Serum levels of miR-199a-5p correlates with blood pressure in premature cardiovascular disease patients homozygous for the MTHFR 677C > T polymorphism.

This investigation profiled circulating serum concentrations of microRNAs (miRNAs) in premature cardiovascular disease (CVD) patients screened for the 677C > T polymorphism in methylenetetrahydrofolate reductase (MTHFR), a risk factor for hypertension. Serum samples from 75 premature CVD patients of known MTHFR genotype were analysed for CVD-related miRNA expression, to identify those that were associated with blood pressure. Samples were collected at baseline and following intervention with riboflavin as part of a randomized controlled trial. In patients with the MTHFR 677TT genotype, expression of miR-199a-5p in serum was inversely correlated with hypertension at baseline, and with change in blood pressure in TT genotype patients who responded to riboflavin intervention. These correlations were not observed in MTHFR 677CC genotype patients. In vitro experiments and in silico data analysis provided evidence that miR-199a-5p targets SMAD4. This is the first study to link miR-199a-5p expression with hypertension in a genetically at-risk cohort of premature CVD patients.

Fungi form interkingdom microbial communities in the primordial human gut that develop with gestational age.

Fungal and bacterial commensal organisms play a complex role in the health of the human host. Expansion of commensal ecology after birth is a critical period in human immune development. However, the initial fungal colonization of the primordial gut remains undescribed. To investigate primordial fungal ecology, we performed amplicon sequencing and culture-based techniques of first-pass meconium, which forms in the intestine prior to birth, from a prospective observational cohort of term and preterm newborns. Here, we describe fungal ecologies in the primordial gut that develop complexity with advancing gestational age at birth. Our findings suggest homeostasis of fungal commensals may represent an important aspect of human biology present even before birth. Unlike bacterial communities that gradually develop complexity, the domination of the fungal communities of some preterm infants by Saccromycetes, specifically Candida, may suggest a pathologic association with preterm birth.-Willis, K. A., Purvis, J. H., Myers, E. D., Aziz, M. M., Karabayir, I., Gomes, C. K., Peters, B. M., Akbilgic, O., Talati, A. J., Pierre, J. F. Fungi form interkingdom microbial communities in the primordial human gut that develop with gestational age.

Upper thoracic pedicle screw loss of fixation causing spinal cord injury: a review of the literature and multicenter case series.

STUDY DESIGN: Case Series and Review of the Literature. OBJECTIVE: To report on cases of spinal cord injury from loss of fixation of upper thoracic pedicle screws. SUMMARY OF BACKGROUND DATA: Despite generally low rates of intraoperative neurological injury from pedicle screws, there is 1 reported case of T2 pedicle screw pullout causing spinal cord injury. METHODS: A review of the literature and an informal poll of 2 professional societies searching for cases in which thoracic pedicle screws migrated postoperatively into the spinal canal was performed. RESULTS: Three patients had failure of spinal instrumentation with the most cephalad pedicle screws (T2, T4 and T4) plowing into the spinal canal, causing direct trauma to the spinal cord with resulting clinical and neurological injury. Failure of fixation occurred at 1 month, 1 year, and 2 years after index procedure. In 2 patients, neurological injury was severe enough that they became nonambulatory; the third patient had rapidly progressive leg weakness. In each case, there were only 1 or 2 pedicle screws at the top of the construct, and a span of 6 to 7 vertebrae without rigid fixation below this. One similar case was found in the literature. CONCLUSIONS: Spinal instrumentation with only 1 to 2 pedicle screws at the top of the construct, and a span of >5 vertebrae below these screws without rigid fixation may be at risk for implant failure and catastrophic spinal cord injury. In the rare instance in which only 1 to 2 pedicle screws can be placed at the cephalad half of long spinal constructs, one may consider using hooks that would fail posteriorly and may present less risk to the spinal cord.

Recurrent posterior circulatory emboli from a mildly stenosed bicuspid aortic valve.

Bicuspid aortic valve (BAV) is a common condition but is only rarely associated with embolic complications. We describe a 42-year-old man with recurrent posterior circulatory ischemic strokes that resulted in ataxia and cognitive impairment. Transesophageal echocardiography demonstrated a BAV with mild stenosis, moderate calcification, and a dilated ascending aorta. The degree of calcification and the valve phenotype might be important factors implicating the BAV as a rare cause of ischemic stroke.

Effect of prenatal marijuana exposure on sleep wake cycles and amplitude-integrated electroencephalogram (aEEG).

OBJECTIVE: To assess whether prenatal exposure to marijuana (THC) results in abnormal amplitude integrated encephalograms (aEEG). DESIGN: This was a (2018-2020) prospective cohort study of prenatally THC-exposed newborns. Maternal and Infant demographics, urine (UDS) and umbilical cord drug screening (UCDS) were recorded. A limited channel continuous aEEG was obtained within 48 h of birth. Statistical analysis included univariate, multivariate, and logistical regression. RESULTS: A total of 30 mother/infant dyads were enrolled. 60% (18/30) of neonates had abnormal aEEGs with sleep wake cycle (SWC) disturbances (p < 0.001). UCDS Carboxy-THC pg/g levels were similar in infants with abnormal [1758 (296,2838)] and normal aEEG [1589 (332,2794)], p = 0.82. CONCLUSIONS: Absence of SWCs on aEEG is associated with prenatal THC exposure. While THC UCDS levels did not correlate to aEEG results future longitudinal studies are necessary to obtain detailed history of THC use and to evaluate its association with abnormal aEEG and the neurodevelopmental outcomes.

DNA methylation of hypertension-related genes and effect of riboflavin supplementation in adults stratified by genotype for the MTHFR C677T polymorphism.

BACKGROUND: The interaction between genetic, epigenetic and environmental factors plays an important role in the aetiology of hypertension. GWAS and observational studies link the C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) with hypertension, while riboflavin, the MTHFR cofactor, has been shown to reduce blood pressure and global DNA methylation in homozygous (TT genotype) individuals. It is currently unclear whether riboflavin modulates DNA methylation of other hypertension-related genes. OBJECTIVES: To compare DNA methylation of hypertension-related genes in adults stratified by MTHFR genotype and effect of riboflavin intervention in adults with the variant MTHFR 677TT genotype. METHOD: Pyrosequencing was carried out for hypertension-related genes (ACE, AGTR1, GCK, GNA12, IGF2, MMP9 and NOS3) in blood samples from participants in previous trials (CC, n = 40; TT, n = 40). The effect of intervention with riboflavin (1.6 mg/d for16 weeks) or placebo on DNA methylation was investigated in adults with the variant MTHFR 677TT genotype (n = 80). RESULTS: Individuals with the MTHFR 677TT v CC genotype had significantly higher average DNA methylation at NOS3 (+1.66%, P = 0.044). In response to riboflavin supplementation in TT individuals, there was an increase in average DNA methylation at IGF2 (+1.09%, P = 0.019) and a decrease at ACE (-0.44%, P = 0.021) in females only. Specific CpG sites were hypomethylated in GNA12 and hypermethylated in AGTR1. CONCLUSION: This study provides the first RCT evidence that riboflavin alters DNA methylation of hypertension-related genes in adults with the MTHFR 677TT genotype, providing some insight into mechanisms linking hypertension with the genotype-specific response of BP to riboflavin.

Parachute-like asymmetric tricuspid valve in an asymptomatic adult.

A parachute deformity of an atrioventricular valve occurs when the chordae tendineae arise from one papillary muscle or muscle group. Sometimes, the normal number of papillary muscles is seen, but one muscle is much larger than its peers and shows some characteristic features. This is known as a parachute-like asymmetric valve and has been well described in the mitral position. We present a young, asymptomatic adult with an abnormal tricuspid valve possessing typical features of a parachute-like asymmetric valve.

Riboflavin supplementation alters global and gene-specific DNA methylation in adults with the MTHFR 677 TT genotype.

DNA methylation is important in regulating gene expression and genomic stability while aberrant DNA methylation is associated with disease. Riboflavin (FAD) is a cofactor for methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate recycling, which generates methyl groups for homocysteine remethylation to methionine, the pre-cursor to the universal methyl donor S-adenosylmethionine (SAM). A polymorphism (C677T) in MTHFR results in decreased MTHFR activity and increased homocysteine concentration. Previous studies demonstrated that riboflavin modulates this phenotype in homozygous adults (MTHFR 677 TT genotype), however, DNA methylation was not considered. This study examined DNA methylation, globally and at key MTHFR regulatory sites, in adults stratified by MTHFR genotype and the effect of riboflavin supplementation on DNA methylation in individuals with the 677 TT genotype. Samples were accessed from participants, screened for the MTHFR C677T polymorphism, who participated in observational (n = 80) and targeted riboflavin (1.6 mg/day) RCTs (n = 80). DNA methylation at LINE-1 and key regulatory regions of the MTHFR locus were analysed by pyrosequencing in peripheral blood leukocytes. LINE-1 (+1.6%; p = 0.011) and MTHFR south shelf (+4.7%, p < 0.001) were significantly hypermethylated in individuals with the MTHFR 677 TT compared to CC genotype. Riboflavin supplementation resulted in decreased global methylation, albeit only significant at one CpG. A significant reduction in DNA methylation at the MTHFR north shore (-1.2%, p < 0.001) was also observed in TT adults following intervention with riboflavin. This provides the first RCT evidence that DNA methylation may be modulated by riboflavin in adults with the MTHFR 677 TT genotype.

Anomalous Left Main Coronary Artery: Not Always a Simple Surgical Reimplantation.

We present the case of 56-year-old woman who required complex coronary artery bypass grafting for high-risk anomalous left main coronary artery (LMCA) originating from right coronary cusp including conventional reimplantation of the LMCA plus left internal mammary artery (LIMA) graft to the left anterior descending (LAD) and saphenous vein graft (SVG) to the left circumflex (LCx). On subsequent cardiac computed tomography screening and cardiac catheterization, the LIMA graft was occluded after just a few centimeters, but the SVG graft was patent with good run-off into the native LCx and also filled the LAD retrogradely. The reimplanted left main stem demonstrated at least moderate ostial stenosis although pressure wire assessment of this was not significant (fractional flow reserve 0.89), probably due to good retrograde filling of the LAD from the SVG to LCx, therefore, we did not proceed with ostial LMCA stenting. She remains on yearly review with a low threshold for further revascularization should the SVG to LCx develop progressive stenosis. This case illustrates how patients with anomalous LMCA may sometimes benefit from grafting in addition to conventional reimplantation.

Riboflavin offers a targeted strategy for managing hypertension in patients with the MTHFR 677TT genotype: a 4-y follow-up.

BACKGROUND: We recently reported that the elevated blood pressure (BP) observed in patients with cardiovascular disease who are homozygous for the 677C→T polymorphism (TT genotype) in the gene encoding methylenetetrahydrofolate reductase (MTHFR) was responsive to supplementation with riboflavin-the cofactor for MTHFR. OBJECTIVE: The objective was to investigate the effect of riboflavin on BP targeted at patients with the TT genotype 4 y after initial investigation, during which time major changes in the clinical guidelines for antihypertensive therapy were introduced. DESIGN: A total of 83 patients (representing all 3 genotypes) who participated in a placebo-controlled riboflavin intervention for 16 wk in 2004 agreed to take part. Nested within this follow-up, those with the TT genotype (n = 31) proceeded to intervention with riboflavin (1.6 mg/d for 16 wk) or placebo, conducted in a crossover style whereby the 2004 treatment groups were reversed. RESULTS: At follow-up in 2008, as in 2004, patients with the TT genotype had higher systolic BP (P < 0.01), with a nonsignificant trend noted for higher diastolic BP (P = 0.051). Despite the marked changes in antihypertensive therapy that had occurred, BP remained unchanged in patients with the TT genotype at the time of follow-up. Riboflavin supplementation (administered in 2004 and 2008) produced an overall decrease in systolic (-9.2 ± 12.8 mm Hg; P = 0.001) and diastolic (-6.0 ± 9.9 mm Hg; P = 0.003) BP. CONCLUSIONS: Optimizing riboflavin status offers a low-cost targeted strategy for managing elevated BP in this genetically at-risk group. These findings, if confirmed in the general population, could have important implications for the prevention of hypertension.