Aging regulates 5-HT(1B) receptors and serotonin reuptake sites in the SCN

Middle age is associated with changes in circadian rhythms (e.g., alterations in the timing of the circadian wheel running rhythm) which resemble changes induced by selective destruction of the serotonergic input to the suprachiasmatic nucleus (SCN), the principal mammalian circadian pacemaker. We hypothesized that serotonergic neurotransmission in the SCN is decreased in middle-aged hamsters, as compared to young adults. This hypothesis was tested indirectly by investigating the effect of aging on two markers of serotonin neurotransmission, 5-HT(1B) receptors and serotonin reuptake sites, which are regulated by serotonin. Previous studies have shown that experimentally induced decreases in serotonergic neurotransmission increase 5-HT(1B) receptors but decrease serotonin reuptake sites. Quantitative autoradiography was conducted using [125I]iodocyanopindolol ([125I]ICYP) and [3H]paroxetine, selective radioligands for the 5-HT(1B) receptors and the serotonin reuptake sites, respectively. Consistent with the hypothesis, specific ([125I]ICYP binding was significantly elevated in the SCN of middle-aged hamsters, as compared to young hamsters. The results also showed that serotonin reuptake sites in the SCN were significantly increased in both middle-aged and old hamsters, as compared to young controls. This result could not have been caused by decreased serotonin release. Alternatively, increased serotonin reuptake, which would reduce serotonin levels in the synaptic cleft, may cause or contribute to the increase in 5-HT(1B) receptor binding in the SCN in middle aged animals. These results show that the SCN exhibits changes in serotonergic function during middle age, which has been characterized by changes in the expression of circadian rhythms. Because these changes occur during middle age, they probably reflect the aging process, rather than senescence or disease.     

Cyclin d1 is a valuable prognostic marker in oropharyngeal squamous cell carcinoma.

BACKGROUND: The current tumor-node-metastasis system is inadequate to accurately classify patients in terms of prognosis. Thus, with the availability of recently developed molecular tools, considerable interest lies in discovering prognostic markers in order to guide treatment decisions. In this study, we sought to determine the prognostic significance of the cell cycle regulator cyclin D1 in oropharyngeal squamous cell carcinoma (OSCC). EXPERIMENTAL DESIGN: We studied the protein expression levels of cyclin D1 on a tissue microarray composed of 63 OSCCs with long-term follow-up data available. Protein expression was analyzed with an automated in situ quantitative (AQUA) method which allows preservation of tissue morphology while quantifying protein expression in paraffin-embedded tissue. RESULTS: The mean follow-up time was 35 months. High cyclin D1 nuclear expression was associated with increased 5-year local recurrence rate (48% versus 15%), inferior 5-year disease-free survival (16% versus 58%), and inferior 5-year overall survival (17% versus 53%). In multivariate Cox regression, high nuclear cyclin D1 expression was an independent predictor for local recurrence, disease-free survival, and overall survival at 5 years. CONCLUSIONS: Our results indicate that quantitative assessment of nuclear cyclin D1 expression level by automated in situ quantitative analysis is a strong predictor for outcome in OSCC. Thus, cyclin D1 may be a potential target for molecular intervention in patients with oropharyngeal squamous cell cancer.     

Cathepsins in neuronal plasticity

Proteases comprise a variety of enzymes defined by their ability to catalytically hydrolyze the peptide bonds of other proteins, resulting in protein lysis. Cathepsins, specifically, encompass a class of at least twenty proteases with potent endopeptidase activity. They are located subcellularly in lysosomes, organelles responsible for the cell's degradative and autophagic processes, and are vital for normal lysosomal function. Although cathepsins are involved in a multitude of cell signaling activities, this chapter will focus on the role of cathepsins(with a special emphasis on Cathepsin B) in neuronal plasticity. We will broadly define what is known about regulation of cathepsins in the central nervous system and compare this with their dysregulation after injury or disease. Importantly, we will delineate what is currently known about the role of cathepsins in axon regeneration and plasticity after spinal cord injury. It is well established that normal cathepsin activity is integral to the function of lysosomes. Without normal lysosomal function, autophagy and other homeostatic cellular processes become dysregulated resulting in axon dystrophy. Furthermore, controlled activation of cathepsins at specialized neuronal structures such as axonal growth cones and dendritic spines have been positively implicated in their plasticity. This chapter will end with a perspective on the consequences of cathepsin dysregulation versus controlled, localized regulation to clarify how cathepsins can contribute to both neuronal plasticity and neurodegeneration.     

Participatory Systems Mapping for Municipal Prioritization and Planning

Rapidly growing cities face new and compounding health challenges, leading governments and donors to seek innovative ways to support healthier, more resilient urban growth. One such approach is the systems mapping process developed by Engaging Inquiry (EI) for the USAID-funded Building Healthy Cities project (BHC) in four cities in Asia. This paper provides details on the theory and methods of the process. While systems mapping is not new, the approach detailed in this paper has been uniquely adapted to the purpose of municipal planning. Strategic stakeholder engagement, including participatory workshops with a diverse group of stakeholders, is at the core of this approach and led to deeper insights, greater buy-in, and shared understanding of the city’s unique opportunities and challenges. This innovative mapping process is a powerful tool for defining municipal priorities within growing cities across the globe, where the situation is rapidly evolving. It can be used to provide evidence-based information on where to invest to gain the biggest impact on specific goals. This paper is part of a collection in this issue providing a detailed accounting of BHC’s systems mapping approach across four project cities.     

Body Fat Moderates the Association of Olfactory Dysfunction with Dietary Intake in U.S. Middle-Aged and Older Adults: A Cross-Sectional Analysis of NHANES 2013–2014

Background: Obesity relates to impaired olfactory function. Abnormal olfactory function is also associated with poor diet; however, whether obesity-related markers shape this relationship is unknown. Methods: Cross-sectional analysis (n = 1415, age > 40 years) of NHANES 2013–2014 examined body fat percent (BF%) and waist circumference (WC) as moderators of the relationship between olfactory function and diet. The olfactory function test identified adults with olfactory dysfunction (OD) or normal olfaction (NO). Validated 24 h recall captured nutrient intake and Healthy Eating Index-2010 scores. BF% and WC were measured. We tested adjusted linear regression models, with an interaction term between olfactory function and BF%/WC, for each nutrient or HEI score, and reported coefficients (β), standard errors (SE), and p-values for significant interaction terms. Results: In OD (9.5%; mean age 50.9 years, 95% CI 49.6, 52.2) compared with NO (mean age 49.3 years, 95% CI 48.8, 49.9), higher BF% was associated with higher intake of saturated fat (β (SE): 0.2 (0.1) g; p = 0.06) and percent of total calories from total fat (0.2 (0.1); p = 0.07), saturated (0.1 (0.004); p = 0.02), and monounsaturated fat (0.1 (0.1); p = 0.08); lower percent of total calories from carbohydrates (−0.2 (0.1); p = 0.09) and mg of sodium (−17.8 (09.6); p = 0.08); and a higher (healthier) refined grain score (0.1 (0.1); p = 0.04). Higher WC was associated with higher refined grain scores (0.01 (0.02); p = 0.01) in OD. Conclusion: BF% may shape dietary intake and quality in OD. Longitudinal studies are needed to elucidate the directionality of these relationships and develop strategies to improve dietary intake among OD.     

Timely follow‐up of positive cancer screening results: A systematic review and recommendations from the PROSPR Consortium

Timely follow‐up for positive cancer screening results remains suboptimal, and the evidence base to inform decisions on optimizing the timeliness of diagnostic testing is unclear. This systematic review evaluated published studies regarding time to follow‐up after a positive screening for breast, cervical, colorectal, and lung cancers. The quality of available evidence was very low or low across cancers, with potential attenuated or reversed associations from confounding by indication in most studies. Overall, evidence suggested that the risk for poorer cancer outcomes rises with longer wait times that vary within and across cancer types, which supports performing diagnostic testing as soon as feasible after the positive result, but evidence for specific time targets is limited. Within these limitations, we provide our opinion on cancer‐specific recommendations for times to follow‐up and how existing guidelines relate to the current evidence. Thresholds set should consider patient worry, potential for loss to follow‐up with prolonged wait times, and available resources. Research is needed to better guide the timeliness of diagnostic follow‐up, including considerations for patient preferences and existing barriers, while addressing methodological weaknesses. Research is also needed to identify effective interventions for reducing wait times for diagnostic testing, particularly in underserved or low‐resource settings. CA Cancer J Clin 2018;68:199–216 . © 2018 American Cancer Society .