3-Hydroxyanthranilic Acid Delays Paralysis in Caenorhabditis elegans Models of Amyloid-Beta and Polyglutamine Proteotoxicity.

Age is the primary risk factor for neurodegenerative diseases such as Alzheimer's and Huntington's disease. Alzheimer's disease is the most common form of dementia and a leading cause of death in the elderly population of the United States. No effective treatments for these diseases currently exist. Identifying effective treatments for Alzheimer's, Huntington's, and other neurodegenerative diseases is a major current focus of national scientific resources, and there is a critical need for novel therapeutic strategies. Here, we investigate the potential for targeting the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3HAA) using Caenorhabditis elegans expressing amyloid-beta or a polyglutamine peptide in body wall muscle, modeling the proteotoxicity in Alzheimer's and Huntington's disease, respectively. We show that knocking down the enzyme that degrades 3HAA, 3HAA dioxygenase (HAAO), delays the age-associated paralysis in both models. This effect on paralysis was independent of the protein aggregation in the polyglutamine model. We also show that the mechanism of protection against proteotoxicity from HAAO knockdown is mimicked by 3HAA supplementation, supporting elevated 3HAA as the mediating event linking HAAO knockdown to delayed paralysis. This work demonstrates the potential for 3HAA as a targeted therapeutic in neurodegenerative disease, though the mechanism is yet to be explored.

On the benefits of the tryptophan metabolite 3-hydroxyanthranilic acid in Caenorhabditis elegans and mouse aging.

Tryptophan metabolism through the kynurenine pathway influences molecular processes critical to healthy aging including immune signaling, redox homeostasis, and energy production. Aberrant kynurenine metabolism occurs during normal aging and is implicated in many age-associated pathologies including chronic inflammation, atherosclerosis, neurodegeneration, and cancer. We and others previously identified three kynurenine pathway genes-tdo-2, kynu-1, and acsd-1-for which decreasing expression extends lifespan in invertebrates. Here we report that knockdown of haao-1, a fourth gene encoding the enzyme 3-hydroxyanthranilic acid (3HAA) dioxygenase (HAAO), extends lifespan by ~30% and delays age-associated health decline in Caenorhabditis elegans. Lifespan extension is mediated by increased physiological levels of the HAAO substrate 3HAA. 3HAA increases oxidative stress resistance and activates the Nrf2/SKN-1 oxidative stress response. In pilot studies, female Haao knockout mice or aging wild type male mice fed 3HAA supplemented diet were also long-lived. HAAO and 3HAA represent potential therapeutic targets for aging and age-associated disease.

Medical Students' Knowledge and Attitudes Toward Shared Decision Making: Results From a Multinational, Cross-Sectional Survey.

Introduction. We aimed to conduct a multinational cross-sectional online survey of medical students' attitudes toward, knowledge of, and experience with shared decision making (SDM). Methods. We conducted the survey from September 2016 until May 2017 using the following: 1) a convenience sample of students from four medical schools each in Canada, the United States, and the Netherlands (n = 12), and 2) all medical schools in the United Kingdom through the British Medical School Council (n = 32). We also distributed the survey through social media. Results. A total of 765 students read the information sheet and 619 completed the survey. Average age was 24, 69% were female. Mean SDM knowledge score was 83.6% (range = 18.8% to 100%; 95% confidence interval [CI] = 82.8% to 84.5%). US students had the highest knowledge scores (86.2%, 95% CI = 84.8% to 87.6%). The mean risk communication score was 57.4% (range = 0% to 100%; 95% CI = 57.4% to 60.1%). Knowledge did not vary with age, race, gender, school, or school year. Attitudes were positive, except 46% believed SDM could only be done with higher educated patients, and 80.9% disagreed that physician payment should be linked to SDM performance (increased with years in training, P < 0.05). Attitudes did not vary due to any tested variable. Students indicated they were more likely than experienced clinicians to practice SDM (72.1% v. 48.8%). A total of 74.7% reported prior SDM training and 82.8% were interested in learning more about SDM. Discussion. SDM knowledge is high among medical students in all four countries. Risk communication is less well understood. Attitudes indicate that further research is needed to understand how medical schools deliver and integrate SDM training into existing curricula.

The effect of preoperative penicillin allergy testing on perioperative non-beta-lactam antibiotic use: A systematic review and meta-analysis.

Background: The majority of patients for elective surgery and with a history of penicillin allergy are placed on alternative prophylactic antibiotic therapies, which have been associated with the emergence of multidrug-resistant pathogens and increased morbidity and mortality rates. However, self-reporting of penicillin allergy alone may overestimate the prevalence of penicillin allergy in the population. Objective: To assess the effects of preoperative antibiotic allergy testing protocols in reducing the use of non-beta-lactam antibiotics. Methods: We searched medical literature data bases through July of 2018. Two reviewers independently extracted data from published studies and assessed the risk of bias in cohort studies by using the Newcastle-Ottawa Scale. We collected information related to study design, methodology, demographics, interventions, and outcomes. We pooled odds ratios for the rate of prescribing non-beta-lactam antibiotics by using a fixed-effects model. Results: Of 905 citations screened for eligibility, nine studies met inclusion criteria for qualitative analysis. Studies reported that the rates of non-beta-lactam use after preoperative skin testing ranged from 6 to 30%. In addition, four of the nine studies had sufficient control data to be included in a meta-analysis. These four studies found that preoperative testing protocols significantly decreased the rates of prescribing non-beta-lactam antibiotics compared with usual care (odds ratio 3.64 [95% confidence interval, 2.67-4.98]; p < 0.0001). Seven studies reported on adverse drug reactions after preoperative skin testing and found that the rate of such reactions was rare. Conclusion: Preoperative antibiotic allergy testing protocols seemed to be a safe and effective tool in reducing the use of non-beta-lactam antibiotics during surgery.

FAR2 is associated with kidney disease in mice and humans.

Mesangial matrix expansion is an important process in the initiation of chronic kidney disease, yet the genetic factors driving its development are unknown. Our previous studies have implicated Far2 as a candidate gene associated with differences in mesangial matrix expansion between mouse inbred strains. Consistent with the hypothesis that increased expression of Far2 leads to mesangial matrix expansion through increased production of platelet-activating factor precursors, we show that FAR2 is capable of mediating de novo platelet-activating factor synthesis in vitro and driven by the transcription factor NKX3.2. We demonstrate that knockdown of Far2 in mice delays the progression of mesangial matrix expansion with at least six months (equivalent to ~15 yr in human). Furthermore, we show that increased FAR2 expression in human patients is associated with diabetic nephropathy, lupus nephritis, and IgA nephropathy. Taken together, these results highlight FAR2's role in the development of mesangial matrix expansion and chronic kidney disease.

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity.

We report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on orthology to human genes differentially expressed with age. We find substantial enrichment in genes for which knockdown increased lifespan. This enrichment is markedly higher than published genomewide longevity screens in C. elegans and similar to screens that preselected candidates based on longevity-correlated metrics (e.g., stress resistance). Of the 50 genes that affected lifespan, 46 were previously unreported. The five genes with the greatest impact on lifespan (>20% extension) encode the enzyme kynureninase (kynu-1), a neuronal leucine-rich repeat protein (iglr-1), a tetraspanin (tsp-3), a regulator of calcineurin (rcan-1), and a voltage-gated calcium channel subunit (unc-36). Knockdown of each gene extended healthspan without impairing reproduction. kynu-1(RNAi) alone delayed pathology in C. elegans models of Alzheimer's disease and Huntington's disease. Each gene displayed a distinct pattern of interaction with known aging pathways. In the context of published work, kynu-1, tsp-3, and rcan-1 are of particular interest for immediate follow-up. kynu-1 is an understudied member of the kynurenine metabolic pathway with a mechanistically distinct impact on lifespan. Our data suggest that tsp-3 is a novel modulator of hypoxic signaling and rcan-1 is a context-specific calcineurin regulator. Our results validate C. elegans as a comparative tool for prioritizing human candidate aging genes, confirm age-associated gene expression data as valuable source of novel longevity determinants, and prioritize select genes for mechanistic follow-up.

A hypermorphic SP1-binding CD24 variant associates with risk and progression of multiple sclerosis.

A large number of risk alleles have been identified for multiple sclerosis (MS). However, how genetic variations may affect pathogenesis remains largely unknown for most risk alleles. Through direct sequencing of CD24 promoter region, we identified a cluster of 7 new single nucleotide polymorphisms in the CD24 promoter. A hypermorphic haplotype consisting of 3 SNPs was identified through association studies consisting of 935 control and 764 MS patients (P=0.001, odds ratio 1.3). The variant is also associated with more rapid progression of MS (P=0.016, log rank test). In cells that are heterozygous for the risk allele, chromatin immunoprecipitation revealed that risk allele specifically bind to a transcription factor SP1, which is selectively required for the hypermorphic promoter activity of the variant. In MS patients, the CD24 transcript levels associate with the SP1-binding variant in a dose-dependent manner (P=7x10(-4)). Our data revealed a potential role for SP1-mediated transcriptional regulation in MS pathogenesis.