Meta-analysis of brain samples of individuals with schizophrenia detects down-regulation of multiple ATP synthase encoding genes in both females and males.

Schizophrenia is a chronic and debilitating mental disorder, with unknown pathophysiology. Converging lines of evidence suggest that mitochondrial functioning may be compromised in schizophrenia. Postmortem brain samples of individuals with schizophrenia showed dysregulated expression levels of genes encoding enzyme complexes comprising the mitochondrial electron transport chain (ETC), including ATP synthase, the fifth ETC complex. However, there are inconsistencies regarding the direction of change, i.e., up- or down-regulation, and differences between female and male patients were hardly examined. We have performed a systematic meta-analysis of the expression of 16 ATP synthase encoding genes in postmortem brain samples of individuals with schizophrenia vs. healthy controls of three regions: Brodmann Area 10 (BA10), BA22/Superior Temporal Gyrus (STG) and the cerebellum. Eight independent datasets were integrated (overall 294brain samples, 145 of individuals with schizophrenia and 149 controls). The meta-analysis was applied to all individuals with schizophrenia vs. the controls, and also to female and male patients vs. age-matched controls, separately. A significant down-regulation of two ATP synthase encoding genes was detected in schizophrenia, ATP5A1 and ATP5H, and a trend towards down-regulation of five further ATP synthase genes. The down-regulation tendency was shown for both females and males with schizophrenia. Our findings support the hypothesis that schizophrenia is associated with reduced ATP synthesis via the oxidative phosphorylation system, which is caused by reduced cellular demand of ATP. Abnormal cellular energy metabolism can lead to alterations in neural function and brain circuitry, and thereby to the cognitive and behavioral aberrations characteristic of schizophrenia.

Octogenarian patients with colorectal cancer: Characterizing an emerging clinical entity.

AIM: To characterize colorectal cancer (CRC) in octogenarians as compared with younger patients. METHODS: A single-center, retrospective cohort study which included patients diagnosed with CRC at the age of 80 years or older between 2008-2013. A control group included consecutive patients younger than 80 years diagnosed with CRC during the same period. Clinicopathological characteristics, treatment and outcome were compared between the groups. Fisher's exact test was used for dichotomous variables and χ2 was used for variables with more than two categories. Overall survival was assessed by Kaplan-Meier survival analysis, with the log-rank test. Cancer specific survival (CSS) and disease-free survival were assessed by the Cox proportional hazards model, with the Fine and Gray correction for non-cancer death as a competing risk. RESULTS: The study included 350 patients, 175 patients in each group. Median follow-up was 40.2 mo (range 1.8-97.5). Several significant differences were noted. Octogenarians had a higher proportion of Ashkenazi ethnicity (64.8% vs 47.9%, P < 0.001), a higher rate of personal history of other malignancies (22.4% vs 13.7%, P = 0.035) and lower rates of family history of any cancer (36.6% vs 64.6%, P < 0.001) and family history of CRC (14.4% vs 27.3%, P = 0.006). CRC diagnosis by screening was less frequent in octogenarians (5.7% vs 20%, P < 0.001) and presentation with performance status (PS) of 0-1 was less common in octogenarians (71% vs 93.9%, P < 0.001). Octogenarians were more likely to have tumors located in the right colon (45.7% vs 34.3%, P = 0.029) and had a lower prevalence of well differentiated histology (10.4% vs 19.3%, P = 0.025). They received less treatment and treatment was less aggressive, both in patients with metastatic and non-metastatic disease, regardless of PS. Their 5-year CSS was worse (63.4% vs 77.6%, P = 0.009), both for metastatic (21% vs 43%, P = 0.03) and for non-metastatic disease (76% vs 88%, P = 0.028). CONCLUSION: Octogenarians presented with several distinct characteristics and had worse outcome. Further research is warranted to better define this growing population.