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Background and Purpose: Patients with dementia with Lewy bodies (DLB) are characterized by hypometabolism in the parieto–occipital cortex and the cingulate island sign (CIS) on 18F-fluorodeoxyglucose (FDG) PET. Whether this pattern of hypometabolism is present as early as the prodromal stage of DLB is unknown. We investigated the pattern of hypometabolism in patients with mild cognitive impairment (MCI) who progressed to probable DLB compared to MCI patients who progressed to Alzheimer’s disease (AD) dementia and clinically unimpaired (CU) controls. Methods: Patients with MCI from the Mayo Clinic Alzheimer’s Disease Research Center who underwent FDG PET at baseline and progressed to either probable DLB (MCI-DLB; n = 17) or AD dementia (MCI-AD; n = 41) during follow-up, and a comparison cohort of CU controls (n = 100) were included. Results: Patients with MCI-DLB had hypometabolism in the parieto-occipital cortex extending into temporal lobes, substantia nigra and thalamus. When compared to MCI-AD, medial temporal and posterior cingulate metabolism were preserved in patients with MCI-DLB, accompanied by greater hypometabolism in the substantia nigra in MCI-DLB compared to MCI-AD. In distinguishing MCI-DLB from MCI-AD at the maximum value of Youden’s index, CIS ratio was highly specific (90%) but not sensitive (59%), but a higher medial temporal to substantia nigra ratio was both sensitive (94%) and specific (83%). Conclusion: FDG PET is a potential biomarker for the prodromal stage of DLB. A higher medial temporal metabolism and CIS ratio, and lower substantia nigra metabolism have additive value in distinguishing prodromal DLB and AD.

Although flush toilets and sewerage are usually considered the height of comfort in 21st-century urban societies and the technical and sanitary culmination of human excreta management, they are increasingly being challenged for their environmental footprint and financial cost. Alternative management methods, broadly termed “source separation”, are being developed to address these issues. However, the widely shared belief in the absolute superiority of sewerage for public health is hindering the development of such systems. In this paper, we briefly re-examine the contribution to public health of sewerage as a means of managing human feces, in both its historical development and current implementation. We suggest that management of feces by sewerage is just one element among others in a systemic change, that it usually occurred much later than the others, and that the epidemiological transition usually attributed to sewerage only was, as a matter of fact, strongly supported by associated improvements in drinking water, health care, hygiene practices and good nutrition. We show that risk control in sewered cities is not based on a barrier between human feces and the environment (what we might call sanitation), but on barriers between a contaminated environment and the different uses of water. We call for a more comprehensive analysis of the effects of sewerage on public health, in present times and historically, not only at the scale of a city but at the broader scale of all impacted communities. We also call for a comparison of these effects with those of other sanitation systems that have much lower environmental footprint.

Summary: Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically, however, karyotype heterogeneity drives tumor evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate glycolysis and avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones. We also show that p38 deficiency upregulates the hypoxia-inducible transcription factor Hif-1α and that inhibiting Hif-1α restores apoptosis in p38-deficent cells. Because hypoxia and aneuploidy are both barriers to tumor progression, the ability of Hif-1α to promote cell survival following chromosome missegregation raises the possibility that aneuploidy tolerance coevolves with adaptation to hypoxia. : Simões-Sousa et al. show that chromosome missegregation induces metabolic collapse and apoptosis, mediated by the p38 stress response kinase. Inhibiting p38 elevates Hif-1α, boosts glycolysis, and limits metabolic collapse, in turn allowing expansion of aneuploid clones. Adapting to hypoxia during tumor development may therefore also permit aneuploidy tolerance. Keywords: mitosis, chromosome instability, aneuploidy

It is now recognized that small noncoding RNA sequences have the ability to mediate transcriptional activation of specific target genes in human cells. Using bioinformatics analysis and functional screening, we screened short-activating RNA (saRNA) oligonucleotides designed to target the promoter regions of the pluripotency reprogramming factors, Kruppel-like factor 4 (KLF4) and c-MYC. We identified KLF4 and c-MYC promoter-targeted saRNA sequences that consistently induced increases in their respective levels of nascent mRNA and protein expression in a time- and dose-dependent manner, as compared with scrambled sequence control oligonucleotides. The functional consequences of saRNA-induced activation of each targeted reprogramming factor were then characterized by comprehensively profiling changes in gene expression by microarray analysis, which revealed significant increases in mRNA levels of their respective downstream pathway genes. Notably, the microarray profile after saRNA-mediated induction of endogenous KLF4 and c-MYC showed similar gene expression patterns for stem cell- and cell cycle-related genes as compared with lentiviral vector-mediated overexpression of exogenous KLF4 and c-MYC transgenes, while divergent gene expression patterns common to viral vector-mediated transgene delivery were also noted. The use of promoter-targeted saRNAs for the activation of pluripotency reprogramming factors could have broad implications for stem cell research.