41 research outputs found
Hickey MM, Lam JC, Bezman NA, Rathmell WK, Simon MC.. von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis. J Clin Invest 117: 3879-3889
The R200W mutation in the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL) is unique in that it is not associated with tumor development, but rather with Chuvash polycythemia, a heritable disease characterized by elevated hematocrit and increased serum levels of erythropoietin and VEGF. Previous studies have implicated hypoxia-inducible factor-1alpha (HIF-1alpha) signaling in this disorder, although the effects of this mutation on pVHL function are not fully understood. In order to explore the mechanisms underlying the development of this polycythemia, we generated mice homozygous for the R200W mutation (Vhl(R/R)). Vhl(R/R) mice developed polycythemia highly similar to the human disease. The activity of HIF proteins, specifically the HIF-2alpha isoform, was upregulated in ES cells and tissues from Vhl(R/R) mice. Furthermore, we observed a striking phenotype in Vhl(R/R) spleens, with greater numbers of erythroid progenitors and megakaryocytes and increased erythroid differentiation of Vhl(R/R) splenic cells in vitro. These findings suggest that enhanced expression of key HIF-2alpha genes promotes splenic erythropoiesis, resulting in the development of polycythemia in Vhl(R/R) mice. This mouse model is a faithful recapitulation of this VHL-associated syndrome and represents a useful tool for studying polycythemias and investigating potential therapeutics
LOSS OF JAK2 REGULATION VIA VHL-SOCS1 E3 UBIQUITIN HETEROCOMPLEX UNDERLIES CHUVASH POLYCYTHEMIA
Chuvash polycythemia (CP) is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the von Hippel-Lindau (VHL) gene whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark features of CP such as hypersensitivity to erythropoietin are unclear. Here, we show that VHL directly binds suppressor of cytokine signalling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated (p)JAK2 for ubiquitin-mediated destruction. In contrast, CP-associated VHL mutants have altered affinity for SOCS1 and fail to engage and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reverses the disease phenotype in vhlR200W/R200W knock-in mice, a model that faithfully recapitulates human CP. These results reveal VHL as a SOCS1-cooperative negative regulator of JAK2 and provide compelling biochemical and preclinical evidence for JAK2- targeted therapy in CP patients
Pregnancy Intentions and Happiness Among Pregnant Black Women at High Risk for Adverse Infant Health Outcomes
CONTEXT:Unintended pregnancy is associated with risk behaviors and increased morbidity or mortality for mothers and infants, but a woman\u27s feelings about pregnancy may be more predictive of risk and health outcomes than her intentions.
METHODS: A sample of 1,044 black women who were at increased risk were enrolled at prenatal care clinics in the District of Columbia in 2001-2003. Bivariate and multivariate analyses assessed associations between pregnancy intentions or level of happiness about being pregnant and multiple psychosocial and behavioral risk factors, and identified correlates of happiness to be pregnant.
RESULTS: Pregnancy intentions and happiness were strongly associated, but happiness was the better predictor of risk. Unhappy women had higher odds than happy women of smoking, being depressed, experiencing intimate partner violence, drinking and using illicit drugs (odds ratios, 1.7-2.6). The odds of being happy were reduced among women who had other children or a child younger than two, who were single or did not have a current partner, who had had more than one sexual partner in the past year and who reported that the baby\u27s father did not want the pregnancy (0.3-0.6). In contrast, the odds of being happy were elevated among women who had better coping strategies (1.03), who had not used birth control at conception (1.6) and who had 1-2 household members, rather than five or more (2.1).
CONCLUSIONS: Additional psychosocial screening for happiness about being pregnant and for partner characteristics, particularly the father\u27s desire to have this child, may help improve prenatal care services and prevent adverse health outcomes
The James Webb Space Telescope Mission
Twenty-six years ago a small committee report, building on earlier studies,
expounded a compelling and poetic vision for the future of astronomy, calling
for an infrared-optimized space telescope with an aperture of at least .
With the support of their governments in the US, Europe, and Canada, 20,000
people realized that vision as the James Webb Space Telescope. A
generation of astronomers will celebrate their accomplishments for the life of
the mission, potentially as long as 20 years, and beyond. This report and the
scientific discoveries that follow are extended thank-you notes to the 20,000
team members. The telescope is working perfectly, with much better image
quality than expected. In this and accompanying papers, we give a brief
history, describe the observatory, outline its objectives and current observing
program, and discuss the inventions and people who made it possible. We cite
detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space
Telescope Overview, 29 pages, 4 figure
Recommended from our members
Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.
Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (nâ=â143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (nâ=â152), or no hydrocortisone (nâ=â108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (nâ=â137), shock-dependent (nâ=â146), and no (nâ=â101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707
Perivascular macrophages in health and disease
Macrophages are a heterogeneous group of cells that are capable of carrying out distinct functions in different tissues, as well as in different locations within a given tissue. Some of these tissue macrophages lie on, or close to, the outer (abluminal) surface of blood vessels and perform several crucial activities at this interface between the tissue and the blood. In steady-state tissues, these perivascular macrophages maintain tight junctions between endothelial cells and limit vessel permeability, phagocytose potential pathogens before they enter tissues from the blood and restrict inappropriate inflammation. They also have a multifaceted role in diseases such as cancer, Alzheimer disease, multiple sclerosis and type 1 diabetes. Here, we examine the important functions of perivascular macrophages in various adult tissues and describe how these functions are perturbed in a broad array of pathological conditions
Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19
IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.
DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 nonâcritically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).
INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (nâ=â257), ARB (nâ=â248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; nâ=â10), or no RAS inhibitor (control; nâ=â264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ supportâfree days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.
RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ supportâfree days among critically ill patients was 10 (â1 to 16) in the ACE inhibitor group (nâ=â231), 8 (â1 to 17) in the ARB group (nâ=â217), and 12 (0 to 17) in the control group (nâ=â231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ supportâfree days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).
CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570
The role of von Hippel -Lindau mutation in polycythemia and pulmonary hypertension
Adaptation to low oxygen, or hypoxia, is primarily mediated by hypoxia-inducible factor (HIF) proteins, which regulate a wide range of genes involved in processes such as glycolysis, angiogenesis, and erythropoiesis. HIF activity is regulated in an oxygen-dependent manner by the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL), which promotes ubiquitin-mediated degradation of HIF-α subunits. Most mutations in the VHL gene predispose patients to the formation of highly vascular tumors, due in large part to constitutive HIF signaling. In contrast, germline homozygosity for the unique Chuvash mutation in VHL, 598C\u3eT (R200W in pVHL), results in polycythemia and pulmonary hypertension. To understand the effects of this substitution on pVHL function and to gain insights into the pathogenesis of these diseases, we have generated mice expressing this mutation (VhlR/R). These mice developed polycythemia, with increased hematocrits and elevated serum levels of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) highly similar to the human disease, likely resulting from enhanced erythropoiesis in the spleen. In addition, VhlR/R mice also developed pulmonary hypertension, with elevated pulmonary arterial pressures, hemorrhage, accumulation of extracellular matrix proteins, and macrophage infiltration in the lungs. Therefore, these mice faithfully recapitulate human Chuvash disease and represent a good model for further analysis of the effects of this mutation on both HIF-dependent and HIF-independent pVHL functions. Interestingly, we detected upregulation of many HIF targets in VhlR/R tissues, especially the spleen and lung, and in particular genes preferentially activated by the HIF-2α isoform. These results suggest that increased expression of HIF-2α-regulated genes plays a prominent role in the development of both polycythemia and pulmonary pathology in mice expressing the R200W mutation. Furthermore, these findings offer important insights into the mechanisms underlying these diseases in humans and suggest potential therapeutic implications
The role of von Hippel -Lindau mutation in polycythemia and pulmonary hypertension
Adaptation to low oxygen, or hypoxia, is primarily mediated by hypoxia-inducible factor (HIF) proteins, which regulate a wide range of genes involved in processes such as glycolysis, angiogenesis, and erythropoiesis. HIF activity is regulated in an oxygen-dependent manner by the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL), which promotes ubiquitin-mediated degradation of HIF-α subunits. Most mutations in the VHL gene predispose patients to the formation of highly vascular tumors, due in large part to constitutive HIF signaling. In contrast, germline homozygosity for the unique Chuvash mutation in VHL, 598C\u3eT (R200W in pVHL), results in polycythemia and pulmonary hypertension. To understand the effects of this substitution on pVHL function and to gain insights into the pathogenesis of these diseases, we have generated mice expressing this mutation (VhlR/R). These mice developed polycythemia, with increased hematocrits and elevated serum levels of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) highly similar to the human disease, likely resulting from enhanced erythropoiesis in the spleen. In addition, VhlR/R mice also developed pulmonary hypertension, with elevated pulmonary arterial pressures, hemorrhage, accumulation of extracellular matrix proteins, and macrophage infiltration in the lungs. Therefore, these mice faithfully recapitulate human Chuvash disease and represent a good model for further analysis of the effects of this mutation on both HIF-dependent and HIF-independent pVHL functions. Interestingly, we detected upregulation of many HIF targets in VhlR/R tissues, especially the spleen and lung, and in particular genes preferentially activated by the HIF-2α isoform. These results suggest that increased expression of HIF-2α-regulated genes plays a prominent role in the development of both polycythemia and pulmonary pathology in mice expressing the R200W mutation. Furthermore, these findings offer important insights into the mechanisms underlying these diseases in humans and suggest potential therapeutic implications