Aging in Fragile X Premutation Carriers

It is now recognized that FMR1 premutation carriers (PC) are at risk to develop a range of neurological, psychiatric, and immune-mediated disorders during adulthood. There are conflicting findings regarding the incidence of hypertension, hypothyroidism, diabetes, and cancer in these patients that warrant further study. A retrospective controlled study was performed in a convenience sample of 248 controls (130 men, 118 women) and 397 FMR1 PC with and without fragile X-associated tremor ataxia syndrome (FXTAS) (176 men, 221 women); all participants were at least 45 years old (men: mean 62.4, SD 9.5; women: mean 62.8, SD 9.9; p?=?0.63). Memory and cognitive assessments (Wechsler Adult Intelligence Scale (WAIS-III), Wechsler Memory Scale (WMS-III)) and molecular testing (CGG repeats and FMR1-mRNA levels) were performed. Additional data included body mass index (BMI), cholesterol levels, blood pressure, hemoglobin A1c (HbA1c) levels, and medical history. A higher percentage of PC subjects self-reported having a diagnosis of hypertension (50.0 vs. 35.0 %, p?=?0.006) and thyroid problems (20.4 vs. 10.0 %, p?=?0.012) than control subjects. When comparing controls versus PC with FXTAS, the association was higher for diabetes (p?=?0.043); however, the effect was not significant after adjusting for demographic predictors. Blood pressure, blood glucose levels, HbA1c, and BMI values were not significantly different between the two groups. The PC with FXTAS group performed consistently lower in neuropsychological testing compared with the PC without FXTAS group, but the differences were very small for all but the WAIS full-scale IQ. Based on these findings, it appears that the risk for hypertension, thyroid problems, and diabetes may be more frequent in PC with FXTAS, which will require verification in future studies.     

MAC1 mediates LPS-induced production of superoxide by microglia: the role of pattern recognition receptors in dopaminergic neurotoxicity

Microglia-derived superoxide is critical for the inflammation-induced selective loss of dopaminergic (DA) neurons, but the underlying mechanisms of microglial activation remain poorly defined. Using neuron-glia and microglia-enriched cultures from mice deficient in the MAC1 receptor (MAC1-/-), we demonstrate that lipopolysaccharide (LPS) treatment results in lower TNFalpha response, attenuated loss of DA neurons, and absence of extracellular superoxide production in MAC1-/- cultures. Microglia accumulated fluorescently labeled LPS in punctate compartments associated with the plasma membrane, intracellular vesicles, and the Golgi apparatus. Cytochalasin D (CD), an inhibitor of phagocytosis, blocked LPS internalization. However, microglia derived from Toll-like receptor 4 deficient mice and MAC1-/- mice failed to show a significant decrease in intracellular accumulation of labeled LPS, when compared with controls. Pretreatment with the scavenger receptor inhibitor, fucoidan, inhibited 79% of LPS accumulation in microglia without affecting superoxide, indicating that LPS internalization and superoxide production are mediated by separate phagocytosis receptors. Together, these data demonstrate that MAC1 is essential for LPS-induced superoxide from microglia, implicating MAC1 as a critical trigger of microglial-derived oxidative stress during inflammation-mediated neurodegeneration.     

The effect of socioeconomic status on survival from colorectal cancer in the Melbourne Collaborative Cohort Study

Previous research relating lower socioeconomic status (SES) with poorer survival from colorectal cancer has varied in adjustment for confounding factors and in the use of individual-level or aggregate-level indicators of SES. We investigated the effect of SES and country of birth on survival from colorectal cancers diagnosed in participants of the Melbourne Collaborative Cohort Study. A total of 526 colorectal cancer cases diagnosed since baseline were followed from diagnosis to 1 June 2006 or death. Information on tumour site and stage, and treatments given were obtained from systematic medical record review. SES at diagnosis was assigned using both an area-based measure of social disadvantage and individual level of educational attainment. Cox regression models were used to estimate hazard ratios associated with socioeconomic disadvantage, educational attainment, and country of birth. During an average follow-up of 5.6 years from diagnosis, 230 deaths occurred, 197 from colorectal cancer. After adjusting for age, sex, tumour stage, waist circumference and adjuvant chemotherapy and radiotherapy, the hazard ratios of dying from all causes and from colorectal cancer associated with living in the least disadvantaged areas compared with most disadvantaged areas were 0.73 (95% CI 0.53–1.00, p for trend = 0.06) and 0.80 (95% CI 0.57–1.12, p for trend = 0.22) respectively. Further adjustment for hospital case-load, tumour characteristics, and lifestyle factors did not change the estimates materially. Level of educational attainment and country of birth were not independent predictors of the risk of dying from colorectal cancer. Despite a universal health care system in Australia, socioeconomic inequalities in survival from colorectal cancer exist, and an enduring challenge is to ensure that improvements in colorectal cancer survival are shared equally across the population.     

Stroke in rural areas and small communities

The management of stroke in rural and regional areas is variable in both the developed and developing world. Informed by best-practice guidelines and recommendations for systems of stroke care, adaptable models of care that are appropriate for local needs should be devised for rural and regional settings. This review addresses the issue of the provision of appropriate services in rural and regional settings, with particular attention to the barriers involved, according to the classification of Low Human Development Country (LHDC), Medium Human Development Country (MHDC) and High Human Development Country (HHDC). We discuss the need and feasibility of developing implementing stroke care in rural settings according to best-practice recommendations, within models of care adapted to local conditions.     

The rs743572 common variant in the promoter of CYP17A1 is not associated with prostate cancer risk or circulating hormonal levels

OBJECTIVE

To use a large population‐based case‐control study to test the association between the common genetic variant rs743572 (?34 T to C), prostate cancer risk and circulating levels of several hormones.

SUBJECTS AND METHODS

A previous meta‐analysis concluded that reported associations between rs743572 in the promoter of CYP17A1 and prostate cancer risk might reflect publication bias, but a few recent studies reported associations with prostate cancer risk and data suggesting that rs743572 is functional. We genotyped 824 prostate cancer cases and 737 population‐based controls, and applied unconditional logistic regression to estimate the association between rs743572 and prostate cancer risk. We also used linear regression of transformed testosterone, androstanediol glucuronide, dehydroepiandrosterone sulphate, androstenedione, sex hormone‐binding globulin and oestradiol (circulating levels) measured for controls, to estimate the association between these levels and rs743572. The linear models were adjusted for age and laboratory batch.

RESULTS

Men with different genotypes had similar circulating levels of all the hormones measured (all P < 0.05). In the case‐control comparison using unconditional unadjusted logistic regression, the odds ratios (95% confidence interval) for prostate cancer were 1.07 (0.87–1.32) and 0.94 (0.71–1.25) for the dominant and recessive models, respectively, and for the co‐dominant model, 1.10 (0.88–1.36) and 0.99 (0.73–1.35) for carriers of one or two copies of the C allele, respectively. There was no evidence of heterogeneity in the odds ratios by tumour stage (all P > 0.3) and grade (all P > 0.3).

CONCLUSION

The results of the present study are consistent with the conclusions of the previous meta‐analysis, and suggest that rs743572 has no role in the risk of prostate cancer for men of Caucasian origin.     

Modulatory influence of stimulus parameters on optokinetic head-tracking response

Optokinetic testing is a non-invasive technique, widely used for visual functional evaluation in rodents. The modulatory influence of optokinetic stimulus parameters such as contrast level and grating speed on head-tracking response in normal and retinal degenerate (RD) mice (rd10) and rats (S334ter-line-3) was evaluated using a computer-based testing apparatus. In normal (non-RD) mice and rats, specific stripe width and grating speed was found to evoke maximum optokinetic head-tracking response. In line-3 RD rats, the contrast sensitivity loss was slow and remained close to the baseline (normal control) level until very late in the disease, whereas, in rd10 mice the progression of the contrast sensitivity loss was more rapid. Observed differences between rd10 mice and line-3 RD rats in the progression of contrast sensitivity loss may not be directly related to the degree of photoreceptor loss. In young RD mice, the modulatory influence of stimulus parameters on optokinetic head-tracking response was similar to normal control animals. During later stages, slower grating speed was required to evoke the maximum optokinetic response. Grating speed had lesser apparent influence on the response properties of line-3 RD rats. Discrepancies between the two RD models in the modulatory influence of optokinetic stimulus parameters can be the manifestation of fundamental species differences and/or differences in the degeneration pattern. This study highlights the importance of careful selection of appropriate stimulus parameters for testing optokinetic head-tracking response in RD animals.     

Lifetime alcohol intake and risk of non‐Hodgkin lymphoma: Findings from the Melbourne Collaborative Cohort Study

Cohort studies have reported inconsistent evidence regarding alcohol intake and risk of non‐Hodgkin lymphoma (NHL), mostly based on alcohol intake assessed close to study enrolment. We examined this association using alcohol intake measured from age 20 onwards. We calculated usual alcohol intake for 10‐year periods from age 20 using recalled frequency and quantity of beverage‐specific consumption for 37,990 participants aged 40–69 years from the Melbourne Collaborative Cohort Study. Cox regression was performed to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between alcohol intake (g/day) and NHL risk. After a mean follow‐up of 19.3 years, 538 NHL cases were diagnosed. Approximately 80% of participants were either lifetime abstainers or consumed below 20 g of ethanol/day. All categories of lifetime alcohol intake were associated with about 20% lower incidence of NHL compared with lifetime abstention, but there was no evidence of a trend by amount consumed (HR = 0.97 per 10 g/day increment in intake, 95% CI: 0.92–1.03; p value = 0.3). HRs for beer, wine and spirits were 0.91 (95% CI: 0.83–1.00; p value = 0.05), 1.03 (95% CI: 0.94–1.12; p value = 0.6), and 1.06 (95% CI: 0.83–1.37; p value = 0.6), respectively, per 10 g/day increment in lifetime intake. There were no significant differences in associations between NHL subtypes. In this low‐drinking cohort, we did not detect a dose‐dependent association between lifetime alcohol intake and NHL risk.