Maternal Choline Supplementation Alters Fetal Growth Patterns in a Mouse Model of Placental Insufficiency

Impairments in placental development can adversely affect pregnancy outcomes. The bioactive nutrient choline may mitigate some of these impairments, as suggested by data in humans, animals, and human trophoblasts. Herein, we investigated the effects of maternal choline supplementation (MCS) on parameters of fetal growth in a Dlx3+/− (distal-less homeobox 3) mouse model of placental insufficiency. Dlx3+/− female mice were assigned to 1X (control), 2X, or 4X choline intake levels during gestation. Dams were sacrificed at embryonic days E10.5, 12.5, 15.5, and 18.5. At E10.5, placental weight, embryo weight, and placental efficiency were higher in 4X versus 1X choline. Higher concentrations of hepatic and placental betaine were detected in 4X versus 1X choline, and placental betaine was positively associated with embryo weight. Placental mRNA expression of Igf1 was downregulated by 4X (versus 1X) choline at E10.5. No differences in fetal growth parameters were detected at E12.5 and 15.5, whereas a small but significant reduction in fetal weight was detected at E18.5 in 4X versus 1X choline. MCS improved fetal growth during early pregnancy in the Dlx3+/− mice with the compensatory downregulation of Igf1 to slow growth as gestation progressed. Placental betaine may be responsible for the growth-promoting effects of choline

One-carbon metabolism in children with marasmus and kwashiorkor

BACKGROUND: Kwashiorkor is a childhood syndrome of edematous malnutrition. Its precise nutritional precipitants remain uncertain despite nine decades of study. Remarkably, kwashiorkor\u27s disturbances resemble the effects of experimental diets that are deficient in one-carbon nutrients. This similarity suggests that kwashiorkor may represent a nutritionally mediated syndrome of acute one-carbon metabolism dysfunction. Here we report findings from a cross-sectional exploration of serum one-carbon metabolites in Malawian children. METHODS: Blood was collected from children aged 12-60 months before nutritional rehabilitation: kwashiorkor (N = 94), marasmic-kwashiorkor (N = 43) marasmus (N = 118), moderate acute malnutrition (N = 56) and controls (N = 46). Serum concentrations of 16 one-carbon metabolites were quantified using LC/MS techniques, and then compared across participant groups. FINDINGS: Twelve of 16 measured one-carbon metabolites differed significantly between participant groups. Measured outputs of one-carbon metabolism, asymmetric dimethylarginine (ADMA) and cysteine, were lower in marasmic-kwashiorkor (median µmol/L (± SD): 0·549 (± 0·217) P = 0·00045 & 90 (± 40) P \u3c 0·0001, respectively) and kwashiorkor (0·557 (± 0·195) P \u3c 0·0001 & 115 (± 50) P \u3c 0·0001), relative to marasmus (0·698 (± 0·212) & 153 (± 42)). ADMA and cysteine were well correlated with methionine in both kwashiorkor and marasmic-kwashiorkor. INTERPRETATION: Kwashiorkor and marasmic-kwashiorkor were distinguished by evidence of one-carbon metabolism dysfunction. Correlative observations suggest that methionine deficiency drives this dysfunction, which is implicated in the syndrome\u27s pathogenesis. The hypothesis that kwashiorkor can be prevented by fortifying low quality diets with methionine, along with nutrients that support efficient methionine use, such as choline, requires further investigation. FUNDING: The Hickey Family Foundation, the American College of Gastroenterology, the NICHD, and the USDA/ARS

Surgery for pituitary tumor apoplexy is associated with rapid headache and cranial nerve improvement

Pituitary tumor apoplexy (PTA) classically comprises sudden-onset headache, loss of vision, ophthalmoparesis, and decreased consciousness. It typically results from hemorrhage and/or infarction within a pituitary adenoma. Presentation is heterologous, and optimal management is debated. The time course of recovery of cranial nerve deficits (CNDs) and headaches is not well established. In this study, a retrospective series of consecutive patients with PTA managed at a single academic institution over a 22-year period is presented. Headaches at the time of surgery were more severe in the early and subacute surgical cohort and improved significantly within 72 h postoperatively

A Cross-Sectional Analysis of Products Marketed as Plant-Based Across the United States, United Kingdom, and Canada Using Online Nutrition Information.

The food industry is responding to a rising demand for plant-based foods by developing and marketing an ever-wider range of vegan and vegetarian products under the banner of "plant-based." Understanding the nutritional properties of these products is critical. To assess the number, meal type, and nutritional content of products marketed as plant-based (MaPB) from the perspective of the consumer across multiple sectors in the United States, United Kingdom, and Canada. An online search for products MaPB was performed across supermarkets, restaurants, food manufacturers, and plant-based meal delivery companies in the United Kingdom, the United States, and Canada using the terms: "vegan," "vegetarian," and "plant-based." Online nutrition data were extracted, and whole meals that comprised >50% of ingredients such as fruits, vegetables, legumes, nuts, and seeds were identified. The nutritional content of dishes MaPB in restaurants was also directly compared with meat-containing dishes. Further, 3488 unique products were identified, of which 962 were whole meals and 1137 were a replacement for the main protein component in a meal, including 771 meat alternatives. Across all sectors, 45% of whole meals had >15-g protein, 70% had 10-g fiber per meal, and 86% had <1000 mg sodium. At restaurants, 1507 meat-containing dishes were identified and compared with 191 vegetarian and 81 vegan dishes. The meat-containing dishes were higher in protein [35.4 g (24.0-51.4)] compared with vegetarian [19.0 g (13.0-26.1)] and vegan [16.2 g (10.5-23.2) dishes ( < 0.001)]. The vegan dishes were low in saturated fat and sodium (SFA: 6.3 g ± 6.4, Sodium: 800 mg (545.0-1410.0) compared with both meat [SFA: 11.6 g ± 10.0; Sodium: 1280 mg (820.0-1952.0)] and vegetarian [SFA: 9.4 g ± 7.6; Sodium: 1011 mg (603.0-1560.0)] options ( < 0.001 for all comparisons). Products MaPB tend to have lower concentrations of saturated fat and sodium than their meat-containing counterparts, but improvements are needed to optimize their nutritional composition

Impairment of Vowel Articulation as a Possible Marker of Disease Progression in Parkinson's Disease

Purpose: The aim of the current study was to survey if vowel articulation in speakers with Parkinson’s disease (PD) shows specific changes in the course of the disease. Method: 67 patients with PD (42 male) and 40 healthy speakers (20 male) were tested and retested after an average time interval of 34 months. Participants had to read a given text as source for subsequent calculation of the triangular vowel space area (tVSA) and vowel articulation index (VAI). Measurement of tVSA and VAI were based upon analysis of the first and second formant of the vowels /a/, /i/and /u / extracted from defined words within the text. Results: At first visit, VAI values were reduced in male and female PD patients as compared to the control group, and showed a further decrease at the second visit. Only in female Parkinsonian speakers, VAI was correlated to overall speech impairment based upon perceptual impression. VAI and tVSA were correlated to gait impairment, but no correlations were seen between VAI and global motor impairment or overall disease duration. tVSA showed a similar reduction in the PD as compared to the control group and was also found to further decline between first and second examination in female, but not in male speakers with PD. Conclusions: Measurement of VAI seems to be superior to tVSA in the description of impaired vowel articulation and its further decline in the course of the disease in PD. Since impairment of vowel articulation was found to be independent fro

Phosphatidylcholines: Beyond the Membrane

Phosphatidylcholines (PC) are the most abundant phospholipids in mammalian cells, where they serve well-characterized structural roles, maintaining membrane integrity, facilitating lipoprotein assembly and serving as a surfactant in the lung. Over the past decade, seminal papers have been published that describe novel roles for specific PC species derived from both the cytidine diphosphate-choline (CDP-choline) and phosphatidylethanolamine N-methyltransferase (PEMT) pathways of PC synthesis; these roles include both nuclear receptor agonism and generating critical physiological pools of the omega 3 fatty acid, docosahexaenoic acid (DHA). In addition to these novel functions, complex interactions between PC and its substrate, choline, with growth and energetic status have emerged, following the observation that the mammalian target of rapamycin complex 1 (mTORC1) is a major regulator of PC synthesis through the CDP-choline pathway. Presented in this dissertation are the tests of our primary hypotheses informed directly from these emerging areas of phosphatidylcholine biology. Chapter 2 of this dissertation examines the impact of diet on the production of dilauroylphosphatidylcholine (DLPC), a phosphatidylcholine species enriched in lauric acid that was recently identified as a ligand for the nuclear receptor, liver receptor homolog-1 (LRH-1). DLPC binding to LRH-1 results in modulation of LRH-1-dependent hepatic gene expression and improvements in glucose and lipid handling. While DLPC has been convincingly shown to bind and activate LRH-1 when provided exogenously to cultured cells and mice, endogenous production of DLPC has not been observed, questioning its significance in the regulation of mammalian physiology. We hypothesized that the absence of DLPC in mammalian tissues results from substrate insufficiency (i.e. low lauric acid supply) and that provision of lauric acid, either in the culture media or the mammalian diet, will result in endogenous DLPC production, and be associated with functional LRH-1 activation. Cell culture models, animal feeding experiments, and a single-blind, randomized, controlled crossover acute feeding study in human participants were used to test this hypothesis. As hypothesized, provision of lauric acid in the cell culture media, animal diet, and human diet resulted in the acute and chronic production of DLPC. In cultured cells, this was associated with upregulation of LRH-1 dependent transcripts, an effect that was blunted by co-treatment with a LRH-1 antagonist. In animals, feeding of high fat diets containing lauric acid, utilizing purified lauric acid or coconut oil-based diets, resulted in substantial improvements in glucose handling as indicated by an oral glucose tolerance test. Chapter 3 of this dissertation examines the association of dietary choline intake and reproductive stage with plasma lysophosphatidylcholine (LPC)-DHA among women participants of a 10 week controlled feeding study. LPC-DHA has been recently highlighted as a physiological pool of DHA for maintaining the supply of this critical polyunsaturated fatty acid to extrahepatic organs during growth and development. We hypothesized that reproductive life-stage, dietary choline intake (22% provided as deuterium-labeled choline) and genetic variants in one-carbon metabolism would impact plasma unlabeled and labeled LPC-DHA in response to controlled feeding. To address these hypotheses, we measured unlabeled and deuterium-labeled plasma LPC-DHA in samples from a previously conducted controlled feeding study performed in non-pregnant, pregnant, and lactating women randomized to either 480 or 930mg of choline per day. Consistent with our hypotheses, we observed a significant reduction in unlabeled plasma LPC-DHA in pregnant and lactating women relative to non-pregnant women at week 10; only non-pregnant women exhibited significant increases in LPC-DHA from baseline to week 10 while consuming the study diets. Choline intake and one-carbon metabolism variants were not associated with unlabeled plasma LPC-DHA. However, both choline intake and reproductive life-stage altered the enrichment of PEMT- and CDP-choline-derived LPCs. In Chapter 4 of this dissertation, we explore roles for choline and phospholipid metabolism in the context of a novel animal model of adolescent severe acute malnutrition (aSAM). This complex disorder is characterized by negative energy balance, impaired growth, and multiple micronutrient deficiencies; severe forms of aSAM, namely kwashiorkor, are further complicated by an idiopathic fatty liver. The sensitivity of this fatty liver to dietary choline remains unknown. To characterize the potential for choline supplementation to serve as a metabolic therapy in aSAM, we developed a maize vegetable diet (MVD), comprised of foods typically consumed by children who will go on to develop kwashiorkor. The MVD was fed to weanling mice with or without choline supplementation, and compared to typical chow diets, to determine impacts on growth, body composition, and potential to alleviate the hallmark characteristic of kwashiorkor, fatty liver. We further explored the metabolic fate of dietary choline, hypothesizing that choline would be oxidized to betaine to support PC synthesis through the PEMT pathway in this context of lower mTORC1 activity and reduced CDP-choline pathway activity. Mice consuming our novel maize vegetable diet exhibited impaired growth relative to chow fed mice, and developed hepatic steatosis, consistent with human kwashiorkor. The addition of choline to the maize vegetable diet resulted in amelioration of the hepatic steatosis, and a greater hepatic concentration of betaine; choline partitioning to betaine is consistent with a role for the PEMT pathway in supporting PC synthesis in the context of malnutrition

Chowing down: diet considerations in rodent models of metabolic disease.

Diet plays a substantial role in the etiology, progression, and treatment of chronic disease and is best considered as a multifaceted set of modifiable input variables with pleiotropic effects on a variety of biological pathways spanning multiple organ systems. This brief review discusses key issues related to the design and conduct of diet interventions in rodent models of metabolic disease and their implications for interpreting experiments. We also make specific recommendations to improve rodent diet studies to help better understand the role of diet on metabolic physiology and thereby improve our understanding of metabolic disease

The premack principle, response deprivation, and establishing operations

This paper describes response deprivation as an establishing operation. In this context, we review the concept of establishing operation, in particular, its reinforcer-establishing and evocative effects; we place response deprivation in the literature on the reinforcing effects of behavioral activity, wherein response deprivation subsumes the Premack principle; we describe the reinforcer-altering and evocative effects of response deprivation; and we address a methodological concern about the evocative effect. In closing, we discuss some conceptual and empirical implications of the foregoing analyses