Hartleybyers8177
porting method that provides clinically relevant information about treatment toxicity by incorporating two longitudinal adverse event metrics to the traditional maximum grade approach. Future research should establish clinical benchmarks for metrics included in this adverse event reporting method.Chronic low-grade inflammation contributes to the development of several diseases, including cardiovascular disease. Adequate strategies to target inflammation in cardiovascular disease are in their infancy and remain an avenue of great interest. The purinergic receptor P2X7 is a ubiquitously expressed receptor that predominately mediates inflammation and cellular death. P2X7 is a ligand-gated cation channel that is activated in response to high concentrations of extracellular ATP, triggering the assembly and activation of the NLRP3 (nuclear oligomerization domain like receptor family pyrin domain containing 3) inflammasome and subsequent release of proinflammatory cytokines IL (interleukin)-1β and IL-18. Increased P2X7 activation and IL-1β and IL-18 concentrations have been implicated in the development of many cardiovascular conditions including hypertension, atherosclerosis, ischemia/reperfusion injury, and heart failure. P2X7 receptor KO (knockout) mice exhibit a significant attenuation of the inflammatory response, which corresponds with reduced disease severity. P2X7 antagonism blunts blood pressure elevation in hypertension and progression of atherosclerosis in animal models. IL-1β and IL-18 inhibition has shown efficacy in clinical trials reducing major adverse cardiac events, including myocardial infarction, and heart failure. With several P2X7 antagonists available with proven safety margins, P2X7 antagonism could represent an untapped potential for therapeutic intervention in cardiovascular disorders.
LCAT (lecithin cholesterol acyltransferase) deficiency results in severe low HDL (high-density lipoprotein). Although whether LCAT is pro- or antiatherosclerosis was in debate in mouse studies, our previous study clearly shows that LCAT deficiency (LCAT
) in hamster accelerates atherosclerotic development on high-fat diet. However, unlike in hypercholesterolemia and hypertriglyceridemia, whether LCAT deficiency could lead to spontaneous atherosclerosis has not been studied yet in animal models. We, therefore, sought to investigate the atherosclerosis in LCAT
hamsters on standard laboratory diet and explore the potential underlying mechanisms. Approach and Results Young (<8 months) and aged (>16 months) male and female wild-type and LCAT
hamsters on standard laboratory diet were used. Compared with age- and sex-matched wild-type hamsters, LCAT
hamsters showed a complete loss of plasma HDL and an increase in triglyceride by 2- to 8-fold at different stages of age. In aged LCAT
hamsters, the lesion areas at the aortic roots were ≈40×10
μm
in males and 18×10
μm
in females, respectively, which were consistent with the en face plaques observed in male (1.2%) and (1.5%) female groups, respectively. The results of plasma malondialdehyde measurement showed that malondialdehyde concentrations were markedly elevated to 54.4 μmol/L in males and 30 μmol/L in females, which are significantly associated with the atherosclerotic lesions.
Our study demonstrates the development of spontaneous atherosclerotic lesions in aged male and female LCAT
hamsters with higher plasma oxidative lipid levels independent of plasma total cholesterol levels, further confirming the antiatherosclerotic role of LCAT.
Our study demonstrates the development of spontaneous atherosclerotic lesions in aged male and female LCAT-/- hamsters with higher plasma oxidative lipid levels independent of plasma total cholesterol levels, further confirming the antiatherosclerotic role of LCAT.
In patients with peripheral artery disease, blockages in arterioles <1 mm cannot be treated surgically, and there are currently few effective medicines. Studies have shown that inflammation in ischemic tissue is related to injury recovery and angiogenesis, but insufficient attention has been paid to this area. Studies have suggested that HMGB1 (high mobility group protein 1), which is released by ischemic tissue, promotes angiogenesis, but the mechanism is not entirely clear. In this study, we tested the internalization of HMGB1 in endothelial cells and investigated a novel proangiogenic pathway. Approach and Results Using green fluorescent protein-tagged HMGB1 to stimulate endothelial cells, we demonstrated HMGB1 internalization via dynamin and RAGE (receptor for advanced glycation end products)-dependent signaling. Using a fluorescence assay, we detected internalized protein fusion to lysosomes, followed by activation of CatB (cathepsin B) and CatL (cathepsin L). The latter promoted the release of VEGFon and opens a new door to understand the relationship between inflammation and angiogenesis in ischemic diseases.
Compare the postprandial fatty acid metabolism of isotopically labeled stearate (U-
C180) and oleate (U-
C181). Approach and Results In conjunction with a randomized-controlled crossover trial, 6 hypercholesterolemic postmenopausal women (≥50 years; body mass index 25.6±3.0 kg/m
; LDL [low-density lipoprotein]-cholesterol ≥110 mg/dL) consumed isocaloric diets enriched in 180 or 181 (10%-15% E) for 5 weeks each. On day 1 of week 5, following a 12-hour fast, participants receive their experimental diet divided into 13 hourly meals beginning at 8 am. U-
C180 or U-
C181 was incorporated into the 100 pm meal (1.0 mg/kg body weight). Serial blood and breath samples were collected over 12 hours and fasting samples at 24 and 48 hours. Plasma and lipid subfraction fatty acid profiles were assessed by gas chromatography-flame ionization detector, isotope-enrichment by liquid chromatography time-of-flight mass spectrometry, and fatty acid oxidation rate (expired
CO
) by isotope ratio mass spectrometry. Both dir plasma area under the curve because of lower clearance and oxidation rates, underwent both a direct and a multistage conversion to 181, and was preferentially incorporated into cholesteryl esters and triglycerides.
Pulmonary arterial hypertension is a disease of proliferative vascular occlusion that is strongly linked to mutations in
-the gene encoding the BMPR-II (BMP [bone morphogenetic protein] type II receptor). The endothelial-selective BMPR-II ligand, BMP9, reverses disease in animal models of pulmonary arterial hypertension and suppresses the proliferation of healthy endothelial cells. However, the impact of
loss on the antiproliferative actions of BMP9 has yet to be assessed. Approach and Results BMP9 suppressed proliferation in blood outgrowth endothelial cells from healthy control subjects but increased proliferation in blood outgrowth endothelial cells from pulmonary arterial hypertension patients with
mutations. This shift from growth suppression to enhanced proliferation was recapitulated in control human pulmonary artery endothelial cells following siRNA-mediated
silencing, as well as in mouse pulmonary endothelial cells isolated from endothelial-conditional
knockout mice (
). BMP9-indggests the need for focused patient selection in clinical trials.
To describe the management of a 5-year old female with a painless, mobile cheek mass.
A retrospective chart review of presentation, imaging, pathology and management.
Magnetic resonance imaging showed a heterogenous mass with solid and lipomatous components. The mass was a lipoblastoma on histopathology and was excised completely with no evidence of recurrence.
The diagnosis and management of a cheek mass in a child is challenging. Imaging is important but not diagnostic. Surgical excision is the primary management of a lipoblastoma.
The diagnosis and management of a cheek mass in a child is challenging. Imaging is important but not diagnostic. Surgical excision is the primary management of a lipoblastoma.
Lyme disease, caused by Borrelia burgdorferi, is a spirochetal disease. Lyme disease-related ocular findings may also provide important clues. Ocular involvement is most commonly seen as uveitis, chorioretinitis, conjunctivitis, keratitis, episcleritis, papillitis, panuveitis, ischemic optic neuropathy, papilledema, and retinal vasculitis.
A 27-year-old male patient was admitted with a history of fatigue, malaise, and sudden loss of vision in his left eye for 3 days. The best visual acuity was found 20/20 in the right eye and 20/400 in the left eye. Fluorescein fundus angiography showed no pathological findings in the right eye; but hyperfluorescence that was compatible with choroiditis foci was seen in the left eye. Optical coherence tomography (OCT) showed choroidal thickening in the left eye compared to the right eye. Lyme IgM antibody was found to be positive, explaining choroiditis etiology, while IgG values were found to be negative. Western blot verification test was positive. The patient was treated with 2 × 100 mg doxycycline (21 days) with a diagnosis of Lyme disease, prednol 1 mg/kg/day (10 days) for choroiditis. Omeprazole tablets were given 1 × 1 during the period of cortisone intake. On the third day of treatment, visual acuity increased to 20/200 and continued to increase until reaching 20/20 in the second week.
Lyme disease is rare, but must be kept in mind when investigating the etiology of chorioretinitis and retinal vasculitis. The patient reported here is, to our knowledge, the second case reported in literature that shows atypical clinic for Lyme disease with unilateral chorioretinitis without Erythema chronicum migrans (ECM).
Lyme disease is rare, but must be kept in mind when investigating the etiology of chorioretinitis and retinal vasculitis. The patient reported here is, to our knowledge, the second case reported in literature that shows atypical clinic for Lyme disease with unilateral chorioretinitis without Erythema chronicum migrans (ECM).Although COVID-19 is predominantly a respiratory disease, it is known to affect multiple organ systems. In this article, we highlight the impact of SARS-CoV-2 (the coronavirus causing COVID-19) on the central nervous system as there is an urgent need to understand the longitudinal impacts of COVID-19 on brain function, behaviour and cognition. Furthermore, we address the possibility of intergenerational impacts of COVID-19 on the brain, potentially via both maternal and paternal routes. Selleck Ionomycin Evidence from preclinical models of earlier coronaviruses has shown direct viral infiltration across the blood-brain barrier and indirect secondary effects due to other organ pathology and inflammation. In the most severely ill patients with pneumonia requiring intensive care, there appears to be additional severe inflammatory response and associated thrombophilia with widespread organ damage, including the brain. Maternal viral (and other) infections during pregnancy can affect the offspring, with greater incidence of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy. Available reports suggest possible vertical transmission of SARS-CoV-2, although longitudinal cohort studies of such offspring are needed. The impact of paternal infection on the offspring and intergenerational effects should also be considered. Research targeted at mechanistic insights into all aspects of pathogenesis, including neurological, neuropsychiatric and haematological systems alongside pulmonary pathology, will be critical in informing future therapeutic approaches. With these future challenges in mind, we highlight the importance of national and international collaborative efforts to gather the required clinical and preclinical data to effectively address the possible long-term sequelae of this global pandemic, particularly with respect to the brain and mental health.
