Testosterone reinforcement : intravenous and intracerebroventricular self-administration in male rats and hamsters

Rationale: Anabolic steroids are drugs of abuse. However, the potential for addiction remains unclear. Testosterone induces conditioned place preference in rats and oral self-administration in hamsters. Objectives: To determine if male rats and hamsters consume testosterone by intravenous (IV) or intracerebroventricular (ICV) self- administration. Methods: With each nose-poke in the active hole during daily 4-h tests in an operant condi- tioning chamber, gonad-intact adult rats and hamsters received 50 mg testosterone in an aqueous solution of b-cyclodextrin via jugular cannula. The inactive nose- poke hole served as a control. Additional hamsters received vehicle infusions. Results: Rats (n=7) expressed a significant preference for the active nose-poke hole (10.0€2.8 responses/4 h) over the inactive hole (4.7€1.2 responses/4 h). Similarly, during 16 days of testosterone self-administration IV, hamsters (n=9) averaged 11.7€2.9 responses/4 h and 6.3€1.1 responses/4 h in the active and inactive nose-poke holes, respectively. By contrast, vehicle controls (n=8) failed to develop a preference for the active nose-poke hole (6.5€0.5 and 6.4€0.3 responses/4 h). Hamsters (n=8) also self-administered 1 mg testosterone ICV (active hole:39.8€6.0 nose-pokes/ 4 h; inactive hole: 22.6€7.1 nose-pokes/4 h). When testosterone was replaced with vehicle, nose-poking in the active hole declined from 31.1€7.6 to 11.9€3.2 responses/ 4 h within 6 days. Likewise, reversing active and inactive holes increased nose-poking in the previously inactive hole from 9.1€1.9 to 25.6€5.4 responses/4 h. However, reducing the testosterone dose from 1 mg to 0.2 mg per 1 ml injection did not change nose-poking. Conclu- sions: Compared with other drugs of abuse, testosterone reinforcement is modest. Nonetheless, these data support the hypothesis that testosterone is reinforcing.

Searching for a social democratic narrative in criminal justice

Paul Keating recently noted that what the Rudd Government lacked was an overall narrative or story. I would like to argue that Paul Keating is correct and suggest a narrative: that of retrieving and defending aspects of our social democratic heritage from some of the damaging effects wrought by neo-liberalism. Moreover I want to argue that criminal justice policy needs to be seen as a part of this broader narrative, which requires it being prised from its current site, where it is wedged firmly in the narrative of law and order.

Ghrelin receptor (GHS-R1A) antagonism suppresses both operant alcohol self-administration and high alcohol consumption in rats

The mechanisms involved in alcohol use disorders are complex. It has been shown that ghrelin is an important signal for the control of body weight homeostasis, preferably by interacting with hypothalamic circuits, as well as for drug reward by activating the mesolimbic dopamine system. The ghrelin receptor (GHS-R1A) has been shown to be required for alcohol-induced reward. Additionally, ghrelin increases and GHR-R1A antagonists reduce moderate alcohol consumption in mice, and a single nucleotide polymorphism in the GHS-R1A gene has been associated with high alcohol consumption in humans. However, the role of central ghrelin signaling in high alcohol consumption is not known. Therefore, the role of GHS-R1A in operant self-administration of alcohol in rats as well as for high alcohol consumption in Long-Evans rats and in alcohol preferring [Alko alcohol (AA)] rats was studied here. In the present study, the GHS-R1A antagonist, JMV2959, was found to reduce the operant self-administration of alcohol in rats and to decrease high alcohol intake in Long-Evans rats as well as in AA rats. These results suggest that the ghrelin receptor signaling system, specifically GHS-R1A, is required for operant self-administration of alcohol and for high alcohol intake in rats. Therefore, the GHS-R1A may be a therapeutic target for treatment of addictive behaviors, such as alcohol dependence.

ICANN and the concept of democratic deficit

The Internet Corporation for Assigned Names and Numbers (ICANN) is an institution besieged. It has endeavored to be democratic but its attempts to do so have been disastrous. The typical explanation for this is that the problem is with ICANN: it fails to meet its democratic obligations. My view is that the problem is with our understanding of "democracy." Democracy is an empty concept that fails to describe few, if any, of our genuine political commitments. In the real world, the failings inherent in "democracy" have been papered over by some unusual characteristics of the physical political process. However, in online trans-national institutions like ICANN, democracy is exposed as a poor substitute for a number of other conceptions of our political commitments. This Article seeks to articulate these political commitments and to explain why democracy and ICANN are such a poor mix. It begins by charting the rise of ICANN and its attempts to be democratic. It then explains why democracy is an empty shell of a concept. It then explores some features of democracy and ICANN, explaining why the online world exposes limitations in implications of democracy such as the nature of the demos, the idea of constituencies, direct democracy, voting, and the like. It concludes that ICANN's example demonstrates that democracy is in fact anything but a coherent general theory of political action. We need to consider, then, whether we should continue to berate ICANN for its undemocratic actions.

Crushed tablets : does the administration of food vehicles and thickened fluids to aid medication swallowing alter drug release?

Purpose. To evaluate the influence of co-administered vehicles on in vitro dissolution in simulated gastric fluid of crushed immediate release tablets as an indicator for potential drug bioavailability compromise. Methods. Release and dissolution of crushed amlodipine, atenolol, carbamazepine and warfarin tablets were tested with six foods and drinks that are frequently used in the clinical setting as mixers for crushed medications (water, orange juice, honey, yoghurt, strawberry jam and water thickened with Easythick powder) in comparison to whole tablets. Five commercial thickening agents (Easythick Advanced, Janbak F, Karicare, Nutilis, Viscaid) at three thickness levels were tested for their effect on the dissolution of crushed atenolol tablets. Results. Atenolol dissolution was unaffected by mixing crushed tablets with thin fluids or food mixers in comparison to whole tablets or crushed tablets in water, but amlodipine was delayed by mixing with jam. Mixing crushed warfarin and carbamazepine tablets with honey, jam or yoghurt caused them to resemble the slow dissolution of whole tablets rather than the faster dissolution of crushed tablets in water or orange juice. Crushing and mixing any of the four medications with thickened water caused a significant delay in dissolution. When tested with atenolol, all types of thickening agents at the greatest thickness significantly restricted dissolution, and products that are primarily based on xanthan gum also delayed dissolution at the intermediate thickness level. Conclusions. Dissolution testing, while simplistic, is a widely used and accepted method for comparing drug release from different formulations as an indicator for in vivo bioavailability. Thickened fluids have the potential to retard drug dissolution when used at the thickest levels. These findings highlight potential clinical implications of the addition of these agents to medications for the purpose of dose delivery and indicate that further investigation of thickened fluids and their potential to influence therapeutic outcomes is warranted.

Oral testosterone self-administration in male hamsters

The addiction potential of anabolic steroids remains largely unexplored. Here, we demonstrate voluntary oral testosterone intake in hamsters. Using a 2-bottle choice test, males preferred an aqueous solution of 200 microg/ml testosterone over vehicle. However, the taste of testosterone is not highly preferred. Addition of testosterone at 400 microg/ml increased fluid consumption from the nonpreferred bottle in a 2-bottle choice test, but cholesterol at the same concentration reduced drinking, suggesting that testosterone reward is not common to all sterols. With food-induced drinking, testosterone maintained fluid intake when food was withdrawn. These data demonstrate that oral self-administration of testosterone is reinforcing in hamsters, suggesting the potential for dependence in human users.

Democratic systems

Digital signature is a breakthrough of modern cryptographic systems. A (t, n) threshold digital signature allows every set of cardinality t or more (out-of n) co-signers to authenticate a message. In almost all existing threshold digital signatures the threshold parameter t is fixed. There are applications, however, in which the threshold parameter needs to be changed from time to time. This paper considers such a scenario, in order to discuss relevant problems, and proposes a model that solves the related problems.

Targeted disruption of the JAK2/STAT3 pathway in combination with systemic administration of paclitaxel inhibits the priming of ovarian cancer stem cells leading to a reduced tumor burden

Chemotherapy resistance associated with recurrent disease is the major cause of poor survival of ovarian cancer patients. We have recently demonstrated activation of the JAK2/STAT3 pathway and the enhancement of a cancer stem cell (CSC)-like phenotype in ovarian cancer cells treated in vitro with chemotherapeutic agents. To elucidate further these mechanisms in vivo,we used a two-tiered paclitaxel treatment approach in nude mice inoculated with ovarian cancer cells. In the first approach, we demonstrate that a single intraperitoneal administration of paclitaxel in mice 7 days after subcutaneous transplantation of the HEY ovarian cancer cell line resulted in a significant increase in the expression of CA125, Oct4, and CD117 in mice xenografts compared to control mice xenografts which did not receive paclitaxel. In the second approach, mice were administered once weekly with paclitaxel and/or a daily dose of the JAK2-specific inhibitor, CYT387, over 4weeks. Mice receiving paclitaxel only demonstrated a significant decrease in tumor volume compared to control mice. At the molecular level, mouse tumors remaining after paclitaxel administration showed a significant increase in the expression of Oct4 and CD117 coinciding with a significant activation of the JAK2/STAT3 pathway compared to control tumors. The addition of CYT387 with paclitaxel resulted in the suppression of JAK2/STAT3 activation and abrogation of Oct4 and CD117 expression in mouse xenografts. This coincided with significantly smaller tumors in mice administered CYT387 in addition to paclitaxel, compared to the control group and the group of mice receiving paclitaxel only. These data suggest that the systemic administration of paclitaxel enhances Oct4- and CD117-associated CSC-like marker expression in surviving cancer cells in vivo, which can be suppressed by the addition of the JAK2-specific inhibitor CYT387, leading to a significantly smaller tumor burden. These novel findings have the potential for the development of CSC-targeted therapy to improve the treatment outcomes of ovarian cancer patients.

Facebook Versus Ghaddafi : social networking as a tool for democratic change in Libya

The emergence of the Internet is one of the most significant leaps in the history of humanity. Information, knowledge and culture are exchanged among masses of people through interconnected information platforms. These platforms enable our culture to be analysed and rewritten, and fundamentally opens our perceptions to a wide variety of concepts and beliefs. The connected networks of the Internet have shaped a virtual — but communicative — space where people can cross borders freely within a realm characterised by the ability to go anywhere, see anything, learn, compare and understand. This chapter focuses on the Libyan experience with social networking platforms in actualising democratic change in the uprising of 17 February 2011. After briefly outlining the political and economic situation under the regime of Colonel Mummar Ghaddafi, the chapter discusses the role that social networking platforms played during the struggle of the Libyan people for democratic change. Finally, it points out the positive changes that resulted from the uprising and the potential role that social media might play in the ongoing democratization and development of Libyan society.

Duty to the court and the administration of justice : some examples, implications and clarifications

No liberal democracy can survive without popular trust in its judicial system. The legal profession and the judiciary enjoy a level of independence and autonomy from the executive that makes them both powerful and privileged. A UNIQUE AND ORGANIC DUTY: So long as the courts are seen to fulfil their duty to guard against encroachments by the executive on the freedoms and rights of individual citizens with integrity and credibility, they maintain enough public support to retain their normative authority. But support for those with power and privilege is easily undermined. It is contingent upon trust. Lawyers who breach that trust in ways that go to the heart of the legal system ought to expect to be made examples of and to suffer severe penalties. The good news is that the sorts of breach discussed here should be neither difficult to anticipate nor to avoid – in theory. In practice, smart and honest lawyers sometimes fall foul of these duties for all sorts of understandable (if not condonable) reasons. Law does not get practised in a social or cultural vacuum. Lawyers are people, and people have weaknesses, failings and stresses...

Health and guardianship law : guardianship and administration application in the matter of MDC [2014] QCAT 338

The recent decision of the Queensland Civil and Administrative Tribunal (QCAT) in Guardianship and administration application in the matter of MDC [2014] QCAT 338, provides an important ruling on the limits of who can be appointed as an enduring power of attorney under the Powers of Attorney Act 1998 (Qld). In particular, the tribunal adopted a broad interpretation of the term "health provider" when considering the limits on who can be appointed as an enduring power of attorney under the legislation...

Defining a ‘democratic elite’ : key media in the battle for social responsibility

This paper offers a definition of elite media arguing their content focus will sufficiently meet social responsibility needs of democracy. Its assumptions come from the Finkelstein and Leveson Inquiries and regulatory British Royal Charter (2013). These provide guidelines on how media outlets meet ‘social responsibility’ standards, e.g. press has a ‘responsibility to be fair and accurate’ (Finkelstein); ethical press will feel a responsibility to ‘hold power to account’ (Leveson); news media ‘will be held strictly accountable’ (RC). The paper invokes the British principle of media opting-in to observe standards, and so serve the democracy. It will give examples from existing media, and consider social responsibility of media more generally. Obvious cases of ‘quality’ media: public broadcasters, e.g. BBC, Al-Jazeera, and ‘quality’ press, e.g. NYT, Süddeutscher Zeitung, but also community broadcasters, specialised magazines, news agencies, distinctive web logs, and others. Where providing commentary, these abjure gratuitous opinion -- meeting a standard of reasoned, informational and fair. Funding is almost a definer, many such services supported by the state, private trusts, public institutions or volunteering by staff. Literature supporting discussion on elite media will include their identity as primarily committed to a public good, e.g. the ‘Public Value Test’, Moe and Donders (2011); with reference also to recent literature on developing public service media. Within its limits the paper will treat social media as participants among all media, including elite, and as a parallel dimension of mass communication founded on inter-activity. Elite media will fulfil the need for social responsibility, firstly by providing one space, a ‘plenary’ for debate. Second is the notion of building public recognition of elite media as trustworthy. Third is the fact that elite media together are a large sector with resources to sustain social cohesion and debate; notwithstanding pressure on funds, and impacts of digital transformation undermining employment in media more than in most industries.

Methotrexate-conjugated PEGylated dendrimers show differential patterns of deposition and activity in tumour-burdened lymph nodes after intravenous and subcutaneous administration in rats

The current study sought to explore whether the subcutaneous administration of lymph-targeted dendrimers, conjugated with a model chemotherapeutic (methotrexate, MTX), was able to enhance anticancer activity against lymph node metastases. The lymphatic pharmacokinetics and antitumour activity of PEGylated polylysine dendrimers conjugated to MTX [D-MTX(OH)] via a tumour-labile hexapeptide linker was examined in rats and compared to a similar system where MTX was α-carboxyl O-tert-butylated [D-MTX(OtBu)]. The latter has previously been shown to exhibit longer plasma circulation times. D-MTX(OtBu) was well absorbed from the subcutaneous injection site via the lymph, and 3 to 4%/g of the dose was retained by sentinel lymph nodes. In contrast, D-MTX(OH) showed limited absorption from the subcutaneous injection site, but absorption was almost exclusively via the lymph. The retention of D-MTX(OH) by sentinel lymph nodes was also significantly elevated (approximately 30% dose/g). MTX alone was not absorbed into the lymph. All dendrimers displayed lower lymph node targeting after intravenous administration. Despite significant differences in the lymph node retention of D-MTX(OH) and D-MTX(OtBu) after subcutaneous and intravenous administration, the growth of lymph node metastases was similarly inhibited. In contrast, the administration of MTX alone did not significantly reduce lymph node tumour growth. Subcutaneous administration of drug-conjugated dendrimers therefore provides an opportunity to improve drug deposition in downstream tumour-burdened lymph nodes. In this case, however, increased lymph node biodistribution did not correlate well with antitumour activity, possibly suggesting constrained drug release at the site of action.

Are Australia’s universities in deficit? A tale of generic managers, audit culture, and casualisation

Managerial changes to Australian universities have had considerable impact on employees. In this paper we consider some of these changes and apply a theory known as the democratic deficit to them. This theory was developed from the democratic critique of managerialism, as it has been applied in the public sector in countries with Westminster-type political systems. This deficit covers the weakening of accountability through politicisation, the denial of public values through the use of private sector performance practices, and the hollowing out of the state through the contracting out and privatisation of public goods and services, and the redefinition of citizens as customers and clients. We suggest that the increased power of managers, expansion of the audit culture, and the extensive use of contract employment seem to be weakening the democratic culture and role of universities in part by replacing accountability as responsibility with accountability as responsiveness.