D. G. Le Couteur

Pesticides and Parkinson’s Disease

Epidemiological studies and case reports provide evidence for an association between Parkinsons disease and past exposure to pesticides. Susceptibility to the effects of pesticides and other putative neurotoxins depends on variability in xenobiotic metabolism possibly generated by genetic polymorphisms, aging and variation in exposure to environmental agents including pesticides. The simplest mechanistic hypothesis for the association of pesticides with Parkinsons disease is that pesticides or their metabolites are directly toxic to mitochondria, although modulation of xenobiotic metabolism by pesticides provides an adjunct or alternative hypothesis.

High‐Risk Prescribing and Incidence of Frailty Among Older Community‐Dwelling Men

Evidence about the association between treatment with high–risk medicines and frailty in older individuals is limited. We investigated the relationship between high–risk prescribing and frailty at baseline, as well as 2–year incident frailty, in 1,662 men ≥70 years of age. High–risk prescribing was defined as polypharmacy (≥5 medicines), hyperpolypharmacy (≥10 medicines), and by the Drug Burden Index (DBI), a dose–normalized measure of anticholinergic and sedative medicines. At baseline, frail participants had adjusted odds ratios (ORs) of 2.55 (95% confidence interval, CI: 1.69–3.84) for polypharmacy, 5.80 (95% CI: 2.90–11.61) for hyperpolypharmacy, and 2.33 (95% CI: 1.58–3.45) for DBI exposure, as compared with robust participants. Of the 1,242 men who were robust at baseline, 6.2% developed frailty over two years. Adjusted ORs of incident frailty were 2.45 (95% CI: 1.42–4.23) for polypharmacy, 2.50 (95% CI: 0.76–8.26) for hyperpolypharmacy, and 2.14 (95% CI: 1.25–3.64) for DBI exposure. High–risk prescribing may contribute to frailty in community–dwelling older men.

Variability in Response to Medicines in Older People: Phenotypic and Genotypic Factors

Understanding the causes and consequences of variability in responses to medicines is a foundation of rational therapeutics. This relies on a detailed understanding of the pharmacokinetic and pharmacodynamic characteristics of medicines and the factors that influence them in patients. 1 Ultimately the optimal dose regimen is determined by the pharmacological phenotype of the patient, which is a consequence of the persons genes and the environment in which they are expressed. 1 Older people display considerable variability in responses to medicines, and this makes dose selection a complex process. 2, 3 Pharmacogenomic factors play some part in this variability, but other clinical factors also determine an older persons phenotypic response to a medicine. 1, 2, 3, 4 In this article we conclude that with older age, genotype plays an increasingly small role in determining a persons phenotypic response to a medicine.

The Cys282Tyr polymorphism in the HFE gene in Australian Parkinson's disease patients

Iron homeostasis is altered in Parkinsons disease (PD). The HFE protein is an important regulator of cellular iron homeostasis and variations within this gene can result in iron overload and the disorder known as hereditary haemochromatosis. We studied the Cys282Tyr single nucleotide polymorphism as a genetic risk factor for PD in two distinct and separately collected cohorts of Australian PD patients and controls. In the combined cohort comprising 438 PD patients and 485 control subjects, we revealed an odds ratio for possession of the 282Tyr allele of 0.61 (95% confidence interval, CI=0.42-0.90, P=0.011) from univariate chi-squared and 0.59 (95% CI=0.39-0.90, P=0.014) after logistic regression analyses (correcting for potential confounding factors). These results suggest that possession of the 282Tyr allele may offer some protection against the development of PD.

The dopamine transporter gene and Parkinson's disease in a Chinese population

We studied a variable number tandem repeat polymorphism within the dopamine transporter gene (DAT) for an association with Parkinsons disease in a Chinese population. Five alleles were detected, consisting of 6, 8, 9, 10, and 11 copies of the 40 base pair repeat sequence. The 10-copy allele was most common, accounting for 90% of alleles. There were no significant differences between the patients and the control subjects in the distribution frequencies of the alleles or genotypes. Therefore, this polymorphism is not associated with Parkinsons disease in Chinese populations.

TOXICITY OF PASSIFLORA INCARNATA L

Background: Herbal medicines may have significant adverse effects which are not suspected or recognized. Case Report: A 34-year-old female developed severe nausea, vomiting, drowsiness, prolonged QTc, and episodes of nonsustained ventricular tachycardia following self-administration of a herbal remedy, Passiflora incarnata L., at therapeutic doses. The possible association of symptoms with passiflora was not recognized for several days. She required hospital admission for cardiac monitoring and intravenous fluid therapy. Conclusions: Passiflora incarnata was associated with significant adverse effects in this patient. It is important to ask specifically about the use of herbal medicines in patients with undiagnosed illnesses.

The monoamine oxidase B gene GT repeat polymorphism and Parkinson's disease in a Chinese population

Abstract Monoamine oxidase B (MAOB) metabolises dopamine and activates neurotoxins known to induce parkinsonism in humans and primates. Therefore the MAOB gene (MAOB; Xp15.21–4) is a candidate gene for Parkinson’s disease (PD). Longer length dinucleotide repeat sequences in a highly polymorphic GT repeat region of intron 2 of this gene showed an association with PD in an Australian cohort. We repeated this allele-association study in a population of 176 Chinese PD patients ¶(90 men, 86 women) and 203 age-matched controls (99 men, 104 women). Genomic DNA was extracted from venous blood and the polymerase chain reaction was used to amplify the appropriate regions of the MAOB gene. The length of each (GT) repeat sequence was determined by 5% polyacrylamide denaturing gel electrophoresis. There was no significant difference in allele frequencies of the (GT) repeat allelic variation between patients and controls (χ2 = 2.48; df = 5, P < 0.75). Therefore the longer length GT repeat alleles are not associated with PD in this Chinese population. Possible reasons for the discrepancy between Chinese and Australian populations include a different interaction between this genetic factor and environmental factors in the two populations and the possibility that the long length GT repeat alleles may represent a marker mutation, genetically linked to another susceptibility allele in whites but not in Chinese. Methodological differences in the ascertainment of cases and controls in this cohort could also explain the observed differences. Further study is required to determine whether the longer length GT repeat alleles are true susceptibility alleles in PD.

Do medical courses adequately prepare interns for safe and effective prescribing in New South Wales public hospitals

Aims: To assess ability of interns immediately before starting clinical practice in New South Wales (NSW) teaching hospitals to prescribe medications safely and appropriately and to describe their impressions of the adequacy of their clinical pharmacology training in medical school.

Physicians need to take the lead in deprescribing

Inappropriate polypharmacy and its associated harm pose a significant threat to older patients. The prescribing decisions of physicians greatly influence what other practitioners prescribe. Minimising medication‐related harm requires physicians to adopt a systematic approach to the deliberate and judicious deprescribing of potentially inappropriate medicines in at‐risk individuals.

Lifestyle factors, medications, and disease influence bone mineral density in older men: findings from the CHAMP study

SummaryAging alone is not the only factor accounting for poor bone health in older men. There are modifiable factors and lifestyle choices that may influence bone health and result in higher bone density and lower fracture risk even in very old men.IntroductionThe aim of this cross-sectional analysis was to identify the factors associated with areal bone mineral density (BMD) and their relative contribution in older men.MethodsThe Concord Health and Ageing in Men Project is a population-based study in Sydney, Australia, involving 1,705 men aged 70–97. Data were collected using questionnaires and clinical assessments. BMD of the hip and spine was measured by dual X-ray absorptiometry.ResultsIn multivariate regression models, BMD of the hip was associated with body weight and bone loading physical activities, but not independently with age. The positive relationship between higher BMD and recreational activities is attenuated with age. Factors independently associated with lower BMD at the hip were inability to stand from sitting, a history of kidney stones, thyroxine use, and Asian birth and at the spine, chronic obstructive pulmonary disease, paternal fracture history, and thyroxine use. Higher body weight, participation in dancing, tennis or jogging, quadriceps strength, alcohol consumption, and statin use were associated with higher hip BMD, while older age, osteoarthritis, higher body weight, and aspirin use were associated with higher spinal BMD.ConclusionMaintaining body weight, physical activity, and strength were positively associated with BMD even in very elderly men. Other parameters were also found to influence BMD, and once these were included in multivariate analysis, age was no longer associated with BMD. This suggests that age-related diseases, lifestyle choices, and medications influence BMD rather than age per se.