Epigenetic silencing of the dual-role signal mediator, ANGPTL4 in tumor tissues and its overexpression in the urothelial carcinoma microenvironment.

Urothelial carcinoma (UC) carcinogenesis has been hypothesized to occur through epigenetic repression of tumor-suppressor genes (TSGs). By quantitative real-time polymerase chain reaction array, we found that one potential TSG, angiopoietin-like 4 (ANGPTL4), was expressed at very low levels in all bladder cancer cell lines we examined. Previous studies had demonstrated that ANGPTL4 is highly expressed in some cancers, but downregulated, by DNA methylation, in others. Consequently, owing to these seemingly conflicting functions in distinct cancers, the precise role of ANGPTL4 in the etiology of UC remains unclear. In this study, using methylation-specific PCR and bisulfite pyrosequencing, we show that ANGPTL4 is transcriptionally repressed by DNA methylation in UC cell lines and primary tumor samples, as compared with adjacent noncancerous bladder epithelium. Functional studies further demonstrated that ectopic expression of ANGPTL4 potently suppressed UC cell proliferation, monolayer colony formation in vitro, and invasion, migration, and xenograft formation in vivo. Surprisingly, circulating ANGPTL4 was significantly higher in plasma samples from UC patients than normal control, suggesting it might be secreted from other cell types. Interestingly, our data also indicated that exogenous cANGPTL4 could promote cell proliferation and cell migration via activation of signaling through the Erk/focal adhesion kinase axis. We further confirmed that mouse xenograft tumor growth could be promoted by administration of exogenous cANGPTL4. Finally, immunohistochemistry demonstrated that ANGPTL4 was downregulated in tumor cells but overexpressed in tumor adjacent stromal tissues of muscle-invasive UC tissue samples. In conclusion, our data support dual roles for ANGPTL4 in UC progression, either as a tumor suppressor or oncogene, in response to microenvironmental context.

Correlation between the flow pattern of the circle of Willis and segmental perfusion asymmetry after carotid artery revascularization.

BACKGROUND: To correlate cerebral perfusion and flow patterns after carotid artery revascularization within the circle of Willis (CoW). METHODS: Sixty-five patients (male/female ratio: 38/27; mean age: 63.2±8.4years; range: 44-82years) with symptomatic carotid artery stenosis underwent magnetic resonance (MR) angiography and perfusion imaging prior to and after carotid artery stenting (CAS). Regions of interest (ROIs) on the MR perfusion maps included the corona radiata (CR), centrum semiovale (CSO), occipital region (O), and basal ganglia region (BA) in both stented and non-stented hemispheres. The non-stented hemisphere was used as internal control. RESULTS: Subjects were assigned to the altered CoW group (N=31) vs. the static CoW group (N=34). Thirty-one subjects (47.6%) had an altered flow pattern in the CoW after CAS, and thirty-four (52.4%) retained a static CoW configuration. Relative cerebral blood volume (rCBV) interhemispheric index correlated with CoW morphologic alterations after carotid stenting. Altered CoW group had a higher regional interhemispheric index of rCBV in the CR (1.23±0.15 vs. 0.87±0.13; P=0.03) and basal ganglia (1.25±0.12 vs. 0.91±0.11; P=0.03) compared to the static group. CONCLUSIONS: An association between the regional cerebral blood volume (rCBV) interhemispheric asymmetry and CoW collateralization was observed. In addition, the CR, rather than CSO, was found to have topographic significance.

Contribution of intracranial vertebral artery asymmetry to vestibular neuropathy.

OBJECTIVES: To test the hypothesis that vertebral artery hypoplasia (VAH) may affect the lateralisation of vestibular neuropathy (VN), probably through haemodynamic effect on the vestibular labyrinth. METHODS: 69 patients with unilateral VN were examined with a magnetic resonance angiographic (MRA) and caloric test. 50 healthy subjects served as controls. The diagnosis of intracranial VAH was based on MRA if <0.22 cm in VA diameter and a diameter asymmetry index >40%. The authors then correlated the canal paretic side with the VAH side. RESULTS: MRA study revealed 29 VAH (right/left: 23/6) in VN subjects and six VAH in controls (right/left: 5/1). The RR of VAH in VN subjects compared with controls was elevated (RR=2.2; 95% CI 1.8 to 2.8). There was a high accordance rate between the side of VAH and VN. Among 29 patients with unilateral VAH, 65.5% (N=19) had an ipsilateral VN, in which left VAH showed a higher accordance rate (83.3%) than the right side (60.9%). VN subjects with vascular risk factors also had a higher VAH accordance rate (81%) than those without (25%). CONCLUSIONS: VAH may serve as a regional haemodynamic negative contributor and impede blood supply to the ipsilateral vestibular labyrinth, contributing to the development of VN, which could be enhanced by atherosclerotic risk factors and the left-sided location.

Disseminated Cryptococcus neoformans var. grubii infections in intensive care units.

A retrospective study of clinical characteristics, outcome and prognostic factors of patients with cryptococcosis was undertaken in intensive care units (ICUs) of a medical centre for the period 2000-2005. Twenty-six patients with Cryptococcus neoformans var. grubii infection were identified (16 males, median age 58 years). The most frequent underlying diseases were liver cirrhosis (38.5%), diabetes mellitus (26.9%) and HIV infection (19.2%). The most frequently identified sites of infection were blood (61.5%), cerebrospinal fluid (38.5%) and airways (34.6%). The mean Acute Physiologic and Chronic Health Evaluation II score at ICU admission was 22.46. The ICU mortality rate in these patients was 73.1% (19/26) and there were a further two mortalities recorded after discharge from ICU, reaching a total mortality rate of 80.8% (21/26). Patients with ICU survival >2 weeks had lower rates of HIV infection (P=0.004), less use of inotropic agents during ICU stay (P<0.001) and lower white blood cell counts (P=0.01). After adjusting for clinical variables in the multivariate Cox regression model, diabetes and cryptococcal infection after ICU admission were independent predictors of good long-term prognosis (P=0.015) and HIV infectious status was associated with poor outcome (P=0.012).

Disseminated cryptococcosis in HIV-uninfected patients.

Cryptococcus neoformans usually causes disease in patients with human immunodeficiency virus (HIV) infection. This descriptive study was based on a retrospective review of 33 HIV-uninfected patients with disseminated cryptococcosis from 1998 to 2005. An underlying condition associated with immunocompromise was documented in 30 patients (90.9%), including liver cirrhosis (36.4%), diabetes mellitus (33.3%) and autoimmune disease (27.3%). Disseminated cryptococcosis carried a high mortality rate in this series, reaching 63% overall, with a median survival of 21 days. All patients (12/12) with liver cirrhosis died within the first month after the diagnosis of cryptococcosis. Otherwise, high Acute Physiology and Chronic Health Evaluation II (APACHE II) score, female gender and smoking history were associated with worse one-month outcome.

Noninvasive assessment of spontaneous baroreflex sensitivity and heart rate variability in patients with carotid stenosis.

BACKGROUND: Previous limited observations have suggested that atherosclerosis may affect the distensibility of the carotid sinus and then impair the baroreflex sensitivity (BRS). No studies have been done to compare the BRS and heart rate variability (HRV) in patients with carotid stenosis and normal controls. METHODS: A convenience-consecutive sample of 118 patients with transient ischemic attack or minor stroke 3 months to 1 year before (mean 6 months) who met the study criteria were referred to the neurovascular laboratory of the study hospital. Forty-three age-matched healthy adults were recruited as the normal controls. The inclusion criteria for participation were (1) no diabetes mellitus, (2) no history, symptoms or ECG signs of coronary artery disease or myocardial infarction, and (3) presence of carotid stenosis greater than or equal to 50%. The diagnosis of carotid stenosis was made using color-coded duplex ultrasound with published criteria. We categorized the patients into two groups: group 1 had moderate stenosis (50-75%) and group 2 had high-grade stenosis (75-99%). Instantaneous systolic blood pressure (SBP) and heart rate of all participants were assessed noninvasively using servo-controlled infrared finger plethysmography. The fluctuation in SBP as well as the interpulse interval (IPI) was divided into three components at specific frequency ranges by fast Fourier transform as high frequency (HF; 0.15-0.4 Hz), low frequency (LF; 0.04-0.15 Hz) and very low frequency (VLF; 0.004-0.04 Hz). The BRS was expressed as (1) transfer function with its magnitude in the HF and LF ranges, (2) BRS index alpha, and (3) regression coefficient by sequence analysis. The HRV was expressed as total power and power in the three frequency ranges (HF, LF and VLF). RESULTS: The final analysis included 99 patients (mean age 72 +/- 6 years, 79 male) and 43 healthy controls (mean age 68 +/- 7 years, 30 male). Forty-three patients were classified as group 1 (stenosis 50-75%) and 56 as group 2 (stenosis 75-99%). There was no significant difference in the IPI between patients and controls (p value = 0.8637). We observed a significant decrease in all three HRV components (VLF, LF and HF) in the patients; however, there were no differences between the two patient groups with various degrees of stenosis. All the indices of BRS, including the magnitude of SBP-IPI transfer function at LF and HF, the computed BRS index alpha and the regression coefficient of sequence analysis, revealed similar results. Patients exhibited a significant reduction in the BRS (p < 0.001) compared with controls, and no difference was found between the two groups of patients. CONCLUSIONS: Our study linked significant carotid stenosis to two important autonomic markers (BRS and HRV) that may have prognostic value for patients with cardiovascular events. Further prospective studies are needed to explore whether or not the decreased BRS and HRV can be predictors for poor cardiovascular prognosis, or even for shortened life span in general, in patients with significant carotid stenosis.

Radiological and manometric diagnosis of cricopharyngeal dysphagia in a Japanese encephalitis survivor.

Japanese encephalitis (JE) is endemic throughout most of the western Pacific region where Taiwan is located. About half the survivors are left with neurological damages. We report a 55-year-old male who survived from JE and was left with sequela of parkinsonism and severe swallowing disorder. Later, it was proved to be cricopharyngeal dysphagia (CPD) using esophagogram and manometry, which disclosed involuntary hypertonic and hyperreflexic cricopharyngeal muscle contraction. CPD, a life-threatening neurological sequel of JE, has never been reported in the JE survivors before and possibly results from disseminated lesions over pyramidal and extrapyramidal systems.

Early recognition of cerebral hyperperfusion syndrome after carotid stenting--a case report.

The hyperperfusion syndrome is a recognized complication of carotid endarterectomy. Reports of cerebral hyperperfusion injury following internal carotid artery angioplasty and stenting are few We report a case of 76-year-old hypertensive man who was admitted to our hospital for assessment 2 years after experiencing an ischemic stroke of right hemisphere. Angiography confirmed 60% stenosis of left internal carotid artery (ICA). Percutaneous transluminal stenting of left internal carotid artery was performed without any immediate complications. Two hours after the procedure, the patient suddenly deteriorated. Computed tomography (CT) of the brain revealed extensive intracerebral hemorrhage and he died 5 days later. There was precipitating migranous headache, and his blood pressure was moderately elevated at the time of deterioration. Sentinel headache could solely indicate the early sign of hyperperfusion injury after carotid stenting, especially in the presence of arterial hypertension. Patients with sentinel headache after angioplasty should be recognized early and they deserve intensive study for other features of cerebral hyperperfusion injury and prompt early management.

Effects of extracted Cordyceps sinensis on steroidogenesis in MA-10 mouse Leydig tumor cells.

Extracts from the mycelium of Cordyceps sinensis (CS) were tested to determine the in vitro effect on Leydig cell function. MA-10 mouse Leydig tumor cells were used to conduct the experiments. Results showed that progesterone production gradually increased as the dosage of combined water and ethanol extracted CS increased, and there was a statistically significant difference in progesterone production stimulated by 20 mg/ml of CS extracts compared to the control. The combined water and ethanol extracted CS significantly stimulated MA-10 cell steroid production at 12 and 24 h of incubation. In addition, a protein synthesis inhibitor, cycloheximide, did not block the stimulatory effects of CS extracts on MA-10 cell steroid production or total protein expression. Moreover, the expression of steroidogenic acute regulatory (StAR) protein, which is a critical protein for steroidogenesis, stimulated by CS extracts, could not be detected by Western blot analysis. These data indicate that CS extracts might not induce StAR protein and/or other protein expressions to stimulate steroidogenesis in MA-10 mouse Leydig tumor cells.

A scalpel blade as a substitute for the calibrator of the dermatome.

In using the Padgett-Hood dermatome, a scalpel blade can be utilized as a substitute for the calibrator. The thickness of the scalpel blade shows very little discrepancy in comparison with 1/1000 in statistically, so it is better to check the indicator with this method than by empirical sense.