Ambient fine particulate matter induces apoptosis of endothelial progenitor cells through reactive oxygen species formation.

BACKGROUND/AIMS: Bone marrow (BM)-derived endothelial progenitor cells (EPCs) play a critical role in angiogenesis and vascular repair. Some environmental insults, like fine particulate matter (PM) exposure, significantly impair cardiovascular functions. However, the mechanisms for PM-induced adverse effects on cardiovascular system remain largely unknown. The present research was to study the detrimental effects of PM on EPCs and explore the potential mechanisms. METHODS: PM was intranasal-distilled into male C57BL/6 mice for one month. Flow cytometry was used to measure the number of EPCs, apoptosis level of circulating EPCs and intracellular reactive oxygen species (ROS) formation. Serum TNF-α and IL-1ß were measured using ELISA. To determine the role of PM-induced ROS in EPC apoptosis, PM was co-administrated with the antioxidant N-acetylcysteine (NAC) in wild type mice or used in a triple transgenic mouse line (TG) with overexpression of antioxidant enzyme network (AON) composed of superoxide dismutase (SOD)1, SOD3, and glutathione peroxidase (Gpx-1) with decreased in vivo ROS production. RESULTS: PM treatment significantly decreased circulating EPC population, promoted apoptosis of EPCs in association with increased ROS production and serum TNF-α and IL-1ß levels, which could be effectively reversed by either NAC treatment or overexpression of AON. CONCLUSION: PM exposure significantly decreased circulating EPCs population due to increased apoptosis via ROS formation in mice.

Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

Effect of five genetic variants associated with lung function on the risk of chronic obstructive lung disease, and their joint effects on lung function.

RATIONALE: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied. OBJECTIVES: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP. METHODS: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD. MEASUREMENTS AND MAIN RESULTS: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10-12 risk alleles was associated with a reduction in FEV1 (ß = -72.21 ml, P = 3.90 × 10(-4)) and FEV1/FVC (ß = -1.53%, P = 6.35 × 10(-6)), and with COPD (odds ratio = 1.63, P = 1.46 × 10(-5)). CONCLUSIONS: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.

Dermatologic Manifestation of Acro-Ischemia Associated With COVID-19.

Background: The common dermatologic manifestations seen in patients with coronavirus disease 2019 (COVID-19) include morbilliform, pernio-like, urticarial, macular erythematous, vesicular, and papulosquamous disorders, as well as retiform purpura. Although cases of acro-ischemia have been demonstrated, they are not well studied or reported. Case Report: A 73-year-old male was admitted for acute hypoxic respiratory failure secondary to COVID-19 infection. During the patient's hospital course, his oxygen requirement progressively increased, and he developed painful, violaceous purpura on his right lower extremity digits. The patient was treated with therapeutic doses of enoxaparin and nitroglycerin ointment in the hospital and apixaban on discharge. The patient was lost to follow-up. Conclusion: The multiorgan dysfunction associated with COVID-19 includes dermatologic manifestations. This case illustrates that acro-ischemia can resolve with guideline-based medical treatment.

Uncommon Cause of Internal Mammary Artery Pseudoaneurysm.

Background: Internal mammary artery pseudoaneurysms most commonly develop from thoracic penetrating trauma or procedures. However, other important etiologies should not be overlooked. Case Report: A 27-year-old female presented with antiphospholipid antibody syndrome, thrombotic microangiopathy, end-stage renal disease on hemodialysis, and epilepsy. On admission, the patient had pulseless electrical activity and hypertensive emergency. After the patient was successfully resuscitated, she developed status epilepticus. Laboratory workup on admission revealed a subtherapeutic international normalized ratio, elevated C-reactive protein and sedimentation rate, and acute anemia. Imaging showed a right-sided subdural hematoma with a midline shift and likely internal mammary artery pseudoaneurysm. Angiography demonstrated aneurysmal dilation, segmental narrowing, and a string of beads appearance. Because of our patient's demographics, string of beads appearance on diagnostic angiography, history of renal disease, and negative hepatitis serology, fibromuscular dysplasia was considered the etiology of the internal mammary artery pseudoaneurysm. The family opted for 2 burr holes and a subdural drain but declined further diagnostic and therapeutic interventions because of anoxic brain injury and poor prognosis. Conclusion: In this patient, the etiology of the internal mammary artery pseudoaneurysm was attributed to fibromuscular dysplasia. Although this patient's family chose comfort measures, treatment methods are available for internal mammary artery pseudoaneurysms.

Effect of Immunosuppressive Diseases and Rituximab Infusions on Allowing COVID-19 Infection to Relapse.

INTRODUCTION: Relapsing COVID-19 infections have been reported, but their etiology and severity are still unknown. In addition, there have been no cases in the literature that associate relapsing infection with immunosuppression, either from a disease course or medications. CASE PRESENTATION: This case series illustrates two patients who developed a relapsed infection, likely from recent rituximab infusions. In addition, both cases depicted a severe form of infection than the initial one. Laboratory investigations revealed these patients were unable to produce COVID-19 antibodies, even though one of the patients received convalescent plasma. CONCLUSION: Clinicians should be aware of the possibility of relapsing COVID-19, especially in immunosuppressed patients. Because rituximab induces B-cell depletion, it can also decrease the effectiveness of the COVID-19 vaccine. Therefore, these patients should receive the vaccine before their scheduled rituximab infusion.

Oxidized low-density lipoprotein alters endothelial progenitor cell populations.

Oxidized low-density lipoprotein (ox-LDL) is critical to atherosclerosis in hyperlipidemia. Bone marrow (BM)-derived endothelial progenitor cells (EPCs) are important to preventing atherosclerosis, and significantly decreased in hyperlipidemia. This study was to demonstrate ox-LDL and hyperlipidemia could exhibit similar effect on EPC population and the role of reactive oxygen species (ROS). ROS production in BM and blood was significantly increased in male C57BL/6 mice with intravenous ox-LDL treatment, and in hyperlipidemic LDL receptor knockout mice with 4-month high-fat diet. ROS formation was effectively blocked with overexpression of antioxidant enzymes or N-acetylcysteine treatment. In hyperlipidemic and ox-LDL-treated mice, c-Kit(+)/CD31(+) cell number in BM and blood, and Sca-1(+)/Flk-1(+) cell number in blood, not in BM, were significantly decreased, which were not affected by inhibiting ROS production, while blood CD34(+)/Flk-1(+) cell number was significantly increased that was prevented with reduced ROS formation. However, blood CD34(+)/CD133(+) cell number increased in ox-LDL-treated mice, while decreased in hyperlipidemic mice. These data suggested that ox-LDL produced significant changes in BM and blood EPC populations similar (but not identical) to chronic hyperlipidemia with predominantly ROS-independent mechanism(s).

Meta-analysis and imputation refines the association of 15q25 with smoking quantity.

Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.