Mechanisms of endothelial cell dysfunction in cystic fibrosis

Although cystic fibrosis (CF) patients exhibit signs of endothelial perturbation, the functions of the cystic fibrosis conductance regulator (CFTR) in vascular endothelial cells (EC) are poorly defined. We sought to uncover biological activities of endothelial CFTR, relevant for vascular homeostasis and inflammation. We examined cells from human umbilical cords (HUVEC) and pulmonary artery isolated from non-cystic fibrosis (PAEC) and CF human lungs (CF-PAEC), under static conditions or physiological shear. CFTR activity, clearly detected in HUVEC and PAEC, was markedly reduced in CF-PAEC. CFTR blockade increased endothelial permeability to macromolecules and reduced trans‑endothelial electrical resistance (TEER). Consistent with this, CF-PAEC displayed lower TEER compared to PAEC. Under shear, CFTR blockade reduced VE-cadherin and p120 catenin membrane expression and triggered the formation of paxillin- and vinculin-enriched membrane blebs that evolved in shrinking of the cell body and disruption of cell-cell contacts. These changes were accompanied by enhanced release of microvesicles, which displayed reduced capability to stimulate proliferation in recipient EC. CFTR blockade also suppressed insulin-induced NO generation by EC, likely by inhibiting eNOS and AKT phosphorylation, whereas it enhanced IL-8 release. Remarkably, phosphodiesterase inhibitors in combination with a β2 adrenergic receptor agonist corrected functional and morphological changes triggered by CFTR dysfunction in EC. Our results uncover regulatory functions of CFTR in EC, suggesting a physiological role of CFTR in the maintenance EC homeostasis and its involvement in pathogenetic aspects of CF. Moreover, our findings open avenues for novel pharmacology to control endothelial dysfunction and its consequences in CF

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Complex fracture-dislocations of the proximal ulna and radius in adults: a comprehensive classification.

Background: Complex fracture-dislocations of the proximal ulna and radius include multiple anatomic lesions, the management of which is known to be demanding. Although several classifications have been proposed, none appear to be exhaustive, and most of them have neither therapeutic nor prognostic value. The purpose of this study was to design a comprehensive classification that may provide a guide for the operative management of these injuries. Materials and methods: The classification is aimed at identifying definite anatomic lesions, called the " main lesions," the presence of which can affect the prognosis and require peculiar treatments. The main lesions include (1) ulnar fracture (including its location with respect to the insertion of collateral ligaments and coronoid fracture), (2) radiohumeral dislocation, (3) proximal radioulnar dislocation, (4) radial fracture, (5) distal radioulnar joint and interosseous membrane lesion, and (6) humeral-ulnar dislocation. Intraobserver and interobserver reliability was assessed in 25 complex fracture-dislocations. Standard radiographs and computed tomography scans were analyzed by 3 independent observers. Results: The main lesions were labeled by an alphanumeric system. Numbers 1 through 6 identified the type of ulnar fracture, and letters A through E indicated the dislocated joint or presence of a radial fracture. The direction of dislocation and the type of radial fracture were identified by Roman numerals, from I to III, placed after the letter. A κ value of 0.873 or greater resulted from intraobserver and interobserver evaluation. Conclusion: We created a comprehensive classification of complex fracture-dislocations of the elbow. The classification appeared to be reproducible and may represent a useful tool for the management of such difficult injuries. © 2011 Journal of Shoulder and Elbow Surgery Board of Trustees

Change in Quality of Life and Cost/Utility Analysis in Open Stage-related Surgical Treatment of Elbow Stiffness

The goals of this study were to examine the improvement in quality of life achieved after open surgical treatment of elbow stiffness and to verify the cost/utility ratio of surgery. Thirtythree patients (22 men and 11 women) underwent surgery. The etiologies of elbow stiffness were posttraumatic conditions (n=26), primary osteoarthritis (n=5), and rheumatoid arthritis (n=2). Surgery included 14 ulnohumeral arthroplasties, 6 ulnohumeral arthroplasties associated with radiocapitellar replacement, 5 ulnohumeral arthroplasties associated with radial head replacement, and 8 total elbow arthroplasties. All patients were evaluated pre- and postoperatively with the Mayo Elbow Performance Score, the Mayo Elbow Performance Index, the modified American Shoulder and Elbow Surgeons score, the Quick Disabilities of the Arm, Shoulder and Hand score, and the Short Form 36 after a mean follow-up of 26 months. Possible variables affecting clinical outcome and quality of life improvement were assessed. The cost/utility ratio was evaluated as diagnosis-related group reimbursement per quality-adjusted life year. Mayo Elbow Performance Scores and modified American Shoulder and Elbow Surgeons scores increased, on average, by 43 and 41 points, respectively (P<.0001). Quick Disabilities of the Arm, Shoulder and Hand scores decreased, on average, by 44 points (P<.0001). The improvement in the SF-36 physical and mental component summary score was 7.6 and 7, respectively (P=.0001 and .0018). The cost/utility ratio ranged between 670 and 817 Euro/quality-adjusted life year. A significant correlation was found between pain score and quality of life improvement. An inverse correlation emerged between pre- and postoperative quality of life score. The current study shows that open surgery significantly improves quality of life and elbow function. Selecting the surgical procedure that most effectively reduces pain appears to be the most relevant variable responsible for quality of life improvement. Surgery shows a satisfactory cost/utility ratio, justifying a health spending increase to reduce the social costs resulting from lingering elbow stiffness

GM1 ganglioside therapy in acute ischemic stroke. Italian Acute Stroke Study--Hemodilution + Drug.

Eleven of 31 clinical centers participating in the Italian Acute Stroke Study--Hemodilution carried out a preliminary study on the effectiveness of ganglioside GM1 in acute stroke; 502 patients were randomized to GM1 (GM1, n = 121), GM1 plus hemodilution (GM1 + H, n = 128), placebo (P, n = 130), or placebo plus hemodilution (P + H, n = 123) groups less than or equal to 12 hours after onset of a hemispheric cerebral infarct. The patients were treated for 15 days and were evaluated on Days 21 and 120 after the onset of stroke. Intention-to-treat analysis failed to show any differences in neurologic deficit, mortality, or neurologic disability among the groups. Efficacy analysis showed a significantly higher degree of neurologic improvement in GM1 group patients compared with patients in the P group during the first 15 days. GM1-treated patients (GM1 and GM1 + H groups) showed a significantly higher degree of neurologic improvement during the first 10 days compared with the placebo-treated patients (P and P + H groups). These differences were no longer statistically significant at Day 120. Our results provide a rationale for the planning of a larger, multicenter trial of GM1 ganglioside in acute stroke

The angiogenic properties of human adipose-derived stem cells (HASCs) are modulated by the High mobility group box protein 1 (HMGB1)

Peripheral arterial disease (PAD), is a major health problem. Many studies have been focused on the possibilities of treatment offered by vascular regeneration. Human adipose-derived stem cells (HASCs), multipotent CD34 + stem cells found in the stromal-vascular fraction of adipose tissues, which are capable to differentiate into multiple mesenchymal cell types. The High mobility group box 1 protein (HMGB1) is a nuclear protein involved in angiogenesis. The aim of the study was to define the role of HMGB1 in cell therapy with HASCs, in an animal model of PAD. We induced unilateral ischemia in mice and we treated them with HASCs, with the specific HMGB1-inihibitor BoxA, with HMGB1 protein, and with the specific VEGF inhibitor sFlt1, alternately or concurrently. We measured the blood flow recovery in all mice. Immunohistochemical and ELISA analyses was performed to evaluate the number of vessels and the VEGF tissue content. None auto-amputation occurred and there have been no rejection reactions to the administration of HASCs. Animals co-treated with HASCs and HMGB1 protein had an improved blood flow recovery, compared to HASCs-treated mice. The post-ischemic angiogenesis was reduced when the HMGB1 pathway was blocked or when the VEGF activity was inhibited, in mice co-treated with HASCs and HMGB1. In conclusion, the HASCs treatment can be used in a mouse model of PAD to induce post-ischemic angiogenesis, modulating angiogenesis by HMGB1. This effect is mediated by VEGF activity. Although further data are needed, these findings shed light on possible new cell treatments for patients with PAD

Quinazolinecarboline alkaloid evodiamine as scaffold for targeting topoisomerase I and sirtuins

This paper reports the synthesis of a series of evodiamine derivatives. We assayed the ability to inhibit cell growth on three human tumour cell lines (H460, MCF-7 and HepG2) and we evaluated the capacity to interfere with the catalytic activity of topoisomerase I both by the relaxation assay and the occurrence of the cleavable complex. Moreover, whose effect on sirtuins 1, 2 and 3 was investigated. Finally, molecular docking analyses were performed in an attempt to rationalize the biological results

Quinazolinecarboline alkaloid evodiamine as scaffold for targeting topoisomerase I and sirtuins

This paper reports the synthesis of a series of evodiamine derivatives. We assayed the ability to inhibit cell growth on three human tumour cell lines (H460, MCF-7 and HepG2) and we evaluated the capacity to interfere with the catalytic activity of topoisomerase I both by the relaxation assay and the occurrence of the cleavable complex. Moreover, whose effect on sirtuins 1, 2 and 3 was investigated. Finally, molecular docking analyses were performed in an attempt to rationalize the biological results