Purine Nucleoside Phosphorylase mediated molecular chemotherapy and conventional chemotherapy: A tangible union against chemoresistant cancer

Background Late stage Ovarian Cancer is essentially incurable primarily due to late diagnosis and its inherent heterogeneity. Single agent treatments are inadequate and generally lead to severe side effects at therapeutic doses. It is crucial to develop clinically relevant novel combination regimens involving synergistic modalities that target a wider repertoire of cells and lead to lowered individual doses. Stemming from this premise, this is the first report of two- and three-way synergies between Adenovirus-mediated Purine Nucleoside Phosphorylase based gene directed enzyme prodrug therapy (PNP-GDEPT), docetaxel and/or carboplatin in multidrug-resistant ovarian cancer cells. Methods The effects of PNP-GDEPT on different cellular processes were determined using Shotgun Proteomics analyses. The in vitro cell growth inhibition in differentially treated drug resistant human ovarian cancer cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The involvement of apoptosis and implicated proteins in effects of different treatments was established using flow cytometry based detection of M30 (an early marker of apoptosis), cell cycle analyses and finally western blot based analyses. Results Efficacy of the trimodal treatment was significantly greater than that achieved with bimodal- or individual treatments with potential for 10-50 fold dose reduction compared to that required for individual treatments. Of note was the marked enhancement in apoptosis that specifically accompanied the combinations that included PNP-GDEPT and accordingly correlated with a shift in the expression of anti- and pro-apoptotic proteins. PNP-GDEPT mediated enhancement of apoptosis was reinforced by cell cycle analyses. Proteomic analyses of PNP-GDEPT treated cells indicated a dowregulation of proteins involved in oncogenesis or cancer drug resistance in treated cells with accompanying upregulation of apoptotic- and tumour- suppressor proteins. Conclusion Inclusion of PNP-GDEPT in regular chemotherapy regimens can lead to significant enhancement of the cancer cell susceptibility to the combined treatment. Overall, these data will underpin the development of regimens that can benefit patients with late stage ovarian cancer leading to significantly improved efficacy and increased quality of life.

Against Ingres

Poem

Malnutrition screening tools : comparison against two validated nutrition assessment methods in older medical inpatients

Objective Although several validated nutritional screening tools have been developed to “triage” inpatients for malnutrition diagnosis and intervention, there continues to be debate in the literature as to which tool/tools clinicians should use in practice. This study compared the accuracy of seven validated screening tools in older medical inpatients against two validated nutritional assessment methods. Methods This was a prospective cohort study of medical inpatients at least 65 y old. Malnutrition screening was conducted using seven tools recommended in evidence-based guidelines. Nutritional status was assessed by an accredited practicing dietitian using the Subjective Global Assessment (SGA) and the Mini-Nutritional Assessment (MNA). Energy intake was observed on a single day during first week of hospitalization. Results In this sample of 134 participants (80 ± 8 y old, 50% women), there was fair agreement between the SGA and MNA (κ = 0.53), with MNA identifying more “at-risk” patients and the SGA better identifying existing malnutrition. Most tools were accurate in identifying patients with malnutrition as determined by the SGA, in particular the Malnutrition Screening Tool and the Nutritional Risk Screening 2002. The MNA Short Form was most accurate at identifying nutritional risk according to the MNA. No tool accurately predicted patients with inadequate energy intake in the hospital. Conclusion Because all tools generally performed well, clinicians should consider choosing a screening tool that best aligns with their chosen nutritional assessment and is easiest to implement in practice. This study confirmed the importance of rescreening and monitoring food intake to allow the early identification and prevention of nutritional decline in patients with a poor intake during hospitalization.

Crimes against morality

The purpose of this chapter is to discuss the relationship between crime and morality, with a specific focus on crimes against morality. While we argue that all crimes have a general moral basis, condemned as ‘wrong’ or ‘bad’ and proscribed by a society, there is a specific group of offences in modern democratic nations labelled crimes against morality. Included within this group are offences related to prostitution, pornography and homosexuality. What do these crimes have in common? Most clearly they tend to have a sexual basis and are often argued to do sexual harm, in both a moral and/or psychological sense, as well as physically. Conversely they are often argued to be victimless crimes, especially when the acts occur between consenting adults. Finally, they are considered essentially private acts but they often occur and, are regulated, in the public domain. Most importantly, each of these crimes against morality has only relatively recently (i.e. in the past 150 years) become identified and regulated by the state as a criminal offence. First, we discuss philosophically the issue of morality and its historical relationship to Christianity, especially with regard to the issue of prostitution. Second, we examine the relationship between public and private morality and how this distinction regulates licit and illicit sex in our society through the example of homosexuality. Finally we discuss the notion of the victimless crime through the example of pornography.

Crimes against morality

The purpose of this chapter is to discuss the relationship between crime and morality, with a specific focus on crimes against morality. While we argue that all crimes have a general moral basis, condemned as ‘wrong’ or ‘bad’ and proscribed by a society, there is a specific group of offences in modern democratic nations labelled ‘crimes against morality’. Included within this group are offences related to prostitution, pornography and homosexuality. What do these crimes have in common? Most clearly they tend to have a sexual basis and are often argued to do sexual harm, in both a moral and/or psychological sense, as well as physically. Conversely in some cases they are argued to be victimless crimes, especially when the acts occur between consenting adults. Finally, they are considered essentially private acts but they often occur, and are regulated, in the public domain. Most importantly, each of these crimes against morality has only relatively recently (i.e. in the past 150 years) become identified and regulated by the state as a criminal offence. First, we discuss philosophically the nexus between sex, crime and morality, especially with regard to the issue of prostitution. Second, we examine the relationship between public and private morality and how this dis¬tinction regulates licit and illicit sex in our society through the example of homosexuality. Finally we discuss the notion of sex as harm through the example of pornography.

Practice and Procedure: UCPR r 708 - costs order against several defendants and third party

Glenwood Homes Pty Ltd v Everhard [2008] QSC 192 involved the not uncommon situation where one costs order is made against several parties represented by a single firm of solicitors. Dutney J considered the implications when only some of the parties liable for the payment of the costs file a notice of objection to the costs statement served in respect of those costs.

Vaccination to protect against infection of the female reproductive tract

Infection of the female genital tract can result in serious morbidities and mortalities from reproductive disability, pelvic inflammatory disease and cancer, to impacts on the fetus, such as infant blindness. While therapeutic agents are available, frequent testing and treatment is required to prevent the occurrence of the severe disease sequelae. Hence, sexually transmitted infections remain a major public health burden with ongoing social and economic barriers to prevention and treatment. Unfortunately, while there are two success stories in the development of vaccines to protect against HPV infection of the female reproductive tract, many serious infectious agents impacting on the female reproductive tract still have no vaccines available. Vaccination to prevent infection of the female reproductive tract is an inherently difficult target, with many impacting factors, such as appropriate vaccination strategies/mechanisms to induce a suitable protective response locally in the genital tract, variation in the local immune responses due to the hormonal cycle, selection of vaccine antigen(s) that confers effective protection against multiple variants of a single pathogen (e.g., the different serovars of Chlamydia trachomatis) and timing of the vaccine administration prior to infection exposure. Despite these difficulties, there are numerous ongoing efforts to develop effective vaccines against these infectious agents and it is likely that this important human health field will see further major developments in the next 5 years.

Plant-produced cottontail rabbit papillomavirus L1 protein protects against tumor challenge : A proof-of-concept study

The native cottontail rabbit papillomavirus (CRPV) L1 capsid protein gene was expressed transgenically via Agrobacterium tumefaciens transformation and transiently via a tobacco mosaic virus (TMV) vector in Nicotiana spp. L1 protein was detected in concentrated plant extracts at concentrations up to 1.0 mg/kg in transgenic plants and up to 0.4 mg/kg in TMV-infected plants. The protein did not detectably assemble into viruslike particles; however, immunoelectron microscopy showed presumptive pentamer aggregates, and extracted protein reacted with conformation-specific and neutralizing monoclonal antibodies. Rabbits were injected with concentrated protein extract with Freund's incomplete adjuvant. All sera reacted with baculovirus-produced CRPV L1; however, they did not detectably neutralize infectivity in an in vitro assay. Vaccinated rabbits were, however, protected against wart development on subsequent challenge with live virus. This is the first evidence that a plant-derived papillomavirus vaccine is protective in an animal model and is a proof of concept for human papillomavirus vaccines produced in plants. Copyright © 2006, American Society for Microbiology. All Rights Reserved.

NOS1AP is associated with increased severity of PTSD and depression in untreated combat veterans

Background Post traumatic stress disorder (PTSD) and depressive disorder are over represented in combat veterans. Veterans with both disorders have an increased risk of suicide. The nitric oxide synthase 1 adaptor protein (NOS1AP) gene, which modulates stress-evoked N-methyl-D-aspartate (NMDA) activity, was investigated in combat veterans. Methods A comprehensive genetic analysis of NOS1AP and its association with PTSD was investigated in Vietnam combat veterans with PTSD (n=121) and a group of healthy control individuals (n=237). PTSD patients were assessed for symptom severity and level of depression using the Mississippi Scale for Combat-Related PTSD and the Beck Depression Inventory-II (BDI). Results The G allele of NOS1AP SNP rs386231 was significantly associated with PTSD (p = 0.002). Analysis of variance revealed significant differences in BDI-II and Mississippi scores between genotypes for rs386231 with the GG genotype associated with increased severity of depression (p = 0.002 F = 6.839) and higher Mississippi Scale for Combat-Related PTSD scores (p = 0.033). Haplotype analysis revealed that the C/G haplotype (rs451275/rs386231) was significantly associated with PTSD (p = 0.001). Limitations The sample sizes in our study were not sufficient to detect SNP associations with very small effects. In addition the study was limited by its cross sectional design. Conclusions This is the first study reporting that a variant of the NOS1AP gene is associated with PTSD. Our data also suggest that a genetic variant in NOS1AP may increase the susceptibility to severe depression in patients with PTSD and increased risk for suicide.

Extreme architecture : can architects future proof us against fire and flood.

In the face of Australia’s disaster-prone environment, architects Ian Weir and James Davidson are reconceptualising how our residential buildings might become more resilient to fire, flood and cyclone. With their first-hand experience of natural disasters, James, director of Emergency Architects Australia (EAA), and Ian, one of Australia’s few ‘bushfire architects’, discuss the ways we can design with disaster in mind. Dr Ian Weir is one of Australia’s few ‘bushfire architects’. Exploring a holistic ‘ground up’ approach to bushfire where landscape, building design and habitation patterns are orchestrated to respond to site-specific fire characteristics. Ian’s research is developed through design studio teaching at QUT and through built works in Western Australia’s fire prone forests and heathlands.

Book review : Olivier Corten, The Law Against War

Olivier Corten’s The Law Against War is a comprehensive, meticulously-researched study of contemporary international law governing the use of armed force in international relations. As a translated and updated version of a 2008 book published in French, it offers valuable insights into the positivist methodology that underpins much of the European scholarship of international law. Corten undertakes a rigorous analysis of state practice from 1945 onwards, with a view to clarifying the current meaning and scope of international law’s prohibition on the use of force. His central argument is that the majority of states remain attached to a strict interpretation of this rule. For Corten, state practice indicates that the doctrines of anticipatory self-defence, pre-emptive force and humanitarian intervention have no basis in contemporary international law. His overall position accords with a traditional, restrictive view of the circumstances in which states are permitted to use force...

Sleep Disturbances and Nightmares in Combat Veterans

Book Description: Life is a mix of good and bad happenings and sometimes terrible things happen to people. Trauma is evident across our lifespan; it is part of our lives. Trauma may not exert the same demands on the individual when they get on with their lives or experience other positive aspects of what life has to offer; however, it does not change its form from trauma to growth – it stays there etched into our psyche as trauma. In simple terms, growth occurs alongside the traumatic etchings. This is a book that will provide some answers to psychologists, counselors, social workers and mental health workers about what happens to people who are traumatized and how they ‘get on with their lives’; it also gives some excellent examples of how therapies can assist them in moving forward in life’s journey.