Right axillosubclavian vein thrombosis resolved by percutaneous rheolytic thrombectomy in a patient with a recurrent gastrointestinal stromal tumour undergoing imatinib mesylate treatment.

The manifestation and management of spontaneous axillosubclavian vein thrombosis in patients with gastrointestinal stromal tumour (GIST) undergoing oral chemotherapy have never been described. We report a patient with a recurrent GIST who was receiving maintenance imatinib yet developed a right axillosubclavian vein thrombotic occlusion. The occluded vein was unresponsive to systemic anticoagulation but was reopened by percutaneous rheolytic thrombectomy and has shown good long-term patency. Thus, for patients with recurrent GIST undergoing imatinib therapy, axillosubclavian vein thrombosis might manifest as a complication and could be managed with rheolytic thrombectomy, which thoroughly removes intravascular thrombus and effectively re-vascularizes the thrombosed vessel uneventfully.

Propofol ameliorates doxorubicin-induced oxidative stress and cellular apoptosis in rat cardiomyocytes.

BACKGROUND: Propofol is an anesthetic with pluripotent cytoprotective properties against various extrinsic insults. This study was designed to examine whether this agent could also ameliorate the infamous toxicity of doxorubicin, a widely-used chemotherapeutic agent against a variety of cancer diseases, on myocardial cells. METHODS: Cultured neonatal rat cardiomyocytes were administrated with vehicle, doxorubicin (1µM), propofol (1µM), or propofol plus doxorubicin (given 1h post propofol). After 24h, cells were harvested and specific analyses regarding oxidative/nitrative stress and cellular apoptosis were conducted. RESULTS: Trypan blue exclusion and MTT assays disclosed that viability of cardiomyocytes was significantly reduced by doxorubicin. Contents of reactive oxygen and nitrogen species were increased and antioxidant enzymes SOD1, SOD2, and GPx were decreased in these doxorubicin-treated cells. Mitochondrial dehydrogenase activity and membrane potential were also depressed, along with activation of key effectors downstream of mitochondrion-dependent apoptotic signaling. Besides, abundance of p53 was elevated and cleavage of PKC-δ was induced in these myocardial cells. In contrast, all of the above oxidative, nitrative and pro-apoptotic events could be suppressed by propofol pretreatment. CONCLUSIONS: Propofol could extensively counteract oxidative/nitrative and multiple apoptotic effects of doxorubicin in the heart; hence, this anesthetic may serve as an adjuvant agent to assuage the untoward cardiac effects of doxorubicin in clinical application.

Late proximal coronary artery stenosis complicating percutaneous endovascular catheterisation procedures.

BACKGROUND: Late-onset proximal coronary artery stenosis caused by preceding percutaneous catheterisation procedures remains under-surveyed. METHODS: From 1993, all patients undergoing percutaneous coronary procedures and a second session within 3 years were included except those ever treated by coronary bypass surgery or chest radiotherapy during this 3-year period. Emergence of a new lesion or worsening of an initially insignificant lesion to >50% of diameter stenosis at the never-treated ostial/proximal coronary segment on the follow-up angiogram was defined as late coronary stenosis caused by the previous catheterisation procedure and was analysed. RESULTS: From January 1993 to December 2005, 3240 patients who underwent 5025 procedures met the inclusion criteria. Of them, 23 patients experienced an event of late coronary artery stenosis (overall incidence 0.46%), and interventional procedures, specifically shaped catheters (Voda, XB, Amplatz Left) and atherosclerosis vulnerability correlated with risks of adverse events. Most of these events could be managed by contemporary medical, interventional, or surgical strategies, yet hazards of mortality and long-term restenosis still existed from this catheter-induced complication. CONCLUSIONS: Percutaneous catheterisation procedures could be complicated by late proximal coronary artery stenosis. Thus, when conducting these procedures, operators should select and manipulate catheters with caution, especially in patients with susceptible clinical characteristics.

A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor.

Because angiotensin-converting enzyme (ACE) activity is implicated widely in biological systems, we aimed to identify its novel quantitative trait loci for the purposes of understanding ACE activity regulation and pharmacogenetics relating to ACE inhibitor (ACEI). We performed a two-stage genome-wide association study: (1) from 400 young-onset hypertension (YOH) subjects and (2) a confirmation study with an additional 623 YOH subjects. In the first stage, eight single nucleotide polymorphisms (SNPs) of the ACE structural gene and one SNP of ABO genes were significantly associated with ACE activity. SNP rs4343 in exon17 near the well-known insertion/deletion polymorphism had the strongest association. We confirmed in the second stage that three SNPs: rs4343 in ACE gene (P=3.0 x 10⁻²5), rs495828 (P=3.5 x 10⁻8) and rs8176746 (P=9.3 x 10⁻5) in ABO gene were significantly associated with ACE activity. We further replicated the association between ABO genotype/blood types and ACE activity in an independent YOH family study (428 hypertension pedigrees), and showed a potential differential blood pressure response to ACEI in subjects with varied numbers of ACE-activity-raising alleles. These findings may broaden our understanding of the mechanisms controlling ACE activity and advance our pharmacogenetic knowledge on ACEI.

Impact of chronic advanced aortic regurgitation on the perioperative outcome of noncardiac surgery.

BACKGROUND: Whether and how chronic advanced aortic regurgitation (AR) impacts the perioperative outcome of noncardiac surgery remains unclear. METHODS: From November 1999 to December 2006, all patients undergoing noncardiac operations and ever examined by echocardiography within the last 6 months were screened. Those with chronic moderate-severe or severe AR were enrolled, provided they were not already trachea-intubated or aortic valve operated, and the surgery was not performed under local anesthesia. Case-matched subjects without significant AR served as controls. The perioperative outcomes of these patients were analyzed, and independent prognostic correlates were investigated by multivariate logistic regression analysis. RESULTS: A total of 167 patients (male 131, mean age of 75 years) complying with the enrollment criteria were studied. Compared with the other 167 case-matched control peers, patients with advanced AR risked potential hazards of serious hemodynamic instability (0.6%) and circulatory collapse (1.2%) during surgery despite the similar incidence of overall cardiac adverse events, and were further distressed with more cardiopulmonary complications (16.2% vs. 5.4%, P=0.003) and in-hospital deaths (9% vs. 1.8%, P=0.008) post-operatively. Multivariate regression analysis confirmed the correlation of advanced AR with perioperative mortality, and identified depressed left ventricular function, renal dysfunction, high surgical risk, and lack of cardiac medication as predictors of in-hospital death. CONCLUSION: Chronic advanced AR complicates the perioperative outcome of noncardiac surgery as reflected by frequent cardiopulmonary morbidities and in-hospital deaths, especially when coexisting with specified high-risk clinical and surgical characteristics.

Caffeic acid phenethyl ester inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using a local delivery system.

Over the last two decades, significant advances have been made in percutaneous coronary intervention (PCI) for the treatment of atherosclerotic plaques. However, restenosis after PCI still challenges both vascular biologists and interventional cardiologists. In this study, we found that caffeic acid phenethyl ester (CAPE) displayed an inhibitory effect on human coronary smooth muscle cell (HCSMC) growth and migration. Flow cytometry analysis showed that the ratio of S phase increased after exposing cells to CAPE for 48-72 h. Pretreatment of cells with CAPE significantly suppressed Cyclin E, CDK2, Cyclin A, and proliferating-cell nuclear antibody expression. We demonstrated that CAPE inhibited AKT 1 and MEK1/2 activation. Using a local infusion system, CAPE was able to regress the intima thickening of the iliac artery in rabbits after balloon injury. The percentage of intimal thickening decreased significantly to 55.0 +/- 0.12 in the group after local CAPE infusion compared to the group after saline infusion (98.3 +/- 0.41%). In conclusion, CAPE can inhibit the proliferation and migration of HCSMCs by inducing cell cycle arrest. Decreased cell cycle genes and associated signaling pathway target gene expression may mediate anti-proliferative and anti-migration effects of CAPE. Furthermore, CAPE prevents intima thickening in rabbits after balloon angioplasty. These results indicate that CAPE may have therapeutic relevance for the prevention of restenosis during PCI in the treatment of coronary artery diseases.

A standardized extract of Ginkgo biloba suppresses doxorubicin-induced oxidative stress and p53-mediated mitochondrial apoptosis in rat testes.

BACKGROUND AND PURPOSE: Doxorubicin evokes oxidative stress and precipitates cell apoptosis in testicular tissues. The aim of this study was to investigate whether the Ginkgo biloba extract 761 (EGb), a widely used herbal medicine with potent anti-oxidant and anti-apoptotic properties, could protect testes from such doxorubicin injury. EXPERIMENTAL APPROACH: Sprague-Dawley male rats (8 weeks old) were given vehicle, doxorubicin alone (3 mg kg(-1) every 2 days for three doses), EGb alone (5 mg kg(-1) every 2 days for three doses), or EGb followed by doxorubicin (each dose administered 1 day after EGb). At 7 days after the first drug treatment oxidative and apoptotic testicular toxicity was evaluated by biochemical, histological and flow cytometric analyses. KEY RESULTS: Compared with controls, testes from doxorubicin-treated rats displayed impaired spermatogenesis, depleted haploid germ cell subpopulations, increased lipid peroxidation products (malondialdehyde), depressed antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase and glutathione), reduced antioxidant enzyme expression (superoxide dismutase) and elevated apoptotic indexes (pro-apoptotic modulation of Bcl-2 family proteins, intensification of p53 and Apaf-1, release of mitochondrial cytochrome c, activation of caspase-3 and increase of terminal deoxynucleotidyl transferase nick-end labelling/sub-haploid cells), while EGb pretreatment effectively alleviated all of these doxorubicin-induced abnormalities in testes. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that EGb protected against the oxidative and apoptotic actions of doxorubicin on testes. EGb may be a promising adjuvant therapy medicine, potentially ameliorating testicular toxicity of this anti-neoplastic agent in clinical practice.

Bivariate genome-wide scan for metabolic phenotypes in non-diabetic Chinese individuals from the Stanford, Asia and Pacific Program of Hypertension and Insulin Resistance Family Study.

AIMS/HYPOTHESIS: Hypertension, obesity, impaired glucose tolerance and dyslipidaemia are metabolic abnormalities that often cluster together more often than expected by chance alone. Since these metabolic variables are highly heritable and are at least partially genetically determined, the clustering of defects in these traits implies that pleiotropic effects, where a common set of genes influences more than one trait simultaneously, are likely. METHODS: We conducted bivariate linkage analyses for highly correlated traits, aiming to dissect the genetic architecture affecting these traits, in 411 Chinese families participating in the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance Study. RESULTS: We confirmed the pleiotropic effects of the locus at 37 cM on chromosome 20 on the following pairs: (1) fasting insulin and insulin AUC (empirical p = 0.0006); (2) fasting insulin and homeostasis model assessment of beta cell function (HOMA-beta) (empirical p = 0.0051); and (3) HOMA of insulin resistance (IR) and HOMA-beta (empirical p = 0.0044). In addition, the peak logarithm of the odds (LOD) scores of linkage between a chromosomal locus and a trait for the pair fasting insulin and HOMA-IR rose to 5.10 (equivalent LOD score in univariate analysis, LOD([1]) = 4.01, empirical p = 8.0 x 10(-5)) from 3.67 and 3.42 respectively for these two traits in univariate analysis. Additional significant linkage evidence, not shown in single-trait analysis, was identified at 45 cM on chromosome 16 for the pair 1 h insulin and the AUC for insulin, with a LOD score of 4.29 (or LOD([1]) = 3.27, empirical p = 2.0 x 10(-4)). This new locus is also likely to harbour the common genes regulating these two traits (p = 1.73 x 10(-6)). CONCLUSIONS/INTERPRETATION: These data help provide a better understanding of the genomic structure underlying the metabolic syndrome.

Severe pulmonary hypertension complicates postoperative outcome of non-cardiac surgery.

BACKGROUND: Whether and how pulmonary hypertension (PH) impacts perioperative outcome in non-cardiac surgery is incompletely understood. METHODS: From November 1999, all patients undergoing non-cardiac, non-local anaesthetic surgery and ever examined by echocardiography within 30 days before surgery were screened. Those having echocardiographic pulmonary artery systolic pressure >70 mm Hg were enrolled provided they were not already intubated. Case-matched peers with normal pulmonary pressures served as controls. Perioperative outcomes were compared between the two groups, and predictors of adverse perioperative outcomes were investigated by multivariate logistic regression analysis. RESULTS: From November 1999 to August 2004, a total of 62 patients (male 38, mean age 67 yr) with PH were found. Compared with the case-matched controls, patients with PH experienced equivalently smooth operative courses, but significantly more frequent postoperative heart failure (9.7 vs 0%, P = 0.028), delayed tracheal extubation (21 vs 3%, P = 0.004), and in-hospital deaths (9.7 vs 0%, P = 0.028). Multivariate regression analysis identified emergency surgery [odds ratio (OR), 44.738; P = 0.028], coronary artery disease (CAD; OR, 9.933; P = 0.042), and systolic pulmonary artery pressure (OR, 1.101; P = 0.026) as independent predictors of postoperative mortality and surgery-specific cardiac risk level (OR, 6.791; P = 0.033) and CAD (OR 6.546, P = 0.017) as predictors of morbidity. CONCLUSION: PH is an important predictor of adverse cardiopulmonary outcome in non-cardiac surgery as reflected by markedly increased postoperative complications, especially in patients with coexistent high-risk clinical and surgical characteristics.

Progressive action potential duration shortening and the conversion from atrial flutter to atrial fibrillation in the isolated canine right atrium.

OBJECTIVES: We sought to evaluate the effects of progressive shortening of the action potential duration (APD) on atrial wave front stability. BACKGROUND: The mechanisms of conversion from atrial flutter to atrial fibrillation (AF) are unclear. METHODS: Isolated canine right atria were perfused with 1 to 5 micromol/l of acetylcholine (ACh). We mapped the endocardium by using 477 bipolar electrodes and simultaneously recorded transmembrane potentials from the epicardium. The APD(90) was measured during regular pacing (S(1)) with cycle lengths of 300 ms. Atrial arrhythmia was induced by a premature stimulus (S(2)). RESULTS: At baseline, only short runs of repetitive beats (<10 cycles) were induced. After shortening the APD(90) from 124 +/- 15 ms to 72 +/- 9 ms (p < 0.01) with 1 to 2.5 micromol/l of ACh, S(2) pacing induced single, stable and stationary re-entrant wave fronts (307 +/- 277 cycles). They either anchored to pectinate muscles (5 tissues) or used pectinate muscles as part of the re-entry (4 tissues). When ACh was raised to 2.5 to 5 micromol/l, the APD(90) was further shortened to 40 +/- 12 ms (p < 0.01); S(2) pacing induced in vitro AF by two different mechanisms. In most episodes (n = 13), AF was characterized by rapid, nonstationary re-entry and multiple wave breaks. In three episodes with APD(90) <30 ms, AF was characterized by rapid, multiple, asynchronous, but stationary wave fronts. CONCLUSIONS: Progressive APD shortening modulates atrial wave front stability and converts atrial flutter to AF by two mechanisms: 1) detachment of stationary re-entry from the pectinate muscle and the generation of multiple wave breaks; and 2) formation of multiple, isolated, stationary wave fronts with different activation cycle lengths.

The incidence of coronary artery disease in patients with symptomatic bradyarrhythmias.

Symptomatic bradyarrhythmia occurs most often in aged patients. Most of these patients have multiple coronary risk factors and present with angina-like symptoms. The coexistence of CAD not only has major effects on their prognosis but also influences the long-term care. This study was designed to evaluate the incidence of coexistent CAD in patients with symptomatic bradyarrhythmias and its relationship to conventional coronary risk factors in Chinese people. From May 1996 to April 1998, we prospectively studied all consecutive patients admitted to our institution for symptomatic bradyarrhythmias requiring permanent pacemaker implantation. Coronary angiographies were performed non-selectively at the same session of pacemaker implantation. Based on the presence or absence of CAD, patients were divided into two groups for analysis. Multivariate logistic regression analysis was performed to determine independent predictors of CAD including sex, age, diabetes mellitus (DM), hypertension, hypercholesterolemia, and smoking. The odds-ratio (OR) and 95% confidence interval (CI) were determined. A total of 113 patients [68 males and 45 females, mean age 70.4+/-8.2 years old (range 45-86)] were included in our study. The diagnosis was sick sinus syndrome in 69 patients (61%) and atrioventricular block in 44 patients (39%). The incidence of CAD based on coronary angiography was 20%. The nodal-related artery was seldom involved among patients with coexistent CAD and symptomatic bradyarrhythmias (9%), and most patients had significant stenosis over LAD (74%). The baseline characteristics and presenting symptoms were not different statistically between patients with or without CAD. Hypercholesterolemia (OR 6.6, 95% CI 2.0-22.2, p=0.002) and DM (OR 4.7, 95% CI 1.3-17.2, p=0.020) were the two most significant independent predictors of CAD. In our patients with symptomatic bradyarrhythmias requiring permanent cardiac pacing, the incidence of CAD was 20% as determined by coronary angiography (CAG). Hypercholesterolemia and DM were the two most significant independent predictors for CAD in these patients. The nodal artery was seldom involved in patients with coexistent CAD and symptomatic bradyarrhythmias.

Genetic variation in the human urea transporter-2 is associated with variation in blood pressure.

The kidney, by regulating the volume of fluid in the body, plays a key role in regulating blood pressure (BP). The kidney uses primarily sodium and, to a lesser extent, urea to maintain the appropriate volume of fluid. Genetic variation in proteins that determine sodium reabsorption and excretion is known to significantly influence BP. However, the influence of genetic variation in urea transporters on BP has not been examined. We determined therefore whether nucleotide variation in the kidney-specific human urea transporter, HUT2, is associated with variation in BP. After determining the genomic structure of the coding sequence, seven single nucleotide polymorphisms (SNPs) were identified. Two of the SNPs result in Val/Ile and Ala/Thr amino acid substitutions at positions 227 and 357 in the HUT2 open reading frame, respectively. Another SNP is silent and four others are in introns or the 3' untranslated region. Over 1000 hypertensive and low-normotensive individuals of Chinese origin were typed for five of these SNPs using a high-throughput genotyping method. The Ile227 and Ala357 alleles were associated with low diastolic BP in men but not women, with odds ratios 2.1 [95% confidence interval (CI) 1.5-2.7, P < 0.001] and 1.5 (95% CI 1.2-1.8, P < 0.001), respectively. There was a similar trend for systolic BP, and odds ratios for the Ile227 and Ala357 alleles were 1.7 (95% CI 1.2-2.3, P = 0.002) and 1.3 (95% CI 1.1-1.6, P = 0.007), respectively, in men.

High-throughput genotyping with single nucleotide polymorphisms.

To make large-scale association studies a reality, automated high-throughput methods for genotyping with single-nucleotide polymorphisms (SNPs) are needed. We describe PCR conditions that permit the use of the TaqMan or 5' nuclease allelic discrimination assay for typing large numbers of individuals with any SNP and computational methods that allow genotypes to be assigned automatically. To demonstrate the utility of these methods, we typed >1600 individuals for a G-to-T transversion that results in a glutamate-to-aspartate substitution at position 298 in the endothelial nitric oxide synthase gene, and a G/C polymorphism (newly identified in our laboratory) in intron 8 of the 11-beta hydroxylase gene. The genotyping method is accurate-we estimate an error rate of fewer than 1 in 2000 genotypes, rapid-with five 96-well PCR machines, one fluorescent reader, and no automated pipetting, over one thousand genotypes can be generated by one person in one day, and flexible-a new SNP can be tested for association in less than one week. Indeed, large-scale genotyping has been accomplished for 23 other SNPs in 13 different genes using this method. In addition, we identified three "pseudo-SNPs" (WIAF1161, WIAF2566, and WIAF335) that are probably a result of duplication.

Relation between the rapid focal activation in the pulmonary vein and the maintenance of paroxysmal atrial fibrillation.

This case report describes a patient with drug refractory paroxysmal atrial fibrillation (PAF). Rapid focal activations with multiple sharp spikes were continuously identified inside the left superior pulmonary vein (PV) during sustained AF. Among seven episodes of AF, cessation of rapid focal activations coincided with the conversion of AF to flutter (n = 4) or immediate AF termination (n = 3). Guided by sharp spikes in the PV, abrupt termination of AF occurred during radiofrequency energy application. Conclusively, rapid focal activations inside the PV are critical in AF maintenance. Cessation of these rapid focal activations underlies the mechanism by which AF converts to flutter.

Incipient speciation by sexual isolation in Drosophila: concurrent evolution at multiple loci.

Drosophila melanogaster from Zimbabwe and nearby regions shows strong but asymmetric sexual isolation from its cosmopolitan counterparts. By creating stable chromosome-substitution lines, earlier studies were able to show that the two major autosomes have very large effects on both male mating success and female mating preference. In this study, we genetically dissect this sexual isolation by recombination analysis between a whole-chromosome substitution line (which carries a Zimbabwe-derived third chromosome) and a strain with seven visible markers on that chromosome. Four loci are responsible for male mating success and three others are found to control female mating preference. Because male and female traits are not closely linked, their strong association among isofemale lines is most likely a reflection of sexual selection in nature. The results suggest that a large number of behavioral loci may evolve concurrently in the incipient stage of speciation before other aspects of reproductive isolation (such as hybrid sterility) have become evident. The results shed light on the population genetic processes underlying the formation of nascent species, as well as modes of speciation.

Orbital adenocarcinoma of lacrimal gland origin in a dog.

A 13-year-old intact female mixed-breed dog was presented for a progressive enlargement of the right eye, which had been treated previously for conjunctivitis. A round, firm mass, approximately 4 cm in diameter, was protruding from the superotemporal aspect of the right orbit, displacing the eyeball anteriorly and ventromedially. The mass was encapsulated, distinct from the eyeball, and not associated with the eyelids. On cut surface, there was a pale multilobulated periphery, with a dark red, soft, and depressed core. Histologically, tumor cells formed cords and tubules, which were stained with mouse anti-human cytokeratin antibody AE1/AE3. Residual glands were serous, and the majority of tumor cells were negative for mucin. The supraorbital location, encapsulation, and residual serous glands suggest that this mass was a low-grade adenocarcinoma of the lacrimal gland.

Successful resuscitation of patient with massive coronary air embolism occluding two vessels during coronary angiography--a case report.

Massive coronary air embolism is usually disastrous although successful resuscitation has been reported previously. To what extent a patient with coronary air embolism can be resuscitated is not known. The authors report a rare case of massive air embolism to the left coronary arteries and successful resuscitation by vigilantly maintaining an effective driving force to dissipate the air lock.

Pulmonary veins and ligament of Marshall as sources of rapid activations in a canine model of sustained atrial fibrillation.

BACKGROUND: In dogs, chronic rapid pacing may result in sustained atrial fibrillation (AF). However, activation patterns in pacing-induced sustained AF are unclear. METHODS AND RESULTS: We induced sustained AF (>48 hours) in 6 dogs by rapid pacing for 139+/-84 days. We then performed computerized atrial epicardial mappings and recorded the activations in the ligament of Marshall (LOM) and the pulmonary veins (PVs). During AF, mean activation cycle length in the right atrial free wall (126+/-17 ms) was significantly longer than that in the left atrial free wall (96+/-5 ms, P:=0.006). In addition, mean activation cycle length in the left atrial free wall was significantly longer than that in the LOM (84+/-5 ms, P:<0.001), the left inferior PV (81+/-4 ms, P:=0.001), and the left superior PV (85+/-7 ms, P:=0.003). Similarly, the dominant frequency was highest in the LOM and the PVs (range 11.2 to 13.3 Hz), followed by the left and right atria (P:<0.001). In all dogs studied, rapid and complicated electrograms were consistently observed at the LOM and the PVs. During AF, both wandering wavelets and organized reentry were present. There were more wave fronts in the left atrium than in the right atrium (P:<0.001). CONCLUSIONS: In chronic pacing-induced sustained AF, the LOM and the PVs are the sources of rapid activations. The mechanism by which the left atrium activates faster and has more wave fronts than the right atrium may relate to the fact that the left atrium is closer to the sources of rapid activations.

Sudden changes in heart rate variability during the 1999 Taiwan earthquake.

Sympathovagal imbalance resulting from reactions to an earthquake was not prominent in patients who were taking beta-blockers.