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Severe trauma can lead to a coagulopathy in patients, which is associated with increased mortality. We developed a rat polytrauma model that demonstrates a similar progression of coagulopathy. Because coagulation is influenced by changes in inflammation, and this interrelationship is poorly understood, we have studied the progression of inflammation, and its correlation with coagulation, in this rat model of severe polytrauma. Sprague-Dawley rats were anesthetized with isoflurane. Polytrauma was induced by damaging 10 cm of small intestines, right and medial liver lobes, right leg skeletal muscle, femur fracture, and hemorrhaging 40% of blood volume. No resuscitation was given. Polytrauma and hemorrhage resulted in a significant decrease in the number of lymphocytes and an increase in monocytes and granulocytes. There was an increase in plasma proinflammatory cytokines: tumor necrosis factor α (40×), interleukin (IL)-6 (20×), IL-1ß (16×), IL-17 (15×), interferon γ (10×), IL-1α (8×) and IL-12p70 (5×); anti-inflammatory cytokines: IL-10 (100×), IL-13 (16×), and IL-4 (5×); chemokines: growth-regulated protein/keratinocyte chemoattractant (30×), macrophage inflammatory protein 3α (10×), regulated and normal T-cell expressed and secreted (3×); and growth factors: vascular endothelial growth factor (5×), granulocyte macrophage colony-stimulating factor (6×), macrophage colony-stimulating factor (3×), granulocyte colony-stimulating factor (2×), and IL-5 (3×). There was a strong and significant correlation between prothrombin time, activated partial thromboplastin time, fibrinogen, and fibrin monomer concentration, and many cytokines. Polytrauma with hemorrhage is associated with a coagulopathy and a complex inflammatory response consisting of a concurrent rise in both proinflammatory and anti-inflammatory cytokines. The rise in plasma concentrations of chemokines and growth factors likely contribute to the mobilization of monocytes and granulocytes. There is strong correlation between prothrombin time, activated partial thromboplastin time, and IL-10 and IL-1ß. This relationship could be exploited for the development of resuscitation strategies that attenuate these cytokines and allow for better outcomes in patients with trauma through concomitant modulation of inflammation and coagulopathy.

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OBJECTIVE: To determine whether it is possible to predict, at the time of hospice enrollment, which patients will die within 6 months. DESIGN: Electronic health record-based retrospective cohort study. SETTING: Patients admitted to 10 hospices in the CHOICE network (Coalition of Hospices Organized to Investigate Comparative Effectiveness). PARTICIPANTS: Hospice patients. MAIN OUTCOME MEASURES: Mortality at 6 months following hospice admission. RESULTS: Among 126,620 patients admitted to 10 hospices, 118,532 (93.6%) died within 6 months. In a multivariable logistic regression model, five characteristics were independent predictors of 6-month mortality. For instance, patients younger than 65 years were less likely to die within 6 months (odds ratio [OR] 0.64; 95% confidence interval [CI] 0.45-0.91; p=0.014). Conversely, male patients were more likely to die within 6 months (OR 1.47; 95% CI 1.05-2.02; p=;0.036). After adjusting for other variables in this model, there were several subgroups with a low probability of 6-month probability (e.g., stroke and Palliative Performance Scale [PPS] score=50; adjusted probability of 6-month mortality=39.4%; 95% CI: 13.9%-72.5%). However, 95% confidence intervals of these 6-month mortality predictions extended above 50%. CONCLUSIONS: Hospices might use several variables to identify patients with a relatively low risk for 6-month mortality and who therefore may become ineligible to continue hospice services if they fail to show significant disease progression.

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BACKGROUND: Although hospices need to be able to anticipate patient acuity, there are currently no published models that predict the frequency of visits that a new hospice patient is likely to receive. OBJECTIVES: To identify patient characteristics that are associated with the frequency of health care provider visits in the first 8 days of hospice care. METHODS: An electronic health record (EHR)-based retrospective cohort study was conducted in seven hospice programs in the United States. Participants were 35,232 patients who were admitted between October 1, 2008 and May 31, 2011 and received hospice care at home on the day of enrollment. The main outcome measure was the average number of visits per day by nurses, social workers, chaplains, and home health aides in the first 8 days of home hospice care (day of admission plus up to 7 subsequent days). RESULTS: In a mixed effects regression model, 14 independent predictors of visit frequency were identified. For instance, several demographic characteristics were associated with more frequent visits, as were lower Palliative Performance Scale (PPS) scores (<40: 1.78 visits/day, 95% confidence interval [CI] 1.74-1.82 versus 40-60: 1.65 visits/day, 95% CI 1.61-1.69 versus >60: 1.41 visits/day, 95% CI 1.36-1.47; p<0.001), the presence of pain (pain: 1.77 visits/day; 95% CI 1.72-1.82 versus no pain: 1.44 visits/day, 95% CI .39-1.59; p<0.001). Patients admitted to home hospice from a hospital also received more frequent visits compared with other patients (hospital: 1.73 visits/day, 95% CI 1.67-1.79 versus home: 1.42 visits/day, 95% CI 1.40-1.44; p<0.001). CONCLUSIONS: An acuity index based on these variables could help hospices to better anticipate patient needs and staff workload, and could be used to guide strategic planning as hospices take part in accountable care organizations (ACOs).

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INTRODUCTION: Acute coagulopathy of trauma (aCOT) is a state of disordered coagulation developing soon after severe injury and blood loss and has been defined in the clinical literature as an elevation in prothrombin time (PT) and activated partial thromboplastin time (aPTT). OBJECTIVE: The purpose of this study was to develop a rat model of aCOT resulting from polytrauma and hemorrhage and showing an elevation in PT and aPTT. METHODS: Sprague-Dawley rats (300-400 g) were anesthetized with isoflurane. Polytrauma was induced by damaging 10 cm of small intestines, the right and medial liver lobes, the right leg skeletal muscle, and fracture of the right femur. Rats were hemorrhaged 40% of their estimated blood volume. No resuscitation was given. Venous and arterial blood samples were taken at times up to 4 h. RESULTS: Polytrauma and hemorrhage resulted in a significant rise in PT, aPTT, potassium, lactate, and glucose. There was a significant decrease in plasma bicarbonate, base excess, and sodium. Blood urea nitrogen and creatinine rose steadily throughout the 4 h indicative of progressive renal failure. Hematocrit decreased significantly immediately after hemorrhage and trauma indicating a movement of fluid into the vascular space from extravascular sources, which was mirrored by a decrease in plasma fibrinogen concentration. In contrast, platelet count initially decreased, rose at 2 h, and decreased again at 3 to 4 h, indicating that platelets were released into the vascular space. The change in platelet count was mirrored by the changes in thrombin-antithrombin and plasmin-antiplasmin complexes. Rotational thromboelastometry showed complex changes. Clotting firmness fell initially, rose at 2 h, and fell again at 3 to 4 h similar to the changes in platelet count. α Angle was elevated, and clotting time was shortened over the 4 h. Treatment with cytochalasin D (platelet function inhibitor) eliminated the increases in clotting firmness and thrombin generation seen at 2 h with rising platelet count. CONCLUSIONS: This model of aCOT in rats showed complex changes in clotting parameters over 4 h that included a rise in PT and aPTT. At 4 h, there was a decrease in clotting firmness, even though the clot formation was faster (elevated α angle and decrease in clotting time). The decrease in clotting firmness correlated with falling fibrinogen and platelet count. This model affords an opportunity to evaluate interventions in the treatment of aCOT.

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Extracts from leaves, peels or flowers of Passiflora are noted for their medicinal effects. Passiflora edulis peel extract (PFPE) has been proposed to lower blood pressure (BP); however, only indirect measurement techniques have been employed. To more accurately measure the effect of PFPE on hemodynamic parameters and determine the minimal effective dose, hemodynamic parameters were directly measured in spontaneously hypertensive rats (SHR) implanted with radiotelemeters. PFPE was given orally at 0, 2.5, 50 or 200 mg/kg body weight (BW) to determine the minimal effective dose. Once this dose was determined, the potential active components, edulilic acid (EA), anthocyanin fraction (AF) or γ-aminobutyric acid (GABA), were tested to determine which may contribute to the reductions in BP. The 50 mg PFPE/kg BW dose was the lowest dose that significantly reduced all hemodynamic parameters from baseline when compared to control. When the potential actives were provided at equivalent doses to those found in 50 mg PFPE/kg BW, the EA and AF significantly reduced all measured hemodynamic parameters from baseline when compared to control. GABA did not significantly affect any hemodynamic parameters compared to control and significantly increased heart rate. These direct measurements indicate that PFPE can decrease hemodynamic parameters in SHR and indicate that EA and AF are active compounds that contribute to the antihypertensive effects of PFPE supplementation. While these results are encouraging, detailed mechanistic studies are needed to determine the putative value of PFPE for blood pressure control in humans.

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OBJECTIVES: To describe the trajectory of functional decline after an individual is referred to hospice. DESIGN: Electronic health record-based retrospective cohort study. SETTING: Three hospice programs in the U.S. southeast, northeast, and midwest. PARTICIPANTS: Individuals in hospice. MAIN OUTCOME MEASURES: Palliative Performance Scale (PPS) scores measured at intervals between hospice enrollment and death, on a scale from 10 to 100. RESULTS: In 8,669 decedents, there was an average 13.8-point decline in PPS score. After adjusting for baseline PPS score and length of stay in hospice, three distinct trajectories were identified, each of which consisted of two diagnoses whose rates of decline had 95% confidence intervals (CIs) that overlapped. The most rapid decline was observed for individuals with cancer (adjusted decline 8.44 points/wk; 95% CI = 8.03-8.82) and stroke (adjusted decline 7.67 points/wk, 95% CI = 7.08-8.29). A significantly slower decline was observed in individuals with pulmonary disease (adjusted decline 5.02 points/wk, 95% CI = 4.24-5.75) and cardiac disease (adjusted decline 4.53 points/wk, 95% CI = 4.05-5.05). Individuals with debility (adjusted decline 1.86 points/wk, 95% CI = 0.95-2.78) and dementia (adjusted decline 1.98 points/wk, 95% CI = 1.01-2.89) had the slowest decline. In an inverse probability-weighted sample of individuals who had a PPS score recorded in the last day of life (n = 1,959, 22.6%), 35.9% had a PPS score of at least 40, indicating some oral intake, variable mental status, limited self-care, and an ability to get out of bed for at least part of the day. CONCLUSION: Although functional status generally declines in individuals in hospice, this decline is heterogeneous. Some individuals retain some physical and cognitive function until the last day of life.

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BACKGROUND: Although many patients enter hospice close to death, some enroll for more than six months. In 2011 the U.S. Centers for Medicare and Medicaid Services (CMS) required that these long-stay patients receive a face-to-face visit by a physician or nurse practitioner to ensure that they continue to meet eligibility criteria. OBJECTIVES: This study proposed to determine whether the face-to-face visit requirement increased the rate at which patients were decertified from hospice. DESIGN: The study was a retrospective cohort study in six U.S. hospices. Decertification from hospice within 10 months of enrollment was measured. RESULTS: Of 23,638 patients, 11,788 (49.9%) would have been affected by the face-to-face requirement. In bivariate analysis, there was a significant decrease in the decertification rate after the requirement was implemented-371/11,788 (3.2%) versus 578/11,850 (4.9%); odds ration (OR): 0.63; 95% CI 0.55-0.72; p<0.001. In a multivariable logistic regression model adjusting for changes in patient characteristics and clustered by hospice, there was still a reduction in decertifications-3.4% versus 5.2%; OR 0.67; 95% CI 0.47-0.97; p=0.034. Although the impact of the face-to-face requirement varied among hospices, all hospices had a decrease in decertification rates (absolute adjusted reduction between 1.4% and 3.6%). CONCLUSIONS: The face-to-face requirement may decrease hospice discharges, contrary to its intention.

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PURPOSE: To determine which hospice patients with cancer prefer to die at home and to define factors associated with an increased likelihood of dying at home. METHODS: An electronic health record-based retrospective cohort study was conducted in three hospice programs in Florida, Pennsylvania, and Wisconsin. Main measures included preferred versus actual site of death. RESULTS: Of 7,391 patients, preferences regarding place of death were determined at admission for 5,837 (79%). After adjusting for other characteristics, patients who preferred to die at home were more likely to die at home (adjusted proportions, 56.5% v 37.0%; odds ratio [OR], 2.21; 95% CI, 1.77 to 2.76). Among those patients (n = 3,152) who preferred to die at home, in a multivariable logistic regression model, patients were more likely to die at home if they had at least one visit per day in the first 4 days of hospice care (adjusted proportions, 61% v 54%; OR, 1.23; 95% CI, 1.07 to 1.41), if they were married (63% v 54%; OR, 1.35; 95% CI, 1.10 to 1.44), and if they had an advance directive (65% v 50%; OR, 2.11; 95% CI, 1.54 to 2.65). Patients with moderate or severe pain were less likely to die at home (OR, 0.56; 95% CI, 0.45 to 0.64), as were patients with better functional status (higher Palliative Performance Scale score: < 40, 64.8%; 40 to 70, 50.2%; OR, 0.79; 95% CI, 0.67 to 0.93; > 70, 40.5%; OR, 0.53; 95% CI, 0.35 to 0.82). CONCLUSION: Increased hospice visit frequency may increase the likelihood of patients being able to die in the setting of their choice.

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Burn and toll-like receptors (TLR) are associated with innate immune system activation, but the impact of burn on TLR-induced inflammation responses by circulating leukocytes is unknown. To study this, C57BL/6 mice were subjected to burn (3(rd) degree, 25% TBSA) or sham procedure and 1-7 days later blood was collected. Whole blood cell suspensions were incubated for 24 hr in the presence of zymosan (TLR-2 agonist) or LPS (TLR-4 agonist). The blood cultures were responsive to TLR2 and TLR4-mediated activation, resulting in the production of IL-6, IL-10, IL-17, TNF-α, MIP-1α, MIP-1ß, KC and RANTES. TLR2-induced KC and MIP-1ß production was greater in the burn group at 3-7 days post-injury, whereas IL-6, IL-10, KC and MIP-1ß were greater for TLR4-induced activation after burn. In conclusion, circulating leukocytes were responsive to TLR-induced activation and TLR-mediated inflammatory responses were enhanced 3-7 days post-injury, as evidenced by increased production of these inflammatory mediators.

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OBJECTIVE: To determine whether a prognostic index could predict one-week mortality more accurately than hospice nurses can. METHOD: An electronic health record-based retrospective cohort study of 21,074 hospice patients was conducted in three hospice programs in the Southeast, Northeast, and Midwest United States. Model development used logistic regression with bootstrapped confidence intervals and multiple imputation to account for missing data. The main outcome measure was mortality within 7 days of hospice enrollment. RESULTS: A total of 21,074 patients were admitted to hospice between October 1, 2008 and May 31, 2011, and 5562 (26.4%) died within 7 days. An optimal predictive model included the Palliative Performance Scale (PPS) score, admission from a hospital, and gender. The model had a c-statistic of 0.86 in the training sample and 0.84 in the validation sample, which was greater than that of nurses' predictions (0.72). The index's performance was best for patients with pulmonary disease (0.89) and worst for patients with cancer and dementia (both 0.80). The index's predictions of mortality rates in each index category were within 5.0% of actual rates, whereas nurses underestimated mortality by up to 18.9%. Using the optimal index threshold (<3), the index's predictions had a better c-statistic (0.78 versus 0.72) and higher sensitivity (74.4% versus 47.8%) than did nurses' predictions but a lower specificity (80.6% versus 95.1%). CONCLUSIONS: Although nurses can often identify patients who will die within 7 days, a simple model based on available clinical information offers improved accuracy and could help to identify those patients who are at high risk for short-term mortality.

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Within the paraventricular nucleus (PVN), there is a balance between the excitatory and inhibitory neurotransmitters that regulate blood pressure; in hypertension, the balance shifts to enhanced excitation. Nitric oxide (NO) is an atypical neurotransmitter that elicits inhibitory effects on cardiovascular function. We hypothesized that reduced PVN NO led to elevations in blood pressure during both the onset and sustained phases of hypertension due to decreased NO synthase (NOS) and increased asymmetrical dimethylarginine (ADMA; an endogenous NOS inhibitor) and symmetric dimethylarginine (SDMA). Elevated blood pressure, in response to PVN bilateral microinjections of a NO inhibitor, nitro-L-arginine methyl ester, was blunted in renal wrapped rats during the onset of hypertension (day 7) and sustained renal wrap hypertension (day 28) compared with sham-operated rats. Adenoviruses (Ad) encoding endothelial NOS (eNOS) or LacZ microinjected into the PVN [1 × 10(9) plaque-forming units, bilateral (200 nl/site)] reduced mean arterial pressure compared with control (Day 7, Ad LacZ wrap: 144 ± 7 mmHg and Ad eNOS wrap: 117 ± 5 mmHg, P ≤ 0.05) throughout the study (Day 28, Ad LacZ wrap: 123 ± 1 mmHg and Ad eNOS wrap: 108 ± 4 mmHg, P ≤ 0.05). Western blot analyses of PVN NOS revealed significantly lower PVN neuronal NOS during the onset of hypertension but not in sustained hypertension. Reduced SDMA was found in the PVN during the onset of hypertension; however, no change in ADMA was observed. In conclusion, functional indexes of NO activity indicated an overall downregulation of NO in renal wrap hypertension, but the mechanism by which this occurs likely differs throughout the development of hypertension.

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BACKGROUND: Major trauma often causes hemorrhage and predisposes to transfusion-related acute lung injury (TRALI). TRALI is a leading cause of transfusion-related deaths; however, its pathophysiology is uncertain. In the existing two-event models of TRALI, infection (lipopolysaccharide injection) is followed by the infusion of aged blood products. Our objective was to develop a trauma-relevant two-event model of TRALI by examining the effect of aged packed red blood cells (PRBC) on lung injury in rats with trauma-hemorrhage. METHODS: Male Lewis rats were used. Rat PRBC were prepared similar to human PRBC. Recipients were implanted with femoral arterial and venous catheters (isoflurane anesthesia) and then subjected to 30% controlled arterial hemorrhage after 16-hour recovery. After a 60-minute shock period, rats were resuscitated with crystalloid and PRBC (0-35 days old; 3:1 ratio) and followed for up to 6 hours. Lung edema was evaluated by Evans blue dye (EBD), protein, and cytokine-induced neutrophil chemoattractant-1 (CINC-1) accumulation in bronchoalveolar lavage fluid, and arterial blood gases were measured (iSTAT). RESULTS: CINC-1 levels increased over time in our PRBC stored for over 21 days. Transfusion survival was reduced, and Evans blue dye, protein, and CINC-1 accumulation in bronchoalveolar lavage fluid were increased in rats transfused with 28-day-old and 35-day-old PRBC compared with the 0-day group. Arterial PO2 and O2 saturation were decreased in rats transfused with 28-day-old and 35-day-old PRBC. However, pH and PCO2 were not different between groups. CONCLUSIONS: These results suggest that transfusion of 28-day-old and 35-day-old PRBC reliably promotes lung edema in a rat model of catheter surgery and hemorrhage. We propose that this model can be used as a trauma-relevant two-event model of TRALI.

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BACKGROUND: Hemorrhagic shock causes hypoperfusion of peripheral tissues and promotes endothelial dysfunction, which may lead to further tissue injury. Trauma increases extrahepatic activity of arginase, an enzyme which competes for l-arginine with nitric oxide synthase, and plays a key role in the development of endothelial dysfunction during aging, hypertension, and diabetes. However, the role of arginase in hemorrhage-induced endothelial dysfunction has not been studied. This study tests the hypothesis that arginase inhibition improves endothelial function after hemorrhage. METHODS: Male Sprague-Dawley rats were implanted with indwelling arterial catheters for blood pressure measurements and blood removal. Awake animals were subjected to a 45% fixed volume controlled hemorrhage and blood pressure was monitored. Unbled rats served as controls. Skeletal muscle arterioles were isolated 24 hours after hemorrhage and cannulated in a pressure myograph system. To study endothelial function, arterioles were exposed to constant midpoint, but altered endpoint pressures, to establish graded levels of luminal flow and internal diameter was measured. RESULTS: Hemorrhage lowered mean arterial pressure that spontaneously recovered to 78% and 88% of baseline in 2 hours and 20 hours, respectively. Vascular arginase II and blood glucose levels were elevated, whereas hemoglobin and insulin levels were decreased 24 hours after blood loss. In posthemorrhage arterioles, flow-induced dilation was abolished. Acute in vitro treatment with an inhibitor of arginase, N-hydroxy-nor-l-arginine, restored flow-induced dilation to unbled control levels. Similarly, the arginase and nitric oxide synthase substrate, l-arginine, but not the inactive isomer, d-arginine, restored flow-induced dilation. CONCLUSIONS: These results indicate that arginase contributes to endothelial dysfunction in resistance vessels after significant hemorrhage.

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The left ventricle (LV) remodels with age and in response to pressure overload. While aging and pressure overload are superimposed in the clinical context, the structural and functional consequences of the individual processes are not well-understood. Accordingly, the objective of this study was to compare the effects of both early and late chronic hypertension on extracellular matrix (ECM) remodeling. The following groups of Dahl rats were studied: 1) young salt-resistant (control, n=6); 2) young salt-sensitive (early phase of chronic hypertension, n=6); 3) middle-aged salt-resistant (aging, n=5); and 4) middle-aged salt-sensitive (late phase of chronic hypertension, n=6). We measured LV mass (LVM) and body weight (BW) and immunoblotted a panel of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and ECM proteins. Total collagen increased, several MMPs decreased, and TIMP-1 increased in the early phase of hypertension, consistent with fibrosis. Active MMP-8 decreased from 8,010+/-81 U in young salt-resistant to 5,260+/-313 U in young salt-sensitive (p<0.05) rats. During the late phase, chronic hypertension decreased total collagen levels and increased MMP-8 and MMP-14 (all p<0.05). Based on good-fit modeling analysis, MMP-14 (45 kDa) correlated positively with changes in LVM/BW during the early phase. In conclusion, this is the first study to evaluate MMP levels during both early and late chronic phases of hypertension. Our results highlight that ECM remodeling in response to pressure overload is a dynamic process involving excessive ECM accumulation and degradation.

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BACKGROUND: Female Dahl salt-sensitive (DS) rats fed a low-salt diet develop hypertension at 6 months of age. Ovariectomy at 2 months of age accelerates the development of hypertension, and estrogen replacement delays it. Although acute pressure overload induces structural changes in the left ventricle (LV) further effects of gradual hypertension on LV remodeling have not been examined in the DS rat model. OBJECTIVE: The purpose of this study was to test the hypothesis that aging and estrogen loss in hypertensive DS rats are accompanied by changes in LV remodeling. METHODS: Four groups of DS rats were examined: young intact, middle-aged (MA) intact, MA ovariectomized (MA-OVX), and MA-OVX with 17beta-eestradiol (E(2)) supplementation (MA-OVX+E(2)). Myocardial matrix metalloproteinases (MMPs),tissue inhibitors of metalloproteinases (TIMPs),and extracellular matrix (ECM) proteins were assessed by immunoblotting. RESULTS: Each of the 4 groups comprised 6 animals. Mean (SEM) LV mass was significantly greater in the MA-intact and the MA-OVX groups (1257 [31] mg and 1199 [25] mg, respectively; both, P < 0.05) compared with the young-intact group (697 [6] mg). LV mass in the MA-OVX+E(2) group was significantly lower compared with the MA-intact and MA-OVX groups (both, P < 0.05), suggesting that estrogen may attenuate LV remodeling. Fibronectin and collagen III and IV concentrations increased significantly in the MA-intact and MA-OOVX groups (all, P < 0.05),indicating increased fibrosis. Multiple MMPs also increased in the MA-intact an nd MA-OVX rats, including MMP-3, -7, -99, -113, and -114, and all TIMPs. In contrast, estrogen attenuated fibrosis by increasing MMP-8 concentrations and increasing collagen III fragments. From good-fit regression modeling, MMP-13 and MMP-14 concentrations correlated positively with LV mass for the MA-intact and MA-OVX groups, respectively. CONCLUSIONS: Gradual hypertension stimulated ECM turnover by increasing both MMP/TIMP production and ECM degradation. Estrogen loss or gain resulted in a shift in MMP profiles, suggesting that MMP-13 and MMP-14 may be differentially regulated in postmenopausal hypertension.

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This study evaluated the effect of ovariectomy on renal estrogen receptor (ER)-alpha and ERbeta expression in young female Dahl salt-sensitive and salt-resistant rats. Our hypothesis was that estrogen depletion results in an imbalance in ERalpha and ERbeta expression in salt-sensitive rats. Rats were subjected to sham surgery (intact), ovariectomy, and ovariectomy with estrogen replacement. Kidneys were harvested 8 weeks later. Western blot was used to measure ERalpha and ERbeta expression in the cortex and medulla. In intact rats, ERalpha was 2.7- and 4.3-fold higher in salt-sensitive compared with salt-resistant rats in the renal cortex and medulla, respectively. In salt-sensitive rats, ovariectomy caused 42% and 52% decreases in ERalpha and 107% and 314% increases in ERbeta in renal cortex and medulla, respectively. In salt-resistant rats, ovariectomy caused 33% and 150% increases in ERalpha and 107% and 100% increases in ERbeta in renal cortex and medulla, respectively. Estrogen replacement did not alter ERalpha but restored ERbeta expression levels similar to levels in intact rats in both salt-sensitive and salt-resistant rats. Thus, estrogen loss had opposite effects on ERalpha in salt-sensitive (downregulation) and salt-resistant rats (upregulation). We propose that the decrease in ERalpha expression in salt-sensitive rats after estrogen loss alters the balance of renal ERs and may play a role in accelerating the development of hypertension and renal damage.

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The ovariectomized (OVX) Dahl salt-sensitive (DS) rat fed a low-salt diet is a model of postmenopausal hypertension. In addition to estrogen loss, aging can also contribute to postmenopausal hypertension. We hypothesized that: (1) female DS rats on a low-salt diet become hypertensive with age; (2) ovariectomy accelerates age-dependent hypertension in the DS rat caused by estrogen depletion; and (3) this hypertension correlates with increased type 1 angiotensin receptor (AT1R) number (Bmax). Blood pressure was monitored by telemetry from 3 to 12 months and AT1R Bmax was determined by Scatchard analysis in glomeruli and adrenal cortex. Three groups of DS rats were studied: intact, OVX, and 17beta-estradiol-replaced OVX (OVX+E). In intact rats, aging to 12 months resulted in hypertension (159+/-6 mm Hg) and an 82% decrease in estrogen. Blood pressure in OVX was significantly higher than OVX+E through 12 months of age (173+/-4 versus 150+/-8 mm Hg). At 4 months, OVX increased AT1R Bmax compared with intact and OVX+E in both glomeruli and adrenal cortex. Aging also increased AT1R Bmax in these tissues in intact rats. In summary, female DS rats fed a low-salt diet have hypertension develop with age, that is accelerated by OVX and attenuated by estrogen replacement. Concurrently, AT1Rs are upregulated by age and OVX, which is prevented by estrogen replacement. This study suggests that an increased activity of the renin angiotensin system contributes to the development of hypertension, and estrogen protects against this process.

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Financial staff and clinical staff do not necessarily see eye-to-eye. However, mutual understanding of one another's areas of expertise is essential to the success of a hospice. Financial and clinical staff can work together to streamline employee reporting, such as on time sheets and during annual reviews, to ensure that important data is being collected and staff don't waste time reporting on and analyzing extraneous data.

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