After Charlie: free speech and the political economy of communication

Three significant events at the start of 2015 have put freedom of speech firmly on the global agenda. The first was the carry-over from the December 2014 illegal entry to the Sony Corporation’s file servers by anonymous hackers, believed to be linked to the North Korean regime. The second was the horrible attack on journalists, editors, and cartoonists at the French satirical magazine, Charlie Hebdo on 7 January. The third was the election of leftwing anti-austerity party Syrzia in Greece on 25 January.While each event is different in scope and size, they are important to scholars of the political economy of communication because they all speak to ongoing debates about freedom of expression, freedom of speech and freedom of the press. I name each of these concepts separately because, despite popular confusion, they are not the same thing (Patching and Hirst, 2014) . Freedom of expression is the right to individual self-expression through any means; it is an inalienable human right. Freedom of speech refers to the right (and the physical ability) to utter political speech, to say what others wish to repress and to demand a voice with which to express a range of social and political thoughts. Freedom of the press is a very particular version of freedom of expression that is intimately bound with the political economy of speech and of the printing press. Freedom of the press is impossible without the press and, despite its theoretical availability to all of us, this principle is impossible to articulate without the material means (usually money) to actually deploy a printing press (or the electronic means of broadcasting and publishing).Freedom of expression is immutable; freedom of speech subject to legal, ethical and ideological restriction (for better, or worse) and freedom of the press is peculiar to bourgeois society in that it entails the freedom to own and operate a press, not the right to say or publish on a level playing field. Access to freedom of the press is determined in the marketplace and is subject to the unequal power relationships that such determination implies.It is fitting to start with the Charlie Hebdo massacre because the loss of 17 lives makes this the most chilling of the three events and demands that it be given prominence in any analysis. No lives have been lost yet because Sony’s computers were hacked and the election of Syriza has not (yet) led to mass deaths in Greece.

Charlie Yankos and Warren Spink

Two Socceroos in close-quarter action for their clubs. Charlie Yankos (left) and Warren Spink (right), c.1980s.

Role of P-glycoprotein in limiting the brain penetration of glabridin, an active isoflavan from the root of Glycyrrhiza glabra.

Purpose. Glabridin is a major active constituent of Glycyrrhiza glabra which is commonly used in the treatment of cardiovascular and central nervous system (CNS) diseases. Recently, we have found that glabridin is a substrate of P-glycoprotein (PgP/MDR1). This study aimed to investigate the role of PgP in glabridin penetration across the blood–brain barrier (BBB) using several in vitro and in vivo models.
Materials and Methods. Cultured primary rat brain microvascular endothelial cells (RBMVECs) were used in the uptake, efflux and transcellular transport studies. A rat bilateral in situ brain perfusion model was used to investigate the brain distribution of glabridin. The brain and tissue distribution of glabridin in rats with or without coadministered verapamil or quinidine were examined with correction for the tissue residual blood. In addition, the brain distribution of glabridin in mdr1a(-/-) mice was compared with the wild-type mice. Glabridin in various biological matrices was determined by a validated liquid chromatography mass spectrometric method.
Results. The uptake and efflux of glabridin in cultured RBMVECs were ATP-dependent and significantly altered in the presence of a PgP or multi-drug resistance protein (Mrp1/2) inhibitor (e.g. verapamil or MK-571). A polarized transport of glabridin was found in RBMVEC monolayers with
facilitated efflux from the abluminal (BL) to luminal (AP) side. Addition of a PgP or Mrp1/2 inhibitor in both luminal and abluminal sides attenuated the polarized transport across RBMVECs. In a bilateral in situ brain perfusion model, the uptake of glabridin into the cerebrum increased from 0.42 T 0.09% at 1 min to 9.27 T 1.69% (ml/100 g tissue) at 30 min and was significantly greater than that for sucrose. Coperfusion of a PgP or Mrp1/2 inhibitor significantly increased the brain distribution of glabridin by 33.6j142.9%. The rat brain levels of glabridin were only about 27% of plasma levels when corrected by tissue residual blood and it was increased to up to 44% when verapamil or quinidine was coadministered. The area under the brain concentration-time curve (AUC) of glabridin in mdr1a(-/-) mice was 6.0-fold higher than the wild-type mice.
Conclusions. These findings indicate that PgP limits the brain penetration of glabridin through the BBB and PgP may cause drug resistance to glabridin (licorice) therapy for CNS diseases and potential drugglabridin interactions. However, further studies are needed to explore the role of other drug transporters (e.g. Mrp1-4) in restricting the brain penetration of glabridin.

Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development

Human contains 49 ATP-binding cassette (ABC) transporter genes and the multidrug resistance associated proteins (MRP1/ABCC1, MRP2/ABCC2, MRP3/ABCC3, MRP4/ABCC4, MRP5/ABCC5, MRP6/ABCC6, MRP7/ABCC10, MRP8/ABCC11 and MRP9/ABCC12) belong to the ABCC family which contains 13 members. ABCC7 is cystic fibrosis transmembrane conductance regulator; ABCC8 and ABCC9 are the sulfonylurea receptors which constitute the ATP-sensing subunits of a complex potassium channel. MRP10/ABCC13 is clearly a pseudo-gene which encodes a truncated protein that is highly expressed in fetal human liver with the highest similarity to MRP2/ABCC2 but without transporting activity. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. MRP/ABCC members transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. The human MRP/ABCC transporters except MRP9/ABCC12 are all able to transport organic anions, such as drugs conjugated to glutathione, sulphate or glucuronate. In addition, selected MRP/ABCC members may transport a variety of endogenous compounds, such as leukotriene C(4) (LTC(4) by MRP1/ABCC1), bilirubin glucuronides (MRP2/ABCC2, and MRP3/ABCC3), prostaglandins E1 and E2 (MRP4/ABCC4), cGMP (MRP4/ABCC4, MRP5/ABCC5, and MRP8/ABCC11), and several glucuronosyl-, or sulfatidyl steroids. In vitro, the MRP/ABCC transporters can collectively confer resistance to natural product anticancer drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and in concert with alterations in phase II conjugating or biosynthetic enzymes, classical alkylating agents, alkylating agents. Several MRP/ABCC members (MRPs 1-3) are associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. Drug targeting of these transporters to overcome MRP/ABCC-mediated multidrug resistance may play a role in cancer chemotherapy. Most MRP/ABCC transporters are subject to inhibition by a variety of compounds. Based on currently available preclinical and limited clinical data, it can be expected that modulation of MRP members may represent a useful approach in the management of anticancer and antimicrobial drug resistance and possibly of inflammatory diseases and other diseases. A better understanding of their substrates and inhibitors has important implications in development of drugs for treatment of cancer and inflammation.

Clincial pharmacogenetics and potential application in personalized medicine

The current `fixed-dosage strategy' approach to medicine, means there is much inter-individual variation in drug response. Pharmacogenetics is the study of how inter-individual variations in the DNA sequence of specific genes affect drug responses. This article will highlight current  pharmacogenetic knowledge on important drug metabolizing enzymes, drug transporters and drug targets to understand interindividual variability in drug clearance and responses in clinical practice and potential use in  personalized medicine. Polymorphisms in the cytochrome P450 (CYP) family may have had the most impact on the fate of pharmaceutical drugs. CYP2D6, CYP2C19 and CYP2C9 gene polymorphisms and gene duplications account for the most frequent variations in phase I metabolism of drugs since nearly 80% of drugs in use today are metabolised by these enzymes. Approximately 5% of Europeans and 1% of Asians lack CYP2D6 activity, and these  individuals are known as poor metabolizers. CYP2C9 is another clinically significant drug metabolising enzyme that demonstrates genetic variants. Studies into CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and CYP2C9*3 alleles. Extensive polymorphism also occurs in a majority of Phase II drug metabolizing enzymes. One of the most important polymorphisms is thiopurine S-methyl transferases (TPMT) that catalyzes the S-methylation of thiopurine drugs. With respect to drug transport  polymorphism, the most extensively studied drug transporter is  P-glycoprotein (P-gp/MDR1), but the current data on the clinical impact is limited. Polymorphisms in drug transporters may change drug's distribution, excretion and response. Recent advances in molecular research have revealed many of the genes that encode drug targets demonstrate genetic polymorphism. These variations, in many cases, have altered the targets sensitivity to the specific drug molecule and thus have a profound effect on drug efficacy and toxicity. For example, the β2-adrenoreceptor, which is encoded by the ADRB2 gene, illustrates a clinically significant genetic variation in drug targets. The variable number tandem repeat polymorphisms in serotonin transporter (SERT/SLC6A4) gene are associated with response to antidepressants. The distribution of the common variant alleles of genes that encode drug metabolizing enzymes, drug transporters and drug targets has been found to vary among different populations. The promise of pharmacogenetics lies in its potential to identify the right drug at the right dose for the right individual. Drugs with a narrow therapeutic index are thought to benefit more from pharmacogenetic studies. For example, warfarin serves as a good practical example of how pharmacogenetics can be utilized prior to commencement of therapy in order to achieve maximum efficacy and minimum toxicity. As such, pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and licensed drugs.

The influence of medical enduring power of attorney and advance directives on decision making by Australian intensive care doctors

OBJECTIVE: Despite government encouragement for patients to make advance plans for medical treatment, and the increasing numbers of patients who have done this, there is little research that examines how doctors regard these plans.
DESIGN: We surveyed Australian intensive care doctors, using a hypothetical clinical scenario, to evaluate how potential end-of-life treatment decisions might be influenced by advance planning - the appointment of a medical enduring power of attorney (MEPA) or an advance care plan (ACP). Using open-ended questions we sought to explore the reasoning behind the doctors' decisions.
RESULTS: 275 surveys were returned (18.3% response rate). We found that opinions expressed by an MEPA and ACP have some influence on treatment decisions, but that intensive care doctors had major reservations. Most did not follow the request for palliation made by the MEPA in the hypothetical scenario.
CONCLUSIONS: Many intensive care doctors believe end-of-life decisions remain medical decisions, and MEPAs and ACPs need only be respected when they accord with the doctor's treatment decision. This study suggests a need for further education of doctors, particularly those working in intensive care, who are responsible for initiating and maintaining life support treatment.

Predicting future intensive care demand in Australia

BACKGROUND: Predicting future demand for intensive care is vital to planning the allocation of resources.

METHOD: Mathematical modelling using the autoregressive integrated moving average (ARIMA) was applied to intensive care data from the Australian and New Zealand Intensive Care Society (ANZICS) Core Database and population projections from the Australian Bureau of Statistics to forecast future demand in Australian intensive care.

RESULTS: The model forecasts an increase in ICU demand of over 50% by 2020, with current total ICU bed-days (in 2007) of 471 358, predicted to increase to 643 160 by 2020. An increased rate of ICU use by patients older than 80 years was also noted, with the average bed-days per 10 000 population for this group increasing from 396 in 2006 to 741 in 2007.

CONCLUSION: An increase in demand of the forecast magnitude could not be accommodated within current ICU capacity. Significant action will be required.

Increased energy intake entirely accounts for increase in body weight in women but not in men in the UK between 1986 and 2000

There is debate over the casual factors for the rise in body weight in the UK. The present study investigates whether increases between 1986 and 2000 for men and women were a result of increases in mean total energy intake, decreases in mean physical activity levels or both. Estimates of mean total energy intake in 1986 and 2000 were derived from food availability data adjusted for wastage. Estimates of mean body weight for adults aged 19–64 years were derived from nationally representative dietary surveys conducted in 1986–7 and 2000–1. Predicted body weight in 1986 and 2000 was calculated using an equation relating body weight to total energy intake and sex. Differences in predicted mean body weight and actual mean body weight between the two time points were compared. Monte Carlo simulation methods were used to assess the stability of the estimates. The predicted increase in mean body weight due to changes in total energy intake between 1986 and 2000 was 4·7 (95 % credible interval 4·2, 5·3) kg for men and 6·4 (95 % credible interval 5·9, 7·1) kg for women. Actual mean body weight increased by 7·7 kg for men and 5·4 kg for women between the two time points. We conclude that increases in mean total energy intake are sufficient to explain the increase in mean body weight for women between 1986 and 2000, but for men, the increase in mean body weight is likely to be due to a combination of increased total energy intake and reduced physical activity levels.