Plasma levels of IL-6 correlate with high blood pressure under many circumstances, and ANG II has been shown to stimulate IL-6 production from various cell types. This study tested the role of IL-6 in mediating the hypertension caused by high-dose ANG II and a high-salt diet. Male C57BL6 and IL-6 knockout (IL-6 KO) mice were implanted with biotelemetry devices and placed in metabolic cages to measure mean arterial pressure (MAP), heart rate (HR), sodium balance, and urinary albumin excretion. Baseline MAP during the control period averaged 114 +/- 1 and 109 +/- 1 mmHg for wild-type (WT) and IL-6 KO mice, respectively, and did not change significantly when the mice were placed on a high-salt diet (HS; 4% NaCl). ANG II (90 ng/min sc) caused a rapid increase in MAP in both groups, to 141 +/- 9 and 141 +/- 4 in WT and KO mice, respectively, on day 2. MAP plateaued at this level in KO mice (134 +/- 2 mmHg on day 14 of ANG II) but began to increase further in WT mice by day 4, reaching an average of 160 +/- 4 mmHg from days 10 to 14 of ANG II. Urinary albumin excretion on day 4 of ANG II was not different between groups (9.18 +/- 4.34 and 8.53 +/- 2.85 microg/2 days for WT and KO mice). By day 14, albumin excretion was nearly fourfold greater in WT mice, but MAP dropped rapidly back to control levels in both groups when the ANG II was stopped after 14 days. Thus the approximately 30 mmHg greater ANG II hypertension in the WT mice suggests that IL-6 contributes significantly to ANG II-salt hypertension. In addition, the early separation in MAP, the albumin excretion data, and the rapid, post-ANG II recovery of MAP suggest an IL-6-dependent mechanism that is independent of renal injury.

Introduction-Erectile dysfunction (ED) is considered an early clinical manifestation of vascular disease and an independent risk factor for cardiovascular events associated with endothelial dysfunction and increased levels of pro-inflammatory cytokines. Tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine, suppresses endothelial nitric oxide synthase (eNOS) expression.Aim-Considering that nitric oxide (NO) is of critical importance in penile erection, we hypothesized that blockade of TNF-α actions would increase cavernosal smooth muscle relaxation through an increase in NOS expression.Methods-In vitro organ bath studies were used to measure cavernosal reactivity in wild type and TNF-α knockout (TNF-α KO) mice and NOS expression was evaluated by western blot. In addition, spontaneous erections (in vivo) were evaluated by videomonitoring the animals (30 min.). Collagen and elastin expression were evaluated by Masson trichrome and Verhoff-van Gieson stain reaction, respectively.Main Outcome Measures-Corpora cavernosa from TNF-α KO mice exhibited increased NOdependent relaxation, which was associated with increased eNOS and neuronal NOS (nNOS) cavernosal expression. Conclusion-Corpora cavernosa from TNF-α KO mice display alterations that favor penile tumescence, indicating that TNF-α plays a detrimental role in erectile function. A key role for TNF-α in mediating endothelial dysfunction in ED is markedly relevant since we now have access to anti-TNF-α therapies. Results-Cavernosal Keywordstumor necrosis factor alpha; corpus cavernosum; endothelial nitric oxide synthase; neuronal nitric oxide synthase; mouse INTRODUCTIONErectile dysfunction (ED), defined as the consistent inability to achieve and maintain penile erection sufficient for adequate sexual relations, is a prevalent condition affecting more than 150 million men worldwide. ED, which is considered the early clinical manifestation of generalized vascular disease and an independent risk factor for cardiovascular events, is NIH Public Access

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Study objective: This was a prospective, pre-post, 13-year observational study documenting the multiyear implementation of an observation unit sickle cell pathway for patients with uncomplicated vaso-occlusive events. Methods: The sickle cell pathway begins with rapid triage to identify patients with uncomplicated vaso-occlusive events for immediate transfer to the observation unit and initiation of patient-controlled analgesia followed by repeated evaluations of pain and identification of other complications. Data were abstracted from the electronic medical record or observation unit database. The sickle cell pathway was initiated in April 2006. Major revisions of it were carried out in June 2009 (physician evaluation occurs in sickle cell pathway and only patient-controlled analgesia administration of medications) and October 2010 (multidisciplinary management and individual dosing). Results: Annual ED visits ranged between 287 and 528. The preimplementation hospital admission rate was 33% (123/368), 3-day return rate 16% (60/368), and 30-day return rate 67% (248/368). Refinements to the sickle cell pathway have resulted in a decrease in admission rate to 20% (258/1276); 3-day return rate, to 3.6% (46/1,276); and 30-day return rate, to 41% (525/ 1,276) for the past 3 years. Conclusion: The use of a sickle cell pathway for the treatment of uncomplicated vaso-occlusive events has been effective in providing rapid treatment and reducing hospital admissions. However, it was not only the intervention and its refinement that made the sickle cell pathway successful. With the Consolidated Framework for Implementation Research, it was discerned that outer setting factors of organizational commitment to the care of patients with SCD, inner setting factors of learning climate and leadership engagement, individuals, and process contributed to the success of the sickle cell pathway. [

How to Be an AntiracistRacism and bias are antithetical to the oaths, moral commitments, and ethical responsibilities upheld by health professionals who are dedicated to the missions of medicine. Accordingly, educators, healers, and role models for the next generation of physicians must redouble their efforts to work alongside leaders at medical schools, academic health centers, and teaching hospitals to address racism, bias, and other factors that negatively affect the health and well-being of students and trainees, colleagues, patients, and communities.The horrific deaths of numerous unarmed Black people-such as the killing of George Floyd in May 2020-highlight the twin traumas of racism and police brutality that affect the lives of Black people in the US. Overt acts of racism such as violence and public harassment constitute only the tip

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Background: Patients with sickle cell disease (SCD) vaso-occlusive crisis (VOC) frequently seek care in the emergency department (ED). To improve and increase consistency of care patients with uncomplicated VOC, are treated in the Emergency Department Observation Unit (EDOU) where they are treated with an individualized protocol-based pathway. EDOUs have been shown to be effective in meeting treatment guidelines and reducing hospital admission. Objective: This study examines the admission rates of individuals with SCD stratified by frequency of presentation at the EDOU. Methods: A retrospective review of an ED database was completed to explore the relationship between EDOU utilization and admission rate for patients with uncomplicated VOC. All patient records meeting pathway inclusion criteria for uncomplicated VOC during the time period September 2013 through May 2015 were included in the study. Visits were first associated with individual patients. Then, based on the number of visits per time period, patients were categorized as high users, moderate users, or low users. Categorization was done using the number of visits during the first, 12-month period (9/11/13 - 9/10/14), or the second, nine-month period (9/10/14 - 5/31/15). Adaptations to the categorization scheme for the nine-month time period were as follows. Low users were patients that had no more than one visit in either the first or second time period; moderate users were patients with two or three visits in the first time period or two visits in the second; high users were patients with four or more visits in the first time period, or three or more visits in the second time period. Admission rates were calculated as percentages of visits to the EDOU. Rates of admission for high, middle, and low users were compared using an unpaired, one-tailed Student's t-test. This study was approved by expedited review by the institution's Institutional Review Board (IRB). Results: A total of 727 visits for 154 patients were included in the analysis. High users (n=44) had a total of 539 visits and an average patient admission rate of 22% (n=118). Moderate users (n=49) had a total of 108 visits and an admission rate of 31% (n=33). Low users (N=61) had a total of 80 visits and an admission rate of 36% (n=29). The difference between the number of high user admissions and low user admissions was significant (p<0.01) as was the difference between the number of moderate-user visits and the number of high-user visits (p=0.04). The difference between the number of moderate and low user admissions was not significant (p=0.14). Conclusion: This study found that the difference in the number of admissions between high and low users and between high and moderate users was significant. The findings provide support for the value of the EDOU in reducing unnecessary hospital admissions. These findings also raise important questions regarding the phenotypic expression of pain in SCD and the availability of care. Although the criteria for categorization of patients in this study was limited and the time periods unequal the results suggest different patterns of personal response to pain and treatment seeking. It is unknown how these groups may be different in regards to access to care, treatment preferences, self-care practices, or severity of disease. It can be hypothesized from these results that there may be two different patterns of care seeking with some patients only using the EDOU when crisis is severe (low users) and other patients (high users) using the EDOU as part of their regular pain treatment strategy. To address these questions it is necessary to further examine the differences between these groups to look for explanations that can address increased utilization of the EDOU among some patients. Disclosures No relevant conflicts of interest to declare.

We recently reported that the JAK2 inhibitor AG490 prevented JAK/STAT pathway activation and hypertension during chronic iv. ANG II infusion. It is unknown, however, whether activation of JAK2 is required for ANG II to prevent blood pressure from decreasing in the physiologic response to low salt intake. This was tested by blocking JAK2 activation chronically in rats that were switched from normal‐ to low‐salt intake. Male SD rats with instrumented with artery and vein catheters for 24 hr/day mean arterial pressure (MAP) measurement and iv. infusions. Rats were maintained on a normal‐salt (NS) intake (~ 3 mEq/day), and after baseline measurements chronic iv. infusions of either: vehicle (Veh; saline), the AT1 receptor antagonist Losartan (LOS; 10 mg/kg/day) or AG490 (AG; 10 ng/kg/min) were begun. After a 4‐day control period, rats were switched to low‐salt intake (LS; 0.4 mEq/day), while Veh, LOS and AG infusions continued. There were no differences in MAP between any group under baseline conditions. During the control period, MAP averaged 93+4, 97+3 and 80+2 mm Hg in Veh, AG, and LOS groups, respectively. Switching to LS intake did not change MAP in Veh and AG rats (102+4 and 101+3 mm Hg, respectively); but MAP decreased significantly in LOS rats to 72+4 mm Hg by day 5. These data suggest that JAK2 activation is not involved in ANG II's role in the blood pressure response to LS intake. (HL74167 MWB; HL91177 AB)