Mitochondrial DNA Repair in Neurodegenerative Diseases and Ageing.

Mitochondria are the only organelles, along with the nucleus, that have their own DNA. Mitochondrial DNA (mtDNA) is a double-stranded circular molecule of ~16.5 kbp that can exist in multiple copies within the organelle. Both strands are translated and encode for 22 tRNAs, 2 rRNAs, and 13 proteins. mtDNA molecules are anchored to the inner mitochondrial membrane and, in association with proteins, form a structure called nucleoid, which exerts a structural and protective function. Indeed, mitochondria have evolved mechanisms necessary to protect their DNA from chemical and physical lesions such as DNA repair pathways similar to those present in the nucleus. However, there are mitochondria-specific mechanisms such as rapid mtDNA turnover, fission, fusion, and mitophagy. Nevertheless, mtDNA mutations may be abundant in somatic tissue due mainly to the proximity of the mtDNA to the oxidative phosphorylation (OXPHOS) system and, consequently, to the reactive oxygen species (ROS) formed during ATP production. In this review, we summarise the most common types of mtDNA lesions and mitochondria repair mechanisms. The second part of the review focuses on the physiological role of mtDNA damage in ageing and the effect of mtDNA mutations in neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Considering the central role of mitochondria in maintaining cellular homeostasis, the analysis of mitochondrial function is a central point for developing personalised medicine.

Is Drp1 a link between mitochondrial dysfunction and inflammation in Alzheimer's disease?

Recent advances highlight that inflammation is critical to Alzheimer Disease (AD) pathogenesis. Indeed, several diseases characterized by inflammation are considered risk factors for AD, such as type 2 diabetes, obesity, hypertension, and traumatic brain injury. Moreover, allelic variations in genes involved in the inflammatory cascade are risk factors for AD. AD is also characterized by mitochondrial dysfunction, which affects the energy homeostasis of the brain. The role of mitochondrial dysfunction has been characterized mostly in neuronal cells. However, recent data are demonstrating that mitochondrial dysfunction occurs also in inflammatory cells, promoting inflammation and the secretion of pro-inflammatory cytokines, which in turn induce neurodegeneration. In this review, we summarize the recent finding supporting the hypothesis of the inflammatory-amyloid cascade in AD. Moreover, we describe the recent data that demonstrate the link between altered mitochondrial dysfunction and the inflammatory cascade. We focus in summarizing the role of Drp1, which is involved in mitochondrial fission, showing that altered Drp1 activation affects the mitochondrial homeostasis and leads to the activation of the NLRP3 inflammasome, promoting the inflammatory cascade, which in turn aggravates Amyloid beta (Ab) deposition and tau-induced neurodegeneration, showing the relevance of this pro-inflammatory pathway as an early event in AD.

Tumor Deposits in Stage III Colon Cancer: Correlation With Other Histopathologic Variables, Prognostic Value, and Risk Stratification-Time to Consider "N2c".

OBJECTIVES: National Comprehensive Cancer Network (NCCN) guidelines for stage III colon cancer define low-risk versus high-risk patients based on T (1 to 3 vs. 4) and N (1 vs. 2) status, with some variations in treatment. This study analyzes the impact of tumor deposits (TDs), T and N status, poor differentiation (PD), perineural invasion (PNI), and lymphovascular invasion (LVI) on survival. MATERIALS AND METHODS: A retrospective analysis (2010-2015) of the National Cancer Database of stage III colon cancer patients treated with both surgery and chemotherapy was conducted. Data was extracted on sex, race, age at diagnosis, Charlson-Deyo Score, histopathologic variables, and survival rates. Statistical analysis used the test of proportions, log-rank test for Kaplan-Meier curves, and Cox proportional hazard models. RESULTS: For the 42,901 patients analyzed, 5-year survival rates were similar for LNTD (59.8%) and LNTD (58.2%), but significantly worse for LNTD (41.5%) (P<0.001). The presence of LNTD was more often associated with T4 (36.9%), N2 (55.1%), PD (37.4%), PNI (34.5%), and LVI (69.1%), than LNTD or LNTD (P<0.001). The hazard ratios for each variable were: TD: 1.34; T4: 1.71; N2: 1.44; PD: 1.37; PNI: 1.11; LVI: 1.18. LN patients with ≥3 TD (N1c) had worse overall survival than those with 1 to 2 TD (P<0.01), but similar to ≥4 LNTD (N2) and 1 to 3 LNTD (N1a-b). In our model, 5-year survival ranged from 23.4% for high-risk to 78.1% for low-risk patients (P<0.001). CONCLUSION: This National Cancer Database (NCDB) analysis offers greater risk stratification and may prompt consideration of changes in American Joint Committee on Cancer (AJCC) classification (N2c, in addition to N1c) to reflect the different prognosis and guide management, as well as survivorship strategies, for TD stage III colon cancer patients.

Documented electronic medical record-based pain intensity scores at a tertiary pediatric medical center: a cohort analysis.

CONTEXT: Previous surveys have suggested that pain in hospitalized patients remains undertreated. However, little is known about those with persistently high pain scores. OBJECTIVES: To document the distribution of scores and analyze the clinical characteristics of outliers with persistently high pain scores. METHODS: With institutional review board approval, a retrospective cohort analysis of more than 1.5 million documented scores was completed in a tertiary pediatric medical center during a three-year period. Patients with persistently high pain scores were identified for subgroup analysis. RESULTS: The median score was 0 (all years), and the means were 1.46, 1.34, and 1.3 in 2010, 2011, and 2012, respectively. Approximately 68% of admissions had at least one score of 4 or greater, although this level did not persist. Only 9% had mean scores of 4 or greater, and 1% (n = 492) had mean scores of 7 or greater. Scores remained high in patients within identifiable groups, that is, those with chronic pain (n = 311), sickle cell vaso-occlusive episodes (n = 52), and pain in children with developmental and neuromuscular disorders (n = 32). Few had persistently high scores with acute pain but without known comorbidities (n = 56). CONCLUSION: Detailed review of clinical characteristics of patients with persistently high scores led to the strong impression that, in most cases, persistently high pain was not simply because of inadequate administration of opioids. Instead, the first step in improving pain management of hospitalized children may be the identification of outliers with high pain scores to direct efforts on the development of interventions for patient groups with mechanistically similar pain.

Resource utilization and costs following hospitalization of patients with chronic heart failure in the US.

BACKGROUND: Despite advances in its management and the identification of preventable risk factors, heart failure (HF) is a growing health problem in the US. The objective of this study was to describe treatment patterns, medical resource utilization and costs following hospitalization for chronic HF for patients stratified by age. METHODS: Patients with at least one hospitalization with chronic HF were identified in a US commercial insurance claims database from 2004-2008. Patients were followed from the 1st day of chronic HF hospitalization (index hospitalization) until disenrollment or end of data availability. Inpatient, outpatient and prescription drug utilization rates were calculated per person per month (PPPM). Costs included payments made by insurers and, where available, patient out-of-pocket payments and sick-leave costs were also calculated. Utilization rates and costs were stratified by patient age. RESULTS: There were 7814 patients included in the study. Index hospitalization was the most resource intensive and expensive ($31,023 age <65, $12,426 age ≥ 65). The rate of outpatient visits was the highest within 3 months following index hospitalization (3.6/PPPM age <65, 4.1/PPPM age ≥ 65). For the older age group, rate of re-hospitalizations was highest (0.06/PPPM) within 3-6 months following index hospitalization, while the younger group had its highest rate (0.08/PPPM) during the first 3 months following index hospitalization. Prescription dispensing rates were similar between age groups; average reimbursement PPPM for cardiovascular drugs did not exceed $92 (age <65) and $221 (age ≥ 65), which represents less than 3% of hospitalization costs for both groups. CONCLUSIONS: Treating chronic HF patients is resource intensive. The greatest burden occurs within 6 months after index hospitalization for both age groups; patients continue to be burdened after hospitalization by high inpatient and outpatient visit rates. Outpatient cardiovascular drug costs account for a small proportion of total healthcare costs.

Treatment of COPD: relationships between daily dosing frequency, adherence, resource use, and costs.

BACKGROUND: Medication adherence is important in managing COPD. This study analyzed real-world use of inhaled medications for COPD to characterize relationships between daily dosing frequency, adherence, healthcare resource utilization, and cost. METHODS: This retrospective study used a large administrative claims database covering 8 million insured lives in the US from 1999 to 2006. Patients were stratified based on the recommended daily dosing frequency of their first COPD drug claim following COPD diagnosis. Adherence was measured using proportion of days covered (PDC) over 12 months following treatment initiation. Healthcare resource use included inpatient, outpatient, and emergency room visits. A multivariate regression model assessed the relationship between adherence and one-year healthcare resource use, controlling for demographics, comorbidities, and baseline resource use. Unit healthcare costs were obtained from the 2005 Medical Expenditure Panel Survey, adjusted to 2008 dollars. RESULTS: Based on a sample of 55,076 COPD patients, adherence was strongly correlated with dosing frequency. PDC was 43.3%, 37.0%, 30.2% and 23.0% for QD, BID, TID, and QID patient cohorts, respectively. Regression analysis showed that one-year adherence was correlated with healthcare resource utilization. For 1000 COPD patients, a 5% point increase in PDC reduced the annual number of inpatient visits (-2.5%) and emergency room visits (-1.8%) and slightly increased outpatient visits (+.2%); the net reduction in annual cost was approximately $300,000. CONCLUSION: COPD patients who initiated treatment with once-daily dosing had significantly higher adherence than other daily dosing frequencies. Better treatment adherence was found to yield reductions in healthcare resource utilization and cost.