Second best toll and capacity optimisation in network: solution algorithm and policy implications

This paper looks at the first and second-best jointly optimal toll and road capacity investment problems from both policy and technical oriented perspectives. On the technical side, the paper investigates the applicability of the constraint cutting algorithm for solving the second-best problem under elastic demand which is formulated as a bilevel programming problem. The approach is shown to perform well despite several problems encountered by our previous work in Shepherd and Sumalee (2004). The paper then applies the algorithm to a small sized network to investigate the policy implications of the first and second-best cases. This policy analysis demonstrates that the joint first best structure is to invest in the most direct routes while reducing capacities elsewhere. Whilst unrealistic this acts as a useful benchmark. The results also show that certain second best policies can achieve a high proportion of the first best benefits while in general generating a revenue surplus. We also show that unless costs of capacity are known to be low then second best tolls will be affected and so should be analysed in conjunction with investments in the network

Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin A-4 phosphate

BACKGROUND: This study was designed to assess the safety, tolerability, and efficacy of intravenous infusion of CA4P in patients with neovascular age-related macular degeneration (AMD). METHODS: Prospective, interventional, dose-escalation clinical trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly intravenous infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and physical examinations, electrocardiogram, routine laboratory tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiography, optical coherence tomography, and best corrected visual acuity (BCVA). RESULTS: The most common adverse events were elevated blood pressure (46.7%), QTc prolongation (23.3%), elevated temperature (13.3%), and headache (10%), followed by nausea and eye injection (6.7%). There were no adverse events that were considered severe in intensity and none resulted in discontinuation of treatment. There was reduction of the excess foveal thickness by 24.15% at end of treatment period and by 43.75% at end of the two-month follow-up (p = 0.674 and 0.161, respectively). BCVA remained stable throughout the treatment and follow-up periods. CONCLUSIONS: The safety profile of intravenous CA4P was consistent with that reported in oncology trials of CA4P and with the class effects of vascular disruptive agents; however, the frequency of adverse events was different. There are evidences to suggest potential efficacy of CA4P in neovascular AMD. However, the level of systemic safety and efficacy indicates that systemic CA4P may not be suitable as an alternative monotherapy to current standard-of-care therapy

Effects of a contoured articular prosthetic device on tibiofemoral peak contact pressure: a biomechanical study

Many middle-aged patients are affected by localized cartilage defects that are neither appropriate for primary, nor repeat biological repair methods, nor for conventional arthroplasty. This in vitro study aims to determine the peak contact pressure in the tibiofemoral joint with a partial femoral resurfacing device (HemiCAP®, Arthrosurface Inc., Franklin, MA, USA). Peak contact pressure was determined in eight fresh-frozen cadaveric specimens using a Tekscan sensor placed in the medial compartment above the menisci. A closed loop robotic knee simulator was used to test each knee in static stance positions (5°/15°/30°/45°) with body weight ground reaction force (GRF), 30° flexion with twice the body weight (2tBW) GRF and dynamic knee-bending cycles with body weight GRF. The ground reaction force was adjusted to the living body weight of the cadaver donor and maintained throughout all cycles. Each specimen was tested under four different conditions: Untreated, flush HemiCAP® implantation, 1-mm proud implantation and 20-mm defect. A paired sampled t test to compare means (significance, P ≤ 0.05) was used for statistical analysis. On average, no statistically significant differences were found in any testing condition comparing the normal knee with flush device implantation. With the 1-mm proud implant, statistically significant increase of peak contact pressures of 217% (5° stance), 99% (dynamic knee bending) and 90% (30° stance with 2tBW) compared to the untreated condition was seen. No significant increase of peak contact pressure was evaluated with the 20-mm defect. The data suggests that resurfacing with the HemiCAP® does not lead to increased peak contact pressure with flush implantation. However, elevated implantation results in increased peak contact pressure and might be biomechanically disadvantageous in an in vivo application

Cigarettes and alcohol in relation to colorectal cancer: the Singapore Chinese Health Study

The relations were examined between colorectal cancer and cigarette smoking and alcohol consumption within the Singapore Chinese Health Study, a population-based, prospective cohort of 63 257 middle-aged and older Chinese men and women enrolled between 1993 and 1998, from whom baseline data on cigarette smoking and alcohol consumption were collected through in-person interviews. By 31 December 2004, 845 cohort participants had developed colorectal cancer (516 colon cancer, 329 rectal cancer). Compared with nondrinkers, subjects who drank seven or more alcoholic drinks per week had a statistically significant, 72% increase in risk of colorectal cancer hazard ratio (HR)=1.72; 95% confidence interval (CI)=1.33–2.22). Cigarette smoking was associated with an increased risk of rectal cancer only. Compared with nonsmokers, HRs (95% CIs) for rectal cancer were 1.43 (1.10–1.87) for light smokers and 2.64 (1.77–3.96) for heavy smokers. Our data indicate that cigarette smoking and alcohol use interact in the Chinese population in an additive manner in affecting risk of rectal cancer, thus suggesting that these two exposures may share a common etiologic pathway in rectal carcinogenesis

Image informatics strategies for deciphering neuronal network connectivity

Brain function relies on an intricate network of highly dynamic neuronal connections that rewires dramatically under the impulse of various external cues and pathological conditions. Among the neuronal structures that show morphologi- cal plasticity are neurites, synapses, dendritic spines and even nuclei. This structural remodelling is directly connected with functional changes such as intercellular com- munication and the associated calcium-bursting behaviour. In vitro cultured neu- ronal networks are valuable models for studying these morpho-functional changes. Owing to the automation and standardisation of both image acquisition and image analysis, it has become possible to extract statistically relevant readout from such networks. Here, we focus on the current state-of-the-art in image informatics that enables quantitative microscopic interrogation of neuronal networks. We describe the major correlates of neuronal connectivity and present workflows for analysing them. Finally, we provide an outlook on the challenges that remain to be addressed, and discuss how imaging algorithms can be extended beyond in vitro imaging studies

Selective Down-Regulation of Nuclear Poly(ADP-Ribose) Glycohydrolase

The formation of ADP-ribose polymers on target proteins by poly(ADP-ribose) polymerases serves a variety of cell signaling functions. In addition, extensive activation of poly(ADP-ribose) polymerase-1 (PARP-1) is a dominant cause of cell death in ischemia-reperfusion, trauma, and other conditions. Poly(ADP-ribose) glycohydrolase (PARG) degrades the ADP-ribose polymers formed on acceptor proteins by PARP-1 and other PARP family members. PARG exists as multiple isoforms with differing subcellular localizations, but the functional significance of these isoforms is uncertain.Primary mouse astrocytes were treated with an antisense phosphorodiamidate morpholino oligonucleotide (PMO) targeted to exon 1 of full-length PARG to suppress expression of this nuclear-specific PARG isoform. The antisense-treated cells showed down-regulation of both nuclear PARG immunoreactivity and nuclear PARG enzymatic activity, without significant alteration in cytoplasmic PARG activity. When treated with the genotoxic agent MNNG to induced PARP-1 activation, the antisense-treated cells showed a delayed rate of nuclear PAR degradation, reduced nuclear condensation, and reduced cell death.These results support a preferentially nuclear localization for full-length PARG, and suggest a key role for this isoform in the PARP-1 cell death pathway

Separability of neural responses to standardised mechanical stimulation of limbs

Abstract Considerable scientific and technological efforts are currently being made towards the development of neural prostheses. Understanding how the peripheral nervous system responds to electro-mechanical stimulation of the limb, will help to inform the design of prostheses that can restore function or accelerate recovery from injury to the sensory motor system. However, due to differences in experimental protocols, it is difficult, if not impossible, to make meaningful comparisons between different peripheral nerve interfaces. Therefore, we developed a low-cost electronic system to standardise the mechanical stimulation of a rat’s hindpaw. Three types of mechanical stimulations, namely, proprioception, touch and nociception were delivered to the limb and the electroneurogram signals were recorded simultaneously from the sciatic nerve with a 16-contact cuff electrode. For the first time, results indicate separability of neural responses according to stimulus type as well as intensity. Statistical analysis reveal that cuff contacts placed circumferentially, rather than longitudinally, are more likely to lead to higher classification rates. This flexible setup may be readily adapted for systematic comparison of various electrodes and mechanical stimuli in rodents. Hence, we have made its electro-mechanical design and computer programme available onlin

Cardio-Protection of Salvianolic Acid B through Inhibition of Apoptosis Network

Targeting cellular function as a system rather than on the level of the single target significantly increases therapeutic potency. In the present study, we detect the target pathway of salvianolic acid B (SalB) in vivo. Acute myocardial infarction (AMI) was induced in rats followed by the treatment with 10 mg/kg SalB. Hemodynamic detection and pathological stain, 2-dimensional electrophoresis, MALDI-TOF MS/MS, Western blot, pathway identification, apoptosis assay and transmission electron microscope were used to elucidate the effects and mechanism of SalB on cardioprotection. Higher SalB concentration was found in ischemic area compared to no-ischemic area of heart, correlating with improved heart function and histological structure. Thirty-three proteins regulated by SalB in AMI rats were identified by biochemical analysis and were classified as the components of metabolism and apoptosis networks. SalB protected cardiomyocytes from apoptosis, inhibited poly (ADP-ribose) polymerase-1 pathway, and improved the integrity of mitochondrial and nucleus of heart tissue during AMI. Furthermore, the protective effects of SalB against apoptosis were verified in H9c2 cells. Our results provide evidence that SalB regulates multi-targets involved in the apoptosis pathway during AMI and therefore may be a candidate for novel therapeutics of heart diseases