Hamish A. Jamieson

Resveratrol improves health and survival of mice on a high-calorie diet.

Resveratrol (3,5,4′-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.

Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span

A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.

Caloric restriction reduces age-related pseudocapillarization of the hepatic sinusoid

Age-related changes in the hepatic sinusoid, called pseudocapillarization, may contribute to the pathogenesis of dyslipidemia. Caloric restriction (CR) is a powerful model for the study of aging because it extends lifespan. We assessed the effects of CR on the hepatic sinusoid to determine whether pseudocapillarization is preventable and hence a target for the prevention of age-related dyslipidemia. Livers from young (6 months) and old (24 months) CR and ad libitum fed (AL) F344 rats were examined using electron microscopy and immunohistochemistry. In old age, there was increased thickness of the liver sinusoidal endothelium and reduced endothelial fenestration porosity. In old CR rats, endothelial thickness was less and fenestration porosity was greater than in old AL rats. Immunohistochemistry showed that CR prevented age-related decrease in caveolin-1 expression and increase in peri-sinusoidal collagen IV staining, but did not alter the age-related increase of von Willebrands factor. CR reduces age-related pseudocapillarization of the hepatic sinusoid and correlates with changes in caveolin-1 expression.

The liver sieve and atherosclerosis

Summary The ‘liver sieve’ is a term developed to describe the appearance and the role of fenestrations in the liver sinusoidal endothelial cell (LSEC). LSECs are gossamer-thin cells that line the hepatic sinusoid and they are perforated with pores called fenestrations clustered in sieve plates. There is growing evidence that fenestrations act like a permselective ultrafiltration system which is important for the hepatic uptake of many substrates, particularly chylomicron remnant lipoproteins. The liver sieve is a very efficient exchange system, however in conditions such as hepatic cirrhosis and fibrosis, diabetes mellitus and old age, there is defenestration of the liver sieve. Such defenestration has been shown to influence the hepatic uptake of various substrates including lipoproteins. In the future, pharmacological manipulation of the liver sieve may play a number of therapeutic roles including the management of dyslipidaemia; increasing the efficiency of liver-targeted gene therapy; and improving regeneration of old livers.

‘Real-world’ haemorrhagic rates for warfarin and dabigatran using population-level data in New Zealand ☆

BACKGROUND Anticoagulants such as warfarin and dabigatran can significantly reduce the risk of stroke in individuals with atrial fibrillation that may lead to increased risk of bleeding, especially in older people. Evidence for bleeding risks with anticoagulants within the context of doses, multimorbidity and impaired renal function in real world setting is lacking. Therefore we aimed to assess and compare real world bleeding risks with warfarin and dabigatran. Secondary analyses involved examining risk of fatal haemorrhages. METHODS AND RESULTS We formed two inception cohorts of propensity score (PS) matched older patients (≥ 65 years), who initiated dabigatran or warfarin between July 2011 and December 2012. A total of 4835 dabigatran users were matched to 4385 warfarin users in dose independent binary PS matching. A dose dependent PS matching resulted in 2383 warfarin, 2153 dabigatran 150 mg and 3395 dabigatran 110 mg users. In the first cohort, compared to warfarin, the hazard ratios (95% confidence intervals) for dabigatran were 0.45 (0.37-0.55) for any haemorrhage; 1.16 (0.87-1.56) for gastrointestinal haemorrhage; and 0.29 (0.09-0.86) for intracerebral haemorrhage. Similar associations were observed in the first 30 days of treatment. In dose dependent matched cohort, the risk of any haemorrhage was lower in individuals receiving dabigatran 110 mg (HR; 95% CI: 0.40 (0.31-0.52)) and 150 mg (HR; 95% CI: 0.29 (0.19-0.41)) compared to warfarin. CONCLUSIONS The risk of any haemorrhage and intracerebral haemorrhage was lower in dabigatran users compared to warfarin users. Importantly no increased risk of gastrointestinal haemorrhage was found in dabigatran users. The incidence rates for any haemorrhage were found to be higher in first 30 days of any anticoagulant treatment, but hazard ratios remained similar during the study period.

Comprehensive clinical assessment of home-based older persons within New Zealand: an epidemiological profile of a national cross-section.

Objective: Since 2012, all community care recipients in New Zealand have undergone a standardised needs assessment using the Home Care International Residential Assessment Instrument (interRAI‐HC). This study describes the national interRAI‐HC population, assesses its data quality and evaluates its ability to be matched.

The effect of Pseudomonas aeruginosa virulence factor, pyocyanin, on the liver sinusoidal endothelial cell

1 Dieulafoy G. Exulceratio simplex. L’intervention chirurgicale dans les hématémèses foudroyantes consécutives à l’exulcération simple de l’estomac. Bull. Acad. Med. 1898; 39: 49–84. 2 Reilly HF, Al-Kawas FH. Dieulafoy’s lesion. Diagnosis and management. Dig. Dis. Sci. 1991; 36: 1702–7. 3 Lee YT, Walmsley RS, Leong RW, Sung JJ. Dieulafoy’s lesion. Gastrointest. Endosc. 2003; 58: 236–43. 4 Juler GL, Labitzke HG, Lamb R, Allen R. The pathogenesis of Dieulafoy’s gastric erosion. Am. J. Gastroenterol. 1984; 79: 195–200. 5 Willemsen PJ, Vanderveken ML, De Caluwe DO, Tielliu IF. Hemobilia: a rare complication of chelecystitis and cholecystolithiasis. Acta Chir. Belg. 1996; 96: 93–4.

New Zealand's interRAI: A Resource For Examining Health Outcomes in Geriatric Pharmacoepidemiology

The international Residential Assessment Instrument (interRAI) was developed by an international consensus using the best available evidence. The interRAI-Home Care (interRAI-HC) is mandatory and used throughout New Zealand (NZ) for all older people requiring assessment for government funded support or for entry into aged residential care. As of March 2015, over 80,000 assessments have been completed. Data is continuously gathered by trained assessors who undergo a 2-day training program overseen by the Ministry of Health. They then have to complete 10 assessments, which are quality reviewed, prior to carrying out interRAI-HC assessments without supervision. To ensure quality is maintained, each assessor has two interRAI-HC assessments randomly reviewed each year and they also have to complete and pass an annual online coding assessment. Individual-level data that are available from the interRAI-HC suite include, but are not limited to, medical conditions, social demographics, frailty, cognitive function, and physical function. The interRAI-HC tool also has a changes in health, end-stage disease, and signs and symptoms (CHESS) scale which is designed to identify individuals at risk of serious decline. There are also other interRAI-HC measurements. For example, a method for assigning priority levels (MAPLe) score, which is a predictor of nursing home placement need and caregiver distress. The use of interRAI-HC allows these important factors to be extracted and assessed as potential confounding factors in examining health outcomes at a population level. Evidence from clinical trials can be rarely extrapolated to the geriatric population given representation of older people is often low in clinical trials and more importantly, they are a diverse and heterogeneous group that are difficult to subject a clinical trial investigation to. Geriatric pharmacoepidemiology can potentially provide important information from large and representative sample of real world patients. There is more scope to examine multiple drug exposures (type and dose) together with social and clinical risk factors for a longer period of follow up time. However, the main challenge of geriatric pharmacoepidemiological research is in the area of confounding. Only few epidemiological studies have controlled for important confounders, and it is accepted as a caveat in pharmacoepidemiological research that residual confounding and confounding by indication cannot be completely eliminated The novelty of the interRAI-HC assessments is that it accounts for numerous social, psychological and, clinical risk factors when examining health outcomes in a geriatric population. Therefore, by utilizing a vast reservoir of variables contained in the interRAI-HC suite, reliable population-level evidence with appropriate confounding control can be generated. The interRAI-HC database (Figure 1) can be linked to several of NZ Ministry of Health national collections including prescription use (Pharms database), hospital discharges (National Minimum Dataset), mortality data, and laboratory collections. Individual records in these national collections include a unique 7-digit alpha-numeric identifier, the National Health Index identifier (NHI). The NHIs

Urinary incontinence, but not fecal incontinence, is a risk factor for admission to aged residential care of older persons in New Zealand

To determine if urinary incontinence (UI) and fecal incontinence (FI) were independent risk factors for aged resident care (ARC) admissions for older people, after controlling for confounders and applying apposite statistical methods.

An epidemiological profile of bipolar disorder among older adults with complex needs: a national cross-sectional study

Research on bipolar disorder (BD) among community‐living older adults is scant and often suffers from important methodological limitations. Using a national database, this study presents an epidemiological profile of BD in older community residents within New Zealand.