Androgen receptor activation inhibits endothelial cell migration in vitro and angiogenesis in vivo.

Our previous research revealed that androgen receptor (AR) activation reduces endothelial cell proliferation via non-genomic pathways. We hypothesized that AR activation might also affect endothelial cell migration, a critical step in angiogenesis. Our data demonstrates that treatment of human umbilical vein endothelial cells (HUVECs) with AR agonists, metribolone (R1881) or dihydrotestosterone (DHT), results in a dose-dependent reduction in migration, which can be reversed by AR antagonists or AR knockdown. Mechanistically, R1881 inhibits HUVEC migration by suppressing RhoA activity through the cSrc/FAK/paxillin pathway and promoting RhoA degradation via RhoA-p27 complex formation, ultimately resulting in RhoA ubiquitination. Transfection with constitutively active RhoA-V14 rescues the inhibitory effect of R1881 on HUVEC migration. Furthermore, R1881 elevates intracellular vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) levels but reduces VEGF secretion from HUVECs. This reduction is attributed to the formation of VEGF-CTGF complexes in the cytosol induced by R1881. Transfection with RhoA-V14 reduces CTGF levels and VEGF-CTGF complex formation, leading to enhanced VEGF secretion. Pre-treatment with WP631, a CTGF inhibitor, mitigates the R1881-induced reduction in VEGF secretion and HUVECs migration. In vivo assessments using zebrafish angiogenesis and mouse matrigel plug assays validate the anti-angiogenic effects of R1881. These findings provide insight into the molecular mechanisms through which AR activation modulates endothelial cell migration and angiogenesis.

Heat stress-induced platelet dysfunction is associated with loss of fibrinogen and is improved by fibrinogen supplementation.

INTRODUCTION: Heatstroke is a critical heat-related condition characterized by coagulopathy and multiple organ dysfunction. One of the most severe complications of heatstroke is disseminated intravascular coagulation. This condition manifests as excessive clot formation and bleeding that are primarily due to platelet depletion and dysfunction. Fibrinogen plays a crucial role in hemostasis because it links integrin αIIbß3 on adjacent platelets, thereby promoting the platelet activation and aggregation necessary for clot formation. However, reduced fibrinogen levels may impair the formation of the initial platelet plug and increase the risk of bleeding. The current study explored the effect of fibrinogen on platelet dysfunction in a heatstroke model. MATERIALS AND METHODS: Male Wistar rats were subjected to heat stress, and subsequent changes in hemodynamic, biochemical, and coagulation parameters were analyzed. Platelet viability, aggregation, adhesion, spreading and fibrin clot retraction were assessed. RESULTS: The rats with heatstroke exhibited a variety of clinical symptoms, including hypotension, tachycardia, multiple organ dysfunction, and coagulopathy. Platelet viability in the heatstroke group was comparable to that in the healthy control group. However, the heatstroke group exhibited significant reductions in plasma fibrinogen levels and platelet aggregation, adhesion, spreading, and fibrin clot retraction. Notably, fibrinogen supplementation markedly augmented the aggregation responses of platelets in the heatstroke group. The impairment of platelet adhesion, spreading, and fibrin clot retraction in the rats with heatstroke was partially ameliorated by fibrinogen supplementation. CONCLUSIONS: An early use of fibrinogen replacement may serve as a therapeutic intervention to alleviate platelet hyporeactivity and prevent the complications in patients with heatstroke.

Loss of plasma fibrinogen contributes to platelet hyporeactivity in rats with septic shock.

INTRODUCTION: Dysregulated host response to infection causes life-threatening organ dysfunction. Excessive inflammation and abnormal blood coagulation can lead to disseminated intravascular coagulation (DIC) and multiple-organ failure in the late sepsis stages. Platelet function impairment in sepsis contributes to bleeding, secondary infection, and tissue injury. Platelet transfusion is considered in patients with sepsis with DIC and bleeding; however, its benefits are limited and of low quality. Fibrinogen plays a crucial role in platelet function, and establishing a fibrin network binds to activated integrin αIIbß3 and promotes outside-in signaling that amplifies platelet functions. However, the role of fibrinogen in sepsis-induced platelet dysfunction remains unclear. MATERIALS AND METHODS: We evaluated the effects of fibrinogen on platelet hyporeactivity during septic shock in adult male Wistar rats using lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP) surgery. Changes in the hemodynamic, biochemical, and coagulation parameters were examined. Platelet activation and aggregation were measured using whole-blood assay, 96-well plate-based aggregometry, and light-transmission aggregometry. Additionally, platelet adhesion, spreading, and fibrin clot retraction were evaluated. RESULTS: Rats with LPS- and CLP-induced sepsis displayed considerable decreases in plasma fibrinogen levels and platelet aggregation, adhesion, spreading, and clot retraction. The aggregation of platelets obtained from rats with sepsis was markedly augmented by fibrinogen supplementation. Additionally, fibrinogen administration improved platelet adhesion, spreading, and clot retraction in rats with sepsis. CONCLUSIONS: Fibrinogen supplementation could serve as a potential therapeutic intervention for alleviating platelet hyporeactivity in patients with sepsis and bleeding.

A Man with Severe, Left Lower Quadrant Abdominal Pain.

CASE PRESENTATION: An 84-year-old man presented to the emergency department with sudden, left lower quadrant cramping pain. Because critical hypotension was noted, point-of-care ultrasonography (POCUS) was performed immediately. The study revealed a pulsatile flow extravasating from the left common iliac artery into the left psoas muscle with hypoechoic para-aortic fluid collection. DISCUSSION: Common iliac artery rupture is rare and has nonspecific clinical presentations. A quick disposition can be made with a combination of clinical manifestations and POCUS results.

Antimicrobial peptide cathelicidin LL-37 preserves intestinal barrier and organ function in rats with heat stroke.

Global warming increases the incidence of heat stroke (HS) and HS causes the reduction of visceral blood flow during hyperthermia, leading to intestinal barrier disruption, microbial translocation, systemic inflammation and multiple organ failure. Cathelicidin LL-37 exhibits antimicrobial activities, helps innate immunity within the gut to maintain intestinal homeostasis, and augments intestinal wound healing and barrier function. Thus, we evaluated the effects and possible mechanisms of cathelicidin LL-37 on HS. Wistar rats were placed in a heating-chamber of 42 ̊C to induce HS. Changes in rectal temperature, hemodynamic parameters, and survival rate were measured during the experimental period. Blood samples and ilea were collected to analyze the effects of LL-37 on systemic inflammation, multiple organ dysfunction, and intestinal injury. Furthermore, LS174T and HT-29 cells were used to assess the underlying mechanisms. Our data showed cathelicidin LL-37 ameliorated the damage of intestinal cells induced by HS. Intestinal injury, systemic inflammation, and nitrosative stress (high nitric oxide level) caused by continuous hyperthermia were attenuated in HS rats treated with cathelicidin LL-37, and hence, improved multiple organ dysfunction, coagulopathy, and survival rate. These beneficial effects of cathelicidin LL-37 were attributed to the protection of intestinal goblet cells (by increasing transepithelial resistance, mucin-2 and Nrf2 expression) and the improvement of intestinal barrier function (less cyclooxygenase-2 expression and FITC-dextran translocation). Interestingly, high cathelicidin expression in the ileal samples of inflammatory bowel disease patients was associated with better clinical outcome. These results suggest that cathelicidin LL-37 could prevent heat stress-induced intestinal damage and heat-related illnesses.

Extracorporeal Life Support for Severely Burned Patients with Concurrent Inhalation Injury and Acute Respiratory Distress Syndrome: Experience from a Military Medical Burn Center.

BACKGROUND: Both inhalation injury and acute respiratory distress syndrome (ARDS) are risk factors that predict mortality in severely burned patients. Extracorporeal life support (ECLS) is widely used to rescue these patients; however, its efficacy and safety in this critical population have not been well defined. We report our experience of using ECLS for the treatment of severely burned patients with concurrent inhalation injury and ARDS. METHODS: This was a retrospective analysis of 14 patients collected from a single medical burn center from 2012 to 2019. All patients suffered from major burns with inhalation injury and ARDS, and were treated with ECLS. RESULTS: The median total body surface area of deep dermal or full thickness burns was 94.5%, ranging 47.7-99.0 %. The median revised Baux score was 122.0, ranging 90.0-155.0. All patients developed ARDS with a median partial pressure of arterial oxygen to a fraction of inspired oxygen ratio of 61.5, ranging 49.0-99.0. Indications for ECLS included sustained hypoxemia and unstable hemodynamics. The median interval for initiating ECLS was 2.5 days, ranging 1.0-156.0 days. The median duration of ECLS was 2.9 days, ranging 0.3-16.7 days. The overall survival to discharge was 42.8%. Causes of death included sepsis and multiple organ failure. ECLS-related complications included cannulation bleeding, catheter-related infection, and hemolysis. The incidence of risk factors reported in literature were higher in non-survivors, including Baux>120, albumin < 3.0 g/dL, and lactate > 8 mmol/L. CONCLUSIONS: For severely burned patients with concurrent inhalation injury and ARDS, ECLS could be a salvage treatment to improve sustained hypoxemia. However, the efficacy of hemodynamic support was limited. Identifying definite ECLS indications and rigorous patient selection would contribute to better clinical outcomes.

Cerebral Oximetry-Monitored Nitroglycerin Infusion and Tissue Perfusion during Rewarming of Cardiopulmonary Bypass in Cardiac Surgery: A Prospective Randomized Trial.

BACKGROUND: Nitroglycerin facilitates microcirculation and oxygen delivery through vasodilation. The purpose of this study was to clarify the effects of nitroglycerin-induced vasodilation and potential hypotension on tissue perfusion under cerebral oximetry monitoring during rewarming in cardiopulmonary bypass. METHODS: Elective cardiac surgical patients were randomly assigned to either a nitroglycerin group (n = 32) with an intravenous infusion of 1-5 mcg/kg/min or a control group (n = 31) with 0-0.1 mcg/kg/min infusion, since the initiation of rewarming. Perioperative arterial blood gas data were collected in addition to hemodynamic variables, cerebral oximetry values, urine output, and postoperative outcomes. RESULTS: Nearly one-fifth (6/32) of patients in the nitroglycerin group experienced transient (≤5 min) profound hypotension (mean arterial blood pressure ≤40 mmHg) after the initiation of infusion. There were no significant differences between groups in terms of perioperative levels of cerebral oximetry, cardiac index, plasma glucose, lactate, bicarbonate, base excess, or post-bypass activated coagulation time. In the nitroglycerin group, urine output was nonsignificantly higher during cardiopulmonary bypass (p = 0.099) and within 8 h after surgery (p = 0.157). Perioperative transfused blood products, postoperative inotropic doses, extubation time, and intensive care unit stay were comparable for the two groups. CONCLUSIONS: Initiation of intravenous nitroglycerin infusion (at 1-5 mcg/kg/min) during rewarming in hypothermic cardiopulmonary bypass resulted in transient profound hypotension in one-fifth of patients and did not improve perioperative cerebral oxygenation, tissue perfusion, and coagulation in cardiac surgery.

Risk of Aortic Aneurysm and Dissection in Patients with Tuberculosis: A Nationwide Population-Based Cohort Study.

Tuberculosis (TB) can cause chronic inflammation. The occurrence of aortic aneurysm (AA) and aortic dissection (AD) may be associated with chronic inflammatory disease, but whether TB increases the risk of AA and AD remains to be determined. This study aimed to investigate the association between TB and the development of AA and AD. We conducted a population-based cohort study using data obtained from the Taiwan National Health Insurance Database. We selected 31,220 individuals with TB and 62,440 individuals without TB by matching the cohorts according to age, sex, and index year at a ratio of 1:2. Cox regression analysis revealed that the TB cohort had a 1.711-fold higher risk of AA and AD than the non-TB cohort after adjustment for sex, age, socioeconomic status, and comorbidities (adjusted hazard ratio = 1.711; 95% confidence interval = 1.098-2.666). Patients with pulmonary, extrapulmonary, and miliary TB had a 1.561-, 1.892-, and 8.334-fold higher risk of AA and AD, respectively. Furthermore, patients with TB at <6 months, 6-12 months, and 1-5 years of follow-up had a 6.896-, 2.671-, and 2.371-fold risk of AA and AD, respectively. Physicians should consider the subsequent development of AA and AD while treating patients with TB.

Cardiac calcium dysregulation in mice with chronic kidney disease.

Cardiovascular complications are leading causes of morbidity and mortality in patients with chronic kidney disease (CKD). CKD significantly affects cardiac calcium (Ca2+ ) regulation, but the underlying mechanisms are not clear. The present study investigated the modulation of Ca2+ homeostasis in CKD mice. Echocardiography revealed impaired fractional shortening (FS) and stroke volume (SV) in CKD mice. Electrocardiography showed that CKD mice exhibited longer QT interval, corrected QT (QTc) prolongation, faster spontaneous activities, shorter action potential duration (APD) and increased ventricle arrhythmogenesis, and ranolazine (10 µmol/L) blocked these effects. Conventional microelectrodes and the Fluo-3 fluorometric ratio techniques indicated that CKD ventricular cardiomyocytes exhibited higher Ca2+ decay time, Ca2+ sparks, and Ca2+ leakage but lower [Ca2+ ]i transients and sarcoplasmic reticulum Ca2+ contents. The CaMKII inhibitor KN93 and ranolazine (RAN; late sodium current inhibitor) reversed the deterioration in Ca2+ handling. Western blots revealed that CKD ventricles exhibited higher phosphorylated RyR2 and CaMKII and reduced phosphorylated SERCA2 and SERCA2 and the ratio of PLB-Thr17 to PLB. In conclusions, the modulation of CaMKII, PLB and late Na+ current in CKD significantly altered cardiac Ca2+ regulation and electrophysiological characteristics. These findings may apply on future clinical therapies.

Blood Mixing Upregulates Platelet Membrane-Bound CD40 Ligand Expression In Vitro Independent of Abo Compatibility.

Platelets play a central role in the inflammation response via CD40 ligand (CD40L) expression, which may lead to transfusion reactions. The precise role of platelet CD40L-mediated inflammation in transfusion reactions is unclear. Therefore, we assessed the effects of in vitro blood mixing on platelet CD40L expression. In addition, we examined the effect of ABO compatibility on CD40L expression. Donor-packed red blood cells were acquired from a blood bank, and recipient blood was obtained from patients undergoing cardiac surgery and prepared as washed platelets. Donor blood was mixed with suspended, washed recipient platelets to obtain a final mixing ratio of 1%, 5%, or 10% (vol/vol). The blood mixtures were divided into three groups: group M, cross-matched blood-type mixing (n = 20); group S, ABO type-specific uncross-matched blood (n = 20); and group I, ABO incompatibility (not ABO type-specific blood and not process cross-matched) mixing (n = 20). The blood mixtures were used to detect platelet membrane-bound CD40L expression by flow cytometry. Blood mixing resulted in an increase in CD40L expression in group M (P < 0.001), group S (P < 0.001), and group I (P < 0.001). CD40L expression after blood mixing potentially led to a transfusion reaction in each of the groups. There were no differences in CD40L expression among the three groups (P = 0.988) correlated with ABO compatibility or incompatibility. This indicates that the reactions between red blood cell surface antigens and plasma antibodies do not play a role in the induction of CD40L expression.

Impact of Blood Mixing and ABO Compatibility on Platelet-Leukocyte Aggregations and Platelet P-Selectin Expression: An in Vitro Study.

Effects of blood transfusions on platelet- and leukocyte-related inflammation are unclear. We simulated transfusion using in vitro blood mixing to evaluate platelet-leukocyte aggregations (PLA) and platelet P-selectin expression, and the mechanism of PLA. Donor packed red blood cells (pRBCs) were obtained from a blood bank. Recipient whole blood samples were obtained from patients undergoing cardiac surgery. Blood sample mixtures were divided into four groups: group M, cross-matched blood type mixing; group O, donor type O with other blood type mixing (A, B, or AB); group S, ABO type-specific uncross-matched blood mixing; and group I, ABO incompatibility mixing. Donor pRBCs were added to recipient blood to reach 1%, 5%, and 10% (vol/vol) concentrations. Blood sample mixtures were analyzed to determine the PLA; P-selectin expression; and leukocyte CD11a, CD11b, and CD18 subunits of integrin expression. Analysis of variance tests were used to analyze differences. PLA significantly increased only in groups O and I (P = 0.003 and P < 0.001). Subpopulations of leukocytes significantly increased in all groups. There were no significant differences among the four groups (P = 0.578) in PLA increase. Although there was no significant effect on P-selectin expression (P = 1.000) and leukocyte CD11a and CD18 expression (P = 0.999, P = 0.422) within and between the groups, there was an increase in CD11b expression (P = 0.018). Blood mixing can increase PLA, especially in platelet-neutrophil and platelet-monocyte aggregations, possibly through nonhemolytic reactions. The CD11b integrin with CD18 may play a role in the formation of PLA.

A Thrombomodulin Gene Polymorphism (C1418T) Is Associated with Early Outcomes in Patients Undergoing Coronary Artery Bypass Graft Surgery with a Conventional Cardiopulmonary Bypass during Hospitalization.

Background: Thrombomodulin (TM) is a type of cell membrane-bound anticoagulant protein cofactor in the thrombin-mediated activation of protein C. Previous evidence has shown an association between TM polymorphisms and systemic inflammation. Conventional cardiopulmonary bypass (CPB), beating-heart CPB, and off-pump techniques have been widely used in cardiac surgery. However, these techniques may also cause systemic inflammatory responses in the patients. Whether TM polymorphisms are associated with systemic inflammation after cardiac surgery is still unclear. Methods: We analyzed the TM gene C1418T polymorphisms in 347 patients who underwent coronary artery bridge graft (CABG) surgery using allele-specific primers in a PCR assay. The clinical data during the hospital stay were collected and tested for correlations with the TM gene C1418T polymorphisms. Results: We separated the patients into two groups based on their TM C1418T genotype (CC genotype group and CT/TT genotype group). The days spent in an intensive care unit (ICU) and the incidence of fever in the ICU were significantly lower in the beating-heart CPB and off-pump groups than in the conventional CPB group. Additionally, the TM gene C1418T polymorphisms did not affect the early outcomes in patients in the beating-heart CPB and off-pump groups. Interestingly, in the conventional CPB group, patients with the CC genotype had a lower rate of fever, shorter duration of fever, and delay of ICU when compared with the CT/TT genotype. Conclusion: Surgeons may use a patient's TM gene C1418T polymorphism to predict the strength of systemic inflammation and speculate on early outcomes during hospitalization before conventional CPB is performed.

A penetrating atherosclerotic ulcer rupture in the ascending aorta with hemopericardium: a case report.

BACKGROUND: Acute aortic syndrome, including classic aortic dissection, intramural aortic hematoma, and penetrating atherosclerotic ulcer (PAU), is a term used to describe a group of conditions with similar clinical symptoms, but with different pathophysiological mechanisms. PAU is a lesion that penetrates the internal elastic lamina through the media. It is usually located in the descending aorta and rarely observed in the ascending aorta. CASE PRESENTATION: A 76-year-old man with a history of essential hypertension was brought to the emergency department (ED) because of a sudden-onset chest pain at rest. He had not been taking his medication as ordered. His vital signs in the ED were a blood pressure of 82/60 mmHg, heart rate of 158 beats per min, respiratory rate of 22 breaths per min, and a body temperature of 37.2 °C. An electrocardiogram did not show an ST segment elevation, and cardiac enzymes were within normal limits. No widening mediastinum was found on chest radiography, but a large pericardial effusion with an impending cardiac tamponade was revealed on echocardiography. The diagnosis of PAU rupture in the ascending aorta with hemopericardium was made with chest computed tomography. An emergent sternotomy and ascending aorta reconstruction were performed. A ruptured ulcerative plaque through the intima to the adventitia without flap dissection in the ascending aorta was confirmed. The patient was discharged 18 days after the operation. CONCLUSIONS: Although PAU in the ascending aorta is uncommon, it is commonly lethal when it ruptures. With the current advances in endovascular techniques and devices, endovascular repair of PAU in the ascending aorta is currently recommended only for high-risk patients unsuitable for open repair. However, we anticipate that endovascular repair may become feasible in patients with PAU in the ascending aorta in the future.

Cancer Incidence among Heart, Kidney, and Liver Transplant Recipients in Taiwan.

Population-based evidence of the relative risk of cancer among heart, kidney, and liver transplant recipients from Asia is lacking. The Taiwan National Health Insurance Research Database was used to conduct a population-based cohort study of transplant recipients (n = 5396), comprising 801 heart, 2847 kidney, and 1748 liver transplant recipients between 2001 and 2012. Standardized incidence ratios and Cox regression models were used. Compared with the general population, the risk of cancer increased 3.8-fold after heart transplantation, 4.1-fold after kidney transplantation and 4.6-fold after liver transplantation. Cancer occurrence showed considerable variation according to transplanted organs. The most common cancers in all transplant patients were cancers of the head and neck, liver, bladder, and kidney and non-Hodgkin lymphoma. Male recipients had an increased risk of cancers of the head and neck and liver, and female kidney recipients had a significant risk of bladder and kidney cancer. The adjusted hazard ratio for any cancer in all recipients was higher in liver transplant recipients compared with that in heart transplant recipients (hazard ratio = 1.5, P = .04). Cancer occurrence varied considerably and posttransplant cancer screening should be performed routinely according to transplanted organ and sex.

Assessment of the Risk Factors and Outcomes for Postoperative Atrial Fibrillation Patients Undergoing Isolated Coronary Artery Bypass Grafting.

BACKGROUND: Atrial fibrillation is the most common complication of cardiac surgery and is associated with significant morbidity and mortality. Recognizing patients at high risk for developing postoperative atrial fibrillation (POAF) may help identify those who could benefit from strategies to prevent POAF. This study was conducted to delineate outcomes and to assess risk factors for POAF among Taiwanese patients undergoing coronary artery bypass grafting (CABG). METHODS: From January 2009 until February 2012, this prospective study included 266 consecutive patients admitted to our hospital with coronary artery disease. All patients underwent isolated CABG. Patients with preoperative permanent atrial fibrillation and concomitant surgery were excluded. Multiple risk factors associated with the incidence of POAF were collected and evaluated. RESULTS: POAF occurred in 126 of 226 patients (47.37%). Univariate analysis revealed that significant risk factors for the condition were age, gender, diabetes, dyslipidemia, smoking, impaired renal function, impaired cardiac function, and increased serum electrolytes. Multivariate analysis showed dyslipidemia [hazard ratio (HR): 0.418; 95% confidence interval (Cl): 0.190-0.915, p = 0.029], impaired renal function as indicated by an estimated glomerular filtration rate < 60 mL/min/1.73 m(2) (HR: 3.174; 95% CI: 1.432-7.037, p = 0.004), and serum sodium (HR: 1.112; 95% Cl: 1.047-1.182, p = 0.001) prior to cardiopulmonary bypass as significant. Moreover, POAF was associated with lower 30-day, 1- and 3-year cumulative survival rates and higher early postoperative complications. CONCLUSIONS: Patients with isolated CABG who were administered ß-blockers, angiotensin converting enzyme inhibitor/angiotensin receptor blockers treatment, and lipid therapy before CABG were associated with reduced POAF, while those with impaired renal function and higher serum sodium before CABG predisposed POAF in a Taiwanese population. KEY WORDS: Atrial fibrillation (AF); Coronary artery bypass grafting (CABG); Coronary artery disease (CAD); Postoperative atrial fibrillation (POAF).

Monotherapy with anti-CD20 monoclonal antibody in a heart transplant recipient with sick sinus syndrome and posttransplantation lymphoproliferative disorder: a case report.

Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation, with an incidence of 0.8% to 20% in heart transplant (HTx) recipients, and standard treatment may be too toxic in some cases. Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies and has been demonstrated effective in combination with chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone). Cardiotoxicity with CHOP remains a major concern for treating HTx recipients with PTLD, however. We present a case of an HTx recipient with sick sinus syndrome and PTLD who was successfully treated with rituximab alone, avoiding the cardiotoxicity of CHOP. The cardiotoxicity induced by CHOP should be kept in mind in HTx recipients with PTLD, especially when there is an existing heart problem in such recipients. Monotherapy with rituximab can be considered a safe choice.