Guidelines for the management of postmenopausal osteoporosis for GPs

BACKGROUND : Since the last series of guidelines on the management of osteoporosis from Osteoporosis Australia was published in Australian Family Physician (October 2002), there have been further advances in our understanding of the treatment involved in both the prevention of bone loss and the management of established osteoporosis.

OBJECTIVE : This article provides updated guidelines for the management of postmenopausal osteoporosis to assist general practitioners identify those women at risk, and reviews current treatment strategies.

DISCUSSION : Osteoporosis and its associated problems are major health concerns in Australia, especially with an aging population. While important principles of management are still considered to be maximising peak bone mass and preventing postmenopausal bone loss, new clinical trial data about drugs such as the bisphosphonatesr raloxifene and oestrogen have recently become available and the relative role of various agents is gradually becoming clearer. The use of long term hormone therapy has mixed risks and benefits that requires individual patient counselling.

The performance of solarscan : an automated dermoscopy image analysis instrument for the diagnosis of primary melanoma

Objective To describe the diagnostic performance of SolarScan (Polartechnics Ltd, Sydney, Australia), an automated instrument for the diagnosis of primary melanoma.

Design Images from a data set of 2430 lesions (382 were melanomas; median Breslow thickness, 0.36 mm) were divided into a training set and an independent test set at a ratio of approximately 2:1. A diagnostic algorithm (absolute diagnosis of melanoma vs benign lesion and estimated probability of melanoma) was developed and its performance described on the test set. High-quality clinical and dermoscopy images with a detailed patient history for 78 lesions (13 of which were melanomas) from the test set were given to various clinicians to compare their diagnostic accuracy with that of SolarScan.

Setting Seven specialist referral centers and 2 general practice skin cancer clinics from 3 continents. Comparison between clinician diagnosis and SolarScan diagnosis was by 3 dermoscopy experts, 4 dermatologists, 3 trainee dermatologists, and 3 general practitioners.

Patients Images of the melanocytic lesions were obtained from patients who required either excision or digital monitoring to exclude malignancy.

Main Outcome Measures Sensitivity, specificity, the area under the receiver operator characteristic curve, median probability for the diagnosis of melanoma, a direct comparison of SolarScan with diagnoses performed by humans, and interinstrument and intrainstrument reproducibility.

Results The melanocytic-only diagnostic model was highly reproducible in the test set and gave a sensitivity of 91% (95% confidence interval [CI], 86%-96%) and specificity of 68% (95% CI, 64%-72%) for melanoma. SolarScan had comparable or superior sensitivity and specificity (85% vs 65%) compared with those of experts (90% vs 59%), dermatologists (81% vs 60%), trainees (85% vs 36%; P =.06), and general practitioners (62% vs 63%). The intraclass correlation coefficient of intrainstrument repeatability was 0.86 (95% CI, 0.83-0.88), indicating an excellent repeatability. There was no significant interinstrument variation (P = .80).

Conclusions SolarScan is a robust diagnostic instrument for pigmented or partially pigmented melanocytic lesions of the skin. Preliminary data suggest that its performance is comparable or superior to that of a range of clinician groups. However, these findings should be confirmed in a formal clinical trial.

Immunostimulatory principles from Chlorella pyrenoidosa – part 1 : isolation and biological assessment in vitro

Our proprietary preparation obtained by extraction of Chlorella pyrenoidosa cells, ONC-107 (Respondin™), was recently found to selectively boost antibody response to the influenza vaccine in a human clinical trial. Respondin™ is a potent stimulator of mouse B cell proliferation and an activator of macrophages. Bioactivity-guided resolution concluded that Respondin™ is composed of a mixture of immunostimulatory principles of different chemical nature. A combination of size exclusion, anion exchange and hydrophobic interaction chromatography revealed that the bulk of the immunostimulatory activity resides in polysaccharide/protein complexes with molecular masses larger than 100 kDa that are composed primarily of galactose, rhamnose and arabinose.

Laboratory and non-laboratory-based risk prevention models for secondary prevention of cardiovascular disease : the LIPID study

Aims : The aims of this study were to examine whether risk prediction models for recurrent cardiovascular disease (CVD) events have prognostic value, and to particularly examine the performance of those models based on non-laboratory data. We also aimed to construct a risk chart based on the risk factors that showed the strongest relationship with CVD.

Methods and results : Cox proportional hazards models were used to calculate a risk score for each recurrent event in a CVD patient who was enrolled in a very large randomized controlled clinical trial. Patients were then classified into groups according to quintiles of their risk score. These risk models were validated by calibration and discrimination analyses based on data from patients recruited in New Zealand for the same study. Non-laboratory-based risk factors, such as age, sex, body mass index, smoking status, angina grade, history of myocardial infarction, revascularization, stroke, diabetes or hypertension and treatment with pravastatin, were found to be significantly associated with the risk of developing a recurrent CVD event. Patients who were classified into the medium and high-risk groups had two-fold and four-fold the risk of developing a CVD event compared with those in the low-risk group, respectively. The risk prediction models also fitted New Zealand data well after recalibration.

Conclusion : A simpler non-laboratory-based risk prediction model performed equally as well as the more comprehensive laboratory-based risk prediction models. The risk chart based on the further simplified Score Model may provide a useful tool for clinical cardiologists to assess an individual patient's risk for recurrent CVD events.

An aqueous Chlorella extract inhibits IL-5 production by mast cells in vitro and reduces ovalbumin-induced eosinophil infiltration in the airway in mice in vivo

An aqueous extract of the edible microalga, Chlorella pyrenoidosa (CP) (1), has recently been tested for its immunomodulatory effects in a human clinical trial. Here, the CP extract was dialyzed and fractionated using Sephadex G 100 chromatography. The effects of a dialyzed aqueous CP extract, fraction 2, on mast cell mediator release in vitro and ovalbumin-induced allergic airway inflammation in vivo were examined. In vitro, treatment of mouse bone marrow-derived mast cells with 2 for 18 h significantly inhibited antigen (trinitrophenyl-BSA)-induced IL-5 production. In vivo, treatment of mice with 2 during ovalbumin sensitization and stimulation process significantly reduced eosinophil and neutrophil infiltration in the airways. Moreover, fractions obtained by size exclusion chromatography of 2 inhibited IgE-dependent cytokine GM-CSF production from human cord blood-derived mast cells. Taken together, these results suggest that 2 is composed of biopolymers with anti-allergic potential.

Can we reduce disease burden from osteoarthritis?

♦ The comparison of disparate interventions for the prevention and management of osteoarthritis (OA) is limited by the quality and quantity of published efficacy studies and the use of disparate measures for reporting clinical trial outcomes.

♦ The “transfer to utility” technique was used to translate published trial outcomes into a health-related quality-of-life (utility) scale, creating a common metric which supported comparisons between disparate interventions.

♦ Total hip replacement (THR) and total knee replacement (TKR) surgery were the most effective treatments and also highly cost-effective, at estimated cost per quality-adjusted life-year (QALY) of $7500 for THR and $10 000 for TKR (best estimate).

♦ Other apparently highly cost-effective interventions were exercise and strength training for knee OA (< $5000/QALY), knee bracing, and use of capsaicin or glucosamine sulfate (< $10 000/QALY).

♦ The cost per QALY estimates of non-specific and COX-2 inhibitor non-steroidal anti-inflammatory drugs were affected by treatment-related deaths and highly sensitive to the discounting of life-years lost.

♦ OA interventions that have been shown to be ineffective (eg, arthroscopy) are targets for redistribution of healthcare resources.

♦ OA interventions which lack efficacy studies (eg, prevention programs) require further research to assist priority setting.

♦ The application of the Health-sector Wide model to OA demonstrates its role as an evidence-based model that can be successfully applied to identify marginal interventions — those to be expanded and contracted to reduce the expected burden of disease, within current healthcare resources.

Natural history of hepatitis B in perinatally infected carriers

Objectives: To establish natural seroconversion rates and incidence of hepatic pathology in perinatally infected hepatitis B carriers.

Methods: Seventy three perinatally infected hepatitis B carriers identified through maternal screening were evaluated. Fifty three were born to parents from the Indian subcontinent, nine were Oriental, six were Afro-Caribbean, and five were white. Median follow up was 10.24 (range 2.02–20.16) years.

Results: Only three of the children followed up had cleared hepatitis B surface antigen during this period, and 30% of the children had seroconverted to anti-HBe. Seroconversions to anti-HBe were observed in Asian (18/50) and white (4/5) children, but not in Oriental or Afro-Caribbean children. More girls (40%) than boys (23%) had seroconverted, but the difference was not significant. All children were asymptomatic with normal physical examination, growth, and development. Almost half (48%) of the hepatitis B e antigen (HBeAg) positive children had normal hepatic transaminases and liver function. Thirty five liver biopsies were performed in children with active virus replication (HBeAg or hepatitis B virus DNA positive) who were being considered for antiviral treatment as part of a clinical trial and were scored using the Ishak method. Two thirds (62%) of the children had mild hepatitis, 60% had mild fibrosis, and 18% had moderate to severe fibrosis. There was a weak correlation between histological evidence of hepatitis and hepatic transaminase activity, implying that biochemical monitoring of hepatic disease activity may be ineffective.

Conclusions: These asymptomatic hepatitis B virus carrier children remain infectious in the medium to long term with notable liver pathology. They should receive antiviral treatment to reduce infectivity and to prevent further progression of liver disease. Hepatic transaminases alone are not a reliable marker of liver pathology, and liver histology is essential before consideration for antiviral treatment.

A multi-vector, multi-envelope HIV-1 vaccine

The St. Jude Children's Research Hospital (St. Jude) HIV-1 vaccine program is based on the observation that multiple, antigenically distinct HIV-1 envelope protein structures are capable of mediating HIV-1 infection. A cocktail vaccine comprising representatives of these diverse structures (immunotypes) is therefore considered necessary to elicit lymphocyte populations that prevent HIV-1 infection. This strategy is reminiscent of that used to design a currently licensed and successful 23-valent pneumococcus vaccine. Three recombinant vector systems are used for the delivery of envelope cocktails (DNA, vaccinia virus, and purified protein) and each of these has been tested individually in phase I safety trials. A fourth clinical trial, in which diverse envelopes and vectors are combined in a prime-boost vaccination regimen, has been FDA-approved and is expected to commence in 2007. This trial will continue to test the hypothesis that a multivector, multi-envelope vaccine can elicit diverse 8- and T-cell populations that can prevent HIV-1 infections in humans.

Oxidative stress in psychiatric disorders : evidence base and therapeutic implications

Oxidative stress has been implicated in the pathogenesis of diverse disease states, and may be a common pathogenic mechanism underlying many major psychiatric disorders, as the brain has comparatively greater vulnerability to oxidative damage. This review aims to examine the current evidence for the role of oxidative stress in psychiatric disorders, and its academic and clinical implications. A literature search was conducted using the Medline, Pubmed, PsycINFO, CINAHL PLUS, BIOSIS Previews, and Cochrane databases, with a time-frame extending to September 2007. The broadest data for oxidative stress mechanisms have been derived from studies conducted in schizophrenia, where evidence is available from different areas of oxidative research, including oxidative marker assays, psychopharmacology studies, and clinical trials of antioxidants. For bipolar disorder and depression, a solid foundation for oxidative stress hypotheses has been provided by biochemical, genetic, pharmacological, preclinical therapeutic studies and one clinical trial. Oxidative pathophysiology in anxiety disorders is strongly supported by animal models, and also by human biochemical data. Pilot studies have suggested efficacy of N-acetylcysteine in cocaine dependence, while early evidence is accumulating for oxidative mechanisms in autism and attention deficit hyperactivity disorder. In conclusion, multi-dimensional data support the role of oxidative stress in diverse psychiatric disorders. These data not only suggest that oxidative mechanisms may form unifying common pathogenic pathways in psychiatric disorders, but also introduce new targets for the development of therapeutic interventions.

A head mountable deep brain stimulation device for laboratory animals

Deep brain stimulation has emerged as an effective method to treat certain medical conditions. Electrical charges are injected into the target tissue through a conducting electrode exciting the tissue. A variety of DBS devices have been developed based on different operation principles. Majority of these devices, however, employ complex circuitry and are bulky. In clinical trials, laboratory animals need to freely move around and perform activities whilst receiving brain stimulation for days. This paper presents a simple lightweight head mountable deep brain stimulation device that can be carried by the animal during the course of a clinical trial. The device produces continuous current pulses of specific characteristics. It employs passive charge balancing to minimize undesirable effects on the target tissue. The device is constructed and its performance tested.

Randomised controlled trials and 'unexpected' adverse events associated with newly released drugs : improvements in pharmacovigilance systems are necessary for real-time identification of patient safety risks

Adverse drug events are one of the major causes of morbidity in developed countries, yet the drugs involved in these events have been trialled and approved on the basis of randomised controlled trials (RCTs), regarded as the study design that will produce the best evidence.

Though the focus on adverse drug events has been primarily on processes and outcomes associated with the use of these approved drugs, attention needs to be directed to the way in which the RCT study design is structured. The implementation of controls to achieve internal validity in RCTs may be the very controls that reduce external validity, and contribute to the levels of adverse drug events associated with the release of a new drug to the wider patient population.

An examination of these controls, and the effects they can have on patient safety, underscore the importance of knowing about how the clinical trials of a drug are undertaken, rather than relying only on the recorded outcomes.

As the majority of new drugs are likely to be prescribed to older patients who have one or more comorbidities in addition to that targeted by a new drug, and as the RCTs of those drugs typically under-represent the elderly and exclude patients with multiple comorbidities, timely assessment of drug safety signals is essential.

It is unlikely that regulatory jurisdictions will undertake a reassessment of safety issues for drugs that are already approved. Instead, reliance has been placed on adverse drug event reporting systems. Such systems have a very low reporting rate, and most adverse drug events remain unreported, to the eventual cost to patients and healthcare systems.

This makes it essential for near real-time systems that can pick up safety signals as they occur, so that modifications to the product information (or removal of the drug) can be implemented.

Advances in the treatment of malignant gliomas

Local control with surgery, radiation, and temozolomide chemotherapy remain the pillars of treatment for high-grade gliomas. Novel therapeutic strategies, including a variety of antiangiogenic agents, are under investigation. One of these agents, bevacizumab, was recently given accelerated approval by the US Food and Drug Administration as a single agent for recurrent glioblastoma. Recent trial results are generating important clinical questions regarding which patients to treat and when, and how best to monitor response. Encouraging results of recent studies are driving willingness to undertake aggressive treatment and to improve outcomes in this population. In this era, better understanding of biology, molecular aspects of cancer, and clinical trial methodology are crucial for clinicians. This review focuses on recent advances in the treatment malignant gliomas, especially antiangiogenic therapy.

Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer

Background: Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC.

Patients and methods: We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m2 dose every three weeks

Results: Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6–99 weeks) and 1-year survival was 71%.

Conclusions: The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.