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INTRODUCTION This meta-analysis evaluated 14 studies which compared clinical and functional outcomes after different cardiac resynchronization therapy (CRT) modalities. MATERIAL AND METHODS Relevant studies were selected from the Medline, PubMed, Cochrane, and Google Scholar databases until June 27th, 2016. We analyzed and compared the clinical outcomes (peak O2 consumption and LVEF) and functional outcomes (6-min walk distance and quality of life (SF-36)) of HF patients who received different CRT modalities with outcomes in patients who received conventional univentricular therapy. RESULTS There was no significant difference in post-treatment 6-min walking distance between the biventricular (BiV) and left/right univentricular (LUV/RUV) groups (standardized difference in means = 0.049, 95% CI: -0.119 to 0.217, p = 0.566), or between the BiV and triventricular (TriV) groups (standardized difference in means = 0.035, 95% CI: -0.270 to 0.340, p = 0.822). Peak O2 consumption was comparable between BiV and LUV/RUV groups (standardized difference in means = 0.306, 95% CI: -0.002 to 0.614, p = 0.052). Patients in the TriV group had a significant improvement in LVEF compared to the BiV group (standardized difference in means = 0.647, 95% CI: 0.313 to 0.982, p < 0.001). CONCLUSIONS TriV CRT is an attractive alternative to univentricular or BiV pacing for heart failure patients. It is necessary to conduct further large randomized trials to validate our present data.

Background: Both morbidity and mortality of hypertension are high. Whether pneumonia and lung cancer affect the mortality of men with hypertension is not well studied. The aim of the study was to study the association between pneumonia/lung cancer and the mortality among male individuals with hypertension. Methods: A cross-sectional study was performed on hypertensive men, who admitted into our hospital and lived in eligible downtown areas prior to admission. Variety statistical analyses were performed, including logistic regression to assess the association between pneumonia/lung cancer and the mortality. Results: 14354 patients were enrolled. Mean age of them was 68.9±12.4 year old (y) and dead ones was 75.9±9.5y. The hospitalized mortality was 5.9%, which was increased with age: the mortality of group ≦49y, 50-59y, 60-69y, 70-79y, 80-89y and ≧90y was 0.7%, 2.2%, 2.9%, 7.1%, 11.1% and 16.6% respectively. The increased mortality was significantly positively correlated with the prevalence of pneumonia in different age, P Conclusions: The study provides evidence that pneumonia and lung cancer significantly affect mortality of hypertensive men in downtown areas, bringing alert that in order to reduce the mortality of hypertension in mordent life, theses lung diseases should be prevented and treated intensively. Key Words: hypertension, hospitalized mortality, pneumonia, lung cancer

The adipocyte-derived hormone leptin is associated with hypertension. The involvement of cyclooxygenase-2 (COX-2) and its downstream vasomotor products prostaglandin (PG) and thromboxane (TX)A2 in the mechanisms of action of leptin have remained elusive. The aim of the present study was to investigate the effects of leptin on the expression of COX-2 by rat aortic endothelial cells (RAECs) and the concentration of its products, represented by 6-keto PGF1α and TXB2, in the culture media. RAECs were isolated, cultured and identified by immunofluorescence staining. The RAECs were incubated with different concentrations of leptin (10−10, 10−9 and 10−8 M) for various durations (36 or 48 h). COX-2 mRNA and protein expression in the cells was detected by reverse-transcription quantitative PCR and western blot analysis, respectively. The vasodilator 6-keto PGF1α and the vasoconstrictor TXB2 were detected in the supernatant by ELISA. The cultured cells displayed specific factor VIII expression in the cytoplasm. Compared with the PBS-treated control group, leptin significantly increased the expression of COX-2 mRNA and protein in a time- and dose-dependent manner (P0.05). In conclusion, leptin significantly increased the expression of inflammatory marker COX-2 and its downstream product 6-keto PGF1α, while also decreasing the TXB2/6-keto PGF1α ratio in vitro. These observations suggested that COX-2 may have an important role in the effects of leptin on inflammation, such as the low-inflammatory disease hypertension. However, selective COX-2 inhibitors may increase the risk of hypertension due to inhibiting 6-keto PGF1α, the vasodilator product of COX-2.

Background There are few reports describing arterial plaque formation induced by hypertension alone. The aim of this study was to establish a canine model of chronic hypertension and investigate carotid plaque development. Methods Ten beagles were studied; 5 underwent bilateral renal artery constriction via a novel vascular clip, and 5 sham-operated animals served as controls. Systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid values, the intima-media thickness, and the carotid artery plaque score were investigated during 1 year after placement of the clips. Results The mean SBP and DBP over time were significantly greater in the constriction group ( P < 0.001 for SBP, P < 0.01 for DBP). There were no significant differences in blood lipid levels or other biochemical parameters. Carotid plaques were demonstrated at 4 months postoperation in the constriction group; and in the constriction group, intima-media thickness became significantly greater at 4 months ( P < 0.05), and plaque scores became significantly higher at 8 months ( P = 0.034) after clip placement. Carotid stenosis was proved by digital subtraction angiography 1 year after clip placement, and histological examination revealed that the plaques were mainly comprised of smooth muscle cells, proteoglycans, and collagen fibers, but few macrophages and little lipid. Conclusions Carotid proliferative plaques were developed in a canine model of chronic hypertension induced by a novel vascular clip. The plaques were mainly comprised of smooth muscle cells, proteoglycans, and collagen fibers.

Autoimmune cholangitis, immunoglobulin G4-associated cholangitis (IAC), is a part of multiorgan IgG4-related systemic disease, which was recognized as a new clinicopathological entity in recent years. IAC is defined as a biliary stricture that responds to steroid therapy, frequently is associated with other fibrosing conditions, especially autoimmune pancreatitis and is characterized by elevation of IgG4 in serum and infiltration of IgG4 positive plasma cells in bile ducts. Since IAC shares a number of clinical, biochemical, and imaging features with cholangiocarcinoma (CCA), it is often misdiagnosed as CCA, and unnecessary surgery was performed. In this compact review, we clarify the disease of IAC, summarize criteria for diagnosis of IAC, discuss the role of CA 19-9, and provide key information to differentiate diagnosis of IAC from CCA. IAC should be highly suspected in unexplained biliary stricture associated with increased IgG4 (in serum especially in bile) and other organ involvement (kidney, retroperitoneum etc. especially pancreas in which there are abundant IgG4-positive plasmocytes infiltration). Correct diagnosis of IAC will avoid unnecessary surgery because IAC responds well to steroid therapy. In a word, increased IgG4 levels, other organ involvement and response to steroids are keys to distinguishing IAC from CCA.

Aims Leptin is an adipocyte-derived hormone that has been shown to exert both beneficial metabolic effects and potentially adverse vascular effects in preclinical studies. The primary aim of this study was to determine the effects of leptin receptor signaling pathways on atherosclerosis in the setting of obesity and hyperlipidemia. Methods and results Mice were generated with deficiency of apolipoprotein E ( ApoE −/− ) and either wild-type leptin receptor expression ( Lepr +/+ , ApoE −/− ), mutant leptin receptor expression defective in all leptin receptor signaling pathways ( Lepr db/db , ApoE −/− ), or mutant leptin receptor expression with selective deficiency of leptin receptor-STAT3 signaling ( Lepr s/s , ApoE −/− ). At 27 weeks of age (including 7 weeks on a Western diet), Lepr db/db , ApoE −/− developed severe obesity, hypercholesterolemia, and increased atherosclerosis compared to Lepr +/+ , ApoE −/− mice. Despite similar obesity and hyperlipidemia to Lepr db/db , ApoE −/− mice, Lepr s/s , ApoE −/− developed less atherosclerosis than Lepr db/db , ApoE −/− mice. Adipose tissue macrophage content, monocyte chemoattractant protein-1 and fatty-acid-binding protein 4 levels were also reduced in Lepr s/s , ApoE −/− mice compared to Lepr db/db , ApoE −/− mice. Conclusions In a mouse model of obesity and hyperlipidemia, leptin receptor-mediated STAT3-independent signaling pathways confer protection against atherosclerosis. These differences occur independently of leptin effects on energy balance.

Background— Leptin is an adipocyte-derived hormone critical for energy homeostasis and implicated in vascular disease processes. The relevant cellular leptin receptor pools and signaling pathways involved in leptin-related vascular phenotypes in vivo are unclear. Methods and Results— Arterial injury was induced in wild-type ( wt ), leptin-deficient ( lep ob/ob ), and leptin receptor–deficient ( lepr db/db ) mice. Compared with wt mice, lep ob/ob and lepr db/db mice were protected from the development of neointima. Bone marrow transplantation experiments between wt and lepr db/db mice indicated that the vascular protection in lepr db/db mice was not attributable to lack of leptin receptor expression on bone marrow–derived elements. To investigate the role of the lepr- mediated signal transducer and activator of transcription 3 (STAT3) signaling pathway in the response to vascular injury, lepr s/s mice homozygous for a leptin receptor defective in STAT3 signaling underwent femoral arterial injury. Despite similar obesity and blood pressure levels, the neointimal area in lepr s/s mice was significantly increased compared with lepr db/db mice. Conclusions— The molecular mechanism by which the leptin receptor mediates neointima formation and vascular smooth muscle cell proliferation is largely independent of the STAT3-dependent signaling pathways involved in energy balance.

We hypothesized that sustained delivery of vascular endothelial growth factor (VEGF) using a polymer [85:15 poly(lactide-co-glycolide) (PLG)] would enhance angiogenesis and improve perfusion of ischemic tissue.C57BL/6J mice (n = 20/group) underwent unilateral hind limb ischemia surgery and were randomized to groups of no scaffold implantation (0-Implant), unloaded scaffold implantation (Empty-PLG), or implantation of scaffolds incorporating 3 microg of VEGF165 (PLG-VEGF). Endpoints included laser Doppler perfusion imaging (LDPI, ischemic/nonischemic limb, %), local vessel counts, immunohistochemistry for CD31, and alpha-smooth muscle actin. In vitro release kinetics of VEGF from PLG was also measured.PLG-VEGF resulted in improved lower extremity perfusion vs. controls as measured by LDPI% at 7, 14, 21, and 28 days (p0.05). PLG-VEGF was associated with significantly greater percentage of vessels staining for CD31 and alpha-smooth muscle actin compared to the Empty-PLG or 0-Implant (p0.05 for both).The PLG-VEGF scaffolds resulted in sustained VEGF delivery, improved tissue perfusion, greater capillary density, and more mature vasculature compared to the controls. The sustained-release PLG polymer vehicle is a promising delivery system for therapeutic neovascularization applications.

Fabry disease is an X-linked lysosomal storage disorder due to deficiency of α-galactosidase A (GLA) activity that results in the widespread accumulation of neutral glycosphingolipids. Renal failure, neuropathy, premature myocardial infarction, and stroke occur in patients with this condition primarily due to deposition of glycosphingolipids in vascular endothelial cells. The clinical consequences of Fabry disease suggest that vascular thrombosis may play a prominent role in the pathogenesis of this disease; however, the vasculopathy associated with Fabry disease has not been extensively studied. To determine if mice genetically deficient in Gla are susceptible to vascular thrombosis, a photochemical carotid injury model was used to induce occlusive thrombosis. In this model, Gla − /0 mice displayed a progressive age-dependent shortening of the time to occlusive thrombosis after vascular injury that correlated with progressive accumulation of globotriasylceramide (Gb3) in the arterial wall. Bone marrow transplantation from Gla − /0 to Gla+/0 mice and from Gla+/0 to Gla − /0 mice did not change the thrombotic phenotype of the host. These studies reveal a potent vascular prothrombotic phenotype in Gla -deficient mice and suggest that antithrombotic therapies as well as therapies designed to reduce the vascular accumulation of Gb3 may have beneficial effects on thrombotic complications in patients with Fabry disease. E-mail: deitzman@umich.edu

SummaryIncreased fibrin deposition following inflammatory lung injury has been proposed to facilitate the development of pulmonary fibrosis. Therefore, factors predisposing to thrombosis may affect the fibrotic response to injury. Activated protein C (aPC) resistance due to the factor V Leiden mutation (FνL) is a common genetic risk factor for vascular thrombosis. To examine the relationship between aPC resistance and the development of pulmonary fibrosis, lung inflammation was induced by bleomycin in mice carrying the FvL mutation. Three weeks following the instillation of 0.0375 U of bleomycin, the lungs of mice homozygous and heterozygous for FvL contained significantly more hydroxyproline (35 ± 4 and 36 ± 7 ug hydroxyproline/ mg total protein, respectively) than wild-type mice (26 ± 6 ug/mg protein, p

Background— Factor V Leiden (FVL) is a common genetic risk factor for vascular thrombosis in humans. Fabry disease, an X-linked lysosomal storage disorder attributable to α-galactosidase A (GLA) deficiency, is associated with premature vascular events that may be thrombotic in nature. Methods and Results— To examine a potential interaction between FvL and Gla deficiency in vivo, we analyzed tissue fibrin deposition in mice carrying combined mutations in FvL and Gla . Gla deficiency markedly increased tissue fibrin deposition in mice carrying the FvL mutation (0.33±0.03%; n=7) compared with FvL mutation (0.14±0.02%; n=10; P Conclusions— These observations demonstrate a synergistic interaction between Gla deficiency and FvL toward tissue fibrin deposition in mice. Concomitant mutations in these genes may increase the penetrance of vascular thrombotic events in humans.

Autoimmune cholangitis, immunoglobulin G4-associated cholangitis (IAC), is a part of multiorgan IgG4-related systemic disease, which was recognized as a new clinicopathological entity in recent years. IAC is defined as a biliary stricture that responds to steroid therapy, frequently is associated with other fibrosing conditions, especially autoimmune pancreatitis and is characterized by elevation of IgG4 in serum and infiltration of IgG4 positive plasma cells in bile ducts. Since IAC shares a number of clinical, biochemical, and imaging features with cholangiocarcinoma (CCA), it is often misdiagnosed as CCA, and unnecessary surgery was performed. In this compact review, we clarify the disease of IAC, summarize criteria for diagnosis of IAC, discuss the role of CA 19-9, and provide key information to differentiate diagnosis of IAC from CCA. IAC should be highly suspected in unexplained biliary stricture associated with increased IgG4 (in serum especially in bile) and other organ involvement (kidney, retroperitoneum etc. especially pancreas in which there are abundant IgG4-positive plasmocytes infiltration). Correct diagnosis of IAC will avoid unnecessary surgery because IAC responds well to steroid therapy. In a word, increased IgG4 levels, other organ involvement and response to steroids are keys to distinguishing IAC from CCA.

OBJECTIVE The aim of the study was to investigate the computed tomographic (CT) and pathological findings of dermatofibrosarcoma protuberans to improve the awareness and understanding of the tumors from aspect of CT images. METHODS The CT findings of 16 cases (17 tumors) with dermatofibrosarcoma protuberans confirmed by pathological findings were retrospectively selected. Fourteen cases were primary dermatofibrosarcoma protuberans, 2 cases were recurrent tumors. Thirteen patients had CT plain and enhanced scans, 1 patient had direct enhanced CT scan, 2 patients had only unenhanced scan. Images of the tumors were analyzed and compared with pathological results. RESULTS Of the 16 cases (17 tumors total), 9 cases were on the trunk, 7 cases were on the head and the neck; 15 cases appeared as solitary isohypodense, ovoid, or round mass at the cutaneous and subcutaneous tissue, 1 case demonstrated 2 isodense masses on unenhanced CT images. The mean diameter of tumors was 4.0 cm, and the depth was 1.7 cm. The margin was well defined (n = 15 [88.2%]) or ill defined (n = 2 [11.8%]). Fifteen tumors revealed moderate or marked homogeneous (n = 12 [80%], smaller lesion, diameter

Objective To analyze the imaging findings of ovarian thecoma and to better understand the tumor features based on aspect of computed tomography and magnetic resonance images. Methods Nineteen ovarian thecomas confirmed by histopathologic examination were analyzed retrospectively. Image characteristics were analyzed and compared with those of the pathologic features. Results The mean diameter of tumors was 9.6 cm. The masses were well defined (n = 17) or ill defined (n = 2) and appeared solid with cystic areas (n = 11), entirely solid (n = 4), or cystic with solid components (n = 4). On T2-weighted/spectral adiabatic inversion recovery (T2WI/SPAIR) images, 12 cases appeared isointense or slightly hyperintense. Of the 12 cases, 8 had patchy hypersignal areas. On computed tomographic images, 7 cases showed hypodensity or isodensity. All tumors exhibited mild enhancement. On pathologic examination, the tumor was composed of spindle cells with a moderate amount of cytoplasm. Conclusion Imaging manifestations of ovarian thecoma are various and nonspecific. However, a large, well-defined mildly enhanced solid mass with cystic areas and especially isointense or slightly hyperintense on T2WI/SPAIR sequence in pelvic cavity may suggest the diagnosis of ovarian thecoma.

We analyze the computed tomography (CT) findings of a peripheral primitive neuroectodermal tumor (pPNET) arising in the abdominopelvic cavity and to improve understanding of the CT images of the tumor. Twelve cases of pPNET confirmed by histopathology were analyzed retrospectively. Image characteristics of CT scanning were analyzed and compared with the pathology of the tumors. There were 8 males and 4 females with mean age of 34.5 years. Unenhanced CT images showed large heterogeneous and ill-defined or well-defined masses with multiple patchy hypodense areas. The average diameter was 9.8 cm (range 4.0–17.2 cm). Contrast-enhanced CT images showed variable heterogeneous contrast enhancement with multiple non-enhancement areas. 3 cases revealed metastasis and 4 cases invaded into adjacent organs. Pathology showed areas of degeneration and necrosis in all tumors. Cluster of differentiation 99 and neurone specific enolase were detected positive in 11 and 12 cases, respectively. In conclusion, pPNET in the abdominopelvic cavity likely affects young adults with a slight male preponderance and tend to be large and aggressive. Although CT findings are nonspecific and variable, a large ill-defined or well-defined heterogeneous mass with multiple patchy hypodense areas reflecting their cystic degeneration and necrosis on pathology examination may suggest the diagnosis of pPNET.

Leptin is an adipocyte-derived hormone that has been shown to exert both beneficial metabolic effects and potentially adverse vascular effects in preclinical studies. To determine the effects of leptin receptor signaling pathways on atherosclerosis in the setting of obesity and hyperlipidemia, mice were generated with deficiency of apolipoprotein E ( ApoE −/− ) and either wild-type leptin receptor expression ( Lepr +/+ ,ApoE −/− ), mutant leptin receptor expression defective in all leptin receptor signaling pathways ( Lepr db/db ,ApoE −/− ), or mutant leptin receptor with selective deficiency of leptin receptor-STAT3 signaling ( Lepr s/s ,ApoE −/− ). At 27 weeks of age, which included 7 weeks on western chow, Lepr db/db ,ApoE −/− developed increased weight (61.9 ±3.5 vs 28±2.5, pLepr +/+ ,ApoE −/− mice. In contrast, despite similar obesity and hyperlipidemia to Lepr db/db ,ApoE −/− mice, the atherosclerosis in Lepr s/s ,ApoE −/− was less than Lepr db/db ,ApoE −/− mice (7.3±1 vs 13.9±1.7, p=0.003) and not significantly greater than Lepr +/+ ,ApoE −/− mice (7.3±1 vs 4.3±0.9, p=0.06 ). Hepatic steatosis and adipose inflammation were also reduced in Lepr s/s ,ApoE −/− mice compared to Lepr db/db ,ApoE −/− mice. In a mouse model of obesity and hyperlipidemia, leptin receptor signaling confers protection against hepatic steatosis, fat inflammation, and atherosclerosis. These effects are independent of leptin effects on energy balance. This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).

Background— Fat inflammation may play an important role in comorbidities associated with obesity such as atherosclerosis. Methods and Results— To first establish feasibility of fat transplantation, epididymal fat pads were harvested from wild-type C57BL/6J mice and transplanted into leptin-deficient ( Lep ob/ob ) mice. Fat transplantation produced physiological leptin levels and prevented obesity and infertility in Lep ob/ob mice. However, the transplanted fat depots were associated with chronically increased macrophage infiltration with characteristics identical to those observed in fat harvested from obese animals. The inflammation in transplanted adipose depots was regulated by the same factors that have been implicated in endogenous fat inflammation such as monocyte chemoattractant protein-1. To determine whether this inflamed adipose depot could affect vascular disease in mice, epididymal fat depots were transplanted into atherosclerosis-prone apolipoprotein E–deficient ApoE −/− mice. Plasma from ApoE −/− mice receiving fat transplants contained increased leptin, resistin, and monocyte chemoattractant protein-1 compared with plasma from sham-operated ApoE −/− mice. Furthermore, mice transplanted with visceral fat developed significantly more atherosclerosis compared with sham-operated animals, whereas transplants with subcutaneous fat did not affect atherosclerosis despite a similar degree of fat inflammation. Treatment of transplanted ApoE −/− mice with pioglitazone decreased macrophage content of the transplanted visceral fat pad and reduced plasma monocyte chemoattractant protein-1. Importantly, pioglitazone also reduced atherosclerosis triggered by inflammatory visceral fat but had no protective effect on atherosclerosis in the absence of the visceral fat transplantation. Conclusions— Our results indicate that visceral adipose-related inflammation accelerates atherosclerosis in mice. Drugs such as thiazolidinediones might be a useful strategy to specifically attenuate the vascular disease induced by visceral inflammatory fat.

Objective— To determine whether tissue factor (TF) contributes to the progression of atherosclerotic lesions in mice. Methods and Results— We determined the effect of a 50% reduction of TF levels in all cells on atherosclerosis in apolipoprotein E-deficient (apoE −/− ) mice. No differences were observed in the extent of atherosclerosis in apoE −/− /TF +/+ and apoE −/− /TF +/− mice fed regular chow for 34 weeks. Atherosclerosis could not be analyzed in apoE −/− mice expressing low levels of TF because of premature death of these mice. Macrophages are a major source of TF in atherosclerotic plaques. Therefore, in a second series of experiments, we investigated the effect on atherosclerosis of selectively reducing hematopoietic cell-derived TF by transplanting bone marrow from mice expressing low levels of TF into low-density lipoprotein receptor deficient (LDLR −/− ) mice. Atherosclerosis within the arterial tree and aortic root were similar in LDLR −/− mice with low-TF bone marrow compared with control bone marrow (TF +/+ or TF +/− ) after 4 and 16 weeks on an atherogenic diet. Furthermore, the cellular composition of the aortic root lesions was similar between the 2 groups. Conclusions— Our data indicate that either a 50% reduction of TF in all cells or a selective reduction in hematopoietic cell-derived TF does not affect the development of atherosclerotic lesions in mice.

Objective— The direct role of leptin in vascular disease remains controversial. The objective of this study was to examine the effects of leptin treatment on atherosclerosis and thrombosis in atherosclerotic-prone mice. Methods and Results— Sixteen-week-old, male apolipoprotein E–deficient mice were treated with injections of recombinant leptin (125 μg per day IP; n=10) or vehicle (n=10) for 4 weeks. Leptin treatment resulted in reduced epididymal fat (352±30.7 versus 621±61.5 mg; P =0.005) and fasting insulin (0.57±0.25 versus 1.7±0.22 ng/mL; P =0.014). Despite these metabolic benefits, leptin treatment resulted in an increase in atherosclerosis (8.0±0.95% versus 5.4±0.59% lesion surface coverage; P P =0.045). Conclusions— These studies indicate that exogenous leptin promotes atherosclerosis and thrombosis and support the concept that elevations of leptin may increase the risk for cardiovascular disease.

Background— Activated protein C resistance due to factor V Leiden (FVL) is a common genetic risk factor for venous thrombosis in humans. Although the impact of FVL on the development of venous thrombosis is well established, its effect on arterial thrombosis and atherosclerosis is controversial. Methods and Results— To determine the effect of the FVL mutation on arterial thrombosis in the mouse, wild-type ( Fv +/+ ), heterozygous FVL ( Fv Q /+ ), and homozygous FVL ( Fv Q/Q ) mice underwent photochemical carotid arterial injury to induce occlusive thrombosis. Fv Q/Q mice formed occlusive thromboses 27±3 minutes (n=7) after the onset of injury, which was significantly shorter than that observed for Fv +/+ mice (56±7 minutes, n=9, P Fv Q /+ mice (41±7 minutes, n=5) were intermediate ( P =0.5, compared with Fv +/+ ). To determine the source of FVL relevant to the enhanced vascular thrombosis, bone marrow transplantation experiments were performed between Fv +/+ and Fv Q/Q mice. Fv Q/Q mice transplanted with Fv +/+ bone marrow formed occlusive thromboses at 35±5 minutes (n=7, P Fv +/+ mice), whereas Fv +/+ mice transplanted with Fv Q/Q bone marrow occluded at 59±7 minutes (n=6, P Fv Q/Q mice). To assess the effect of the FVL mutation on the development of atherosclerosis, Fv Q/Q mice were crossed with the atherosclerosis-prone apolipoprotein E (ApoE)–deficient strain ( ApoE −/− ) to generate Fv Q/Q ,ApoE −/− mice. By 52 weeks of age, Fv Q/Q ,ApoE −/− mice (n=8) had developed more aortic atherosclerosis (40±6% lesion area) compared with Fv +/+ ,ApoE −/− mice (15±3% lesion area; n=12, P Conclusions— In conclusion, homozygosity for the FVL mutation in mice leads to enhanced arterial thrombosis and atherosclerosis. The source of the FVL leading to accelerated thrombosis appears to be circulating, non–platelet-derived plasma FVL.

Background— α-Galactosidase A ( Gla ) deficiency leads to widespread tissue accumulation of neutral glycosphingolipids and is associated with premature vascular complications such as myocardial infarction and stroke. Glycosphingolipids have been shown to accumulate in human atherosclerotic lesions, although their role in atherogenesis is unclear. Methods and Results— To determine whether Gla affects the progression of atherosclerosis, mice were generated with combined deficiencies of apolipoprotein E and Gla . At 45 weeks of age, Gla -deficient mice had developed more atherosclerosis than mice with normal Gla expression (25.1±14.0 versus 12.3±9.3 mm 2 of total lesion area, P Conclusions— These findings suggest that deficiency of Gla leads to increased inducible nitric oxide synthase expression and accelerated atherosclerosis.

D-amino acid oxidase (DAAO) can catalyze the dehydrogenation of D-amino acids, such as D-alanine, to the corresponding amino acids and is then reoxidized by molecular oxygen to yield hydrogen peroxide, a reactive oxygen species, which reacts with DNA, lipids and protein, inducing cell death. This study investigated whether rat glioma 9L cells infected with the recombinant retrovirus containing the DAAO cDNA fragment can be induced in order to undergo cytotoxic oxidative stress by D-alanine. The recombinant retroviral vector, plzrus-DAAO-FLAG-GFP (pl-Dfg), was constructed and used to transfect packaged phoenix cells. The supernatant containing recombinant retroviral particles from the transfected phoenix cells was harvested and utilized to infect target 9L cells. The cytotoxic oxidative stress of infected 9L cells was induced by the DAAO substrate, D-alanine. The plasmid pl-Dfg was successfully constructed. The high titer retroviral supernatant was obtained from the transfected phoenix cells. Infected 9L cells were less viable after exposure to D-alanine compared to the control group. Anti-apoptotic proteins significantly inhibited cell death. The DAAO/D-alanine system has a potential utility for gene therapy and may be an effective strategy for the treatment of brain cancer and other malignant tumors.

Background Metabolism remodeling has been recognized as an early event following cardiac pressure overload. However, its temporal association with ventricular hypertrophy has not been confirmed. Moreover, whether trimetazidine could favorably affect this process also needs to be determined. The aim of the study was to explore the temporal changes of myocardial metabolism remodeling following pressure-overload induced ventricular hypertrophy and the potential favorable effect of trimetazidine on myocardial metabolism remodeling. Methods A rat model of abdominal aortic constriction (AAC)-induced cardiac pressure overload was induced. These rats were grouped as the AAC (no treatment) or TMZ group according to whether oral trimetazidine (TMZ, 40 mg/kg/d, for 5 days) was administered. Changes in cardiac structures were sequentially evaluated via echocardiography. The myocardial ADP/ATP ratio was determined to reflect the metabolic status, and changes in serum neuropeptide Y systems were evaluated. Results Myocardial metabolic disorder was acutely induced as evidenced by an increased ADP/ATP ratio within 7 days of AAC before the morphological changes in the myocardium, accompanied by up-regulation of serum oxidative stress markers and expression of fetal genes related to hypertrophy. Moreover, the serum NPY and myocardial NPY-1R, 2R, and 5R levels were increased within the acute phase of AAC-induced cardiac pressure overload. Pretreatment with TMZ could partly attenuate myocardial energy metabolic homeostasis, decrease serum levels of oxidative stress markers, attenuate the induction of hypertrophy-related myocardial fetal genes, inhibit the up-regulation of serum NPY levels, and further increase the myocardial expression of NPY receptors. Conclusions Cardiac metabolic remodeling is an early change in the myocardium before the presence of typical morphological ventricular remodeling following cardiac pressure overload, and pretreatment with TMZ may at least partly reverse the acute metabolic disturbance, perhaps via regulation of the NPY system.