Antagonism of sphingosine-1-phosphate receptors by FTY720 inhibits angiogenesis and tumor vascularization

FTY720, a potent immunomodulator, becomes phosphorylated in vivo (FTY-P) and interacts with sphingosine-1-phosphate (S1P) receptors. Recent studies showed that FTY-P affects vascular endothelial growth factor (VEGF)-induced vascular permeability, an important aspect of angiogenesis. We show here that FTY720 has antiangiogenic activity, potently abrogating VEGF- and S1P-induced angiogenesis in vivo in growth factor implant and corneal models. FTY720 administration tended to inhibit primary and significantly inhibited metastatic tumor growth in a mouse model of melanoma growth. In combination with a VEGFR tyrosine kinase inhibitor PTK787/ZK222584, FTY720 showed some additional benefit. FTY720 markedly inhibited tumor-associated angiogenesis, and this was accompanied by decreased tumor cell proliferation and increased apoptosis. In transfected HEK293 cells, FTY-P internalized S1P1 receptors, inhibited their recycling to the cell surface, and desensitized S1P receptor function. Both FTY720 and FTY-P apparently failed to impede VEGF-produced increases in mitogen-activated protein kinase activity in human umbilical vascular endothelial cells (HUVEC), and unlike its activity in causing S1PR internalization, FTY-P did not result in a decrease of surface VEGFR2 levels in HUVEC cells. Pretreatment with FTY720 or FTY-P prevented S1P-induced Ca2+ mobilization and migration in vascular endothelial cells. These data show that functional antagonism of vascular S1P receptors by FTY720 potently inhibits angiogenesis; therefore, this may provide a novel therapeutic approach for pathologic conditions with dysregulated angiogenesis.     

Increased frequency of disease-causing MYH mutations in colon cancer families

The genetic factors that cause clustering of colorectal cancers (CRCs) other than mutations in the mismatch repair (MMR) genes are not well understood. Clustering in families who lack MMR gene mutations may be attributable to low-penetrance mutations. Hypothetically, mono-allelic MYH mutations could contribute to the risk of CRC in these families. Using Fisher's exact test and logistic regression, we compared the frequency of the known disease-causing MYH mutations Y165C, G382D and 466delE in 137 probands (117 cases with CRC and 20 cases diagnosed on the basis of adenomatous polyps only) from families with three or more CRCs but negative for mutations in the MMR genes and in 967 healthy controls with comparable ethnic backgrounds. Of 137 cases, 6 (4.4%) carried mono-allelic MYH mutations compared with 16 of 967 (1.6%) controls. In addition, three bi-allelic MYH mutation carriers, who eventually developed MYH-associated polyposis, were also identified in families with pedigree structures consistent with dominant inheritance of CRC susceptibility. By Fisher's exact tests, there was a statistically different frequency of cases with any MYH mutation (mono- or bi-allelic carriers; P-value = 0.002) and of cases with mono-allelic MYH mutation (P = 0.04) compared with the controls. Using a logistic regression model, the unadjusted odds ratio associated with any MYH mutation was 4.14 (P-value < 0.001); for mono-allelic carriers, it was 2.79 (P-value = 0.04). Adjusting for ethnic backgrounds, gender and age, the odds ratio associated with any disease-causing MYH mutation was 3.23 (P-value = 0.01); for mono-allelic carriers, it was 1.99 (P-value = 0.20). Overall, the results support previous studies suggesting that mono-allelic mutations of MYH constitute low-penetrance CRC-causing alleles. These data further support a model in which low-penetrance alleles are enriched in MMR gene mutation-negative CRC families.     

Anti-diabetic potentials of Momordica charantia and Andrographis paniculata and their effects on estrous cyclicity of alloxan-induced diabetic rats

Momordica charantia and Andrographis paniculata are the commonly used herbs by the diabetic patients in Pampanga, Philippines. While the anti-diabetic potential of Momordica charantia is well established in streptozocin- or alloxan-induced diabetic animals, the anti-diabetic potential of Andrographis paniculata in alloxan-induced diabetic rat is not known. Neither the effects of these herbs on estrous cyclicity of alloxan-induced diabetic rats are elucidated. Thus, in these experiments, Momordica charantia fruit juice or Andrographis paniculata decoction was orally administered to alloxan-induced diabetic rats. Rats that were treated with Momordica charantia and Andrographis paniculata had higher body weight (BW) compared with diabetic positive control (P < 0.01) from day 22 to day 27 (D27) but exhibited lower BW than the non-diabetic control (P < 0.05). These rats had lower feed (P < 0.05) and liquid intakes (P < 0.01) compared with diabetic positive control from day 17 to D27, but similar with the non-diabetic control. The blood glucose levels in these groups were significantly reduced from day 12 to D27 compared with diabetic positive control (P < 0.01), however, comparable with non-diabetic control. The diabetic positive control had extended mean estrous cycles (8 days) compared to Momordica charantia and Andrographis paniculata-treated diabetic rats (5 days; P < 0.05). Our results suggest that the anti-diabetic potentials of Momordica charantia and Andrographis paniculata could restore impaired estrous cycle in alloxan-induced diabetic rats.     

EcoRI polymorphism of the metastasis-suppressor gene NME1 in Mexican patients with breast cancer

Summary Human breast cancer cells with high metastatic potential show reduced expression of the metastasis-suppressor gene NME1. There are two polymorphic sites for the restriction enzymes BglII and EcoRI, both detectable by Southern blot analysis. Although the BglII site has been analyzed for loss of heterozygosity, the biallelic EcoRI site polymorphism has not been studied in association with breast cancer, complications or metastasis. We analyzed EcoRI site allele frequencies in Mexican patients with breast cancer, using polymerase chain reaction -restriction fragment length polymorphisms. The polymorphic allelic frequencies in the cases and reference groups were 0.4215 and 0.3375, respectively; this difference was not statistically significant (χ²=0.8687, p=0.3512). Thus, EcoR1 polymorphic site was not associated with breast cancer in this series, but could be analyzed in association with metastases and might be informative in the evaluation of loss of heterozygosity in women with breast cancer.     

Utilization of contraception and abortion and its relationship to HIV infection among female sex workers in Tashkent, Uzbekistan

OBJECTIVE: This study aimed to describe reported contraceptive and abortion utilization and their relationship to human immunodeficiency virus (HIV) infection among female sex workers (FSW) in Tashkent, Uzbekistan. METHODS: For this cross-sectional study, women were recruited through outreach workers affiliated with Istiqbolli Avlod. Participants completed a self-administered questionnaire and underwent HIV testing. RESULTS: Of 448 participants, the majority (86.2%, n=386) used contraception; 39.6% reported inconsistent use. Methods most frequently utilized were condoms (50.9%) and intrauterine devices (16.1%). One fourth (24.3%, n=109) reported multiple (>or=3) prior abortions. Inconsistent contraceptive users were more likely to be infected with HIV (AOR=2.72, 95% CI=1.19-6.22), but such infection was not related to a specific contraceptive method, including condoms, or utilization of abortion. CONCLUSIONS: Inconsistent contraceptive use is common and may be a predictor of HIV infection among Tashkent FSW. Factors preventing consistent contraceptive use may be related to HIV risk and require further study in this population.     

Traumatic avulsion of the intrapancreatic common bile duct: case report

Injuries of the extra hepatic biliary tree following blunt trauma to the abdomen are rare. We present a case of avulsion of the intrapancreatic common bile duct. Very often the lesion is not identifiable until the signs of jaundice and biliary ascites occur. Intraoperative cholangiography is mandatory for the diagnosis, but the noninvasive magnetic resonance cholangiopancreatography could readily depict the injury of the extrahepatic bile duct preoperatively. When the diagnosis is late the corner stone of treatment is biliary diversion and definitive repair after complete resolution of sepsis with a choledochojejunostomy.     

Effect of challenging neck anatomy on mid-term migration rates in AneuRx endografts

OBJECTIVE: To establish the effect of challenging neck anatomy on the mid- and long-term incidence of migration with the AneuRx bifurcated device in patients treated after Food and Drug Administration approval and to identify the predictive factors for device migration. METHODS: Prospectively maintained databases at the University of North Carolina (UNC) and Washington University (WU) were used to identify 595 patients (UNC, n = 230; WU, n = 365) who underwent endovascular repair of an infrarenal abdominal aortic aneurysm with the AneuRx bifurcated stent graft. Those patients with at least 30 months of follow-up were identified and underwent further assessment of migration (UNC, n = 25; WU, n = 59) by use of multiplanar reconstructed computed tomographic scans. RESULTS: Eighty-four patients with a mean follow-up time of 40.3 months (range, 30-55 months) were studied. Seventy percent of the patients (n = 59) met all inclusion criteria for neck anatomy (length, angle, diameter, and quality) as defined by the revised instructions for use guidelines and are referred to as those with favorable neck anatomy (FNA). The remaining 25 patients retrospectively fell outside of the revised instructions for use guidelines and are referred to as those with unfavorable neck anatomy (UFNA). Life-table analysis for FNA patients at 2 and 4 years revealed a migration rate of 0% and 6.1%, respectively. For UFNA patients, it was 24.0% and 42.1% at 2 and 4 years, respectively (P < .0001). The overall (FNA and UFNA) migration rate was 7.1% and 17.1% at 2 and 4 years, respectively. Overall, late graft-related complications occurred in 38% of patients (FNA, 27%; UFNA, 64%; P = .003; relative risk, 1.7). There was no incidence of late rupture or open conversion. The relative risk of migration for UFNA patients was 2.5 compared with FNA patients (P = .0003). A larger neck angle and a longer initial graft to renal artery distance were predictors of migration, whereas shorter neck length approached but did not reach statistical significance. CONCLUSIONS: Patients who have unfavorable aneurysm neck anatomy experience significantly higher migration, device-related complication, and secondary intervention rates. However, there was no incidence of open conversion, rupture, or abdominal aortic aneurysm-related death, thereby supporting the AneuRx device as a feasible alternative to open repair even in patients with challenging neck characteristics. Enhanced surveillance should be used in these high-risk patients.     

Treatment of asymptomatic carotid artery disease: similar early outcomes after carotid stenting for high-risk patients and endarterectomy for standard-risk patients

BACKGROUND: The role of carotid angioplasty and stenting (CAS) in the treatment of asymptomatic patients with carotid disease remains controversial. The purpose of this report is to compare outcomes in asymptomatic patients treated with CAS and carotid endarterectomy (CEA). This was the initial experience performing CAS for most of the surgeons. For comparison, we also report our outcomes in standard-risk patients treated concurrently with CEA during the same period of time. METHODS: A retrospective, nonrandomized review of asymptomatic patients undergoing CEA or CAS at Washington University Medical Center in St. Louis was done. Patients with >70% asymptomatic carotid stenosis treated between September 2003 and April 2005 were identified. CEA was the first therapeutic consideration in all patients. CAS was reserved for high-risk patients. Thirty-day outcomes of stroke or death were recorded. During this time interval, 248 patients were treated including with 93 CAS and with 145 CEA. Symptomatic or clinically detected adverse outcomes such as myocardial infarction (MI), arrhythmia, renal failure, or pulmonary complications were noted but were not the primary end points of this review. This study addresses only the periprocedural outcomes of CEA and CAS in asymptomatic patients. No data >30-day follow-up are included. RESULTS: During this period, 93 CAS and 145 CEA procedures were done in asymptomatic patients. Patient characteristics in both groups were similar. Carotid protection devices were used in 91.4% of CAS patients. The results in the CAS group showed one death (1.1%) and one stroke (1.1%). In the CEA group, three strokes occurred (2.1%, P = 0.9999), one associated with death (0.7%, P = 0.9999). The CAS group had 1.34 +/- 0.83 risk factors vs 0.39 +/- 0.58 in the CEA group (P < .0001). Median CAS and CEA length of stay was 1 day. CONCLUSIONS: CAS for asymptomatic carotid stenosis demonstrated equivalent outcomes compared with CEA, despite CAS being reserved for use in a disadvantaged subset of high-risk patients owing to anatomic risk factors or medical comorbidities. These results suggest CAS should be considered a reasonable treatment option in the high-risk but asymptomatic patient. Enthusiasm for CAS should be tempered by the recognition that long-term outcomes in CAS-treated asymptomatic patients remain unknown.     

Vascular access outcomes and medication use: a USRDS study

Several medications have been proposed to improve hemodialysis (HD) vascular access outcomes based on potentially favorable anticoagulant, antiplatelet, or pleiotropic properties. The purpose of this study was to evaluate the relationship between medication use and vascular access patency in a group of HD patients. We conducted a historical cohort study of the US Renal Data System Dialysis Mortality and Morbidity Wave II study to identify patients with an arteriovenous fistula (AVF), polytetrafluoroethylene (PTFE) graft, or a permanent catheter for vascular access. Cox regression analysis, adjusted for age, gender, race, history of coronary artery disease, peripheral vascular disease, or coronary artery bypass graft, was used to model the hazard ratio (HR) of permanent vascular access failure. Of the 2001 HD patients in the Wave II study, 901 (45%) were included in the analysis. PTFE graft patency was greater for males (HR, 0.73; 95% CI 0.53-1.00, p = 0.05) and for older individuals (HR, 0.99; 95% CI 0.98-1.00, p = 0.02). Treatment with antiplatelet medications, ticlopidine and dipyridamole (HR, 3.54; 95% CI 1.07-11.76; p = 0.04), or aspirin (HR, 2.49; 95% CI 1.31-4.73; p = 0.005) was associated with significantly worse AVF patency. Antiplatelet agents had a significant negative association with access patency in this cohort. In contrast to other published data, it was difficult to identify any beneficial effect of specific medications on access patency.