αvß3 Integrin as a Link between the Development of Fibrosis and Thyroid Hormones in Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Key players mediating fibrosis are myofibroblasts (MF) that, following transforming growth factor ß (TGFß) exposure, produce a collagen-rich extracellular matrix (ECM) that induces myofibroblast differentiation. Myofibroblasts express αvß3 integrin (a membrane receptor for thyroid hormones) and miRNA-21 that promotes deiodinase-type-3 expression (D3), causing the degradation of triiodothyronine (T3) that attenuates fibrosis. We hypothesized that αvß3 affects the fibrotic processes through its thyroid hormones (THs) binding site. To test this, dermal fibroblasts (DF) were cultured with/without TGFß and removed with a base, leaving only normal/fibrotic ECMs in wells. Then, DF were cultured on the ECMs with/without tetrac (αvß3 ligand, T4 antagonist), and evaluated for pro-fibrotic characteristics, αvß3, miRNA-21, and D3 levels. Blood free-T3 (fT3), miRNA-21 levels, and the modified Rodnan skin score (MRSS) were evaluated in SSc patients. We found that the "fibrotic-ECM" significantly increased the pro-fibrotic characteristics of DF and the levels of miRNA-21, D3, and αvß3, compared to the "normal-ECM." Tetrac significantly inhibited the effects of the "fibrotic-ECM" on the cells. In accordance with tetrac's effect on D3/miRNA-21, a negative correlation was found between the patients' fT3 to miRNA-21 levels, and to the development of pulmonary arterial hypertension (PAH). We conclude that occupying the THs binding site of αvß3 may delay the development of fibrosis.

Needle Embolization: Suspecting Needle Migration in Intravenous Drug Abusers.

BACKGROUND: Thirteen million people inject drugs globally, making intravenous drug abuse a substantial concern worldwide. While intravenous drug users occasionally report the breaking of a needle into the skin or subcutaneous tissue, central needle migration remains a rare but potentially devastating complication. CASE REPORT: A 27-year-old man with a history of intravenous drug abuse presented to the emergency department with the sudden onset of left-sided neck pain, chills, and subjective fever with a history of needle breaking in his left neck 3 weeks earlier while using heroin. A computed tomography scan of his chest revealed a needle lodged in the right ventricle with associated mediastinitis and mass effect on the left brachiocephalic vein, and a left internal jugular thrombus. Broad-spectrum antibiotics were initiated. This patient was managed nonsurgically for several reasons and was discharged on hospital day 12 with oral antibiotics. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Intravenous drug abusers commonly use cervical veins when their peripheral vasculature has become sclerosed. This puts intravenous drug users at increased risk for intravascular embolization. Due to varied symptomology-chest pain, dyspnea, fever, or asymptomatic-and timelines-days, weeks, or months-after reported needle fragmentation, this remains a complex and likely underdiagnosed condition. Case reports describe serious complications of intracardiac needle embolization, such as cardiac perforation, constrictive pericarditis, septic endocarditis, dysrhythmias, granulomas, venous thrombosis, empyema, acute or delayed spontaneous pneumothorax, osteomyelitis, and valvular damage. In this complicated patient population, clinicians should consider needle retention and relocation in patients who report needle breaking or in those who present with chest pain, dyspnea, or fever among other complaints.

MiRNAs in Systemic Sclerosis Patients with Pulmonary Arterial Hypertension: Markers and Effectors.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a major cause of death in systemic sclerosis (SSc). Early detection may improve patient outcomes. METHODS: We searched for circulating miRNAs that would constitute biomarkers in SSc patients with PAH (SSc-PAH). We compared miRNA levels and laboratory parameters while evaluating miRNA levels in white blood cells (WBCs) and myofibroblasts. RESULTS: Our study found: 1) miR-26 and miR-let-7d levels were significantly lower in SSc-PAH (n = 12) versus SSc without PAH (SSc-noPAH) patients (n = 25); 2) a positive correlation between miR-26 and miR-let-7d and complement-C3; 3) GO-annotations of genes that are miR-26/miR-let-7d targets and that are expressed in myofibroblast cells, suggesting that these miRNAs regulate the TGF-ß-pathway; 4) reduced levels of both miRNAs accompanied fibroblast differentiation to myofibroblasts, while macitentan (endothelin receptor-antagonist) increased the levels. WBCs of SSc-noPAH and SSc-PAH patients contained equal amounts of miR-26/miR-let-7d. During the study, an echocardiograph that predicted PAH development, showed increased pulmonary artery pressure in three SSc-noPAH patients. At study initiation, those patients and an additional SSc-noPAH patient, who eventually developed PAH, had miR-let-7d/miR-26 levels similar to those of SSc-PAH patients. This implies that reduced miR-let-7d/miR-26 levels might be an early indication of PAH. CONCLUSIONS: miR-26 and miR-let-7d may be serological markers for SSc-PAH. The results of our study suggest their involvement in myofibroblast differentiation and complement pathway activation, both of which are active in PAH development.