Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis with associated frontotemporal dementia (ALS/FTD) are major neurodegenerative diseases for which there are no ...cures. All are characterised by damage to several seemingly disparate cellular processes. The broad nature of this damage makes understanding pathogenic mechanisms and devising new treatments difficult. Can the different damaged functions be linked together in a common disease pathway and which damaged function should be targeted for therapy? Many functions damaged in neurodegenerative diseases are regulated by communications that mitochondria make with a specialised region of the endoplasmic reticulum (ER; mitochondria-associated ER membranes or ‘MAM’). Moreover, several recent studies have shown that disturbances to ER–mitochondria contacts occur in neurodegenerative diseases. Here, we review these findings.
OBJECTIVE:--To systematically tabulate published and unpublished sources of reliable glycemic index (GI) values. RESEARCH DESIGN AND METHODS--A literature search identified 205 articles published ...between 1981 and 2007. Unpublished data were also included where the data quality could be verified. The data were separated into two lists: the first representing more precise data derived from testing healthy subjects and the second primarily from individuals with impaired glucose metabolism. RESULTS:--The tables, which are available in the online-only appendix, list the GI of over 2,480 individual food items. Dairy products, legumes, and fruits were found to have a low GI. Breads, breakfast cereals, and rice, including whole grain, were available in both high and low GI versions. The correlation coefficient for 20 staple foods tested in both healthy and diabetic subjects was r = 0.94 (P < 0.001). CONCLUSIONS:--These tables improve the quality and quantity of GI data available for research and clinical practice.
Objectives
To evaluate how receipt and timing of nursing home (NH) palliative care consultations (primarily by nurse practitioners with palliative care expertise) are associated with end‐of‐life care ...transitions and acute care use
Design
Propensity score–matched retrospective cohort study.
Setting
Forty‐six NHs in two states.
Participants
Nursing home residents who died from 2006 to 2010 stratified according to days between initial consultation and death (≤7, 8–30, 31–60, 61–180). Propensity score matching identified three controls (n = 1,174) according to strata for each consultation recipient (n = 477).
Measurements
Outcomes were hospitalizations in the last 7, 30, and 60 days of life; emergency department (ED) visits in the last 30 and 60 days; and any potentially burdensome care transition, defined as hospitalization or hospice admission within 3 days of death or two or more hospitalizations or ED visits within 30 days. Weighted multivariate logistic regression analyses were used to evaluate outcomes.
Results
Residents with consultations had lower rates of hospitalization than controls, with rates lowest when initial consultations were furthest from death. For instance, in residents with initial consultations 8 to 30 days before death, the adjusted hospitalization rate in the last 7 days of life was 11.1% (95% confidence interval (CI) = 9.8–12.4%), vs 22.0% (95% CI = 20.6–23.4%) in controls, although in those with initial consultations 61 to 180 days before death, rates were 6.9% (95% CI = 5.5–8.4%), vs 22.9% (95% CI = 20.5–25.4%). Potentially burdensome transition rates were lower when consultations were 61 to 180 days before death (16.2%, 95% CI = 13.7–18.6%), vs 28.2% (95% CI = 25.8–30.6%) for controls.
Conclusion
Palliative care consultations improve end‐of‐life NH care by reducing acute care use and potentially burdensome care transitions.
Quorum sensing is a chemical communication process that bacteria use to regulate collective behaviors. Disabling quorum-sensing circuits with small molecules has been proposed as a potential strategy ...to prevent bacterial pathogenicity. The human pathogen Pseudomonas aeruginosa uses quorum sensing to control virulence and biofilm formation. Here, we analyze synthetic molecules for inhibition of the two P. aeruginosa quorum-sensing receptors, LasR and RhlR. Our most effective compound, meta-bromo-thiolactone (mBTL), inhibits both the production of the virulence factor pyocyanin and biofilm formation. mBTL also protects Caenorhabditis elegans and human lung epithelial cells from killing by P. aeruginosa . Both LasR and RhlR are partially inhibited by mBTL in vivo and in vitro; however, RhlR, not LasR, is the relevant in vivo target. More potent antagonists do not exhibit superior function in impeding virulence. Because LasR and RhlR reciprocally control crucial virulence factors, appropriately tuning rather than completely inhibiting their activities appears to hold the key to blocking pathogenesis in vivo.
Background The epidemiology of esophageal foreign-body impaction (EFBI) is poorly described, and the impact of the increasing prevalence of eosinophilic esophagitis (EoE) on this is unknown. ...Objective To assess the characteristics of patients with EFBI, to determine whether EFBI cases increased in proportion to EoE cases, and to identify predictors of EFBI. Design Retrospective study. Setting Tertiary care center. Patients Cases of EFBI from 2002 to 2009 were identified by querying billing, clinical, and endoscopy databases for the International Classification of Diseases, 9th Revision, Clinical Modification code 935.1, “foreign body in the esophagus.” Charts were reviewed to confirm EFBI and to extract pertinent data. Cases of EoE were defined per guidelines. Results Of 548 patients with EFBI (59% male, 68% white, bimodal age distribution), 482 (88%) required a procedure, 347 (63%) had food impactions, and 51 (9%) had EoE. EFBIs increased over the study time frame, and the number of EGDs performed for EFBI nearly quadrupled. Increasing diagnosis of EoE did not fully account for this trend, but only 27% of patients who underwent EGD had esophageal biopsies. Of patients who underwent biopsy, 46% had EoE. EoE was the strongest predictor of multiple EFBIs (odds ratio 3.5; 95% CI, 1.8-7.0). Limitations Retrospective, single-center study. Conclusions The number of EGDs performed for EFBI has increased dramatically at our center, but increasing EoE prevalence only partially explains this trend. Because only a minority of EFBI patients underwent biopsies and because nearly half of those who did undergo biopsy had EoE, the incidence of EoE may be substantially underestimated. Physician education is needed to increase the proportion of subjects with EFBI who undergo biopsies.
Limiting free sugars to <5% of energy intake is a World Health Organization evidence-based recommendation to protect oral health throughout the life course. Achieving this requires a concerted ...approach with upstream interventions, including legislation underpinning community interventions and health promotion. Global production and trade are the main drivers of sugars consumption, which can be addressed only through prioritization of health impacts in agricultural and trade agreements, including pricing and subsidies. Increasing evidence demonstrates the benefit, including dental benefits, of taxes on sugar-sweetened beverages, a major source of sugars—with taxes based on sugars content being favored due to the dual impact in incentivizing consumers to buy less and encouraging producers to use less through product reformulation. A benefit of product reformulation is that the potential impact on sugars intake occurs independent of consumer behavior change, making the benefits more equitable across social groups. Evidence from meta-analysis indicates that sugars reformulation and portion size reduction could lower energy intake by more than 10% and 16%, respectively. Sophisticated and targeted digital marketing of products high in sugars is another key driver of sugars intake. With the exception of children’s television broadcasting, marketing of products high in sugars is largely unregulated, and increased awareness of modern marketing strategies and more stringent regulation are urgently needed. To ensure a commercial level playing field, mandatory approaches are required. Midstream actions include creating healthier food environments in neighborhoods, community settings (schools, sports centers, hospitals), and workplaces. Only through coalition among authorities responsible for planning and health will “obesogenic and cariogenic” environments be replaced with those that make healthy choices the easiest choice. It is recognized that providing nutrition health education alone is insufficient to achieve necessary sugars reduction; however, education has a key role to play in changing social norms and creating drive for change.
Site-specific genome editing provides a promising approach for achieving long-term, stable therapeutic gene expression. Genome editing has been successfully applied in a variety of preclinical ...models, generally focused on targeting the diseased locus itself; however, limited targeting efficiency or insufficient expression from the endogenous promoter may impede the translation of these approaches, particularly if the desired editing event does not confer a selective growth advantage. Here we report a general strategy for liver-directed protein replacement therapies that addresses these issues: zinc finger nuclease (ZFN) –mediated site-specific integration of therapeutic transgenes within the albumin gene. By using adeno-associated viral (AAV) vector delivery in vivo, we achieved long-term expression of human factors VIII and IX (hFVIII and hFIX) in mouse models of hemophilia A and B at therapeutic levels. By using the same targeting reagents in wild-type mice, lysosomal enzymes were expressed that are deficient in Fabry and Gaucher diseases and in Hurler and Hunter syndromes. The establishment of a universal nuclease-based platform for secreted protein production would represent a critical advance in the development of safe, permanent, and functional cures for diverse genetic and nongenetic diseases.
•AAV- and ZFN-mediated targeting of the albumin locus corrects disease phenotype in mouse models of hemophilia A and B.•Robust expression from the albumin locus provides a versatile platform for liver-directed protein replacement therapy.
User-generated content can assist epidemiological surveillance in the early detection and prevalence estimation of infectious diseases, such as influenza. Google Flu Trends embodies the first public ...platform for transforming search queries to indications about the current state of flu in various places all over the world. However, the original model significantly mispredicted influenza-like illness rates in the US during the 2012-13 flu season. In this work, we build on the previous modeling attempt, proposing substantial improvements. Firstly, we investigate the performance of a widely used linear regularized regression solver, known as the Elastic Net. Then, we expand on this model by incorporating the queries selected by the Elastic Net into a nonlinear regression framework, based on a composite Gaussian Process. Finally, we augment the query-only predictions with an autoregressive model, injecting prior knowledge about the disease. We assess predictive performance using five consecutive flu seasons spanning from 2008 to 2013 and qualitatively explain certain shortcomings of the previous approach. Our results indicate that a nonlinear query modeling approach delivers the lowest cumulative nowcasting error, and also suggest that query information significantly improves autoregressive inferences, obtaining state-of-the-art performance.
Mitochondria and the endoplasmic reticulum (ER) form tight structural associations and these facilitate a number of cellular functions. However, the mechanisms by which regions of the ER become ...tethered to mitochondria are not properly known. Understanding these mechanisms is not just important for comprehending fundamental physiological processes but also for understanding pathogenic processes in some disease states. In particular, disruption to ER-mitochondria associations is linked to some neurodegenerative diseases. Here we show that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER-mitochondria associations. Moreover, we demonstrate that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER-mitochondria interactions and that this is associated with disruption to the VAPB-PTPIP51 interaction and cellular Ca(2+) homeostasis. Finally, we show that overexpression of TDP-43 leads to activation of glycogen synthase kinase-3β (GSK-3β) and that GSK-3β regulates the VAPB-PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43.
Improved knowledge of long-term social and environmental trends and their drivers in coupled human and natural systems is needed to guide nature and society along a more sustainable trajectory. Here ...we combine common property theory and experimental impact evaluation methods to develop an approach for analyzing long-term outcome trajectories in social-ecological systems (SESs). We constructed robust counterfactual scenarios for observed vegetation outcome trajectories in the Indian Himalaya using synthetic control matching. This approach enabled us to quantify the contribution of a set of biophysical and socioeconomic factors in shaping observed outcomes. Results show the relative importance of baseline vegetation condition, governance, and demographic change in predicting long-term ecological outcomes. More generally, the findings suggest the broad potential utility of our approach to analyze long-term outcome trajectories, target new policy interventions, and assess the impacts of policies on sustainability goals in SESs across the globe.
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