Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American's metabolic risk for developing Alzheimer's disease.

Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk. Our results show that 8oxoG levels in both buffy coat and plasma were significantly associated with population, sex, years of education, and reveal a potential association with AD. Furthermore, MAs are significantly burdened by mtDNA oxidative damage in both blood fractions, which may contribute to their metabolic vulnerability to developing AD.

Integrative Blood-Based Characterization of Oxidative Mitochondrial DNA Damage Variants Implicates Mexican Americans' Metabolic Risk for Developing Alzheimer's Disease.

Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65+) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latinx population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk. Our results show that 8oxoG levels in both buffy coat and plasma were significantly associated with population, sex, years of education, and reveal a potential association with AD. Furthermore, MAs are significantly burdened by mtDNA oxidative damage in both blood fractions, which may contribute to their metabolic vulnerability to developing AD.

Mitochondrial DNA oxidative mutations are elevated in Mexican American women potentially implicating Alzheimer's disease.

Mexican Americans (MAs) are the fastest-growing Hispanic population segment in the US; as this population increases in age, so will the societal burden of age-related diseases such as Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) damage may be implicated in MA AD risk since metabolic comorbidities are more prevalent in this group. Oxidative damage to guanosine (8oxoG) is one of the most prevalent DNA lesions and a putative indicator of mitochondrial dysfunction. Testing blood samples from participants of the Texas Alzheimer's Research and Care Consortium, we found mtDNA 8oxoG mutational load to be significantly higher in MAs compared to non-Hispanic whites and that MA females are differentially affected. Furthermore, we identified specific mtDNA haplotypes that confer increased risk for oxidative damage and suggestive evidence that cognitive function may be related to 8oxoG burden. Our understanding of these phenomena will elucidate population- and sex-specific mechanisms of AD pathogenesis, informing the development of more precise interventions and therapeutic approaches for MAs with AD in the future.

Multiplatform plasma metabolic and lipid fingerprinting of breast cancer: A pilot control-case study in Colombian Hispanic women.

Breast cancer (BC) is a highly heterogeneous disease associated with metabolic reprogramming. The shifts in the metabolome caused by BC still lack data from Latin populations of Hispanic origin. In this pilot study, metabolomic and lipidomic approaches were performed to establish a plasma metabolic fingerprint of Colombian Hispanic women with BC. Data from 1H-NMR, GC-MS and LC-MS were combined and compared. Statistics showed discrimination between breast cancer and healthy subjects on all analytical platforms. The differentiating metabolites were involved in glycerolipid, glycerophospholipid, amino acid and fatty acid metabolism. This study demonstrates the usefulness of multiplatform approaches in metabolic/lipid fingerprinting studies to broaden the outlook of possible shifts in metabolism. Our findings propose relevant plasma metabolites that could contribute to a better understanding of underlying metabolic shifts driven by BC in women of Colombian Hispanic origin. Particularly, the understanding of the up-regulation of long chain fatty acyl carnitines and the down-regulation of cyclic phosphatidic acid (cPA). In addition, the mapped metabolic signatures in breast cancer were similar but not identical to those reported for non-Hispanic women, despite racial differences.

Urinary metabolite and lipid alterations in Colombian Hispanic women with breast cancer: A pilot study.

Metabolic biomarkers for breast cancer (BC) prognosis and diagnosis are required, given the increment of BC incidence rates in developing countries and its prevalence in women worldwide. Human urine represents a useful resource of metabolites for biomarker discovery, because it could reflect metabolic alterations caused by a particular pathological state. Furthermore, urine analysis is readily available, it is non-invasive and allows in-time monitoring. Therefore, in present study, a metabolic- and lipid fingerprinting of urine was performed using an analytical multiplatform approach. The study was conducted in order to identify alterated metabolites which can be helpful in the understanding of metabolic alterations driven by BC as well as their potential usage as biomarkers. Urine samples collected from healthy controls and BC subjects were analyzed using LC-MS and GC-MS. Subsequently, significantly altered metabolites were determined by employing univariate and multivariate statistical analyses. An overall decrease of intermediates of the tricarboxylic acid cycle and metabolites belonging to amino acids and nucleotides were observed, along with an increment of lipid-related compounds. Receiver operating characteristic analysis evaluated the combination of dimethylheptanoylcarnitine and succinic acid as potential urinary markers, achieving a sensitivity of 93% and a specificity of 86%. The present analytical multiplatform approach enabled a wide coverage of urine metabolites that revealed significant alterations in BC samples, demonstrating its usefulness for biomarker discovery in selected populations.

The Association Between Lipoproteins, Disability, and Physical Function Among Older Costa Rican Adults.

OBJECTIVE: To examine the relationship between total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) with disability and physical performance. METHOD: Wave 1 data were from Costa Rican Longevity and Healthy Aging Study ( n = 2,827). Lipoprotein profiles were measured using blood samples. Disability and physical functioning were measured with activities of daily living/instrumental activities of daily living (ADLs/IADLs) and objective assessment of physical performance. RESULTS: Lower HDL-C was associated with greater ADL disability, and lower TC with longer time to pick-a-pencil and Time-Up-Go (TUG) test. Age interacted between (a) TG and lung function, chair stands, and pick-a-pencil, and (b) HDL-C and TUG. Stratification showed lower TG and longer time picking up a pencil only for those above 84 years. Based on significant interactions with sex, lower TC was associated with slower chair stand time in women and higher HDL-C with slower chair stand time in men. DISCUSSION: Lower levels of lipoproteins may suggest worse physical function, but the association may differ by sex.

Evaluation of peripheral blood microsampling techniques in combination with liquid chromatography-high resolution mass spectrometry for the determination of drug pharmacokinetics in clinical studies.

New bioanalytical assays were developed, validated, and applied in a clinical study for quantitative measurement of acetaminophen concentrations in blood and plasma samples. Furthermore, after validation, the bioanalytical assays were used for determination of pharmacokinetics within a group of six healthy male human volunteers after admission of a single oral dose of 500 mg of acetaminophen. Quantitative analyses were done by means of liquid chromatography-high resolution mass spectrometry and blood samples were collected at various sampling time points using different peripheral blood microsampling techniques. Post-dose peripheral collected blood samples were applied for the preparation of dry blood spots, dried matrix on paper discs, and peripheral plasma. Pharmacokinetic parameters determined were clearance (Cl), area under the curve (AUC), volume of distribution (Vd ), peak concentration (Cmax ), time of occurrence of peak concentration (Tmax ) and half-life time (T½ ). Observed pharmacokinetic values were not statistically (ANOVA) different compared to in literature reported values based on venous blood collection. The present pilot study demonstrated the feasibility of peripheral blood microsampling techniques in combination with quantitative liquid chromatography-high resolution mass spectrometry analysis for the determination of pharmacokinetics in clinical studies.

Establishment of a functional genomics platform for Leifsonia xyli subsp. xyli.

Leifsonia xyli subsp. xyli, the causal agent of ratoon stunting disease in sugarcane, is a xylem-limited, nutritionally fastidious, slow growing, gram-positive coryneform bacterium. Because of the difficulties in growing this bacterium in pure culture, little is known about the molecular mechanisms of pathogenesis. Currently, the genome sequence of L. xyli subsp. xyli is being completed by the Agronomical and Environmental Genomes group from the Organization for Nucleotide Sequencing and Analysis in Brazil. To complement this work, we produced 712 Lxx::Tn4431 transposon mutants and sequenced flanking regions from 383 of these, using a rapid polymerase chain reaction-based approach. Tn4431 insertions appeared to be widespread throughout the L. xyli subsp. xyli genome; however, there were regions that had significantly higher concentrations of insertions. The Tn4431 mutant library was screened for individuals unable to colonize sugarcane, and one noncolonizing mutant was found. The mutant contained a transposon insertion disrupting two open reading frames (ORF), one of which had homology to an integral membrane protein from Mycobacterium leprae. Sequencing of the surrounding regions revealed two operons, pro and cyd, both of which are believed to play roles in disease. Complementation studies were carried out using the noncolonizing Lxx::Tn4431 mutant. The noncolonizing mutant was transformed with a cosmid containing 40 kbp of wild-type sequence, which included the two ORF disrupted in the mutant, and several transformants were subsequently able to colonize sugarcane. However, analysis of each of these transformants, before and after colonization, suggests that they have all undergone various recombinant events, obscuring the roles of these ORF in L. xyli subsp. xyli pathogenesis.

Neurodevelopmental outcome of infants with hypoplastic left heart syndrome.

The neurodevelopmental outcome of hypoplastic left heart syndrome in infants remains unclear. All 11 survivors of staged surgical repair of hypoplastic left heart syndrome received standardized neurodevelopmental assessments at one regional children's hospital. Seven children (64%) had major developmental disabilities. Quality-of-life outcomes must be considered when management options for children with hypoplastic left heart syndrome are evaluated.

Noninvasive evaluation of ventricular function in cystic fibrosis.

The cardiac function of 21 patients with cystic fibrosis was studied using radionuclides and M-mode echocardiography. The patients (mean age 13.2 years, range 4 to 27) had a wide range of clinical and pulmonary function abnormalities (mean Shwachman-Kulczycki score 62.1). Decreased right ventricular ejection fraction was found in 13 of 18 patients (72%); an additional four patients had abnormal septal motion on ECHO. Left ventricular ejection fraction was abnormal at rest in four patients (19%); an additional four patients had borderline low LVEF. The LV pre-ejection period to ejection time ratio increased significantly (i.e., worsening LV performance) with deterioration of S-K score, chest radiograph score, and forced expiratory volume in 1 second. Three of eight patients with normal LVEF at rest had an abnormal response to supine bicycle exercise: LVEF fell in two patients and was unchanged in one. Thus evidence of LV dysfunction was observed in seven of 21 (33%) of the patients; four at rest and in three only during exercise.