Jun Neng Roan

Transplantation of endothelial progenitor cells improves pulmonary endothelial function and gas exchange in rabbits with endotoxin-induced acute lung injury.

BACKGROUND:Circulating endothelial progenitor cells (EPCs) have been therapeutically applied to aid vascular repair and myocardial regeneration. The number of circulating EPCs also provides invaluable outcome prediction for fatal diseases such as acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). However, evidence for the therapeutic potential of EPCs in subjects with ALI/ADRS is limited. METHODS:Circulating EPCs were obtained from rabbits using Ficoll centrifugation. One week after culturing EPCs in endothelial growth medium-2, ALI was induced in rabbits by intratracheal instillation of lipopolysaccharide (500 &mgr;g/kg). Autologous EPCs or saline were administered IV after induction of ALI and animals were killed 2 days later. Pulmonary artery endothelial function and gas exchange were determined. Degrees of lung injury were assessed by alveolocapillary permeability, lung hemoglobin content, and myeloperoxidase activity. RESULTS:In comparison with controls, PO2 in arterial blood was significantly elevated and pulmonary artery endothelium-dependent relaxation response was restored in rabbits receiving EPC transplantation. Lung water, Evans blue, and bronchoalveolar lavage protein contents were significantly reduced in the EPC transplanted group, indicating a better preservation of the alveolocapillary membrane. Transplantation of EPCs decreased the lung hemoglobin level. Furthermore, expressions of CD11b and myeloperoxidase activity were also suppressed after administration of EPCs. CONCLUSIONS:Transplantation of EPCs restored pulmonary endothelial function, preserved integrity of the alveolocapillary barrier and suppressed the lung inflammatory response, thereby improving pulmonary gas exchange in rabbits with intratracheal lipopolysaccharide-induced ALI. Transplantation of EPCs can be a novel cell-based, endothelium-targeted therapeutic strategy for prevention and treatment of ALI/ARDS.

Incidence of and Mortality from Type I Diabetes in Taiwan From 1999 through 2010: A Nationwide Cohort Study

Objective To evaluate the secular trend in incidence of and mortality from Type 1 diabetes mellitus (T1DM) in Taiwan, 1999–2010. Methods All 7,225 incident cases of T1DM were retrospectively retrieved from Taiwans National Health Insurance Research Database from 1999 to 2010. Trend of bi-annual age- and sex-specific incidence rates of T1DM was calculated and tested with Poisson regression model. Standardized mortality ratios (SMRs) were calculated, using age-, sex-, and calendar years-specific mortality rates of the general population as the reference, to estimate the relative mortality risk of T1DM. Results The number of male and female T1DM was 3,471 (48%) and 3,754 (52%), respectively. The annual number of incident T1DM increased from 543 in 1999 to 737 in 2010. The overall bi-annual incidence rate rose from 1999–00 to 2003–04 and mildly declined thereafter rose to 2009–10, with an insignificant trend (P = 0.489) over the study period. Regardless of gender, the higher age-specific incidence rate was noted in the younger groups (<30 years) and highest at <15 years. The incidence rates in younger groups were constantly higher in female population than in male one. The SMR from all causes was significantly increased at 3.00 (95% Confidence Interval (CI) 2.83–3.16) in patients with T1DM. The sex-specific SMR was 2.66 (95% CI 2.46–2.85) and 3.58 (95% CI 3.28–3.87) for male and female patients, respectively. For both sexes, the age-specific SMR peaked at 15–29 years. Conclusions Among T1DM patients in Taiwan, there were significant increasing trends in males and female aged <15 years. We also noted a significantly increased overall and sex-specific SMR from all causes in patients with TIDM which suggests a need for improvements in treatment and care of patients with T1DM.

Molecular mimicry between streptococcal pyrogenic exotoxin B and endothelial cells

Molecular mimicry between group A streptococcus and host antigens has important roles in the development of post-streptococcal sequelae, including glomerulonephritis and rheumatic heart disease (RHD). The etiology of RHD involves host cross-reactivity with M proteins and carbohydrate antigens. In this study, we show that anti-streptococcal pyrogenic exotoxin B (SPE B) antibodies exhibited characteristics of autoantibodies, which cross-react with endothelial cells. Immunoglobulin G (IgG) deposition and complement activation were observed in the heart valve of SPE B-immunized mice. In addition, apoptosis in the heart valve was detected in SPE B-immunized mice. An anti-SPE B monoclonal antibody (mAb) 10G showed cross-reactivity with human microvascular endothelial (HMEC-1) cells and mouse valve endothelial cells. Passive immunization with mAb 10G also caused IgG deposition, complement activation, and apoptotic cell death in the mouse heart valve. We conducted peptide array and ELISA using synthetic peptides to identify the SPE B antigenic epitope recognized by mAb 10G. Results showed that the major epitope of mAb 10G is localized to amino-acid residues 296–310 of SPE B (P7–8). The cross-reactivity of mAb 10G with endothelial cells was inhibited using P7–8 peptides for competition. These results suggest that anti-SPE B antibodies cross-react with endothelial cells, and that a dominant epitope is located within the amino-acid residues 296–310 of SPE B. Moreover, we found that mAb 10G can also bind to N-acetyl-β-D-glucosamine (GlcNAc) conjugated with bovine serum albumin (BSA), but not to BSA or M1 protein. Competition assay showed that the binding activity of mAb 10G with GlcNAc-BSA and P7–8 of SPE B was inhibited by pretreatment with GlcNAc-BSA or P7–8 peptides. Therefore, our results suggest that conformational molecular mimicry may exist between SPE B and GlcNAc.

Rosuvastatin improves vascular function of arteriovenous fistula in a diabetic rat model.

OBJECTIVE This study investigates the pathogenesis of arteriovenous (AV) fistula failure in patients with diabetes mellitus (DM) and tests the vascular protective effect of rosuvastatin on the fistulous communication of diabetic rats. METHODS DM was induced in rats by a single injection of streptozotocin. One week later, a fistula was created in the descending aorta and the adjacent inferior vena cava (aortocaval [AC] fistula). Rats were then randomly assigned to receive placebo or rosuvastatin (15 mg/kg/d) in chow for 2 weeks. Blood flow in the aortic segments of the fistula was measured. Circulating CD34+/KDR+ endothelial progenitor cells (EPCs) were determined 2 weeks after creation of the AC fistulas using flow cytometry. Vascular function of the AC fistulas was assessed by isometric force testing. The expression of proinflammatory genes and generation of superoxide anions in the fistulas were examined. RESULTS The number of EPCs was reduced in diabetic rats, and rosuvastatin significantly increased the number of circulating EPCs. Reduced blood flow and impaired endothelium-dependent relaxation in the AC fistula of animals with diabetes was significantly potentiated after treatment with rosuvastatin. Rosuvastatin also attenuated the expression of inducible nitric oxide synthase and nicotinamide adenine dinucleotide phosphate oxidase and generation of superoxide anions in the fistula tissues isolated from diabetic rats. CONCLUSIONS We provide the first evidence demonstrating that rosuvastatin improves blood flow and endothelial function of AC fistulas in rats with DM by attenuating the activity of proinflammatory genes and generation of superoxide anions in the remodeled vasculature. CLINICAL RELEVANCE Arteriovenous (AV) fistula is the most common vascular access for hemodialysis in patients with end-stage renal disease. Studies have shown that blood flow in the AV fistula is significantly reduced in patients with diabetes and the period for maturation of an AV fistula is longer in these patients. The underlying mechanisms of AV fistula failure in diabetes are still poorly understood and there are limited therapeutic approaches that can increase the lifespan of these fistulas. The present study demonstrates that oral administration rosuvastatin improves blood flow and endothelial function of AC fistulas in rats with diabetes, which results from attenuating the activity of proinflammatory genes in the remodeled vasculature, thereby reducing the generation of tissue superoxide anions. Our results may thus enhance our ability to prevent and manage vascular access failure in patients with diabetes with chronic renal disease.

Bilateral Persistent Sciatic Arteries Complicated with Acute Left Lower Limb Ischemia

Persistent sciatic artery (PSA) is a rare congenital malformation. In the early embryonic stage, the sciatic artery is the major blood supply for the lower limb bulb and is later replaced by the iliofemoral artery as the limb develops. Its failure to regress, sometimes associated with femoral arterial hypoplasia, and therefore becoming the dominant inflow to the lower extremity is called PSA. This anomaly is often associated with a higher rate of aneurysm formation or thromboembolic complications causing lower extremity ischemia. Here, we describe a 79-year-old male patient who presented with acute left lower extremity ischemia. He was treated initially with conventional embolectomy through inguinal and popliteal incisions. The bilateral PSA with thrombosed aneurysms was not identified at first on computed tomographic angiography. It was later diagnosed intraoperatively due to the discontinuity of the superficial femoral artery and popliteal artery found with embolectomy catheter, and was managed successfully with ePTFE graft bypass. Careful interpretation of the imaging study may be helpful in preoperative diagnosis.

Effect of false lumen partial thrombosis on repaired acute type A aortic dissection

OBJECTIVE Studies on the partial thrombosis of a false lumen after repairing a type A acute aortic dissection (TAAAD) have reported conflicting results. We investigated the effects of a partially thrombosed false lumen on the segmental growth rates, distal aortic reoperations, and long-term survival. METHODS The postoperative computed tomography scans of 67 patients were retrospectively reviewed. A false lumen was independently defined at 3 segments of the descending thoracic aorta (DTA) on the last follow-up computed tomography scan: the proximal segment near the aortic arch, the distal segment near the diaphragm, and the middle segment. RESULTS The segmental aortic growth rate of completely thrombosed, completely patent, and partially thrombosed false lumens was -0.10±0.31, 0.09±0.22, and 0.35±0.60 mm/mo at the proximal DTA (P=.001), -0.04±0.18, 0.12±0.19, and 0.28±0.28 mm/mo at the middle DTA (P<.001), and -0.02±0.13, 0.07±0.07, and 0.16±0.14 mm/mo at the distal DTA (P<.001), respectively. The corresponding freedom from reoperation rates for the proximal DTA at 10 years were 100%, 88%, and 62% (P=.013). The overall 10-year survival rate was 89% and was not significantly different among the study groups. CONCLUSIONS Partial thrombosis at each segment of a residual false lumen after TAAAD repair correlated with a faster regional aortic growth rate and predicted a greater reoperation rate but did not affect long-term overall survival.

Pulmonary nodules caused by Schizophyllum commune after cardiac transplantation

The incidence of pulmonary nodules after cardiac transplantation is not uncommon, and prompt diagnostic procedures are necessary to minimize disease-related morbidity and mortality. We report a 56-year-old woman who was found to have bilateral pulmonary nodules four months after cardiac transplantation. The microorganism was identified with a molecular diagnostic method as Schizophyllum commune, which had not been reported in English literature as a pathogen inducing pulmonary nodules after transplantation. She remained asymptomatic during the therapeutic period and the pulmonary nodules resolved six months later.

Xenografted human amniotic fluid-derived stem cell as a cell source in therapeutic angiogenesis

BACKGROUND Amniotic fluid-derived stem cells (AFSCs) are pluripotent with high renewal capacity and are not tumorigenic. We tested whether AFSCs can function as a cell source for therapeutic angiogenesis in a mouse hindlimb ischemia model. METHODS Using a defined culture medium for endothelial lineage cells (ECs), we differentiated human AFSCs into AFSC-derived ECs (AFSC-ECs) in vitro, as evidenced by expression of EC markers, and capillary-like network formation on Matrigel. We assessed the in vivo therapeutic angiogenesis efficacy of AFSC-ECs in an athymic nude mouse model of hindlimb ischemia. One day after high ligation of the external iliac artery in athymic nude mice, AFSC-ECs were intramuscularly injected into ischemic limbs. RESULTS The AFSC-ECs demonstrated endothelial cell characteristics in vitro. Four weeks later, AFSC-ECs transplantation significantly increased limb salvage (85%), compared to AFSCs (56%), human umbilical vein endothelial cells (HUVECs; 25%), or medium (0%). Laser Doppler perfusion analysis revealed that the ischemic/normal limb blood perfusion ratio significantly improved in the AFSC-EC group. AFSC-EC transplantation significantly increased capillary and arteriole densities as compared to AFSCs, HUVECs, and medium. Transplanted AFSC-ECs were incorporated into vessels in the ischemic region, as confirmed by immunofluorescent staining for human smooth muscle 22α or von Willebrand factor. Matrix metalloproteinase (MMP)-3 and MMP-9 expressions were significantly higher in AFSC-ECs. MMP-9 might activate angiogenesis by regulation of vascular endothelial growth factor. CONCLUSIONS Our study indicated that AFSC-EC transplantation improved limb salvage and blood perfusion by promoting neovascularization. Therefore, AFSC-ECs possess the potential for therapeutic angiogenesis.

Pleiotropic vascular protective effects of statins in perioperative medicine

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statins) is one of the most commonly prescribed agents for controlling hyperlipidemia. Apart from their lipid-lowering property, statins are well known for their pleiotropic effects, such as improvement of vascular endothelial dysfunction, attenuation of inflammatory responses, stabilization of atherosclerotic plaques, inhibition of vascular smooth muscle proliferation, and modulation of procoagulant activity and platelet function. The vasculo-protective effect of statins is mainly mediated by inhibition of the mevalonate pathway and oxidized low-density lipoprotein generation, thereby enhancing the biosynthesis of endothelium-derived nitric oxide. Accumulating clinical evidence strongly suggests that administration of statins reduces overall mortality, the development myocardial infarction and atrial fibrillation, and length of hospital stay after a major cardiac/noncardiac surgery. This review updates the clinical pharmacology and therapeutic applications of statins during major operations, and highlights the anesthesia considerations for perioperative statin therapy.

Spinal cord injury enhances arterial expression and reactivity of α1-adrenergic receptors—mechanistic investigation into autonomic dysreflexia

BACKGROUND CONTEXT Autonomic dysreflexia (AD) usually presents with a significant increase in blood pressure, and uncontrollable autonomic response to stimuli below the level of spinal cord injury (SCI). PURPOSE This study analyzed the vasomotor function and molecular changes in the peripheral arteries below the lesion of SCI to characterize the mechanism of autonomic dysreflexia. STUDY DESIGN This was a randomized experimental study in rats. METHODS Contusive SCI was induced using a force-calibrated weight-drop device at the T10 level in anesthetized rats. Two weeks after severe SCI, blood flow in the femoral arteries was measured, and the vasomotor function and expression of α1-adrenergic receptors were analyzed. RESULTS Blood flow in the femoral artery was significantly reduced in rats with SCI (8.0±2 vs. 17.5±4 mL/min, SCI vs. control, respectively; p=.016). The contraction responses of femoral artery segments to cumulative addition of α1-adrenergic agonist phenylephrine were significantly enhanced in rats with SCI. Expression of α1-adrenergic receptor was upregulated in the medial layer of femoral artery vascular homogenates of these rats. CONCLUSION Our study provides evidence demonstrating that prolonged denervation below the lesion level following SCI results in a compensatory increased expression of α1-adrenergic receptors in the arterial smooth muscle layer, thereby enhancing the responsiveness to α1-adrenergic agonist and potentiating the development of AD.