Aging is the main risk factor for Alzheimer’s disease (AD); however, the aspects of the aging process that predispose the brain to the development of AD are largely unknown. Astrocytes perform a myriad of functions in the central nervous system to maintain homeostasis and support neuronal function. In vitro, human astrocytes are highly sensitive to oxidative stress and trigger a senescence program when faced with multiple types of stress. In order to determine whether senescent astrocytes appear in vivo, brain tissue from aged individuals and patients with AD was examined for the presence of senescent astrocytes using p16INK4a and matrix metalloproteinase-1 (MMP-1) expression as markers of senescence. Compared with fetal tissue samples (n = 4), a significant increase in p16INK4a-positive astrocytes was observed in subjects aged 35 to 50 years (n = 6; P = 0.02) and 78 to 90 years (n = 11; P<10−6). In addition, the frontal cortex of AD patients (n = 15) harbored a significantly greater burden of p16INK4a-positive astrocytes compared with non-AD adult control subjects of similar ages (n = 25; P = 0.02) and fetal controls (n = 4; P<10−7). Consistent with the senescent nature of the p16INK4a-positive astrocytes, increased metalloproteinase MMP-1 correlated with p16INK4a. In vitro, beta-amyloid 1–42 (Aβ1–42) triggered senescence, driving the expression of p16INK4a and senescence-associated beta-galactosidase. In addition, we found that senescent astrocytes produce a number of inflammatory cytokines including interleukin-6 (IL-6), which seems to be regulated by p38MAPK. We propose that an accumulation of p16INK4a-positive senescent astrocytes may link increased age and increased risk for sporadic AD.

There is a 30% higher case fatality rate from cancer in psychiatric patients even though their incidence of cancer is no greater than in the general population. The reasons are unclear, but if increased cancer mortality were due to lifestyle only, cancer incidence should be similarly increased. Other hypotheses include delays in presentation, leading to more advanced staging at diagnosis, and difficulties in treatment access following diagnosis.Objective: To assess why psychiatric patients are no more likely than the general population to develop cancer but are more likely to die of it.Design, Setting, and Patients: A population-based record-linkage analysis compared psychiatric patients with the Western Australian population, using an inception cohort to calculate rates and hazard ratios. Mental health records were linked with cancer registrations and death records from January 1, 1988, to December 31, 2007, in Western Australia.Main Outcome Measures: Metastases, incidence, mortality, and access to cancer interventions.Results: There were 6586 new cancers in psychiatric patients. Cancer incidence was lower in psychiatric pa-tients than in the general population in both males (rate ratio = 0.86; 95% CI, 0.82-0.90) and females (rate ratio = 0.92; 95% CI, 0.88-0.96), although mortality was higher (males: rate ratio = 1.52; 95% CI, 1.45-1.60; females: rate ratio=1.29; 95% CI, 1.22-1.36). The proportion of cancer with metastases at presentation was significantly higher in psychiatric patients (7.1%; 95% CI, 6.5%-7.8%) than in the general population (6.1%; 95% CI, 6.0%-6.2%). Psychiatric patients had a reduced likelihood of surgery (hazard ratio = 0.81; 95% CI, 0.76-0.86), especially resection of colorectal, breast, and cervical cancers. They also received significantly less radiotherapy for breast, colorectal, and uterine cancers and fewer chemotherapy sessions.Conclusions: Although incidence is no higher than in the general population, psychiatric patients are more likely to have metastases at diagnosis and less likely to receive specialized interventions. This may explain their greater case fatality and highlights the need for improved cancer screening and detection.

Objective To measure the effectiveness of the quadrivalent human papillomavirus (HPV) vaccine against cervical abnormalities four years after implementation of a nationally funded vaccination programme in Queensland, Australia.Design Case-control analysis of linked administrative health datasets.Setting Queensland, Australia.Participants Women eligible for free vaccination (aged 12-26 years in 2007) and attending for their first cervical smear test between April 2007 and March 2011. High grade cases were women with histologically confirmed high grade cervical abnormalities (n=1062) and "other cases" were women with any other abnormality at cytology or histology (n=10 887). Controls were women with normal cytology (n=96 404).Main outcome measures Exposure odds ratio (ratio of odds of antecedent vaccination (one, two, or three vaccine doses compared with no doses) among cases compared with controls), vaccine effectiveness ((1−adjusted odds ratio)×100), and number needed to vaccinate to prevent one cervical abnormality at first screening round. We stratified by four age groups adjusted for follow-up time, year of birth, and measures of socioeconomic status and remoteness. The primary analysis concerned women whose first ever smear test defined their status as a case or a control. ResultsThe adjusted odds ratio for exposure to three doses of HPV vaccine compared with no vaccine was 0.54 (95% confidence interval 0.43 to 0.67) for high grade cases and 0.66 (0.62 to 0.70) for other cases compared with controls with normal cytology, equating to vaccine effectiveness of 46% and 34%, respectively. The adjusted numbers needed to vaccinate were 125 (95% confidence interval 97 to 174) and 22 (19 to 25), respectively. The adjusted exposure odds ratios for two vaccine doses were 0.79 (95% confidence interval 0.64 to 0.98) for high grade cases and 0.79 (0.74 to 0.85) for other cases, equating to vaccine effectiveness of 21%. ConclusionThe quadrivalent HPV vaccine conferred statistically significant protection against cervical abnormalities in young women who had not started screening before the implementation of the vaccination programme in Queensland, Australia.

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