Aquaporin-4–binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2

Neuromyelitis optica (NMO)-immunoglobulin G (IgG) is a clinically validated serum biomarker that distinguishes relapsing central nervous system (CNS) inflammatory demyelinating disorders related to NMO from multiple sclerosis. This autoantibody targets astrocytic aquaporin-4 (AQP4) water channels. Clinical, radiological, and immunopathological data suggest that NMO-IgG might be pathogenic. Characteristic CNS lesions exhibit selective depletion of AQP4, with and without associated myelin loss; focal vasculocentric deposits of IgG, IgM, and complement; prominent edema; and inflammation. The effect of NMO-IgG on astrocytes has not been studied. In this study, we demonstrate that exposure to NMO patient serum and active complement compromises the membrane integrity of CNS-derived astrocytes. Without complement, astrocytic membranes remain intact, but AQP4 is endocytosed with concomitant loss of Na+-dependent glutamate transport and loss of the excitatory amino acid transporter 2 (EAAT2) . Our data suggest that EAAT2 and AQP4 exist in astrocytic membranes as a macromolecular complex. Transport-competent EAAT2 protein is up-regulated in differentiating astrocyte progenitors and in nonneural cells expressing AQP4 transgenically. Marked reduction of EAAT2 in AQP4-deficient regions of NMO patient spinal cord lesions supports our immunocytochemical and immunoprecipitation data. Thus, binding of NMO-IgG to astrocytic AQP4 initiates several potentially neuropathogenic mechanisms: complement activation, AQP4 and EAAT2 down-regulation, and disruption of glutamate homeostasis

Effect of computerised prescribing on use of antibiotics

Objectives: To examine whether the use of current prescribing software systems might raise rates of repeat prescribing, with a consequent increase in use of antibiotics in the community. Design and setting: A prospective audit of consecutive prescriptions for amoxycillin, cefaclor, roxithromycin and amoxycillin/clavulanate presented to community pharmacies in the Hunter region of New South Wales and a follow-up survey of people who received a repeat prescription, October to November 2000. Main outcome measures: The frequency of repeat prescription ordering on computer-generated and handwritten prescriptions; the proportion of people who filled their repeat prescription. Results: Data were collected for 1667 prescriptions presented to 35 pharmacies; 126 people who received repeat prescriptions completed the survey. The rate of repeat prescription ordering on computer-generated prescriptions was 69%, compared with 40% for handwritten prescriptions (odds ratio, 3.3; 95% CI, 2.6–4.2). Computer-generated repeat prescriptions were as likely to be filled as hand-written prescriptions (61% and 69%, respectively). Conclusions: The default settings on computerised prescribing packages result in a significant increase in the use of antibiotics. We estimate these settings result in about 500 000 additional prescriptions being filled annually in Australia for the four antibiotics in the study

Personal formularies: an index of prescribing quality?

Objectives: (1) To determine the extent to which Australian general practitioners (GPs) restrict the numbers of agents they prescribe within a drug class ('personal formularies'); (2) To assess concordance of these drug choices with standards based on established guidelines or recognised good prescribing practices; (3) To assess the potential of these measures as indicators of the quality of prescribing. Methods: Australian Health Insurance Commission (HIC) prescription data (1994-1997) for around 15,400 GPs providing 1500 or more Medicare services per year were analysed. Measures of an individual GP's use of a personal formulary (determined by number of agents) and concordance with prescribing criteria based on specified drugs for five classes of commonly prescribed drugs were derived. Results: Non-steroidal anti-inflammatory drugs (NSAIDs): GP concordance was higher with a non-specified personal formulary (any five NSAIDs) than with a list of specified drugs (five NSAIDs of 'low' or 'medium' risk of gastrointestinal toxicity), and concordance with both increased over time. In 1997, around 70% of GPs used five or fewer NSAIDs for 90% of their prescribing; 47% of GPs had 90% of prescribing from five selected agents. Angiotensin converting enzyme inhibitors/angiotensin-II receptor antagonists: The introduction of new agents appeared to increase the size of the GPs' personal formularies, and concordance with defined standards decreased over time. Antibacterial agents: Concordance with a specified drug standard (nine drugs listed in the Australian Antibiotic Guidelines) increased substantially over time but was largely due to increased prescribing of two heavily promoted drugs. Beta-blocking agents: Over time, GPs restricted most prescribing to two agents, atenolol and metoprolol. Calcium channel blockers: GPs did not appear to restrict prescribing of these drugs; most GPs prescribed all five agents available. Conclusions: Australian GPs use 'personal formularies'. Formulary size varies with the drug class, can change over time as new agents become available, and its contents can be influenced by promotional activities. Prescribing standards based on numbers of drugs used may not always reflect rational prescribing choices. Criteria based on specified drugs provide more rigorous prescribing standards, but may give a misleading picture of prescribing quality in the absence of information on patients and the indications for treatment. Personal formulary measures are potentially useful prescribing indicators but need to be carefully defined and interpreted. GPs should be encouraged to identify their personal formularies and review the drugs included in them

The impact of specialists on prescribing by general practitioners

Objective: To investigate the direct impact of specialists on prescribing by general practitioners. Design: Cross-sectional, prescription-based study. Subjects and setting: 88 GPs in the Hunter Urban Division of General Practice, Hunter Valley, NSW. Main outcome measure: Proportions of specialist-initiated prescriptions for eight commonly prescribed drug classes. Results: The proportion of specialist-initiated prescriptions was greatest for proton pump inhibitors (85%), and lowest for diuretics (8%), newer antidepressants (10%) and H2-receptor antagonists (13%). Specialists initiated 29% of prescriptions for beta-blockers, 26% for calcium-channel blockers, 20% for statins and 19% for angiotensin-converting enzyme inhibitors or angiotensin II antagonists. Specialists were more likely to have been involved in starting therapy with metoprolol than other beta-blockers (51% v 23%) and diltiazem than other calcium-channel blockers (48% v 19%), and this was related to indication for treatment. In contrast, prescriptions for the more recently introduced drugs (angiotensin II antagonists and atorvastatin) were not more likely to have been specialist-initiated than prescriptions for established angiotensin-converting enzyme inhibitors and statins. Conclusions: The direct impact of specialists on prescribing in the Hunter Urban Division of General Practice is substantial and varies with the drug class. This highlights the need to engage both GPs and specialists in efforts to improve prescribing practices

Limitations of Health Insurance Commission (HIC) data for deriving prescribing indicators

Objectives: To derive indicators of quality prescribing by Australian general practitioners based on Health Insurance Commission (HIC) data and assess the influence of incomplete capture of data on under-copayment drugs on the validity of these indicators. Design: Two expert groups proposed prescribing indicators that can be derived from aggregate prescribing data, and which reflect important clinical or cost-effectiveness issues. Indicators were examined using HIC data and compared with national prescribing trends over time using Australian Statistics on Medicines. The effect of incomplete data capture on indicator interpretation was examined by stratifying GPs into five strata based on the proportion of concession card holders in their practice. Participants: Approximately 14 000 Australian GPs providing ≥ 1500 Medicare services per year. Main outcome measures: Measures of prescribing for individual GPs (based on HIC data 1993–1997). Results: Forty-three potentially useful indicators were identified. These covered a fairly narrow range of prescribing activities and many required additional clinical information for interpretation. Indicators based on prescribing rates gave a misleading picture of prescribing trends where the extent of HIC data capture changed over time. Indicators expressed as ratios that reflected choice of agent within a drug class were less affected by incomplete data capture. Conclusions: Indicators of quality prescribing can be derived from HIC data. However, indicators for under-copayment drugs that represent prescribing rates may unfairly classify doctors practising in areas of socioeconomic disadvantage or high morbidity as "high prescribers". Ratio indicators are more robust, and may be more valid prescribing measures. If HIC data are to be used to monitor the quality of prescribing, data on all prescriptions dispensed will be needed