In vitro studies suggest that collecting duct-derived (CD-derived) endothelin-1 (ET-1) can regulate renal Na reabsorption; however, the physiologic role of CD-derived ET-1 is unknown. Consequently, the physiologic effect of selective disruption of the ET-1 gene in the CD of mice was determined. Mice heterozygous for aquaporin2 promoter Cre recombinase and homozygous for loxP-flanked exon 2 of the ET-1 gene (called CD-specific KO of ET-1 [CD ET-1 KO] mice) were generated. These animals had no CD ET-1 mRNA and had reduced urinary ET-1 excretion. CD ET-1 KO mice on a normal Na diet were hypertensive, while body weight, Na excretion, urinary aldosterone excretion, and plasma renin activity were unchanged. CD ET-1 KO mice on a high-Na diet had worsened hypertension, reduced urinary Na excretion, and excessive weight gain, but showed no differences between aldosterone excretion and plasma renin activity. Amiloride or furosemide reduced BP in CD ET-1 KO mice on a normal or high-Na diet and prevented excessive Na retention in salt-loaded CD ET-1 KO mice. These studies indicate that CD-derived ET-1 is an important physiologic regulator of renal Na excretion and systemic BP. IntroductionEndothelin-1 (ET-1) was initially described as a potent endothelial cell-derived vasoconstrictor (1); however, the peptide is now known to be produced by many cell types and to elicit multiple biologic effects (2). The kidney is likely an important target; ET-1 causes renal vasoconstriction, mesangial cell contraction, glomerular cell proliferation, ECM accumulation, and alterations in nephron fluid and electrolyte transport (2). While many renal cell types synthesize and bind ET-1, the collecting duct (CD) is of particular importance: The renal inner medulla contains the highest concentration of ET-1 in the body (3), and the inner medullary CD (IMCD) is the predominant renal site of ET-1 production (4-8) and receptor expression (9-11).In vitro studies suggest that ET-1 inhibits Na and water reabsorption in the cortical CD (CCD) and IMCD and that this occurs through activation of the ET B receptor (ETRB). ET-1 inhibits vasopressin-stimulated (AVP-stimulated) water flux in isolated CCD (9, 12) and reduces AVP-stimulated cyclic AMP accumulation (13-15) and osmotic water permeability (16, 17) in isolated IMCDs. ET-1 also inhibits mineralocorticoid and AVP-stimulated Na and Cl reabsorption in isolated CCDs (12,18,19) and decreases Na/K-ATPase activity in suspensions of IMCDs (20). Despite these data, demonstrating such an ET-1 effect in vivo and clarifying how CD-derived ET-1 physiologically regulates Na and water transport has been problematic. This difficulty stems, in part, from

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Objective Delirium, an acute organ dysfunction, is common among critically ill patients leading to significant morbidity and mortality; its epidemiology in a mixed cardiology and cardiac surgery intensive care unit (CVICU) is not well established. We sought to determine the prevalence and risk factors for delirium among CVICU patients. Design Prospective observational study. Setting 27-bed medical-surgical CVICU. Patients 200 consecutive patients with an expected CVICU length of stay >24 hours. Interventions None. Measurements Baseline demographic data and daily assessments for delirium using the validated and reliable Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) were recorded, and quantitative tracking of delirium risk factors were conducted. Separate analyses studied the role of admission risk factors for occurrence of delirium during the CVICU stay and identified daily occurring risk factors for the development of delirium on a subsequent CVICU day. Main Results Prevalence of delirium was 26%, similar among cardiology and cardiac surgical patients. Nearly all (92%) exhibited the hypoactive subtype of delirium. Benzodiazepine use on admission was independently predictive of a 3-fold increased risk of delirium [Odds Ratio 3.1 (1, 9.4), p=0.04] during the CVICU stay. Of the daily occurring risk factors, patients who received benzodiazepines [2.6 (1.2, 5.7), p=0.02] or had restraints or devices that precluded mobilization [2.9 (1.3, 6.5), p<0.01] were more likely to have delirium the following day. Hemodynamic status was not associated with delirium. Conclusions Delirium occurred in 1 in 4 patients in the CVICU and was predominately hypoactive in subtype. Chemical restraints via use of benzodiazepines or the use of physical restraints/restraining devices predisposed patients to a greater risk of delirium, pointing to areas of quality improvement that would be new to the vast majority of CVICUs.

In vitro studies suggest that collecting duct-derived (CD-derived) endothelin-1 (ET-1) can regulate renal Na reabsorption; however, the physiologic role of CD-derived ET-1 is unknown. Consequently, the physiologic effect of selective disruption of the ET-1 gene in the CD of mice was determined. Mice heterozygous for aquaporin2 promoter Cre recombinase and homozygous for loxP-flanked exon 2 of the ET-1 gene (called CD-specific KO of ET-1 [CD ET-1 KO] mice) were generated. These animals had no CD ET-1 mRNA and had reduced urinary ET-1 excretion. CD ET-1 KO mice on a normal Na diet were hypertensive, while body weight, Na excretion, urinary aldosterone excretion, and plasma renin activity were unchanged. CD ET-1 KO mice on a high-Na diet had worsened hypertension, reduced urinary Na excretion, and excessive weight gain, but showed no differences between aldosterone excretion and plasma renin activity. Amiloride or furosemide reduced BP in CD ET-1 KO mice on a normal or high-Na diet and prevented excessive Na retention in salt-loaded CD ET-1 KO mice. These studies indicate that CD-derived ET-1 is an important physiologic regulator of renal Na excretion and systemic BP. IntroductionEndothelin-1 (ET-1) was initially described as a potent endothelial cell-derived vasoconstrictor (1); however, the peptide is now known to be produced by many cell types and to elicit multiple biologic effects (2). The kidney is likely an important target; ET-1 causes renal vasoconstriction, mesangial cell contraction, glomerular cell proliferation, ECM accumulation, and alterations in nephron fluid and electrolyte transport (2). While many renal cell types synthesize and bind ET-1, the collecting duct (CD) is of particular importance: The renal inner medulla contains the highest concentration of ET-1 in the body (3), and the inner medullary CD (IMCD) is the predominant renal site of ET-1 production (4-8) and receptor expression (9-11).In vitro studies suggest that ET-1 inhibits Na and water reabsorption in the cortical CD (CCD) and IMCD and that this occurs through activation of the ET B receptor (ETRB). ET-1 inhibits vasopressin-stimulated (AVP-stimulated) water flux in isolated CCD (9, 12) and reduces AVP-stimulated cyclic AMP accumulation (13-15) and osmotic water permeability (16, 17) in isolated IMCDs. ET-1 also inhibits mineralocorticoid and AVP-stimulated Na and Cl reabsorption in isolated CCDs (12,18,19) and decreases Na/K-ATPase activity in suspensions of IMCDs (20). Despite these data, demonstrating such an ET-1 effect in vivo and clarifying how CD-derived ET-1 physiologically regulates Na and water transport has been problematic. This difficulty stems, in part, from

Tumor necrosis factor alpha is a major component of the infection-stimulated cytokine milieux associated with preterm labor and pregnancy termination. As a consequence, this potent factor is thought by some to have exclusively negative effects on the course of pregnancy. Yet in humans and other mammals, messenger RNA hybridizing with tumor necrosis factor alpha cRNA probes and protein detected by anti-tumor necrosis factor alpha have been identified in normal cycling and pregnant uteri, placentas, and embryos, consistent with an important role for tumor necrosis factor in female reproduction and embryonic development. Here, evidence for this intriguing dichotomy is presented, unresolved aspects are discussed, and potential roles for uteroplacental and embryonic tumor necrosis factor are proposed.