👤 Carlos M Restrepo

Herpes simplex virus type 1 (HSV-1) is a neurotropic pathogen capable of invading the central nervous system (CNS) and increasingly associated with chronic neuroinflammation, cognitive impairment, and neurodegenerative disease. While microglia orchestrate the initial immune response to HSV-1, the molecular mechanisms that regulate their sustained neuroinflammatory activity To define the transcriptional and epigenetic mechanisms that shape microglial responses during acute HSV-1 infection Single-cell multiome analysis of CD11b⁺ nuclei identified transcriptionally and epigenetically distinct microglial and macrophage populations. HSV-1 infection redistributed monocyte-lineage states, with a marked overrepresentation of interferon (IFN)-responsive microglia and macrophage-associated populations. These states exhibited amplification of STAT1/2-, IRF1-, and CEBPB-centered regulons, distinguishing IFN-responsive microglia from macrophage-enriched populations rather than reflecting uniform activation. Homeostatic microglial gene signatures ( Using a multiomic framework, we demonstrate that HSV-1 infection drives transcriptional and epigenetic remodeling of microglial populations, characterized by a dominance of IFN-responsive states and a loss of homeostatic signatures. These findings provide mechanistic insight into how localized viral infection can reprogram microglial regulatory landscapes to maintain persistent HSV-1-associated neuroinflammation, contributing to long-term neurological vulnerability and neurodegenerative disease risk. Show less

Given that lipoprotein lipase (LPL) activity assays are not standardized for clinical use, we aimed to define reference values applicable to our clinical setting and identify a cut-off point to help distinguish Familial Chylomicronemia Syndrome from Multifactorial Chylomicronemia Syndrome, particularly in patients with inconclusive genetic findings. We evaluated 28 patients with a history of TG levels above 880 mg/dL (10 mmol/L), and assessed their likelihood of FCS using the Moulin score. LPL activity was measured in post-heparin plasma using a radiometric assay. Thirty normotriglyceridemic controls were used to define reference values. Genetic testing for FCS canonical genes and lipid profile was performed in all sHTG patients. The reference value for LPL activity was 33.3 (18.7-70.3) mIU, with a cut-off of 8.42 mIU (25 % of the median of NTG) to distinguish FCS from MCS. Eighteen patients without genetic variants in canonical genes, a Moulin score <9 and LPL activity >25 % of NTG, were classified as MCS. Five genetic diagnosed FCS patients, with a Moulin score>10 presented LPL activity <25 % of NTG. Four patients with inconclusive genetic results and a Moulin score>10 were classified as FCS according to LPL activity. LPL activity in patients with sHTG could be useful for differentiating FCS and MCS, particularly in patients with ambiguous or negative genetic findings, highlighting the need for specialized laboratory support in diagnostics. Show less

By 2021, the American College of Medical Genetics and Genomics (ACMG) published the last version of their secondary findings (SF) reporting recommendations for cases in which a person receives a genetic test. To determine in a sample of the Colombian population the prevalence of SF for the 59 genes on the ACMG SF v2.0 list associated with 27 genetic diseases. An analytical cross-sectional study was developed by examining the sequences of 160 exomes. Based on the ACMG guidelines, a variant classification algorithm was designed to filter and select reportable SF. Eleven pathogenic variants were identified in 13/160 (8.13%) patients in genes APOB, BRCA2, CACNA1S, COL3A1, LDLR, MYBPC3, PCSK9, PKP2, PMS2 and RYR2. No association was found between the sociodemographic variables and the SF to report (P > 0,05). We reported the first approach of actionable pathogenic variants spectrum in the Colombian population. Given the frequency found in this study and the clinical impact of genomic variants on health, it is essential to actively search for SF having the opportunity to receive genetic counselling, prevention and clinical management. Show less

High levels of triglycerides (TG ≥200 mg/dL) are an emerging risk factor for cardiovascular disease. Conversely, very low levels of TG are associated with decreased risk for cardiovascular disease. Precision medicine aims to capitalize on recent findings that rare variants such as APOC3 R19X (rs76353203) are associated with risk of disease, but it is unclear how population-based associations can be best translated in clinical settings at the individual-patient level. To explore the potential usefulness of screening for genetic predictors of cardiovascular disease, we surveyed BioVU, the Vanderbilt University Medical Center's biorepository linked to de-identified electronic health records (EHRs), for APOC3 19X mutations among adult European American patients (> 45 and > 55 years of age for men and women, respectively) with the lowest percentile of TG levels. The initial search identified 262 patients with the lowest TG levels in the biorepository; among these, 184 patients with sufficient DNA and the lowest TG levels were chosen for Illumina ExomeChip genotyping. A total of two patients were identified as heterozygotes of APOC3 R19X for a minor allele frequency (MAF) of 0.55% in this patient population. Both heterozygous patients had only a single mention of TG in the EHR (31 and 35 mg/dL, respectively), and one patient had evidence of previous cardiovascular disease. In this patient population, we identified two patients who were carriers of the APOC3 19X null variant, but only one lacked evidence of disease in the EHR highlighting the challenges of inclusion of functional or previously associated genetic variation in clinical risk assessment. Show less