Viral Delivery of the Fat-1 Gene to Treat Post-Traumatic Arthritis with Diet-Induced Obesity

Post-traumatic arthritis (PTA) is arthritis that develops following joint injury, including meniscus and ligament tears. Current treatments for PTA range from over-the-counter medication to knee replacement; however, in the presence of obesity, the levels of pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α,) are more elevated than in non-obese individuals. The role of fatty acids, obesity, and PTA has been examined, with omega-3 fatty acids showing promise as an anti-inflammatory after injury due to its ability to suppress IL-1 and TNF-α. Due to the difficulty in switching patients’ diets, an alternative solution to increasing omega-3 levels needs to be developed. The Fat-1 enzyme, an omega-3 desaturase that has the ability to convert omega-6 to omega-3 fatty acids, may be a good target for increasing the omega-3 levels in the body.

In the first study, we examined whether Fat-1 transgenic mice on a high-fat diet would exhibit lower levels of PTA degeneration following the destabilization of the medial meniscus (DMM). Both male and female Fat-1 and wild-type (WT) littermates were put on either a control diet (10% fat) or an omega-6 rich high-fat diet (60% fat) and underwent DMM surgery. Arthritic changes were examined 12 weeks post-surgery. Fat-1 mice on both the control and high-fat diet showed protection from PTA-related degeneration, while WT mice showed severe arthritic changes. These findings suggest that the omega-6/omega-3 ratio plays an important role in reducing PTA following injury, and demonstrates the potential therapeutic benefit of the Fat-1 enzyme in preventing PTA in both normal and obese patients following acute injury.

Following this, we needed to establish a translatable delivery mechanism for getting the Fat-1 enzyme, which is not present in mammalian cells, into patients. In the second study, we examined whether anti-inflammatory gene delivery of the Fat-1 enzyme would prevent PTA following DMM surgery. In vitro testing of both lentivirus (LV) and adeno-associated virus (AAV) was completed to confirm functionality and conformation of the Fat-1 enzyme after transduction. Male WT mice were placed on an omega-6 rich high-fat diet (60% fat) and underwent DMM surgery; either local or systemic AAV injections of the Fat-1 enzyme or Luciferase, a vector control, were given immediately following surgery. 12 weeks post-surgery, arthritic changes were assessed. The systemic administration of the Fat-1 enzyme showed protection from synovial inflammation and osteophyte formation, while administration of Luciferase did not confer protection. These findings suggest the utility of gene therapy to deliver the Fat-1 enzyme, which has potential as a therapeutic for injured obese patients for the prevention of PTA.

An anti-TNF--α antibody mimetic to treat ocular inflammation

Infliximab is an antibody that neutralizes TNF-α and is used principally by systemic administration to treat many inflammatory disorders. We prepared the antibody mimetic Fab-PEG-Fab (FpFinfliximab) for direct intravitreal injection to assess whether such formulations have biological activity and potential utility for ocular use. FpFinfliximab was designed to address side effects caused by antibody degradation and the presence of the Fc region. Surface plasmon resonance analysis indicated that infliximab and FpFinfliximab maintained binding affinity for both human and murine recombinant TNF-α. No Fc mediated RPE cellular uptake was observed for FpFinfliximab. Both Infliximab and FpFinfliximab suppressed ocular inflammation by reducing the number of CD45+ infiltrate cells in the EAU mice model after a single intravitreal injection at the onset of peak disease. These results offer an opportunity to develop and formulate for ocular use, FpF molecules designed for single and potentially multiple targets using bi-specific FpFs.

Predictive modelling : parents’ decision making to use online child health information to increase their understanding and/or diagnose or treat their child’s health

Abstract Background The quantum increases in home Internet access and available online health information with limited control over information quality highlight the necessity of exploring decision making processes in accessing and using online information, specifically in relation to children who do not make their health decisions. Objectives To understand the processes explaining parents’ decisions to use online health information for child health care. Methods Parents (N = 391) completed an initial questionnaire assessing the theory of planned behaviour constructs of attitude, subjective norm, and perceived behavioural control, as well as perceived risk, group norm, and additional demographic factors. Two months later, 187 parents completed a follow-up questionnaire assessing their decisions to use online information for their child’s health care, specifically to 1) diagnose and/or treat their child’s suspected medical condition/illness and 2) increase understanding about a diagnosis or treatment recommended by a health professional. Results Hierarchical multiple regression showed that, for both behaviours, attitude, subjective norm, perceived behavioural control, (less) perceived risk, group norm, and (non) medical background were the significant predictors of intention. For parents’ use of online child health information, for both behaviours, intention was the sole significant predictor of behaviour. The findings explain 77% of the variance in parents’ intention to treat/diagnose a child health problem and 74% of the variance in their intentions to increase their understanding about child health concerns. Conclusions Understanding parents’ socio-cognitive processes that guide their use of online information for child health care is important given the increase in Internet usage and the sometimes-questionable quality of health information provided online. Findings highlight parents’ thirst for information; there is an urgent need for health professionals to provide parents with evidence-based child health websites in addition to general population education on how to evaluate the quality of online health information.

Report to the Government 2.0 Taskforce : Project 4 - Copyright Law and Intellectual Property

This report is the primary output of Project 4: Copyright and Intellectual Property, the aim of which was to produce a report considering how greater access to and use of government information could be achieved within the scope of the current copyright law. In our submission for Project 4, we undertook to address: •the policy rationales underlying copyright and how they apply in the context of materials owned, held and used by government; • the recommendations of the Copyright Law Review Committee (CLRC) in its 2005 report on Crown copyright; • the legislative and regulatory barriers to information sharing in key domains, including where legal impediments such as copyright have been relied upon (whether rightly or wrongly) to justify a refusal to provide access to government data; • copyright licensing models appropriate to government materials and examples of licensing initiatives in Australia and other relevant jurisdictions; and • issues specific to the galleries, libraries, archives and museums (“GLAM”) sector, including management of copyright in legacy materials and “orphan” works. In addressing these areas, we analysed the submissions received in response to the Government 2.0 Taskforce Issues Paper, consulted with members of the Task Force as well as several key stakeholders and considered the comments posted on the Task Force’s blog. This Project Report sets out our findings on the above issues. It puts forward recommendations for consideration by the Government 2.0 Task Force on steps that can be taken to ensure that copyright and intellectual property promote access to and use of government information.

The cost effectiveness of Naltrexone added to cognitive-behavioral therapy in the treatment of alcohol dependence

he purpose of this study was to evaluate the comparative cost of treating alcohol dependence with either cognitive behavioral therapy (CBT) alone or CBT combined with naltrexone (CBT+naltrexone). Two hundred ninety-eight outpatients dependent on alcohol who were consecutively treated for alcohol dependence participated in this study. One hundred seven (36%) patients received adjunctive pharmacotherapy (CBT+naltrexone). The Drug Abuse Treatment Cost Analysis Program was used to estimate treatment costs. Adjunctive pharmacotherapy (CBT+naltrexone) introduced an additional treatment cost and was 54% more expensive than CBT alone. When treatment abstinence rates (36.1% CBT; 62.6% CBT+naltrexone) were applied to cost effectiveness ratios, CBT+naltrexone demonstrated an advantage over CBT alone. There were no differences between groups on a preference-based health measure (SF-6D). In this treatment center, to achieve 100 abstainers over a 12-week program, 280 patients require CBT compared with 160 CBT+naltrexone. The dominant choice was CBT+naltrexone based on modest economic advantages and significant efficiencies in the numbers needed to treat.

Development of novel vaccine strategies to prevent genital tract chlamydial infections

Chlamydia trachomatis is the most prevalent bacterial sexually transmitted infection in the developed world and the leading cause of preventable blindness worldwide. As reported by the World Health Organization in 2001, there are approximately 92 million new infections detected annually, costing health systems billions of dollars to treat not only the acute infection, but also to treat infection-associated sequelae. The majority of genital infections are asymptomatic, with 50-70% going undetected. Genital tract infections can be easily treated with antibiotics when detected. Lack of treatment can lead to the development of pelvic inflammatory disease, ectopic pregnancies and tubal factor infertility in women and epididymitis and prostatitis in men. With infection rates on the continual rise and the large number of infections going undetected, there is a need to develop an efficacious vaccine which prevents not only infection, but also the development of infection-associated pathology. Before a vaccine can be developed and administered, the pathogenesis of chlamydial infections needs to be fully understood. This includes the kinetics of ascending infection and the effects of inoculating dose on ascension and development of pathology. The first aim in this study was to examine these factors in a murine model. Female BALB/c mice were infected intravaginally with varying doses of C. muridarum, the mouse variant of human C. trachomatis, and the ascension of infection along the reproductive tract and the time-course of infection-associated pathology development, including inflammatory cell infiltration, pyosalpinx and hydrosalpinx, were determined. It was found that while the inoculating dose did affect the rate and degree of infection, it did not affect any of the pathological parameters examined. This highlighted that the sexual transmission dose may have minimal effect on the development of reproductive sequelae. The results of the first section enabled further studies presented here to use an optimal inoculating dose that would ascend the reproductive tract and cause pathology development, so that vaccine efficacy could be determined. There has been a large amount of research into the development of an efficacious vaccine against genital tract chlamydial infections, with little success. However, there have been no studies examining the effects of the timing of vaccination, including the effects of vaccination during an active genital infection, or after clearance of a previous infection. These are important factors that need to be examined, as it is not yet known whether immunization will enhance not only the individual's immune response, but also pathology development. It is also unknown whether any enhancement of the immune responses will cause the Chlamydia to enter a dormant, persistent state, and possibly further enhance any pathology development. The second section of this study aimed to determine if vaccination during an active genital tract infection, or after clearance of a primary infection, enhanced the murine immune responses and whether any enhanced or reduced pathology occurred. Naïve, actively infected, or previously infected animals were immunized intranasally or transcutaneously with the adjuvants cholera toxin and CpG-ODN in combination with either the major outer membrane protein (MOMP) of C. muridarum, or MOMP and ribonucleotide reductase small chain protein (NrdB) of C. muridarum. It was found that the systemic immune responses in actively or previously infected mice were altered in comparison to animals immunized naïve with the same combinations, however mucosal antibodies were not enhanced. It was also found that there was no difference in pathology development between any of the groups. This suggests that immunization of individuals who may have an asymptomatic infection, or may have been previously exposed to a genital infection, may not benefit from vaccination in terms of enhanced immune responses against re-exposure. The final section of this study aimed to determine if the vaccination regimes mentioned above caused in vivo persistence of C. muridarum in the upper reproductive tracts of mice. As there has been no characterization of C. muridarum persistence in vitro, either ultrastructurally or via transcriptome analysis, this was the first aim of this section. Once it had been shown that C. muridarum could be induced into a persistent state, the gene transcriptional profiles of the selected persistent marker genes were used to determine if persistent infections were indeed present in the upper reproductive tracts of the mice. We found that intranasal immunization during an active infection induced persistent infections in the oviducts, but not the uterine horns, and that intranasal immunization after clearance of infection, caused persistent infections in both the uterine horns and the oviducts of the mice. This is a significant finding, not only because it is the first time that C. muridarum persistence has been characterized in vitro, but also due to the fact that there is minimal characterization of in vivo persistence of any chlamydial species. It is possible that the induction of persistent infections in the reproductive tract might enhance the development of pathology and thereby enhance the risk of infertility, factors that need to be prevented by vaccination, not enhanced. Overall, this study has shown that the inoculating dose does not affect pathology development in the female reproductive tract of infected mice, but does alter the degree and rate of ascending infection. It has also been shown that intranasal immunization during an active genital infection, or after clearance of one, induces persistent infections in the uterine horns and oviducts of mice. This suggests that potential vaccine candidates will need to have these factors closely examined before progressing to clinical trials. This is significant, because if the same situation occurs in humans, a vaccine administered to an asymptomatic, or previously exposed individual may not afford any extra protection and may in fact enhance the risk of development of infection-associated sequelae. This suggests that a vaccine may serve the community better if administered before the commencement of sexual activity.

The interactions between insulin and androgens in progression to castrate resistant prostate cancer

An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT) in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer.

A microscopic simulation model to estimate Bus Rapid Transit (BRT) station service capacity with mixed stopping and non-stopping bus operation

Bus Rapid Transit (BRT) station is the interface between passenger and service. The station is crucial to line operation as it is typically the only location where buses can pass each other. Congestion may occur here when buses maneuvering into and out of the platform lane interfere with bus flow, or when a queue of buses forms upstream of the platform lane blocking the passing lane. However, some systems include operation where express buses pass the critical station, resulting in a proportion of non stopping buses. It is important to understand the operation of the critical busway station under this type of operation, as it affects busway line capacity. This study uses micro simulation to treat the BRT station operation and to analyze the relationship between station Limit state bus capacity (B_ls), Total Bus Capacity (B_ttl). First, the simulation model is developed for Limit state scenario and then a mathematical model is defined, calibrated for a specified range of controlled scenarios of mean and coefficient of variation of dwell time. Thereafter, the proposed B_ls model is extended to consider non stopping buses and B_ttlmodel is defined. The proposed models provides better understanding to the BRT line capacity and is useful for transit authorities for designing better BRT operation.

The potential contributions of traditional Chinese medicine to emergency medicine

BACKGROUND: Despite the fact that traditional Chinese medicine (TCM) has been developed and used to treat acute and urgent illness for many thousands of years. TCM has been widely perceived in western societies that TCM may only be effective to treat chronic diseases. The aim of this article is to provide some scientific evidence regarding the application of TCM in emergency medicine and its future potential. METHODS: Multiple databases (PubMed, ProQuest, Academic Search Elite and Science Direct) were searched using the terms: Traditional Chinese Medicine/ Chinese Medicine, Emergency Medicine, China. In addition, three leading TCM Journals in China were searched via Oriprobe Information Services for relevant articles (published from 1990—2012). Particular attention was paid to those articles that are related to TCM treatments or combined medicine in dealing with intensive and critical care. RESULTS: TCM is a systematic traditional macro medicine. The clinical practice of TCM is guided by the TCM theoretical framework – a methodology founded thousands of years ago. As the methodologies between TCM and Biomedicine are significantly different, it provides an opportunity to combine two medicines, in order to achieve clinical efficacy. Nowadays, combined medicine has become a common clinical model particular in TCM hospitals in China. CONCLUSIONS: It is evident that TCM can provide some assistance in emergency although to combine them in practice is stillits infant form and is mainly at TCM hospitals in China. The future effort could be put into TCM research, both in laboratories and clinics, with high quality designs, so that TCM could be better understood and then applied in emergency medicine.

A microscopic simulation model to estimate bus rapid transit station bus capacity

The Bus Rapid Transit (BRT) station is the interface between passengers and services. The station is crucial to line operation as it is typically the only location where buses can pass each other. Congestion may occur here when buses maneuvering into and out of the platform lane interfere with bus flow, or when a queue of buses forms upstream of the platform lane blocking the passing lane. Further, some systems include operation where express buses do not observe the station, resulting in a proportion of non-stopping buses. It is important to understand the operation of the station under this type of operation and its effect on BRT line capacity. This study uses microscopic traffic simulation modeling to treat the BRT station operation and to analyze the relationship between station bus capacity and BRT line bus capacity. First, the simulation model is developed for the limit state scenario and then a statistical model is defined and calibrated for a specified range of controlled scenarios of dwell time characteristics. A field survey was conducted to verify the parameters such as dwell time, clearance time and coefficient of variation of dwell time to obtain relevant station bus capacity. The proposed model for BRT bus capacity provides a better understanding of BRT line capacity and is useful to transit authorities in BRT planning, design and operation.

Investigation of a food poisoning outbreak due to nitrite contained in cooked peanut [一起因食用煮花生米引起亚硝酸盐中毒的调查报告]

Two workers were hospitalised with similar symptoms. Information was gathered from patients, doctors, colleagues and food seller. Laboratory tests were undertaken on remaining food and vomits. We identified the source food and toxin responsible for this outbreak, and subsequently helped doctors to treat these patients. The intake was estimated to be over the fatal limit but both were fully recovered after treatment. Abstract in Chinese 2001年11月20日，寿光市植物油厂的2名装卸工人因食用花生米引起亚硝酸盐急性中毒，现报告如下。 1 中毒经过 11月20日下午，市植物油厂装卸工人秦×下班后，到本厂职工食堂买了馒头、大米稀饭和少许咸菜，然后到厂外买了1瓶白酒，又到个体菜摊李×处买了2元钱的煮花生米，约400g。17：40与同事江×一同在宿舍内饮酒吃饭，其中花生米大部分被秦×吃掉，江×吃得少。18：30左右秦×在装卸过程中出现双腿发软、恶心、呕吐、呼吸困难、视物模糊，江×随后也出现类似症状，2人被迅速送往寿光市人民医院进行抢救。到医院时已进入昏迷状态，查体可见全身皮肤粘膜青紫、手指脚趾发黑，经吸氧并心电监护、应用美兰静推后，江×症状减轻，于次日出院；秦×因中毒严重，于次日脱离危险，11月23日痊愈出院。……

The role of epigenetics in resistance to cisplatin chemotherapy in lung cancer

Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in the world. Cisplatin and carboplatin are the most commonly used cytotoxic chemotherapeutic agents to treat the disease. These agents, usually combined with drugs such as gemcitabine or pemetrexed, induce objective tumor responses in only 20-30% of patients. Aberrant epigenetic regulation of gene expression is a frequent event in NSCLC. In this article we review the emerging evidence that epigenetics and the cellular machinery involved with this type of regulation may be key elements in the development of cisplatin resistance in NSCLC. © 2011 by the authors; licensee MDPI, Basel, Switzerland.