γ-甲基-1，4-戊内酯的新合成方法

以丙二酸和异丁醛为起始原料，通过Ｋｎｏｅｖｅｎａｇｅｌ缩合，再经异构化和内酯化反就合成了γ－甲基－１，４－戊内酯，总收率５３％。     

Transcatheter Radiofrequency Ablation of Atrial Tissue Using a Suction Catheter

Closed chest ablative technique that avoid barotrauma would be attractive for ablation at thin walled cardiac structures, such as the atrial free wall or coronary sinus. Transcatheter radiofrequency (RF) currents produce tissue necrosis the size of which is dependent on the contact between the tissue and the electrode. In order to assess the effects of transvenous RF ablation of atrial free wall using a suction electrode catheter, we delivered in ten dogs, one single unmodulated RF pulse 1.2 MHz, in a unipolar mode, through the distal electrode of a lumen catheter (USCI 8F) (USCI, Billerica, MA, USA) located in the right appendage. During the pulse an 80 KPa vacuum depression was applied to the lumen of the catheter. Each pulse had a 10 seconds duration and the mean delivered power was 4.3 ± 1.4 W. Aortic pressure and electrocardiogram were monitored during the procedure. A right airial electrophysiological study was performed at the ablated site, at control, after suction application and after RF pulse delivery. The animals were sacrificed after 14 or 21 days. Atrial pacing threshold values decreased after suction application in comparison to control values after the pulse (0.42 ± 0.06 vs 0.60 ± 0.23 mA, P < 0.05) but increased after the pulse delivery (2.60 ± 1.85 mA, P < 0.01). In contrast, the atrial effective refractory period did not significantly change after suction, nor after RF pulse delivery. Aortic pressure remained unchanged throughout the procedure. Complex arrhythmias were not observed during or after RF pulse delivery. One dog died suddenly at the first day after ablation, but this death was most probably unrelated to RF ablation. Anatomic lesions had a length of 8.8 ± 3.3 mm, a width of 4.6 ± 2.5 mm and a depth of 3.6 ± 1.1 mm. They were transmural in nine of the ten dogs but without atrial wall perforation in any case. Lesions suggesting tissue volatilization were present in four dogs. These results demonstrate that low energy RF currents delivered with a suction electrode catheter can produce transmural necrosis of free wall, without risk of perforation. Such ablative technique would be of interest for ablation of right sided accessory pathways or atrial ectopic foci. Further experimental data are required in order to define the optimal energy level required to avoid tissue volatilization.     

Anti-RhoA and anti-RhoC siRNAs inhibit the proliferation and invasiveness of MDA-MB-231 breast cancer cells in vitro and in vivo.

Overexpression of RhoA or RhoC in breast cancer indicates a poor prognosis, due to increased tumor cell proliferation and invasion and tumor-dependent angiogenesis. Until now, the strategy of blockage of the Rho-signaling pathway has used either GGTI or HMG-CoA reductase inhibitors, but they are not specific to RhoA or RhoC inhibition. In this study, a new approach with anti-RhoA and anti-RhoC siRNAs was used to inhibit specifically RhoA or RhoC synthesis. Two transfections of either RhoA or RhoC siRNA (8.5 nM) into MDA-MB-231 human breast cancer cells or HMEC-1 endothelial cells induced extensive degradation of the target mRNA and led to a dramatic decrease in synthesis of the corresponding protein. In vitro, these siRNAs inhibited cell proliferation and invasion more effectively than conventional blockers of Rho cell signaling. Finally, in a nude mouse model, intratumoral injections of anti-RhoA siRNA (100 microl at 85 nM) every 3 days for 20 days almost totally inhibited the growth and angiogenesis of xenografted MDA-MB-231 tumors. One may infer from these observations that specific inhibition of the Rho-signaling pathway with siRNAs represents a promising approach for the treatment of aggressive breast cancers.     

Oral administration of doxycycline allows tight control of transgene expression: a key step towards gene therapy of retinal diseases

Gene transfer of neurotrophic or antiangiogenic factors has been shown to improve photoreceptor survival in retinal degenerative disorders (that is retinitis pigmentosa) and to prevent neovascularization in retinal vascular diseases (that is age-related macular degeneration, diabetic retinopathy). Expression of such neurotrophic or antiangiogenic factors after gene transfer requires the use of a regulatory system to control transgene expression to avoid unwanted side effects in cases of overexpression. In a previous study, we demonstrated that rAAV-mediated gene transfer of the tetracycline-regulatable (tetR) system allows transgene regulation in the retina of nonhuman primates after intravenous administration of doxycycline (Dox). The purpose of this study was to evaluate oral administration of Dox to control transgene expression in the retina, since the pharmacokinetics after oral administration of the inducer drug represent a key factor when considering advancing to clinical trials. We report on the outcome of this evaluation and demonstrate that oral administration of Dox at a dose that is clinically used in humans (5 mg kg(-1) per day) is capable to continuously induce transgene expression in all macaques tested for 6 months. Moreover, control of transgene expression persists up to 4 years post-subretinal injection, with maximal induced levels of transgene product remaining stable over time.     

Increased glomerular and extracellular malondialdehyde levels in patients and rats with focal segmental glomerulosclerosis

BACKGROUND: Evidence suggests an increase in oxidative stress in patients with chronic kidney disease, as glomerulosclerosis is the prerequisite for chronic kidney disease; whether the oxidative stress already exists early on is not known. MATERIALS AND METHODS: In this study we measured the plasma and urinary levels of malondialdehyde (MDA), the end product of lipid peroxidation, and assessed the immunoreactivity of MDA and superoxide dismutase (SOD) in glomeruli of patients and rats with primary focal segmental glomerulosclerosis (FSGS), and compared our findings with those of minimal change disease (MCD) and normal controls (NC). RESULTS: Our results showed that plasma MDA level was significantly increased in patients with FSGS compared with both patients with MCD and normal controls. The urinary MDA level was also significantly increased and was significantly correlated with plasma MDA level in patients with FSGS. The immunostaining for glomerular MDA and SOD was significantly higher in the patients with FSGS than in either the patients with MCD or NC, and was also significantly higher in rats with puromycin aminonucleoside (PAN)-induced FSGS than in rats with MCD. Glomerular MDA level was significantly correlated with the degree of glomerulosclerosis in the patients with FSGS. CONCLUSIONS: Our data suggest that oxidative stress occurs early on before the onset of renal failure, and may play an important role in the pathogenesis of glomerulosclerosis.     

Effect of multiple doses of fimasartan, an angiotensin II receptor antagonist, on the steady-state pharmacokinetics of digoxin in healthy volunteers

Fimasartan (BR-A-657) is an angiotensin II receptor antagonist, recently approved as an antihypertensive agent. Objective: This study aimed to investigate whether administration of fimasartan has an effect on the steady-state pharmacokinetics of digoxin. Methods: An open-label, two-period, two-treatment, single-sequence, crossover study was conducted in 14 healthy male volunteers. On the first day of each 7-day treatment period, subjects received a loading dose of digoxin 0.5 mg, either alone or together with fimasartan 240 mg in the morning, followed by an additional dose of digoxin 0.25 mg after 6 h. On the subsequent 6 days, digoxin 0.25 mg, either alone or with fimasartan 240 mg was administered once daily. Serial blood samples for pharmacokinetics were collected up to 24 h after the last administration in each period. Results: The geometric mean ratio and 90% confidence intervals (CI) for the Cmax,ss and AUCτ,ss of digoxin (with/without fimasartan) were 1.307 (1.123 - 1.520) and 1.087 (1.015 - 1.165), respectively. Study medications were well-tolerated without serious adverse events or clinically meaningful changes. Conclusions: Coadministration of fimasartan with digoxin does not result in clinically significant changes of digoxin pharmacokinetics at steady-state in healthy subjects.     

Protective activity of the ethanol extract of Cynanchum paniculatum (BUNGE) Kitagawa on treating herpes simplex encephalitis

To date there has been no valid treatment for herpes simplex encephalitis (HSV). This study explores the protective activity of ethanol extract of Cynanchum paniculatum (bunge) kitagawa for treatment of HSV. Cell models and animal models were established and divided into 4 groups: normal group, virus group, cynanchum paniculatum group and Dexamethasone group. Flow cytometry was employed to detect apoptosis of cell model and TUNEL assay was chosen to detect apoptosis of animal tissues. The survival time of the animal models was observed. ELISA was used to measure TNF-alpha expression and the Greiss method to measure Nitric Oxide (NO) expression in the mouse brain. As a result, it was found that extract of Cynanchum paniculatum can improve the survival rate of HSV-infected mice. The extract could prevent apoptosis in the neuron cell model and reduce apoptosis rate in brain tissue after HSV infection. With the extract intervention, TNF-alpha and NO levels in brain tissue were significantly decreased in the animal model. In conclusion, the extract of Cynanchum paniculatum can prevent HSV-inducing impairment in the cell and animal model of HSE.     

Histopathological and immunohistochemical comparison of the brain of human patients with Alzheimer's disease and the brain of aged dogs with cognitive dysfunction

Alzheimer's disease (AD) is the most common progressive form of dementia in aged people. Microscopical changes in the brains of AD patients include the formation of senile plaques (SPs), neurofibrillary tangles (NFTs) and granulovacuolar degeneration and the deposition of amyloid-beta (Aβ). Aged dogs are known to suffer from cognitive dysfunction and this state is associated with deposition of Aβ in the brain. The aim of the present study was to investigate tau phosphorylation of neurons and astrocytes in the brain of aged dogs with progressive cognitive impairment. Changes in the brain of aged dogs with cognitive dysfunction were compared with those in the brain of patients with AD of Braak stage V. Immunohistochemically, Aβ deposition, phosphorylated tau Ser396 (p-tau Ser396) and ubiquitin were observed in the parietal cortex and hippocampus of aged dogs with cognitive dysfunction. Astrocytes with expression of p-tau Ser396 and neurons with co-localization of p-tau Ser396 and ubiquitin were observed. Expression of p-tau Ser396 and accumulation of ubiquitin were significantly increased in the parietal cortex and dorsal part of the hippocampus of the brain of aged dogs when compared with expression of these molecules in human AD.     

GATE V6: a major enhancement of the GATE simulation platform enabling modelling of CT and radiotherapy

GATE (Geant4 Application for Emission Tomography) is a Monte Carlo simulation platform developed by the OpenGATE collaboration since 2001 and first publicly released in 2004. Dedicated to the modelling of planar scintigraphy, single photon emission computed tomography (SPECT) and positron emission tomography (PET) acquisitions, this platform is widely used to assist PET and SPECT research. A recent extension of this platform, released by the OpenGATE collaboration as GATE V6, now also enables modelling of x-ray computed tomography and radiation therapy experiments. This paper presents an overview of the main additions and improvements implemented in GATE since the publication of the initial GATE paper (Jan et al 2004 Phys. Med. Biol. 49 4543-61). This includes new models available in GATE to simulate optical and hadronic processes, novelties in modelling tracer, organ or detector motion, new options for speeding up GATE simulations, examples illustrating the use of GATE V6 in radiotherapy applications and CT simulations, and preliminary results regarding the validation of GATE V6 for radiation therapy applications. Upon completion of extensive validation studies, GATE is expected to become a valuable tool for simulations involving both radiotherapy and imaging.