A Cross-Sectional Study of KLKB1 and PRCP Polymorphisms in Patients with Cardiovascular Disease

Plasma kallikrein formed from prekallikrein (PK) produces bradykinin from kininogens and activates factor XII. Plasma PK is activated by factors XIIa, XIIa or prolylcarboxypeptidase (PRCP). A cross-sectional investigation determined if there is an association of PRCP and KLKB1 polymorphisms with cardiovascular disease. DNA was obtained from 2243 individuals from the PEACE trial. Two PRCP SNPs, rs7104980 and rs2298668 and 2 KLKB1 SNPs, rs3733402 and rs3087505, were genotyped. Logistic regression models were performed for history of diabetes, MI, stroke, angina, angiographic coronary disease, CABG, intermittent claudication, PTCA, and TIA. The PRCP SNP rs7104980 increased the odds of having a history of PTCA by 21% [OR = 1.211; 95% CI = (1.008, 1.454)]; P= 0.041, but was non significant after Bonferroni correction. Alternatively, having the G allele for rs3733402 (KLKB1 gene) decreased the odds of having a history of angiographic coronary disease by 24% [OR = 0.759; 95% CI = (0.622, 0.927)]; P = 0.007 that was statistically significant (p<0.01) after Bonferroni correction for multiple hypothesis testing. When the best-fit model based on the Akaike information criterion (AIC) controlled for age, weight, gender, hypertension, and history of angina. the G allele of KLKB1 rs3733402 that is associated with less plasma kallikrein activity correlated with reduced history of cardiovascular diseas

Colorimetric metal ion binding of catechol-based coatings inspired by melanin and molecular imprinting

Catechol-containing biomolecules and related synthetic materials are of interest for a broad range of applications. Our group has been interested in the potential of eumelanin, a catechol-containing biomaterial and the black-to-brown pigment in humans, and synthetic eumelanin analogues for water purification applications. In an attempt to apply the strategy of molecular imprinting towards lead-binding synthetic eumelanin coatings, we developed a PbO2-mediated synthesis that was subsequently tested with a number of catechols in addition to the eumelanin and polydopamine monomers l-dopa and dopamine. Although this strategy did not provide significant improvements in affinity or selectivity, we found that the PbO2-mediated oxidative polymerisation of 1,2-dihydroxybenzene generates a coating that darkens visibly upon binding Pb2+ and other metal ions. Oxidative polymerisation of catechol with sodium periodate also yields a coating with this colorimetric response. Of eight metal ions tested, the coatings are most responsive to Pb2+ and Cu2+, as analysed by quantitative colorimetry. With further optimisation, these coatings could prove useful for the colorimetric sensing of metal ions

Peripheral Blood Mitochondrial DNA Copy Number Obtained From Genome-Wide Genotype Data Is Associated With Neurocognitive Impairment in Persons With Chronic HIV Infection

BackgroundMitochondrial DNA (mtDNA) copy number varies by cell type and energy demands. Blood mtDNA copy number has been associated with neurocognitive function in persons without HIV. Low mtDNA copy number may indicate disordered mtDNA replication; high copy number may reflect a response to mitochondrial dysfunction. We hypothesized that blood mtDNA copy number estimated from genome-wide genotyping data is related to neurocognitive impairment (NCI) in persons with HIV.MethodsIn the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, peripheral blood mtDNA copy number was obtained from genome-wide genotyping data as a ratio of mtDNA single-nucleotide polymorphism probe intensities relative to nuclear DNA single-nucleotide polymorphisms. In a multivariable regression model, associations between mtDNA copy number and demographics, blood cell counts, and HIV disease and treatment characteristics were tested. Associations of mtDNA copy number with the global deficit score (GDS), GDS-defined NCI (GDS ≥ 0.5), and HIV-associated neurocognitive disorder (HAND) diagnosis were tested by logistic regression, adjusting for potential confounders.ResultsAmong 1010 CHARTER participants, lower mtDNA copy number was associated with longer antiretroviral therapy duration (P &lt; 0.001), but not with d-drug exposure (P = 0.85). mtDNA copy number was also associated with GDS (P = 0.007), GDS-defined NCI (P &lt; 0.001), and HAND (P = 0.002). In all analyses, higher mtDNA copy number was associated with poorer cognitive performance.ConclusionsHigher mtDNA copy number estimated from peripheral blood genotyping was associated with worse neurocognitive performance in adults with HIV. These results suggest a connection between peripheral blood mtDNA and NCI, and may represent increased mtDNA replication in response to mitochondrial dysfunction

Comparative Brain and Central Nervous System Tumor Incidence and Survival between the United States and Taiwan Based on Population-Based Registry

Purpose: Reasons for worldwide variability in the burden of primary malignant brain and central nervous system (CNS) tumors remain unclear. This study compares the incidence and survival of malignant brain and CNS tumors by selected histologic types between the United States (US) and Taiwan. Methods: Data from 2002 to 2010 were selected from two population-based cancer registries for primary malignant brain and CNS tumors: the Central Brain Tumor Registry of the United States (CBTRUS) and the Taiwan Cancer Registry. Two registries had similar process of collecting patients with malignant brain tumor and the quality of two registries were comparative. The age-adjusted incidence rate (IR), IR ratio, and survival by histological types, age and gender were used to study regional differences. Results: The overall age-adjusted IRs were 5.91 per 100,000 in the US and 2.68 per 100,000 in Taiwan. The most common histologic type for both countries was glioblastoma with a 12.9% higher proportion in the US than in Taiwan. Glioblastoma had the lowest survival rate of any histology in both countries (US 1-year survival rate = 37.5%; Taiwan 1-year survival rate = 50.3%). The second largest group was astrocytoma, excluding glioblastoma and anaplastic astrocytoma, with the distribution being slightly higher in Taiwan than in the US. Conclusions: Our findings revealed differences by histological type and grade of primary malignant brain and CNS tumors between two sites

International Differences in Treatment and Clinical Outcomes for High Grade Glioma.

High grade gliomas are the most common type of malignant brain tumor, and despite their rarity, cause significant morbidity and mortality. This study aimed to compare the treatment patterns of high grade glioma to examine survival patterns in patients who receive specific treatments between cohorts in Ohio and Taiwan.Patients aged 18 years and older at age of diagnosis with World Health Organization (WHO) grade III or IV astrocytoma from 2007-2012 were selected from the Ohio Brain Tumor Study and the Taiwan Cancer Registry. The treatment information was derived from medical chart reviews in Ohio and National Health Insurance Research Data in Taiwan. Treatment examined included surgical procedure (brain biopsy and/or resection), radiotherapy (radiation and/or radiosurgery), and alkylating chemotherapy. Kaplan-Meier and parametric survival models were used to examine the effect of treatment on survival, adjusted for age, sex, and comorbidities.294 patients in Ohio and 1,097 patients in Taiwan met the inclusion criteria. 70.3% patients in Ohio and 51.4% in Taiwan received surgical resection, followed by concurrent chemoradiation. Patients who received this treatment had the highest survival rate, with a 1-year survival rate of 72.8% in Ohio and 73.4% in Taiwan. Patients who did not receive surgical resection, followed by concurrent chemoradiation had an increased risk of death (hazard ratio of 5.03 [95% confidence interval (CI): 3.61-7.02] in Ohio and 1.49 [95% CI: 1.31-1.71] in Taiwan) after adjustment for age, sex, and comorbidities.Surgical resection followed by concurrent chemoradiation was associated with higher survival rate of patients with high grade glioma in both Ohio and Taiwan; however, one-third of patients in Ohio and half in Taiwan did not receive this treatment

Cerebrospinal fluid cell-free mitochondrial DNA is associated with HIV replication, iron transport, and mild HIV-associated neurocognitive impairment

Abstract Background Mitochondria are abundant organelles critical for energy metabolism and brain function. Mitochondrial DNA (mtDNA), released during cellular injury and as part of the innate immune response to viral pathogens, contains CpG motifs that act as TLR-9 ligands. We investigated relationships between cerebrospinal fluid (CSF) cell-free mtDNA levels and HIV viral load (VL), biomarkers of inflammation and iron transport, and neurocognitive (NC) function in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort. Methods We quantified cell-free mtDNA in CSF by droplet digital PCR in 332 CHARTER participants who underwent comprehensive neuropsychiatric evaluation. NC performance was assessed using the global deficit score (GDS) as either a continuous or a binary measure (GDS ≥ 0.5, impaired vs. GDS < 0.5, unimpaired). CSF, clinical, and biomarker data from the earliest available time point were analyzed. Cell-free mtDNA associations with CSF inflammation and iron-related biomarkers [CXCL10, IL-6, IL-8, TNF-a, transferrin (TF), ceruloplasmin (CP), and vascular endothelial growth factor (VEGF)], VL, and GDS were evaluated by multivariable regression. Results CSF cell-free mtDNA levels were significantly lower in participants with undetectable (vs. detectable) VL in either plasma (p < 0.001) or CSF (p < 0.001) and in those on antiretroviral therapy (ART; p < 0.001). Participants on ART with undetectable VL in both CSF and plasma had lower mtDNA levels than those with detectable VL in both compartments (p = 0.001). Higher mtDNA levels were observed in participants in the highest vs. lowest tertile (T3 vs. T1) of CSF CXCL10 (T3 vs. T1, p < 0.001) and TNF-a (T3 vs. T1, p < 0.05) in unadjusted analyses. MtDNA levels also correlated with CSF leukocyte count. After adjusting for CSF leukocyte count and VL, mtDNA levels were also associated with other inflammation- and iron-related biomarkers in CSF, including TF (T3 vs. T1, p < 0.05) and CP (T3 vs. T1, p < 0.05). With additional correction for ART use, mtDNA was also negatively associated with CSF VEGF (p < 0.05) and IL-6 (p = 0.05). We observed no associations of CSF mtDNA levels with age or GDS-defined NC impairment. Conclusions CSF cell-free mtDNA levels were associated with HIV RNA and ART status, as well as with biomarkers of iron transport and VEGF, a growth factor with known effects on mitochondrial integrity and autophagy. CSF mtDNA may be a biomarker of iron dysregulation and/or neuroinflammation during HIV infection