Joint effect of maternal plasma homocysteine and prepregnancy obesity on child blood pressure: a prospective birth cohort study.

BACKGROUND/OBJECTIVES: Elevated homocysteine (Hcy) is a known cardiovascular risk factor. However, its role in intergenerational cardiometabolic risk is unknown. We hypothesized that maternal elevated Hcy can act alone or in combination with maternal prepregnancy obesity to increase child systolic blood pressure (SBP). METHODS: This study included 1279 mother-child pairs who were enrolled at birth and followed prospectively up to age 9 years from 2003 to 2014 at the Boston Medical Center. Child SBP percentile was calculated according to US reference data and elevated SBP was defined as SBP⩾75th percentile. RESULTS: A U-shaped relationship between maternal Hcy and her child SBP was observed. The risk for child elevated SBP was higher among those in the lowest quartile (Q1, odds ratio (OR): 1.27; 95% confidence interval (CI): 0.94-1.72), and highest quartile (Q4, OR: 1.34; 95% CI: 1.00-1.81) as compared with those in quartiles 2 and 3. The highest risk of child elevated SBP was found among children born to obese mothers with Hcy in Q4 (OR: 2.22; 95%CI: 1.35-3.64), compared with children of non-obese mothers with Hcy in Q2-Q3. This association was independent from maternal folate and vitamin B12 status, and was not mediated by gestational age or size at birth. CONCLUSIONS: In this prospective birth cohort, we observed a U-shaped association between maternal Hcy levels and child elevated SBP. Maternal high Hcy (Q4) and prepregnancy obesity jointly increased the risk of child elevated SBP by more than two-fold.

Leber's hereditary optic neuropathy differentially affects smaller axons in the optic nerve.

PURPOSE: Leber's hereditary optic neuropathy (LHON), though known to be due to 1 of 3 pathogenic mtDNA point mutations (nucleotide positions 11,778, 3460, and 14,484), usually manifests itself acutely in young adulthood with a stereotypical presentation of dyschromatopsia, loss of central vision, and loss of the papillomacular bundle nerve fiber layer. Histopathologic investigations have demonstrated devastating losses of axons with relative sparing of the most peripherally placed fibers in the optic nerves. This study was designed to morphometrically investigate the nerve fiber spectrum from ultrastructural studies of optic nerves obtained from 2 patients with LHON. METHODS: Two cases of LHON were molecularly characterized and the optic nerves from these cases studied by light microscopy and electron microscopy. Montages were made of electron micrographs cut orthogonal to fibers obtained from the periphery of each optic nerve, and these were then used for the measurement of each axon (short and long axis) and its myelin sheath. From this, a spectrum of nerve fiber layer was generated, yielding axon caliber profiles that could be compared between optic nerves. RESULTS: The total depletion of optic nerve fiber population in the 2 cases of LHON varied from 95% to 99%. Those fibers that were spared were limited to the peripheral optic nerve. The nerve fiber layer spectra of these remaining fibers showed a marked diminution of the first peak of axons of less than 1 micron in diameter, with relative emphasis of a second peak of axons of about 2 microns in diameter. In comparison to normal controls, this reflected a preferential loss of the smallest axons corresponding to the P-cell population. CONCLUSIONS: The clinical features of dyschromatopsia and central scotoma (with preservation of pupils) in LHON suggests the selective loss of the P-cell population known to subserve these (and not pupil) functions. This also correlates well with the fundus findings of early losses of the papillomacular bundle. The present study extends these findings to demonstrate a relative preservation of the M-cells in the optic nerve as reflected by the nerve fiber spectral profile. This selective loss of smaller fibers and their corresponding smaller retinal ganglion cells may, in addition to explaining the clinical features in LHON, provide valuable insights as to the exact pathophysiologic mechanisms by which mitochondrial impairment may induce apoptosis in vulnerable neurons.