalies, congenital infection, aneuploidy, leaving against medical advice >24 hours, and patient instability on admission defined as condition(s) precluding expectant management by the American College of Obstetrics and Gynecology. The primary outcome was delivery before 34 weeks gestation. Secondary outcomes were the mode of delivery and maternal/fetal complications. Patient characteristics and outcomes for normal versus abnormal UA Doppler groups were compared with chi-square, t-tests, and Fisher's exact test. Odds ratios and relative risks were calculated to compare outcomes. Results Of 194 patients with severe preeclampsia, 107 met inclusion criteria. Thirty-four patients had abnormal UA Doppler studies. There were no differences in demographic and clinical data between patients with normal and abnormal UA Doppler studies. Patients with abnormal UA Doppler studies were more likely to deliver before 34 weeks (OR=3.91; 95% CI 1.24-12.33) for worsening severe features (OR=3.85; 95% CI 1.42-10.41), and were less likely to deliver vaginally (OR=0.12; 95% CI 0.03-0.54). Abnormal UA Doppler studies were associated with an increased risk of neonatal complications (OR=6.46; 95% CI 1.42-29.42) and respiratory distress syndrome (RDS) (OR=4.75; 95% CI 1.32-17.16). Abnormal UA Doppler subgroups were divided into patients with elevated S/D >95% Acharya (N=22) and absent end-diastolic flow (EDF) (N=10). The elevated S/D group tended to deliver before 34 weeks gestation for worsening severe features (OR=3.71, 95% CI 1.144-12.050) and had a higher risk of neonatal complications (RR 1.404; 95% CI 1.213-1.624). The absent EDF subgroup was more likely to deliver before 34 weeks (RR=1.52; 95% CI 1.29-1.79) for abnormal fetal testing (OR=6.92; 95% CI 1.71-28.08) and undergo primary cesarean delivery (OR=7.23; 95% CI 1.43-36.61). Conclusion Pregnancies with severe preeclampsia without FGR displayed a high incidence of abnormal UA Doppler waveforms associated with loss of clinical stability and adverse fetal outcomes. The groups with more impedance to umbilical artery flow tended to deliver earlier, and as the Doppler shifted from elevated S/D to absent end-diastolic flow, the mode of delivery shifted to cesarean delivery with increased risk of abnormal fetal testing. These results support the utility of UA Doppler surveillance in severe preeclampsia.
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Legionella pneumophila is an accidental human bacterial pathogen that infects and replicates within alveolar macrophages causing a severe atypical pneumonia known as Legionnaires' disease. As a prototypical vacuolar pathogen L. pneumophila establishes a unique endoplasmic reticulum (ER)-derived organelle within which bacterial replication takes place. Bacteria-derived proteins are deposited in the host cytosol and in the lumen of the pathogen-occupied vacuole via a type IVb (T4bSS) and a type II (T2SS) secretion system respectively. These secretion system effector proteins manipulate multiple host functions to facilitate intracellular survival of the bacteria. Subversion of host membrane glycerophospholipids (GPLs) by the internalized bacteria via distinct mechanisms feature prominently in trafficking and biogenesis of the Legionella -containing vacuole (LCV). Conventional GPLs composed of a glycerol backbone linked to a polar headgroup and esterified with two fatty acids constitute the bulk of membrane lipids in eukaryotic cells. The acyl chain composition of GPLs dictates phase separation of the lipid bilayer and therefore determines the physiochemical properties of biological membranes - such as membrane disorder, fluidity and permeability. In mammalian cells, fatty acids esterified in membrane GPLs are sourced endogenously from de novo synthesis or via internalization from the exogenous pool of lipids present in serum and other interstitial fluids. Here, we exploited the preferential utilization of exogenous fatty acids for GPL synthesis by macrophages to reprogram the acyl chain composition of host membranes and investigated its impact on LCV homeostasis and L. pneumophila intracellular replication. Using saturated fatty acids as well as cis - and trans - isomers of monounsaturated fatty acids we discovered that under conditions promoting lipid packing and membrane rigidification L. pneumophila intracellular replication was significantly reduced. Palmitoleic acid - a C16:1 monounsaturated fatty acid - that promotes membrane disorder when enriched in GPLs significantly increased bacterial replication within human and murine macrophages but not in axenic growth assays. Lipidome analysis of infected macrophages showed that treatment with exogenous palmitoleic acid resulted in membrane acyl chain reprogramming in a manner that promotes membrane disorder and live-cell imaging revealed that the consequences of increasing membrane disorder impinge on several LCV homeostasis parameters. Collectively, we provide experimental evidence that L. pneumophila replication within its intracellular niche is a function of the lipid bilayer disorder and hydrophobic thickness.
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Angioedema is a localized swelling of the dermis, subcutaneous tissues, and/or submucosal tissues caused by fluid extravasation into these tissues. Angioedema is associated with certain vasoactive molecules and is typically mediated by histamine or bradykinin. It manifests clinically as facial edema, swelling of the extremities and urogenital area, and potential involvement of the larynx, leading to dyspnea and inspiratory stridor, which can become life-threatening. Histamine-mediated angioedema is associated with urticaria and pruritus and will show classic signs of allergic (type 1 hypersensitivity) reactions. Bradykinin-mediated angioedema is often familial (hereditary angioedema) and is more often associated with gastrointestinal symptoms (abdominal pain, nausea, vomiting, diarrhea), edema of the extremities and trunk, and a lack of urticaria and pruritus. Angiotensin-converting enzyme inhibitors (ACEIs) are a class of medications commonly prescribed for hypertension, heart failure, and diabetic nephropathy. ACEIs are associated with an increased risk of angioedema, which can range from a mild reaction to severe and life-threatening. ACEI-induced angioedema is a bradykinin-mediated reaction that can occur in individuals with a genetic predisposition. Other medications, such as angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs, and certain antibiotics, most notably those in the beta-lactam class, can also cause drug-induced angioedema. The present investigation describes current knowledge of the pathophysiology, epidemiology, clinical manifestations, predisposing factors, and management of drug-induced angioedema.