ABSTRACT
This study examines the importance of income in determining the diet quality of Canadian adults measured based on Nutrient Rich Food Index version 9.3. We used the latest available data on Canadians' consumption of foods and nutrients from the Canadian Community Health Survey-Nutrition 2015. The Canada' Food Guide classification was used for categorizing food groups based on types of food and their healthiness. Unsupervised and supervised machine learning models were employed in order to examine the links between income and the choice of foods. We first employed cluster analysis to identify the dietary patterns among individuals included in the sample and then we examined whether the intakes of various food groups across the identified clusters vary by income levels. Further, we evaluated the association between diet quality and income using Lasso Regression to determine the most important predictors of diet quality among adults in Canada. The results of both cluster analysis and regularized regression model suggested that behavioral factors and cultural backgrounds are more important determinants of diet quality among adults in Canada.
ABSTRACT
The new Canada's Food Guide (CFG) recommends whole grains foods as the primary choice of grain products in the daily diet. This study examined whether higher shares of whole-grain consumption, beyond the recommended levels (i.e., above half) of the daily grain intake, are linked with optimal diet quality and intakes of some key nutrients, for both children and adolescents and adults in Canada. To meet the objective of this study, we used the Canadian Community Health Survey (CCHS)-Nutrition 2015, which is a nationally representative data. We employed the propensity score matching (PSM) method in this study. PSM estimates the exposure effect when a set of individuals are exposed to a specific treatment (food group intake in this study) in a non-experimental setting. The results of our analyses implied that a high consumption of whole grains is associated with a good diet quality. However, after a certain level of whole-grain consumption, no significant differences can be observed in diet quality scores of children and adolescents and adults. Moreover, it was observed that the proportion of obese and overweight individuals was significantly lower among adults that had balanced intakes of whole and non-whole grains. The results of logistic regression analyses also showed the probability of being obese and overweight is significantly lower in the case of adults with balanced intakes of grains. However, no significant differences were observed in the prevalence of obesity and overweight across whole grains consumption patterns for children and adolescents.
Subject(s)
Diet, Healthy , Energy Intake , Feeding Behavior , Nutrients/administration & dosage , Nutritive Value , Obesity , Whole Grains , Adolescent , Adult , Aged , Canada , Child , Diet , Dietary Fiber/administration & dosage , Edible Grain , Female , Humans , Logistic Models , Male , Middle Aged , Nutrition Policy , Nutrition Surveys , Obesity/etiology , Overweight , Young AdultABSTRACT
In this study, we used the Canadian Community Health Survey-Nutrition (CCHS) 2015 data to examine the consumption patterns of grain-based foods (GBFs) for Canadian adults. We used a k-mean cluster analysis based on the contribution of 21 grain-based foods to total energy intake of adults in Canada to find the dietary patterns of GBFs. Cluster analyses rendered seven dietary patterns including: 'other bread', 'cake and cookies', 'pasta', 'rice', 'mixed', 'white bread', and finally 'whole wheat and whole-grain bread'. 'No grain' and 'rice' consumers had lower intakes of dietary fibre, folate, iron and calcium, which are the nutrients of public health concern in Canada. Adults consuming a 'mixed grain' dietary pattern had a greater daily intake of calcium, potassium, magnesium, riboflavin, and vitamin B6 than those in the 'no grain' dietary pattern. We also observed that a considerable proportion of individuals clustered in the 'rice' group are immigrants and belong to households with lower income levels.
Subject(s)
Diet, Healthy , Eating , Edible Grain , Food Preferences , Adult , Canada , Cluster Analysis , Cross-Sectional Studies , Diet Surveys , Emigrants and Immigrants , Energy Intake , Female , Humans , Income , Male , Middle Aged , Nutritive Value , Recommended Dietary Allowances , Young AdultABSTRACT
OBJECTIVES: Evidence suggests that depression is associated with adverse outcomes in patients with myocardial infarction (MI). Some of the symptoms of depression may also be symptoms of somatic illness and these may confound the association between depression and prognosis. We investigated whether depression following MI is associated with medical prognosis independent of these somatic symptoms. METHOD: The database of an individual patient data meta-analysis was used. Endpoints were all-cause mortality and cardiovascular events. Nine studies were included. Bifactor factor analysis included 13,100 participants and 7,595 participants were included in survival models. Dimensions were generated from the Beck Depression Inventory using factor analyses. The prognostic association was assessed using mixed-effects Cox regression analysis. RESULTS: A bifactor model, consisting of a general factor and 2 general depression-free subgroup factors (a somatic/affective and a cognitive/affective), provided the best fit. There was a significant association between the general depression factor and all-cause mortality (hazard ratio [HR] = 1.25; 95% confidence interval [CI] [1.17, 1.34], p < .001) and cardiovascular events (HR = 1.18; 95% CI [1.13, 1.23], p < .001). After adjustment for demographics, measures of cardiac disease severity, and health-related variables, the association between the general depression factor and all-cause mortality (HR = 1.14; 95% CI [1.04, 1.25], p = .003) and cardiovascular events (HR = 1.16; 95% CI [1.10, 1.23], p = .014) attenuated. Additionally, the general depression-free somatic/affective factor was significantly associated with the endpoints, while the general depression-free cognitive/affective was not. CONCLUSIONS: A general depression factor is associated with adverse medical prognosis following MI independent of somatic/affective symptoms that may be partly attributable to somatic illness. (PsycINFO Database Record
Subject(s)
Depression/diagnosis , Depression/mortality , Myocardial Infarction/diagnosis , Myocardial Infarction/mortality , Psychiatric Status Rating Scales , Aged , Depression/psychology , Factor Analysis, Statistical , Female , Humans , Internationality , Male , Middle Aged , Myocardial Infarction/psychology , Prognosis , Proportional Hazards ModelsABSTRACT
BACKGROUND: Although a number of risk factors are known to predict mortality within the first years after myocardial infarction, little is known about interactions between risk factors, whereas these could contribute to accurate differentiation of patients with higher and lower risk for mortality. This study explored the effect of interactions of risk factors on all-cause mortality in patients with myocardial infarction based on individual patient data meta-analysis. METHODS: Prospective data for 10,512 patients hospitalized for myocardial infarction were derived from 16 observational studies (MINDMAPS). Baseline measures included a broad set of risk factors for mortality such as age, sex, heart failure, diabetes, depression, and smoking. All two-way and three-way interactions of these risk factors were included in Lasso regression analyses to predict time-to-event related all-cause mortality. The effect of selected interactions was investigated with multilevel Cox regression models. RESULTS: Lasso regression selected five two-way interactions, of which four included sex. The addition of these interactions to multilevel Cox models suggested differential risk patterns for males and females. Younger women (age<50) had a higher risk for all-cause mortality than men in the same age group (HR 0.7 vs. 0.4), while men had a higher risk than women if they had depression (HR 1.4 vs. 1.1) or a low left ventricular ejection fraction (HR 1.7 vs. 1.3). Predictive accuracy of the Cox model was better for men than for women (area under the curves: 0.770 vs. 0.754). CONCLUSIONS: Interactions of well-known risk factors for all-cause mortality after myocardial infarction suggested important sex differences. This study gives rise to a further exploration of prediction models to improve risk assessment for men and women after myocardial infarction.
Subject(s)
Myocardial Infarction/mortality , Aged , Diabetes Mellitus , Female , Global Health , Humans , Male , Middle Aged , Myocardial Infarction/complications , Proportional Hazards Models , Prospective Studies , Regression Analysis , Risk Factors , Sex Factors , SmokingABSTRACT
Nucleoside reverse transcriptase inhibitors (NRTIs) are drugs used in the treatment of HIV/AIDS. Despite the distinct benefits of NRTI-based therapies, tissue specific toxicity is a limiting factor. Although the mechanisms of these specific antiretroviral drug-related toxicities remain unclear, it has been hypothesized that as analogs to native nucleosides, NRTIs may potentially inhibit mammalian DNA polymerases, including mitochondrial DNA (mtDNA) polymerase γ. Tenofovir disoproxil fumarate (TDF) is a nucleotide analog of adenosine monophosphate and the only NRTI that is associated with renal disease. The inherent heterogeneity of kidney tissues could affect the outcome and interpretation of molecular studies to define the mechanism(s) of tenofovir tubular toxicity. Laser-capture microdissection (LCM) provided a specific, single-cell isolation of proximal tubules from fixed heterogeneous kidney tissues. LCM-captured renal proximal tubules from transgenic mice (TGs) showed decreased mtDNA abundance with tenofovir, demonstrating a subcellular specific mitochondrial toxicity of tenofovir in an AIDS model.
Subject(s)
Adenine/analogs & derivatives , Cell Separation/methods , Kidney Tubules, Proximal/pathology , Mitochondria/drug effects , Organophosphonates/pharmacology , Reverse Transcriptase Inhibitors/pharmacology , Adenine/adverse effects , Adenine/pharmacology , Animals , Cardiomyopathies/chemically induced , DNA, Mitochondrial/genetics , Female , HIV Infections/drug therapy , HIV-1 , Humans , Kidney Tubules, Proximal/drug effects , Lasers , Liver Failure/chemically induced , Male , Mice , Mice, Inbred C57BL , Microdissection/methods , Organophosphonates/adverse effects , Reverse Transcriptase Inhibitors/adverse effects , Staining and Labeling/methods , TenofovirABSTRACT
Tenofovir disoproxil fumarate (TDF) is an oral prodrug and acyclic nucleotide analog of adenosine monophosphate that inhibits HIV-1 (HIV) reverse transcriptase. A growing subset of TDF-treated HIV(+) individuals presented with acute renal failure, suggesting tenofovir-associated kidney-specific toxicity. Our previous studies using an HIV transgenic mouse model (TG) demonstrated specific changes in renal proximal tubular mitochondrial DNA (mtDNA) abundance. Nucleosides are regulated in biological systems via transport and metabolism in cellular compartments. In this study, the role(s) of organic anion transporter type 1 (OAT1) and multidrug-resistant protein type 4 (MRP4) in transport and regulation of tenofovir in proximal tubules were assessed. Renal toxicity was assessed in kidney tissues from OAT1 knockout (KO) or MRP4 KO compared with wild-type (WT, C57BL/6) mice following treatment with TDF (0.11 mg/day), didanosine (ddI, a related adenosine analog, 0.14 mg/day) or vehicle (0.1 M NaOH) daily gavage for 5 weeks. Laser-capture microdissection (LCM) was used to isolate renal proximal tubules for molecular analyses. mtDNA abundance and ultrastructural pathology were analyzed. mtDNA abundance in whole kidneys from both KO and WT was unchanged regardless of treatment. Renal proximal tubular mtDNA abundance from OAT1 KO also remained unchanged, suggesting prevention of TDF toxicity due to loss of tenofovir transport into proximal tubules. In contrast, renal proximal tubules from MRP4 KO exhibited increased mtDNA abundance following TDF treatment compared with WT littermates, suggesting compensation. Renal proximal tubules from TDF-treated WT and MRP4 KO exhibited increased numbers of irregular mitochondria with sparse, fragmented cristae compared with OAT1 KO. Treatment with ddI had a compensatory effect on mtDNA abundance in OAT1 KO but not in MRP4 KO. Both OAT1 and MRP4 have a direct role in transport and efflux of tenofovir, regulating levels of tenofovir in proximal tubules. Disruption of OAT1 activity prevents tenofovir toxicity but loss of MRP4 can lead to increased renal proximal tubular toxicity. These data help to explain mechanisms of human TDF renal toxicity.
Subject(s)
Adenine/analogs & derivatives , Kidney Tubules, Proximal/drug effects , Kidney Tubules, Proximal/metabolism , Multidrug Resistance-Associated Proteins/metabolism , Organic Anion Transport Protein 1/metabolism , Organophosphonates/toxicity , Adenine/administration & dosage , Adenine/toxicity , Analysis of Variance , Animals , DNA, Mitochondrial/metabolism , Kidney Tubules, Proximal/pathology , Lasers , Mice , Mice, Inbred C57BL , Mice, Knockout , Microdissection , Mitochondria/pathology , Multidrug Resistance-Associated Proteins/genetics , Organic Anion Transport Protein 1/genetics , Organophosphonates/administration & dosage , Reverse Transcriptase Polymerase Chain Reaction , TenofovirABSTRACT
Abacavir (ABC) is a guanosine nucleoside reverse transcriptase inhibitor (NRTI) with potent antiretroviral activity. Since NRTIs exhibit tissue-specific inhibition of mitochondrial DNA (mtDNA) synthesis, the ability of ABC to inhibit mtDNA synthesis in vivo was evaluated. Inbred wild-type (WT) and transgenic mice (TG) treated with ABC (3.125 mg/d p. o., 35 days) were used to define mitochondrial oxidative stress and cardiac function. Chosen TGs exhibited overexpression of HIV-1 viral proteins (NL4-3Deltagag/pol, non-replication competent), hemizygous depletion or overexpression of mitochondrial superoxide dismutase (SOD2(+/-) knock-out (KO) or MnSOD OX, respectively), overexpression of mitochondrially targeted catalase (MCAT), or double "knockout" deletion of aldehyde dehydrogenase activity (ALDH2 KO). Impact on mtDNA synthesis was assessed by comparing changes in mtDNA abundance between ABC-treated and vehicle-treated WTs and TGs. No changes in mtDNA abundance occurred from ABC treatment in any mice, suggesting no inhibition of mtDNA synthesis. Left ventricle (LV) mass and LV end-diastolic dimension (LVEDD) were defined echocardiographically and remained unchanged as well. These results indicate that treatment with ABC has no visible cardiotoxicity in these adult mice exposed for 5 weeks compared to findings with other antiretroviral NRTI studies and support some claims for its relative safety.
Subject(s)
Anti-HIV Agents/toxicity , Dideoxynucleosides/toxicity , Heart Diseases/chemically induced , Heart/drug effects , Mitochondria, Heart/drug effects , Animals , DNA, Mitochondrial/biosynthesis , Echocardiography , Heart Diseases/physiopathology , Heart Ventricles/drug effects , Heart Ventricles/pathology , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Knockout , Mitochondria, Heart/enzymology , Mitochondria, Heart/genetics , Oxidative Stress/drug effects , Superoxide DismutaseABSTRACT
Thymidylate kinase (TMPK) is a nucleoside monophosphate kinase that catalyzes phosphorylation of thymidine monophosphate to thymidine diphosphate. TMPK also mediates phosphorylation of monophosphates of thymidine nucleoside analog (NA) prodrugs on the pathway to their active triphosphate antiviral or antitumor moieties. Novel transgenic mice (TG) expressing human (h) TMPK were genetically engineered using the alpha-myosin heavy chain promoter to drive its cardiac-targeted overexpression. In '2 by 2' protocols, TMPK TGs and wild-type (WT) littermates were treated with the NA zidovudine (a deoxythymidine analog, 3'-azido-3'deoxythymidine (AZT)) or vehicle for 35 days. Alternatively, TGs and WTs were treated with a deoxycytidine NA (racivir, RCV) or vehicle. Changes in mitochondrial DNA (mtDNA) abundance and mitochondrial ultrastructure were defined quantitatively by real-time PCR and transmission electron microscopy, respectively. Cardiac performance was determined echocardiographically. Results showed TMPK TGs treated with either AZT or RCV exhibited decreased cardiac mtDNA abundance. Cardiac ultrastructural changes were seen only with AZT. AZT-treated TGs exhibited increased left ventricle (LV) mass. In contrast, LV mass in RCV-treated TGs and WTs remained unchanged. In all cohorts, LV end-diastolic dimension remained unchanged. This novel cardiac-targeted overexpression of hTMPK helps define the role of TMPK in mitochondrial toxicity of antiretrovirals.
Subject(s)
Anti-HIV Agents/toxicity , DNA, Mitochondrial/metabolism , Myocardium/metabolism , Nucleoside-Phosphate Kinase/metabolism , Nucleosides/metabolism , Zalcitabine/analogs & derivatives , Zidovudine/toxicity , Animals , Anti-HIV Agents/metabolism , DNA Replication/drug effects , DNA, Mitochondrial/drug effects , Echocardiography , Emtricitabine/analogs & derivatives , Female , Humans , Hypertrophy, Left Ventricular/chemically induced , Hypertrophy, Left Ventricular/diagnostic imaging , Male , Mice , Mice, Transgenic , Mitochondria, Heart/drug effects , Mitochondria, Heart/ultrastructure , Myocardium/pathology , Myocardium/ultrastructure , Nucleoside-Phosphate Kinase/genetics , Phosphorylation , Ventricular Function, Left , Zalcitabine/metabolism , Zalcitabine/toxicity , Zidovudine/metabolismABSTRACT
Transgenic mice (TG) were used to define mitochondrial oxidative stress and cardiomyopathy (CM) induced by zidovudine (AZT), an antiretroviral used to treat HIV/AIDS. Genetically engineered mice either depleted or overexpressed mitochondrial superoxide dismutase (SOD2(+/-) KOs and SOD2-OX, respectively) or expressed mitochondrially targeted catalase (mCAT). TGs and wild-type (WT) littermates were treated (oral AZT, 35 days). Cardiac mitochondrial H(2)O(2), aconitase activity, histology and ultrastructure were analyzed. Left ventricle (LV) mass and LV end-diastolic dimension were determined echocardiographically. AZT induced cardiac oxidative stress and LV dysfunction in WTs. Cardiac mitochondrial H(2)O(2) increased and aconitase was inactivated in SOD2(+/-) KOs, and cardiac dysfunction was worsened by AZT. Conversely, the cardiac function in SOD2-OX and mCAT hearts was protected. In SOD2-OX and mCAT TG hearts, mitochondrial H(2)O(2), LV mass and LV cavity volume resembled corresponding values from vehicle-treated WTs. AZT worsens cardiac dysfunction and increases mitochondrial H(2)O(2) in SOD2(+/-) KO. Conversely, both SOD2-OX and mCAT TGs prevent or attenuate AZT-induced cardiac oxidative stress and LV dysfunction. As dysfunctional changes are ameliorated by decreasing and worsened by increasing H(2)O(2) abundance, oxidative stress from H(2)O(2) is crucial pathogenetically in AZT-induced mitochondrial CM.
Subject(s)
Anti-HIV Agents/toxicity , Cardiomyopathies/chemically induced , Cardiomyopathies/prevention & control , Catalase/metabolism , Mitochondria, Heart/drug effects , Mitochondria, Heart/enzymology , Superoxide Dismutase/metabolism , Zidovudine/toxicity , Aconitate Hydratase/metabolism , Animals , Cardiomyopathies/genetics , Cardiomyopathies/metabolism , Catalase/genetics , Female , Gene Expression , Hydrogen Peroxide/metabolism , Male , Mice , Mice, Congenic , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microscopy, Electron, Transmission , Mitochondria, Heart/ultrastructure , Models, Cardiovascular , Myocardium/pathology , Oxidative Stress/drug effects , Phenotype , Superoxide Dismutase/deficiency , Superoxide Dismutase/geneticsABSTRACT
Tenofovir disoproxil fumarate (TDF) is an analog of adenosine monophosphate that inhibits HIV reverse transcriptase in HIV/AIDS. Despite its therapeutic success, renal tubular side effects are reported. The mechanisms and targets of tenofovir toxicity were determined using '2 x 2' factorial protocols, and HIV transgenic (TG) and wild-type (WT) littermate mice with or without TDF (5 weeks). A parallel study used didanosine (ddI) instead of TDF. At termination, heart, kidney, and liver samples were retrieved. Mitochondrial DNA (mtDNA) abundance, and histo- and ultrastructural pathology were analyzed. Laser-capture microdissection (LCM) was used to isolate renal proximal tubules for molecular analyses. Tenofovir increased mtDNA abundance in TG whole kidneys, but not in their hearts or livers. In contrast, ddI decreased mtDNA abundance in the livers of WTs and TGs, but had no effect on their hearts or kidneys. Histological analyses of kidneys showed no disruption of glomeruli or proximal tubules with TDF or ddI treatments. Ultrastructural changes in renal proximal tubules from TDF-treated TGs included an increased number and irregular shape of mitochondria with sparse fragmented cristae. LCM-captured renal proximal tubules from TGs showed decreased mtDNA abundance with tenofovir. The results indicate that tenofovir targets mitochondrial toxicity on the renal proximal tubule in an AIDS model.
Subject(s)
AIDS-Associated Nephropathy/chemically induced , Adenine/analogs & derivatives , Anti-HIV Agents/adverse effects , Kidney Tubules, Proximal/drug effects , Mitochondria/drug effects , Organophosphonates/adverse effects , AIDS-Associated Nephropathy/pathology , Adenine/adverse effects , Animals , DNA, Mitochondrial/metabolism , Didanosine/adverse effects , Female , HIV-1 , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/ultrastructure , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microdissection , Mitochondria/ultrastructure , Tenofovir , Urothelium/ultrastructureABSTRACT
Mitochondrial toxicity results from pyrimidine nucleoside reverse transcriptase inhibitors (NRTIs) for HIV/AIDS. In the heart, this can deplete mitochondrial (mt) DNA and cause cardiac dysfunction (eg, left ventricle hypertrophy, LVH). Four unique transgenic, cardiac-targeted overexpressors (TGs) were generated to determine their individual impact on native mitochondrial biogenesis and effects of NRTI administration on development of mitochondrial toxicity. TGs included cardiac-specific overexpression of native thymidine kinase 2 (TK2), two pathogenic TK2 mutants (H121N and I212N), and a mutant of mtDNA polymerase, pol-gamma (Y955C). Each was treated with antiretrovirals (AZT-HAART, 3 or 10 weeks, zidovudine (AZT) + lamivudine (3TC) + indinavir, or vehicle control). Parameters included left ventricle (LV) performance (echocardiography), LV mtDNA abundance (real-time PCR), and mitochondrial fine structure (electron microscopy, EM) as a function of duration of treatment and presence of TG. mtDNA abundance significantly decreased in Y955C TG, increased in TK2 native and I212N TGs, and was unchanged in H121N TGs at 10 weeks regardless of treatment. Y955C and I212N TGs exhibited LVH during growth irrespective of treatment. Y955C TGs exhibited cardiomyopathy (CM) at 3 and 10 weeks irrespective of treatment, whereas H121N and I212N TGs exhibited CM only after 10 weeks AZT-HAART. EM features were consistent with cardiac dysfunction. mtDNA abundance and cardiac functional changes were related to TG expression of mitochondrially related genes, mutations thereof, and NRTIs.
Subject(s)
Anti-HIV Agents/toxicity , DNA, Mitochondrial/metabolism , Mitochondria, Heart/metabolism , Myocytes, Cardiac/metabolism , Reverse Transcriptase Inhibitors/toxicity , Thymidine Kinase/metabolism , Animals , Antiretroviral Therapy, Highly Active , Cardiomyopathy, Dilated/chemically induced , Cardiomyopathy, Dilated/metabolism , Cardiomyopathy, Dilated/pathology , Cell Line , DNA, Mitochondrial/analysis , Echocardiography , Female , Heart Ventricles/chemistry , Heart Ventricles/drug effects , Heart Ventricles/metabolism , Hypertrophy, Left Ventricular/chemically induced , Hypertrophy, Left Ventricular/diagnostic imaging , Hypertrophy, Left Ventricular/metabolism , Indinavir/toxicity , Lamivudine/toxicity , Male , Mice , Mice, Transgenic , Mitochondria, Heart/drug effects , Mitochondria, Heart/ultrastructure , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/ultrastructure , Phosphorylation , Thymidine Kinase/genetics , Zidovudine/toxicityABSTRACT
Mitochondrial (mt) DNA biogenesis is critical to cardiac contractility. DNA polymerase gamma (Pol gamma) replicates mtDNA, whereas thymidine kinase 2 (TK2) monophosphorylates pyrimidines intramitochondrially. Point mutations in POLG and TK2 result in clinical diseases associated with mtDNA depletion and organ dysfunction. Pyrimidine analogs (NRTIs) inhibit Pol gamma and mtDNA replication. Cardiac "dominant negative" murine transgenes (TGs; Pol gamma Y955C, and TK2 H121N or I212N) defined the role of each in the heart. mtDNA abundance, histopathological features, histochemistry, mitochondrial protein abundance, morphometry, and echocardiography were determined for TGs in "2 x 2" studies with or without pyrimidine analogs. Cardiac mtDNA abundance decreased in Y955C TGs ( approximately 50%) but increased in H121N and I212N TGs (20-70%). Succinate dehydrogenase (SDH) increased in hearts of all mutants. Ultrastructural changes occurred in Y955C and H121N TGs. Histopathology demonstrated hypertrophy in H121N, LV dilation in I212N, and both hypertrophy and dilation in Y955C TGs. Antiretrovirals increased LV mass ( approximately 50%) for all three TGs which combined with dilation indicates cardiomyopathy. Taken together, these studies demonstrate three manifestations of cardiac dysfunction that depend on the nature of the specific mutation and antiretroviral treatment. Mutations in genes for mtDNA biogenesis increase risk for defective mtDNA replication, leading to LV hypertrophy.
Subject(s)
Anti-Retroviral Agents/toxicity , Cardiomyopathies/enzymology , DNA, Mitochondrial/metabolism , DNA-Directed DNA Polymerase/metabolism , Mitochondria, Heart/enzymology , Myocytes, Cardiac/enzymology , Thymidine Kinase/metabolism , Animals , Cardiomyopathies/diagnostic imaging , Cardiomyopathies/etiology , Cardiomyopathy, Dilated/enzymology , Cardiomyopathy, Dilated/etiology , DNA Polymerase gamma , DNA-Directed DNA Polymerase/genetics , Electron Transport Complex I/metabolism , Humans , Hypertrophy, Left Ventricular/enzymology , Hypertrophy, Left Ventricular/etiology , Mice , Mice, Transgenic , Mitochondria, Heart/drug effects , Mitochondria, Heart/ultrastructure , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/ultrastructure , Point Mutation , Succinate Dehydrogenase/metabolism , Thymidine Kinase/genetics , UltrasonographyABSTRACT
Acquired immune deficiency syndrome (AIDS) is a global epidemic that continues to escalate. Recent World Health Organization estimates include over 33 million people currently diagnosed with HIV/AIDS. Another 20 million HIV-infected individuals died over the past quarter century. Antiretrovirals are effective treatments that changed the outcome of HIV infection from a fatal disease to a chronic illness. Cardiomyopathy (CM) is a bona fide component of HIV/AIDS with occurrence that is higher in HIV positive individuals. CM may result from individual or combined effects of HIV, immune reactions, or toxicities of prolonged antiretrovirals. Nucleoside reverse transcriptase inhibitors (NRTIs) are the cornerstone of antiretroviral therapy. Despite pharmacological benefits of NRTIs, NRTI side effects include increased risk for CM. Clinical observations and in vitro and in vivo studies support various mechanisms of CM. This perspective highlights some of the hypotheses and focuses on mitochondrial-associated pathways of NRTI- related CM.
Subject(s)
Cardiomyopathies/chemically induced , Cardiomyopathies/enzymology , DNA, Mitochondrial/genetics , Nucleosides/metabolism , Reverse Transcriptase Inhibitors/adverse effects , Animals , Cardiomyopathies/genetics , HIV Infections/enzymology , HIV Infections/genetics , HumansABSTRACT
OBJECTIVES: To assess the gender differences and the age-related morphometrical changes of the thalamus, interthalamic adhesion, and the right-left differences of the thalamus of the native Fars ethnic group in the South-East of the Caspian Sea border METHODS: This descriptive study was carried out on 97 patients (44 males and 53 females) without neuropathologic changes and symptoms admitted to the Kowsar MRI center in the South-East of the Caspian Sea border (Gorgan City, Northern Iran) in 2006. Thalamic dimensions were measured by MR images. The vertical lengths of the thalami and interthalamic adhesion were measured in the coronal sections, while the anteroposterior and transverse length measurements of the thalami and interthalamic adhesion were obtained in the axial plane. The data were assessed by SPSS 11.5 statistics program. RESULTS: Thalamic dimensions were longer in males. There was no significant correlation between size of thalamus and interthalamic adhesion regarding age; however, we found that thalamic dimensions increase a little with age until the 31-40 years group, and decreased after that. There was no correlation between age and gender groups and dimensions of the interthalamic adhesion. CONCLUSION: This study showed that there are no significant differences between right and left sides of the thalamus, however, the left-side thalamic dimensions were a little longer than the right.
ABSTRACT
Mitochondrial toxicity limits nucleoside reverse transcriptase inhibitors (NRTIs) for acquired immune deficiency syndrome. NRTI triphosphates, the active moieties, inhibit human immunodeficiency virus reverse transcriptase and eukaryotic mitochondrial DNA polymerase pol-gamma. NRTI phosphorylation seems to correlate with mitochondrial toxicity, but experimental evidence is lacking. Transgenic mice (TGs) with cardiac overexpression of thymidine kinase isoforms (mitochondrial TK2 and cytoplasmic TK1) were used to study NRTI mitochondrial toxicity. Echocardiography and nuclear magnetic resonance imaging defined cardiac performance and structure. TK gene copy and enzyme activity, mitochondrial (mt) DNA and polypeptide abundance, succinate dehydrogenase and cytochrome oxidase histochemistry, and electron microscopy correlated with transgenesis, mitochondrial structure, and biogenesis. Antiretroviral combinations simulated therapy. Untreated hTK1 or TK2 TGs exhibited normal left ventricle mass. In TK2 TGs, cardiac TK2 gene copy doubled, activity increased 300-fold, and mtDNA abundance doubled. Abundance of the 17-kd subunit of complex I, succinate dehydrogenase histochemical activity, and cristae density increased. NRTIs increased left ventricle mass 20% in TK2 TGs. TK activity increased 3 logs in hTK1 TGs, but no cardiac phenotype resulted. NRTIs abrogated functional effects of transgenically increased TK2 activity but had no effect on TK2 mtDNA abundance. Thus, NRTI mitochondrial phosphorylation by TK2 is integral to clinical NRTI mitochondrial toxicity.
Subject(s)
Mitochondria/drug effects , Reverse Transcriptase Inhibitors/toxicity , Thymidine Kinase/drug effects , Thymidine Kinase/metabolism , Transgenes , Animals , DNA, Mitochondrial/drug effects , DNA, Mitochondrial/metabolism , Echocardiography , Humans , Immunoblotting , Immunohistochemistry , Isoenzymes/drug effects , Isoenzymes/metabolism , Magnetic Resonance Spectroscopy , Mice , Mice, Transgenic , Microscopy, Electron, Transmission , Mitochondria/metabolism , Myocardium/enzymology , Peptides/drug effects , Phosphorylation/drug effects , Reverse Transcriptase Polymerase Chain Reaction , Succinate Dehydrogenase/drug effects , Up-RegulationABSTRACT
POLG is the human gene that encodes the catalytic subunit of DNA polymerase gamma (Pol gamma), the replicase for human mitochondrial DNA (mtDNA). A POLG Y955C point mutation causes human chronic progressive external ophthalmoplegia (CPEO), a mitochondrial disease with eye muscle weakness and mtDNA defects. Y955C POLG was targeted transgenically (TG) to the murine heart. Survival was determined in four TG (+/-) lines and wild-type (WT) littermates (-/-). Left ventricle (LV) performance (echocardiography and MRI), heart rate (electrocardiography), mtDNA abundance (real time PCR), oxidation of mtDNA (8-OHdG), histopathology and electron microscopy defined the phenotype. Cardiac targeted Y955C POLG yielded a molecular signature of CPEO in the heart with cardiomyopathy (CM), mitochondrial oxidative stress, and premature death. Increased LV cavity size and LV mass, bradycardia, decreased mtDNA, increased 8-OHdG, and cardiac histopathological and mitochondrial EM defects supported and defined the phenotype. This study underscores the pathogenetic role of human mutant POLG and its gene product in mtDNA depletion, mitochondrial oxidative stress, and CM as it relates to the genetic defect in CPEO. The transgenic model pathophysiologically links human mutant Pol gamma, mtDNA depletion, and mitochondrial oxidative stress to the mtDNA replication apparatus and to CM.
Subject(s)
Cardiomyopathies/pathology , DNA, Mitochondrial/metabolism , DNA-Directed DNA Polymerase/physiology , Oxidative Stress , 8-Hydroxy-2'-Deoxyguanosine , Animals , Cardiomyopathies/genetics , Cardiomyopathies/mortality , DNA Polymerase gamma , DNA-Directed DNA Polymerase/genetics , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/metabolism , Heart Ventricles/pathology , Humans , Magnetic Resonance Imaging , Mice , Mice, Transgenic , Mitochondria, Heart/metabolism , Mitochondria, Heart/ultrastructure , Mutation , Myocardium/metabolism , Myocardium/pathologyABSTRACT
DESIGN: Nucleoside reverse transcriptase inhibitors (NRTIs) exhibit mitochondrial toxicity. The mitochondrial deoxynucleotide carrier (DNC) transports nucleotide precursors (or phosphorylated NRTIs) into mitochondria for mitochondrial (mt)DNA replication or inhibition of mtDNA replication by NRTIs. Transgenic mice (TG) expressing human DNC targeted to murine myocardium served to define mitochondrial events from NRTIs in vivo and findings were corroborated by biochemical events in vitro. METHODS: Zidovudine (3'-azido-2',3'-deoxythymidine; ZDV), stavudine (2', 3'-didehydro-2', 3'-deoxythymidine; d4T), or lamivudine ((-)-2'-deoxy-3'-thiacytidine; 3TC) were administered individually to TGs and wild-type (WT) littermates (35 days) at human doses with drug-free vehicle as control. Left ventricle (LV) mass was defined echocardiographically, mitochondrial ultrastructural defects were identified by electron microscopy, the abundance of cardiac mtDNA was quantified by real time polymerase chain reaction, and mtDNA-encoded polypeptides were quantified. RESULTS: Untreated TGs exhibited normal LV mass with minor mitochondrial damage. NRTI monotherapy (either d4T or ZDV) increased LV mass in TGs and caused significant mitochondrial destruction. Cardiac mtDNA was depleted in ZDV and d4T-treated TG hearts and mtDNA-encoded polypeptides decreased. Changes were absent in 3TC-treated cohorts. In supportive structural observations from molecular modeling, ZDV demonstrated close contacts with K947 and Y951 in the DNA pol gamma active site that were absent in the HIV reverse transcriptase active site. CONCLUSIONS: NRTIs deplete mtDNA and polypeptides, cause mitochondrial structural and functional defects in vivo, follow inhibition kinetics with DNA pol gamma in vitro, and are corroborated by molecular models. Disrupted pools of nucleotide precursors and inhibition of DNA pol gamma by specific NRTIs are mechanistically important in mitochondrial toxicity.
Subject(s)
DNA, Mitochondrial/drug effects , Genes, pol , HIV-1/genetics , Membrane Transport Proteins , Reverse Transcriptase Inhibitors/pharmacology , Zidovudine/pharmacology , Animals , DNA/analysis , DNA, Mitochondrial/analysis , Echocardiography , HIV Infections/drug therapy , HIV Infections/pathology , Humans , Immunoblotting , Lamivudine/pharmacology , Mice , Mice, Transgenic , Microscopy, Electron, Transmission , Mitochondria, Heart/ultrastructure , Mitochondrial Membrane Transport Proteins , Models, Molecular , Myocardium/ultrastructure , Reverse Transcriptase Polymerase Chain Reaction , Stavudine/pharmacologyABSTRACT
Mutations in the mtDNA have been found to fulfill all of the criteria expected for pathogenic mutations causing prostate cancer. Focusing on the cytochrome oxidase subunit I (COI) gene, we found that 11-12% of all prostate cancer patients harbored COI mutations that altered conserved amino acids (mean conservation index=83%), whereas <2% of no-cancer controls and 7.8% of the general population had COI mutations, the latter altering less conserved amino acids (conservation index=71%). Four conserved prostate cancer COI mutations were found in multiple independent patients on different mtDNA backgrounds. Three other tumors contained heteroplasmic COI mutations, one of which created a stop codon. This latter tumor also contained a germ-line ATP6 mutation. Thus, both germ-line and somatic mtDNA mutations contribute to prostate cancer. Many tumors have been found to produce increased reactive oxygen species (ROS), and mtDNA mutations that inhibit oxidative phosphorylation can increase ROS production and thus contribute to tumorigenicity. To determine whether mutant tumors had increased ROS and tumor growth rates, we introduced the pathogenic mtDNA ATP6 T8993G mutation into the PC3 prostate cancer cell line through cybrid transfer and tested for tumor growth in nude mice. The resulting mutant (T8993G) cybrids were found to generate tumors that were 7 times larger than the wild-type (T8993T) cybrids, whereas the wild-type cybrids barely grew in the mice. The mutant tumors also generated significantly more ROS. Therefore, mtDNA mutations do play an important role in the etiology of prostate cancer.
Subject(s)
DNA, Mitochondrial/genetics , Mutation/physiology , Prostatic Neoplasms/genetics , Adenosine Triphosphatases/genetics , Animals , Cell Line, Tumor , Cell Proliferation , Cell Transformation, Neoplastic/genetics , Conserved Sequence , DNA Mutational Analysis , Electron Transport Complex IV/genetics , Humans , Male , Mice , Mice, Nude , Mitochondrial Proton-Translocating ATPases , Neoplasm Transplantation , Prostatic Neoplasms/etiology , Prostatic Neoplasms/pathology , Protein Subunits , Reactive Oxygen Species/metabolismABSTRACT
In search of the ancestors of Native American mitochondrial DNA (mtDNA) haplogroups, we analyzed the mtDNA of 531 individuals from nine indigenous populations in Siberia. All mtDNAs were subjected to high-resolution RFLP analysis, sequencing of the control-region hypervariable segment I (HVS-I), and surveyed for additional polymorphic markers in the coding region. Furthermore, the mtDNAs selected according to haplogroup/subhaplogroup status were completely sequenced. Phylogenetic analyses of the resulting data, combined with those from previously published Siberian arctic and sub-arctic populations, revealed that remnants of the ancient Siberian gene pool are still evident in Siberian populations, suggesting that the founding haplotypes of the Native American A-D branches originated in different parts of Siberia. Thus, lineage A complete sequences revealed in the Mansi of the Lower Ob and the Ket of the Lower Yenisei belong to A1, suggesting that A1 mtDNAs occasionally found in the remnants of hunting-gathering populations of northwestern and northern Siberia belonged to a common gene pool of the Siberian progenitors of Paleoindians. Moreover, lineage B1, which is the most closely related to the American B2, occurred in the Tubalar and Tuvan inhabiting the territory between the upper reaches of the Ob River in the west, to the Upper Yenisei region in the east. Finally, the sequence variants of haplogroups C and D, which are most similar to Native American C1 and D1, were detected in the Ulchi of the Lower Amur. Overall, our data suggest that the immediate ancestors of the Siberian/Beringian migrants who gave rise to ancient (pre-Clovis) Paleoindians have a common origin with aboriginal people of the area now designated the Altai-Sayan Upland, as well as the Lower Amur/Sea of Okhotsk region.