Mycophenolate Mofetil Decreases Atherosclerotic Lesion Size by Depression of Aortic T-Lymphocyte and Interleukin-17–Mediated Macrophage Accumulation

ObjectivesThis study tested whether immunosuppression with mycophenolate mofetil (MMF) inhibits atherosclerosis development in apolipoprotein-E–deficient (Apoe−/−) mice and investigated the mechanism.BackgroundChronic vascular inflammation involving both innate and adaptive immunity is central in the development of atherosclerosis, but immunosuppressive treatment is not uniformly beneficial. The immunosuppressive MMF targets lymphocyte proliferation by inhibiting inosine-monophosphate dehydrogenase.MethodsYoung and aged Apoe−/− mice were treated with 30 mg/kg daily MMF during 12 and 3 weeks of a high-fat diet, respectively. Aortic lesion size and composition was investigated by histology and flow cytometry; soluble inflammatory mediators were investigated by enzyme-linked immunosorbent assay.ResultsMacroscopic and histologic aortic atherosclerotic lesions were significantly decreased in both MMF-treated groups. While systemic immunoglobulin G directed against low-density lipoproteins was not significantly altered, the T-cell cytokine interleukin (IL)-17 was significantly reduced in plasma of MMF-treated mice and supernatants from their aortas after T-cell stimulation. The MMF treatment decreased aortic αβ T-cell receptor+ lymphocyte proliferation and cell numbers. Also, aortic contents of CD11b+CD11c+ cells and their proliferation were reduced in MMF-treated Apoe−/− mice. The IL-17 supplementation restored the number of proliferating aortic CD11b+CD11c+ cells in MMF-treated mice. The IL-17 receptor A was highly expressed on circulating monocytes that are macrophage progenitors. Genetic deletion of IL-17 receptor A or IL-17A reduced inflammatory peritoneal CD11b+CD11c+ macrophage accumulation.ConclusionsThe lymphocyte-directed immunosuppressant MMF that curbs IL-17 production was a successful antiatherosclerotic treatment. Our data delineate a role for IL-17 in CD11b+CD11c+ cell accumulation

Heart Rate Responses during Simulated Fire Ground Scenarios among Full-Time Firefighters

International Journal of Exercise Science 13(2): 374-382, 2020. Simulated fire ground scenarios (SFGS) provide firefighters with an opportunity to maintain skills, receive feedback, and optimize performance. Although there is extensive research on heart rate (HR) changes in the firefighter population, few examine the differences between positions. Firefighters are primarily responsible for fire suppression and control (23), officers for emergency operations and organizational management, paramedics for providing on-scene emergency medical care, and drivers are responsible for driving the fire apparatus. Utilizing HR analysis to quantify the physical demands of SFGS among firefighting crews by position. Sixty-seven male (age: 38.97 ± 9.17; ht: 177.99 ± 6.45 cm. wt: 88.83 ± 13.55 kg) firefighters (FF) participated in this investigation. FF crews performed two SFGS involving the suppression and control of a structural fire. Participants were outfitted with heart rate (HR) monitors and average heart rate (HRavg) and maximum heart rate (HRmax) data were collected for each of the two SFGS. Significant differences were observed for Age (P = 0.01), APMHR (P = 0.01), HRmax1(P = 0.04), and HRmax2(P = 0.04) in which firefighters had higher values for Age-predicted maximal heart rate (APMHR), HRmax1, HRmax2compared to the officers. SFGS can be very physically demanding events that may elicit maximal or near maximal HR responses regardless of position. Based on the metabolic demands of these events and the individual firefighter’s capabilities, this information can be used to develop resistance training and conditioning programs that optimize performance at maximal or near maximal heart rates

Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice.

Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes 1 . Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL2-4. Here, to determine the role of OxPL in vivo in the context of atherogenesis, we generated transgenic mice in the Ldlr-/- background that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter. E06-scFv was secreted into the plasma from the liver and macrophages, and achieved sufficient plasma levels to inhibit in vivo macrophage uptake of OxLDL and to prevent OxPL-induced inflammatory signalling. Compared to Ldlr-/- mice, Ldlr -/- E06-scFv mice had 57-28% less atherosclerosis after 4, 7 and even 12 months of 1% high-cholesterol diet. Echocardiographic and histologic evaluation of the aortic valves demonstrated that E06-scFv ameliorated the development of aortic valve gradients and decreased aortic valve calcification. Both cholesterol accumulation and in vivo uptake of OxLDL were decreased in peritoneal macrophages, and both peritoneal and aortic macrophages had a decreased inflammatory phenotype. Serum amyloid A was decreased by 32%, indicating decreased systemic inflammation, and hepatic steatosis and inflammation were also decreased. Finally, the E06-scFv prolonged life as measured over 15 months. Because the E06-scFv lacks the functional effects of an intact antibody other than the ability to bind OxPL and inhibit OxLDL uptake in macrophages, these data support a major proatherogenic role of OxLDL and demonstrate that OxPL are proinflammatory and proatherogenic, which E06 counteracts in vivo. These studies suggest that therapies inactivating OxPL may be beneficial for reducing generalized inflammation, including the progression of atherosclerosis, aortic stenosis and hepatic steatosis

Deficiency of Antigen Presenting Cell Invariant Chain Reduces Atherosclerosis in Mice

August 25, 2010Background: Adaptive immunity and innate immunity play important roles in atherogenesis. Invariant chain (CD74) mediates antigen-presenting cell antigen presentation and T-cell activation. This study tested the hypothesis that CD74-deficient mice have reduced numbers of active T cells and resist atherogenesis. Methods and Results: In low-density lipoprotein receptor–deficient (Ldlr[superscript −/−]) mice, CD74 deficiency (Ldlr[superscript −/−]Cd74[superscript −/−]) significantly reduced atherosclerosis and CD25+-activated T cells in the atheromata. Although Ldlr[superscript −/−]Cd74[superscript −/−] mice had decreased levels of plasma immunoglobulin (Ig) G1, IgG2b, and IgG2c against malondialdehyde-modified LDL (MDA-LDL), presumably as a result of impaired antigen-presenting cell function, Ldlr[superscript −/−]Cd74[superscript −/−] mice showed higher levels of anti–MDA-LDL IgM and IgG3. After immunization with MDA-LDL, Ldlr[superscript −/−]Cd74[superscript −/−] mice had lower levels of all anti–MDA-LDL Ig isotypes compared with Ldlr[superscript −/−] mice. As anticipated, only Ldlr[superscript −/−] splenocytes responded to in vitro stimulation with MDA-LDL, producing Th1/Th2 cytokines. Heat shock protein-65 immunization enhanced atherogenesis in Ldlr[superscript −/−] mice, but Ldlr[superscript −/−] Cd74[superscript −/−] mice remained protected. Compared with Ldlr[superscript −/−] mice, Ldlr[superscript −/−]Cd74[superscript −/−] mice had higher anti–MDA-LDL autoantibody titers, fewer lesion CD25+-activated T cells, impaired release of Th1/Th2 cytokines from antigen-presenting cells after heat shock protein-65 stimulation, and reduced levels of all plasma anti–heat shock protein-65 Ig isotypes. Cytofluorimetry of splenocytes and peritoneal cavity cells of MDA-LDL– or heat shock protein-65–immunized mice showed increased percentages of autoantibody-producing marginal zone B and B-1 cells in Ldlr[superscript −/−]Cd74[superscript −/−] mice compared with Ldlr[superscript −/−] mice. Conclusions: Invariant chain deficiency in Ldlr[superscript −/−] mice reduced atherosclerosis. This finding was associated with an impaired adaptive immune response to disease-specific antigens. Concomitantly, an unexpected increase in the number of innate-like peripheral B-1 cell populations occurred, resulting in increased IgM/IgG3 titers to the oxidation-specific epitopes

Binary systems and their nuclear explosions

Peer ReviewedPreprin

Is Blue Dye Indicated for Sentinel Lymph Node Biopsy in Breast Cancer Patients With a Positive Lymphoscintigram?

The use of isosulfan blue dye in sentinel node biopsy for breast cancer has been questioned because of its risk of allergic reaction. We hypothesized that blue dye could be safely omitted in the subgroup of patients who have evidence of successful sentinel node localization by lymphoscintigraphy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41406/1/10434_2005_Article_6556.pd

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men