Epidemiological modelling (including economic modelling) and its role in preventive drug therapy

In contrast to curative therapies, preventive therapies are administered to largely healthy individuals over long periods. The risk-benefit and cost-benefit ratios are more likely to be unfavourable, making treatment decisions difficult. Drug trials provide insufficient information for treatment decisions, as they are conducted on highly selected populations over short durations, estimate only relative benefits of treatment and offer little information on risks and costs. Epidemiological modelling is a method of combining evidence from observational epidemiology and clinical trials to assist in clinical and health policy decision-making. It can estimate absolute benefits, risks and costs of long-term preventive strategies, and thus allow their precise targeting to individuals for whom they are safest and most cost-effective. Epidemiological modelling also allows explicit information about risks and benefits of therapy to be presented to patients, facilitating informed decision-making.

Altered kinetics and benzodiazepine sensitivity of a GABA(A) receptor subunit mutation [gamma(2)(R43Q)] found in human epilepsy

The gamma-aminobutyric acid type A (GABA(A)) receptor mediates fast inhibitory synaptic transmission in the CNS. Dysfunction of the GABA(A) receptor would be expected to cause neuronal hyperexcitability, a phenomenon linked with epileptogenesis. We have investigated the functional consequences of an arginine-to-glutamine mutation at position 43 within the GABA(A) gamma(2)-subunit found in a family with childhood absence epilepsy and febrile seizures. Rapid-application experiments performed on receptors expressed in HEK-293 cells demonstrated that the mutation slows GABA(A) receptor deactivation and increases the rate of desensitization, resulting in an accumulation of desensitized receptors during repeated, short applications. In Xenopus laevis oocytes, two-electrode voltage-clamp analysis of steady-state currents obtained from alpha(1)beta(2)gamma(2) or alpha(1)beta(2)gamma(2)(R43Q) receptors did not reveal any differences in GABA sensitivity. However, differences in the benzodiazepine pharmacology of mutant receptors were apparent. Mutant receptors expressed in oocytes displayed reduced sensitivity to diazepam and flunitrazepam but not the imiclazopyricline zolpidem. These results provide evidence of impaired GABA(A) receptor function that could decrease the efficacy of transmission at inhibitory synapses, possibly generating a hyperexcitable neuronal state in thalamocortical networks of epileptic patients possessing the mutant subunit.

'You can criticise because you care': Identification, constructiveness, and the intergroup sensitivity effect

Group criticisms judged to be reasonable in the mouth of an ingroup member are aggressively rejected when they stem from an outgroup member (the intergroup sensitivity effect). Mediational analyses suggest that this phenomenon is underpinned by an attributional bias; criticisms from insiders are more likely to be perceived as being motivated for constructive reasons than are criticisms from outsiders, thus arousing lower levels of defensiveness. But what if group members were to receive information that called into question the ingroup critic's commitment to the group? For example, if the ingroup critic was known to be a low identifier with their group, or used language to suggest that they were psychologically distancing themselves from their group, we might expect that ingroup critics will be downgraded as strongly as outgroup critics. Furthermore, it might be possible for people to turn an outgroup criticism into an ingroup criticism by making salient their shared identity at the superordinate level. Three experiments are described that provide support for each of these propositions.

The role of impulsivity in the development of substance use and eating disorders

Impulsivity is now widely viewed as a multidimensional construct consisting of a number of related dimensions. Although many measures of impulsivity are correlated, most recent factor analyses support at least a two-factor model. In the current paper, these two factors have been labelled reward sensitivity, reflecting one of the primary dimensions of Gray's personality theory, and rash-spontaneous impulsiveness. The evidence supporting the existence of two dimensions of impulsivity is reviewed in relation to substance misuse and binge eating. (C) 2004 Elsevier Ltd. All rights reserved.

Reward drive and rash impulsiveness as dimensions of impulsivity: Implications for substance misuse

One of the primary personality dimensions or traits that has consistently been linked to substance abuse is impulsivity. However, impulsivity is not a homogenous construct and although many of the measures of impulsivity are correlated, the most recent review of published factor analytic studies has proposed two independent dimensions of impulsivity: reward sensitivity, reflecting one of the primary dimension of J. A. Gray's personality theory, and rash impulsiveness. These two facets of impulsivity derived from the field of personality research parallel recent developments in the neurosciences where changes in the incentive value of rewarding substances has been linked to alterations in neural substrates involved in reward seeking and with a diminished capacity to inhibit behavior due to chronic drug exposure. In this paper, we propose a model that integrates the findings from research into individual differences with recent models of neural substrates implicated in the development of substance misuse. (C) 2004 Elsevier Ltd. All rights reserved.

The effects of adolescent cannabis use: How should the empirical evidence inform drug policy for young people? : Meeting abstract

Ethics as a subject is now consistently taught in medical schools within Australia. The theoretical Ethical models used, and the associated clinical discussions, vary between schools. Registrars have further theoretical Ethics teaching within Psychiatry Fellowship Training, and ongoing clinical work that is likely to provide exposure to complex and frequent Ethical dilemmas. As Psychiatry Trainees approach subspecialty training in Child and Adolescent Psychiatry they therefore have a rich experience of both theoretical Ethics teaching and clinical exposure to Ethical issues. In this symposium, the difficulties Child and Adolescent Psychiatry Trainees may have in the integration of multiple theoretical Ethical models are discussed. It is suggested that these difficulties make Ethics Teaching for Child and Adolescent Psychiatry Trainees particularly challenging. This is important given the complex Ethical issues often present when working with Children and their Families. The three main Ethical models of Deontology, Virtue Ethics and Consequentialism are described and their usefulness for the Child and Adolescent Psychiatrist examined. Limitations of these models, and “Four Principles” approaches (such as that of Beauchamp and Childress), for Child and Adolescent Psychiatry, are also considered. Clinical cases are included for discussion. Finally, the ways in which these models may be used to enhance Child and Adolescent Psychiatry Training, and subsequent clinical practice as a Child and Adolescent Psychiatrist, are discussed. The integration of different theoretical Ethical models is considered, with implications identified for clinical practice.

Disruption of NaS1 sulfate transport function in mice leads to enhanced acetaminophen-induced hepatotoxicity

Sulfate is required for detoxification of xenobiotics such as acetaminophen (APAP), a leading cause of liver failure in humans. The NaS1 sulfate transporter maintains blood sulfate levels sufficiently high for sulforiation reactions to work effectively for drug detoxification. In the present study, we identified two loss-of-function polymorphisms in the human NaS1 gene and showed the Nas1-null mouse to be hypersensitive to APAP hepatotoxicity. APAP treatment led to increased liver damage and decreased hepatic glutathione levels in the hyposulfatemic Nas1-null mice compared with that in normosulfatemic wild-type mice. Analysis of urinary APAP metabolites revealed a significantly lower ratio of APAP-sulfate to APAP-glucuronide in the Nas1-null mice. These results suggest hyposulfatemia increases sensitivity to APAP-induced hepatotoxicity by decreasing the sulfonation capacity to metabolize APAP. In conclusion, the results of this study highlight the importance of plasma sulfate level as a key modulator of acetaminophen metabolism and suggest that individuals with reduced NaS1 sulfate transporter function would be more sensitive to hepatotoxic agents.

Phonological sensitivity as a proximal contributor to phonological recoding skills in children's reading

Because it permits self-teaching, phonological recoding (the efficient translation of letters or letter groups into sound) is arguably the key skill acquired in learning to read an alphabetic writing system. Deficits in this skill are the most common source of children's reading difficulties. In addition, poor readers tend to perform at a lower level than good readers on a wide variety of phonological processing tasks. These findings have been widely interpreted as implying a latent phonological processing ability as a distal cause of variation in reading skill. Clearly, such an interpretation does not imply that all phonological processing skills contribute directly to the phonological recoding process. This paper outlines a series of studies conducted at the University of Queensland. This work consistently suggests that children's phonological sensitivity contributes more directly than other phonological processing abilities to the development of phonological recoding skills.

A method for drug infusion into the lateral median eminence and arcuate nucleus of sheep

The role of catecholamines in the control of the GnRH pulse generator is unclear as studies have relied on the use of peripheral or intracerebroventricular injections, which lack specificity in relation to the anatomical site of action. Direct brain site infusions have been used, however, these are limited by the ability to accurately target small brain regions. One such area of interest in the control of GnRH is the median eminence and arcuate nucleus within the medial basal hypothalamus. Here we describe a method of stereotaxically targeting this area in a large animal (sheep) and an infusion system to deliver drugs into unrestrained conscious animals. To test our technique we infused the dopamine agonist, quinpirole or vehicle into the medial basal hypothalamus of ovariectomised ewes. Quinpirole significantly suppressed LH pulsatility only in animals with injectors located close to the lateral median eminence. This in vivo result supports the hypothesis that dopamine inhibits GnRH secretion by presynaptic inhibition in the lateral median eminence. Also infusion of quinpirole into the medial basal hypothalamus suppressed prolactin secretion providing in vivo evidence that is consistent with the hypothesis that there are stimulatory autoreceptors on tubero-infundibular dopamine neurons. (C) 1997 Elsevier Science B.V.

On the validity of the dispersion model of hepatic drug elimination when intravascular transit time densities are long-tailed

The dispersion model with mixed boundary conditions uses a single parameter, the dispersion number, to describe the hepatic elimination of xenobiotics and endogenous substances. An implicit a priori assumption of the model is that the transit time density of intravascular indicators is approximated by an inverse Gaussian distribution. This approximation is limited in that the model poorly describes the tail part of the hepatic outflow curves of vascular indicators. A sum of two inverse Gaussian functions is proposed as ail alternative, more flexible empirical model for transit time densities of vascular references. This model suggests that a more accurate description of the tail portion of vascular reference curves yields an elimination rate constant (or intrinsic clearance) which is 40% less than predicted by the dispersion model with mixed boundary conditions. The results emphasize the need to accurately describe outflow curves in using them as a basis for determining pharmacokinetic parameters using hepatic elimination models. (C) 1997 Society for Mathematical Biology.