一种基于积分分离的内模PID主动队列管理算法

针对PI主动队列管理算法存在调节时间长和鲁棒性差的缺点,提出了一种基于积分分离的内模PID主动队列管理算法（IMC PDPID）。其突出特点是控制器参数整定方便,由于采用了积分分离的方法,使其既保持了积分作用,又减小了超调量。仿真结果表明：该算法较PI算法有更小的超调量,队列收敛速度明显加快。     

Treatment of hemangioma by transfection of antisense VEGF gene

The effect of transfection of antisense vascular endothelial growth factor （VEGF） gene on the growth of hemangioma was studied. A total of 49 cases of capillary hemangiomas of the skin were collected. Immunohistochemical method was used to detect the expression of PCNA in hemangioma tissues. According to the finding, 49 cases of hemangiomas fell into proliferating phase （27 cases） and involuting phase （22 cases） respectively. Another 5 cases of normal skin tissues adjacent to the tumor tissues served as control. Immunohistochemical staining was performed to detect the expression of VEGF in the tumor tissues and the normal tissues. The average absorbance （A） values and the average positive area rate of VEGF were measured by image analysis system （HPIAS-2000）. Endothelial cells from the tumor tissues in proliferating phase were cultured. Eukaryotic expression vector was constructed by sub-cloning, and transfected into human hemangioma endothelial cells by using cation liposome as vector. The expression of VEGF mRNA and protein was detected by RT-PCR and indirect immunofluorescence assay （IFA）, respectively, and the biological characteristics of the transfected endothelial cells were examined by MTT assay and flow cytometry （FCM） after transfection. Immunohistochemical results showed that the expression of VEGF in proliferating endothelial cells was remarkably higher than those in involuting endothelial cells and normal endothelial cells （P〈0.01）, but there was no significant difference in the expression of VEGF between involuting endothelial cells and normal ones （P〉0.01）. Electrophoresis and sequencing indicated that the eukaryotic expression vector containing antisense VEGF gene, i.e. pcDNA3.1-VEGF, was success- fully constructed. After VEGF antisense RNA recombinant was transfected into hemangioma endothelial cells, RT-PCR revealed that the expression of VEGF mRNA in pcDNA-VEGF （V） group and blank group was obviously higher than that in pcDNA-VEGF （A） group, and that the expression of endogenous VEGF mRNA in pcDNA-VEGF （A） group was significantly inhibited. Immunohistochemical result demonstrated that, compared with blank group, there was statistically significant difference between pcDNA-VEGF （A） and pcDNA-VEGF （V） groups （P〈0.01）, but there was no significant difference between pcDNA-VEGF （V） group and blank group （P〉0.05）. The activity of endothelial cell proliferation was reduced significantly after transfection, and obvious apoptosis occurred in hemangioma endothelial cells after transfection of antisense VEGF. It was suggested that VEGF plays an important role in the pathological change of hemangiomas by promoting endothelial cell proliferation and angiogenesis. Antisense VEGF gene transfection could effectively inhibit the growth of hemanioma endothelial cells.     

S35225 is a direct inhibitor of Plasminogen Activator Inhibitor type-1 activity in the blood

The increased risk of thrombotic events associated with disease states such as diabetes and hypertension has been correlated with elevated circulating levels of Plasminogen Activator Inhibitor type-1 (PAI-1). In the present study we evaluate the benzothiophene derivative S35225 in comparison with two recently described inhibitors of PAI-1 activity Tiplaxtinin and WAY140312 on a panel of PAI-1 activity assays in vitro and in vivo. In a direct chromogenic assay, S35225 has an IC50 value of 44+/-0.9 microM similar to that of Tiplaxtinin (34+/-7 microM) and of WAY140312 (39+/-1 microM). In a clot lysis assay however, S35225 has a significantly lower IC50 value than Tiplaxtinin and WAY140312 (0.6+/-0.3 versus 22+/-5 and 16+/-2 microM respectively). Using a tPA capture assay to quantify active PAI-1 in rat or human plasma, neither WAY140312, nor Tiplaxtinin attained 50% inhibition of PAI-1 activity at the highest concentration tested (1 mM); S35225 has an IC50 value of 194+/-30 microM against active rat PAI-1 and 260+/-41 microM against active human PAI-1. The ability of the compounds to inhibit endogenous active PAI-1 in the rat following intravenous administration was also tested using the tPA capture assay. Only S35225 reduced circulating active PAI-1 levels in vivo (maximum inhibition of 76+/-5% at 10 mg/kg and 53+/-5% at 3 mg/kg). In contrast to Tiplaxtinin and WAY140312, S35225 is a direct inhibitor of PAI-1 activity in vitro in rat and human plasmas where vitronectin is constitutively present as well as in vivo in the blood after an intravenous administration in the rat.     

Deletion of voltage-gated channel affects glomerular refinement and odorant receptor expression in the mouse olfactory system

Olfactory sensory neurons (OSNs) expressing a specific odorant receptor (OR) gene send axonal projections to specific glomeruli, creating a stereotypic olfactory sensory map. Odorant receptor sequence, G-protein cAMP signaling, and axon guidance molecules have been shown to direct axons of OSNs toward central targets in the olfactory bulb (OB). Although the OR sequence may act as one determinant, our objective was to elucidate the extent by which voltage-dependent activity of postsynaptic projection neurons in the OB centrally influences peripheral development and target destination of OSNs. We bred OR-tagged transgenic mice to homozygosity with mice that had a gene-targeted deletion of the Shaker potassium ion channel (Kv1.3) to elucidate how activity modulates synaptic connections that formulate the sensory map. Here we report that the Kv1.3 ion channel, which is predominantly expressed in mitral cells and whose gene-targeted deletion causes a "super-smeller" phenotype, alters synaptic refinement of axonal projections from OSNs expressing P2, M72, and MOR28 ORs. Absence of Kv1.3 voltage-gated activity caused the formation of small, heterogeneous, and supernumerary glomeruli that failed to undergo neural pruning over development. These changes were accompanied by a significant decrease in the number of P2-, M72-, and MOR28-expressing OSNs, which contained an overexpression of OR protein and G-protein G(olf) in the cilia of the olfactory epithelium. These findings suggest that voltage-gated activity of projection neurons is essential to refine primary olfactory projections and that it regulates proper expression of the transduction machinery at the periphery.     

A pilot study on the immunological effects of oral administration of donor major histocompatibility complex class II peptides in renal transplant recipients

Oral tolerance is an important physiological mechanism of immune hyporesponsiveness to dietary antigens and the commensal flora of the gastrointestinal tract. Feeding of alloantigens, therefore, has the potential to suppress undesirable immune responses after transplantation. To date, there are no published reports on the effects of such an approach in human transplant recipients. In the present pilot study, we demonstrate complete suppression of baseline indirect alloreactivity in patients with chronic renal allograft dysfunction following the oral feeding of low (0.5 mg/d) but not higher (1.0 and 5.0 mg/d) doses of donor major histocompatibility complex (MHC) class II peptides. The regimen was well tolerated with no evidence for sensitization to the donor antigen. Our results indicate that oral feeding of low dose donor MHC peptide may represent a safe and effective therapy to suppress indirect alloreactivity in renal transplant recipients with chronic allograft dysfunction and warrants further clinical investigation.     

Prostate-specific antigen velocity in untreated, localized prostate cancer

OBJECTIVE

To report the results of a prospective study of active surveillance of untreated prostate cancer, with a focus on baseline predictors of prostate‐specific antigen (PSA) velocity, as PSA velocity before treatment is an important predictor of prostate cancer mortality, and patients on active surveillance are monitored for several years to estimate the PSA velocity and thus select patients for radical treatment.

PATIENTS AND METHODS

A prospective study of active surveillance for localized prostate cancer opened at the Royal Marsden Hospital in 2002. Eligible patients had clinical stage T1/T2a, N0/Nx, M0/Mx adenocarcinoma of the prostate with a serum PSA level of <15 ng/mL, a Gleason score of ≤7 with primary grade ≤3, and less than half the biopsy cores positive. The PSA velocity before treatment was analysed in relation to baseline clinical characteristics.

RESULTS

In all, 237 patients on surveillance were followed for a median of 24 months (median age 67 years; median initial PSA level 6.5 ng/mL; median pretreatment PSA velocity 0.44 ng/mL per year). On multivariate analysis, PSA density (i.e. serum PSA level/prostate volume) was the only significant determinant of PSA velocity (P < 0.001). Patients with a PSA density above or below the median (0.185 ng/mL/mL) had a median (interquartile range) PSA velocity of 0.92 (0.34–1.77) ng/mL per year and 0.35 (? 0.06, 0.80) ng/mL per year, respectively.

CONCLUSIONS

PSA density, which is readily available at the time of diagnosis, is an independent determinant of PSA velocity in untreated, localized prostate cancer. If this is confirmed, PSA density could be used to inform the often difficult choice between active surveillance and immediate radical treatment.     

Effects of FAK ablation on cerebellar foliation, Bergmann glia positioning and climbing fiber territory on Purkinje cells

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is widely expressed in the brain, and plays key roles in various cellular processes in response to both extracellular and intracellular stimuli. Here, we explored the role of FAK in cerebellar development. In the mouse cerebellum, FAK was found to be distributed as tiny cytoplasmic aggregates in various neuronal and glial elements, including Purkinje cells (PCs), Bergmann glia (BG), parallel fiber (PF)-terminals and climbing fiber (CF)-terminals. The neuron/glia-specific ablation of FAK impaired cerebellar foliation, such as variable decreases in foliation sizes and the lack of intercrural and precentral fissures. Some of the BG cells became situated ectopically in the molecular layer. Furthermore, the FAK ablation altered the innervation territories of CFs and PFs on PCs. CF innervation regressed to the basal portion of proximal dendrites and somata, whereas ectopic spines protruded from proximal dendrites and PFs expanded their territory by innervating the ectopic spines. Furthermore, the persistence of surplus CFs innervating PC somata caused multiple innervation. When FAK was selectively ablated in PCs, diminished dendritic innervation and persistent somatic innervation by CFs were observed, whereas cerebellar foliation and cell positioning of BG were normally retained. These results suggest that FAK in various neuronal and glial elements is required for the formation of normal histoarchitecture and cytoarchitecture in the cerebellum, and for the construction of proper innervation territory and synaptic wiring in PCs.     

A novel role for MNTB neuron dendrites in regulating action potential amplitude and cell excitability during repetitive firing

Principal cells of the medial nucleus of the trapezoid body (MNTB) are simple round neurons that receive a large excitatory synapse (the calyx of Held) and many small inhibitory synapses on the soma. Strangely, these neurons also possess one or two short tufted dendrites, whose function is unknown. Here we assess the role of these MNTB cell dendrites using patch-clamp recordings, imaging and immunohistochemistry techniques. Using outside-out patches and immunohistochemistry, we demonstrate the presence of dendritic Na⁺ channels. Current-clamp recordings show that tetrodotoxin applied onto dendrites impairs action potential (AP) firing. Using Na⁺ imaging, we show that the dendrite may serve to maintain AP amplitudes during high-frequency firing, as Na⁺ clearance in dendritic compartments is faster than axonal compartments. Prolonged high-frequency firing can diminish Na⁺ gradients in the axon while the dendritic gradient remains closer to resting conditions; therefore, the dendrite can provide additional inward current during prolonged firing. Using electron microscopy, we demonstrate that there are small excitatory synaptic boutons on dendrites. Multi-compartment MNTB cell simulations show that, with an active dendrite, dendritic excitatory postsynaptic currents (EPSCs) elicit delayed APs compared with calyceal EPSCs. Together with high- and low-threshold voltage-gated K⁺ currents, we suggest that the function of the MNTB dendrite is to improve high-fidelity firing, and our modelling results indicate that an active dendrite could contribute to a 'dual' firing mode for MNTB cells (an instantaneous response to calyceal inputs and a delayed response to non-calyceal dendritic excitatory postsynaptic potentials).     

Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs: part 3. Therapeutic efficacy and safety studies in ovarian cancer xenograft model

Purpose The objective of this study was to evaluate the anti-tumor efficacy and lack of systemic toxicity of paclitaxel when administered in pH-sensitive poly(ethylene oxide) (PEO)-modified poly(beta-amino ester) (PbAE) nanoparticles in mice bearing human ovarian adenocarcinoma (SKOV-3) xenograft. Methods Paclitaxel-encapsulated PEO-modified PbAE (PEO–PbAE) nanoparticles were prepared by the solvent displacement method. PEO-modified poly(epsilon-caprolactone) (PCL) (PEO–PCL) nanoparticles were used as a non pH-responsive control formulation. Efficacy studies were conducted in SKOV-3 tumor-bearing athymic (Nu/Nu) mice at an equivalent paclitaxel dose of 20 mg/kg with the control and nanoparticle formulations. Safety of the drug when administered in the control and nanoparticle formulation was determined from blood cell counts and changes in body weight of the animals. Results The formulated paclitaxel-containing PEO–PbAE and PEO–PCL nanoparticles had a particle size in the range of 100–200 nm and a surface charge of + 39.0 and − 30.8 mV, respectively. After intravenous administration of paclitaxel in these formulations, the tumor growth was inhibited significantly. Both of the formulated nanoparticles tested have shown improved therapeutic efficacy as compared to the paclitaxel aqueous solution. Additionally, significantly lower toxicity profile of paclitaxel was observed with PEO-modified nanoparticles as compared to the aqueous solution formulation Conclusion PEO-modified PbAE nanoparticles are a unique pH-sensitive drug delivery system that elicits enhanced efficacy and safety profile in solid tumor therapy.