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Catherine Ricciardi

Bio: Catherine Ricciardi is an academic researcher from Massachusetts Institute of Technology. The author has contributed to research in topics: Vitamin D and neurology & Binocular rivalry. The author has an hindex of 6, co-authored 11 publications receiving 809 citations. Previous affiliations of Catherine Ricciardi include McGovern Institute for Brain Research.

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Journal ArticleDOI
TL;DR: A mass spectrometry‐based strategy to simultaneously measure 191 metabolites following glucose ingestion laid the groundwork for using metabolic profiling to define an individual's ‘insulin response profile’, which could have value in predicting diabetes, its complications, and in guiding therapy.
Abstract: Bioinformatics and Integrative Genomics Award from National Human Genome Research Institute; National Institutes of Health (R01-HL-086875, R01-HL-083197); Heart Failure Society of America and the Harvard/MIT Clinical Investigator Training Program; National Institutes of Health (U01HL083141); Donald W Reynolds Foundation and Fondation Leducq; Burroughs Wellcome Career Award in the Biomedical Sciences; Howard Hughes Medical Institute Early Career Physician Scientist Award; Broad Institute Scientific Planning and Allocation of Resources Committee; National Institutes of Health (General Clinical Research Center grant); General Clinical Research Center (MO1-RR01066); National Institutes of Health/National Heart Lung and Blood Institute (N01-HC-25195).

372 citations

Journal ArticleDOI
TL;DR: The findings have important implications for vitamin D supplementation in vitamin D–deficient states and future studies should continue to explore the relationship between free and bioavailable 25(OH)D and health outcomes.
Abstract: Studies examining the relationship between total circulating 25-hydroxyvitamin D [25(OH)D] levels and bone mineral density (BMD) have yielded mixed results. Vitamin D-binding protein (DBP), the major carrier protein for 25(OH)D, may alter the biologic activity of circulating vitamin D. We hypothesized that free and bioavailable 25(OH)D, calculated from total 25(OH)D, DBP, and serum albumin levels, would be more strongly associated with BMD than levels of total 25(OH)D. We measured total 25(OH)D, DBP, and serum albumin levels in 49 healthy young adults enrolled in the Metabolic Abnormalities in College-Aged Students (MACS) study. Lumbar spine BMD was measured in all subjects using dual-energy X-ray absorptiometry. Clinical, diet, and laboratory information also was gathered at this time. We determined free and bioavailable (free + albumin-bound) 25(OH)D using previously validated formulas and examined their associations with BMD. BMD was not associated with total 25(OH)D levels (r = 0.172, p = .236). In contrast, free and bioavailable 25(OH)D levels were positively correlated with BMD (r = 0.413, p = .003 for free, r = 0.441, p = .002 for bioavailable). Bioavailable 25(OH)D levels remained independently associated with BMD in multivariate regression models adjusting for age, sex, body mass index, and race (p = .03). It is concluded that free and bioavailable 25(OH)D are more strongly correlated with BMD than total 25(OH)D. These findings have important implications for vitamin D supplementation in vitamin D-deficient states. Future studies should continue to explore the relationship between free and bioavailable 25(OH)D and health outcomes.

324 citations

Journal ArticleDOI
TL;DR: While circulating levels of cathelicidin have been most tightly linked to sepsis and mortality, little is known about the association of vitamin D status and plasma cathe Licidin in healthy individuals, or of the ability of vitaminD supplementation to alter these levels.
Abstract: To the Editor: Cathelicidins are a class of widely conserved antimicrobial peptides (AMPs) produced by essentially all mammalian species as part of the innate immune system. They have broad activity against both Gram-positive and Gram-negative bacteria and have additional effects including neutralizing lipopolysaccharide, stimulating leukocyte chemotaxis, promoting angiogenesis. There is only one known cathelicidin in humans. Although it is found in the secondary granules of neutrophils and other leukocyte populations, and a range of squamous epithelia including the skin, airways, mouth and intestine, it also circulates at high levels in the plasma.1, 2 Impairment in cathelicidin or other AMPs has been linked to increased susceptibility to and severity of infection while overexpression of cathelicidin confers protection against sepsis in animal models.3 Dialysis patients with the lowest circulating levels of cathelicidin are at a greater than two-fold risk of death due to infectious causes.4 The transcription of CAMP, the gene encoding cathelicidin in humans, is regulated by the vitamin D receptor. In vitro studies of human tissues, including epithelial cells, macrophages, and neutrophils, have demonstrated that cathelicidin levels can be increased following administration of 1,25-dihydroxyvitamin D.5 Topical and oral vitamin D analogues similarly lead to stimulation of cutaneous cathelicidin production.6 Prior studies of cathelicidin have given particular focus to its anti-tuberculosis properties, and humans given a single dose of oral vitamin D demonstrated improved mycobacterial immunity with an ex vivo assay.7 While circulating levels of cathelicidin have been most tightly linked to sepsis and mortality, little is known about the association of vitamin D status and plasma cathelicidin in healthy individuals, or of the ability of vitamin D supplementation to alter these levels. In order to clarify the relationship between plasma cathelicidin, vitamin D status, and vitamin D supplementation, we conducted a prospective study in our outpatient clinical research center. Plasma levels of cathelicidin and 25-hydroxyvitamin D (25[OH]D) were measured in 60 healthy volunteers, along with calcium and creatinine. All subjects were free of known infection or renal disease and were not taking immunosuppressive medications. Individuals with plasma 25(OH)D levels ≤32 ng/ml (based on the laboratory reference range and previous studies 8) were treated with ergocalciferol, 50,000 IU every other day for 5 days. Post-treatment levels of 25(OH)D, cathelicidin and calcium were then measured in these subjects a median of 10 days after completing treatment. Total plasma cathelicidin (including the protein hCAP18 and its c-terminal peptide, LL37) was measured by ELISA, as described elsewhere.2 Screening 25-hydroxyvitamin D was measured via liquid chromatography-tandem mass spectrometry (LCMS). The study was approved by the institutional review boards at Massachusetts General Hospital and the Massachusetts Institute of Technology and all subjects provided written informed consent. Estimated glomerular filtration rate (eGFR) was calculated using the widely-used Modification of Diet in Renal Disease formula. Spearman correlation was performed to assess the relationship between vitamin D and cathelicidin levels; as vitamin D associated relationships may emerge only below a threshold, levels ≤32 ng/ml and >32 ng/ml were analyzed separately. Multivariate linear spline regression (with an inflection point at 32 ng/ml) was used to confirm this approach and multiple linear regression was used to adjust for potential confounders. Stata 11.1 (StataCorp, College Station, TX) was used for all analysis. Subject characteristics are detailed in table 1. Subjects were predominantly female and white, and all subjects had normal renal function (eGFR > 60 ml/min). Median levels of 25(OH)D and cathelicidin were 30 ng/ml and 698 ng/ml, respectively. A positive correlation between 25(OH)D and cathelicidin was evident at 25(OH)D levels ≤32 ng/ml (r=0.45, P=0.005) but not at higher levels (r=0.12, P=0.58). This relationship was verified using a piecewise polynomial (linear spline) regression with an infection point of 32 ng/ml. The linear relationship was significant at levels ≤32 ng/ml (β=27.8, P=0.003) and remained significant after adjustment for age, sex, race, serum calcium, use of supplements containing vitamin D, and season (p 32 ng/ml (P=0.16). The results are summarized in table E1 in the Online Repository. Table 1 Baseline characteristics of subjects screened (n=60). Continuous variables are reported as median (interquartile range). Based on the presence of a 25(OH)D level ≤ 32 ng/ml, 25 subjects had repeat testing for cathelicidin and 25(OH)D following ergocalciferol treatment. The mean increase in 25(OH)D following treatment was 25 ng/ml. The change in cathelicidin associated with treatment was analyzed by change in 25(OH)D (categorized by tertile; Figure 1). Only in the third tertile (change in 25(OH)D 32–64 ng/ml) was the change in cathelicidin significantly greater than 0 (P=0.04). After adjustment for age, sex, and change in calcium, only change in vitamin D was significantly associated with change in cathelicidin (P=0.03). Furthermore, the change in cathelicidin in tertile 3 was significantly different from that of tertile 1 (P=0.04). When grouped by tertile, subjects with the greatest increase in 25(OH)D had the lowest baseline 25(OH)D levels (p for trend, p=0.048), consistent with prior findings. However, no such relationship was observed with cathelicidin levels (p=0.82), suggesting that changes in cathelicidin levels were driven by the ergocalciferol treatment itself. Figure 1 Change in cathelicidin by change in 25-hydroxyvitamin D following ergocalciferol treatment (n=25). Diamonds represent group means, while black bars represent standard error. *The difference between tertile 1 and 3 was significant (P=0.04), adjusted for ... In recent years, there has been increasing interest in the “non-traditional” effects of vitamin D, actions that are outside the traditional axis of mineral metabolism. With vitamin D receptors identified in many immunologically active cells, data have emerged suggesting an immunologic role for vitamin D. To date, much of this research has been limited to animal studies, in vitro, or ex vivo analysis. Our study of healthy adults demonstrates, for the first time, that 25(OH)D levels correlate with both baseline cathelicidin levels and changes in cathelicidin levels following high-dose ergocalciferol treatment. A recent study by Adams and colleagues did not show a correlation between circulating levels of 25(OH)D and cathelicidin, but this analysis was limited to 50 elderly patients with established bone disease, a group that was considerably older than the current study population.9 It is likely that additional factors confound the relationship between vitamin D and cathelicidin in older individuals. Nevertheless, these authors were able to identify vitamin D-based changes in cathelicidin mRNA production after monocyte stimulation.9 Of note, we found a relationship between baseline cathelicidin and 25(OH)D only at levels ≤32 ng/ml, a relationship analogous to that of 25(OH)D and parathyroid hormone.8 Given the previously observed associations of circulating cathelicidin levels and infection-associated mortality in human studies and animal models of sepsis,3, 4 our findings support the possibility that supplementation with vitamin D may be clinically useful in patients at high risk of infection. However, a treatment-associated increase in cathelicidin was not universal and was statistically significant only in subjects with the greatest increase in 25(OH)D. Given the limited nature of the relationship between cathelicidin and 25(OH)D and the potential for unmeasured confounding variables, randomized controlled trials studying the effect of vitamin D supplementation on clinically relevant infection outcomes (such as infection rates, severity of disease indices, and infection-related mortality) are necessary to definitively establish an immunologic role for vitamin D supplementation.

69 citations

08 Nov 2011
TL;DR: In this article, the relationship between cathelicidin, vitamin D status, and vitamin D supplementation was investigated using multivariate linear spline regression (with an inflection point at 32 ng/ml) and multiple linear regression was used to confirm this approach.
Abstract: To the Editor: Cathelicidins are a class of widely conserved antimicrobial peptides (AMPs) produced by essentially all mammalian species as part of the innate immune system. They have broad activity against both Gram-positive and Gram-negative bacteria and have additional effects including neutralizing lipopolysaccharide, stimulating leukocyte chemotaxis, promoting angiogenesis. There is only one known cathelicidin in humans. Although it is found in the secondary granules of neutrophils and other leukocyte populations, and a range of squamous epithelia including the skin, airways, mouth and intestine, it also circulates at high levels in the plasma.1, 2 Impairment in cathelicidin or other AMPs has been linked to increased susceptibility to and severity of infection while overexpression of cathelicidin confers protection against sepsis in animal models.3 Dialysis patients with the lowest circulating levels of cathelicidin are at a greater than two-fold risk of death due to infectious causes.4 The transcription of CAMP, the gene encoding cathelicidin in humans, is regulated by the vitamin D receptor. In vitro studies of human tissues, including epithelial cells, macrophages, and neutrophils, have demonstrated that cathelicidin levels can be increased following administration of 1,25-dihydroxyvitamin D.5 Topical and oral vitamin D analogues similarly lead to stimulation of cutaneous cathelicidin production.6 Prior studies of cathelicidin have given particular focus to its anti-tuberculosis properties, and humans given a single dose of oral vitamin D demonstrated improved mycobacterial immunity with an ex vivo assay.7 While circulating levels of cathelicidin have been most tightly linked to sepsis and mortality, little is known about the association of vitamin D status and plasma cathelicidin in healthy individuals, or of the ability of vitamin D supplementation to alter these levels. In order to clarify the relationship between plasma cathelicidin, vitamin D status, and vitamin D supplementation, we conducted a prospective study in our outpatient clinical research center. Plasma levels of cathelicidin and 25-hydroxyvitamin D (25[OH]D) were measured in 60 healthy volunteers, along with calcium and creatinine. All subjects were free of known infection or renal disease and were not taking immunosuppressive medications. Individuals with plasma 25(OH)D levels ≤32 ng/ml (based on the laboratory reference range and previous studies 8) were treated with ergocalciferol, 50,000 IU every other day for 5 days. Post-treatment levels of 25(OH)D, cathelicidin and calcium were then measured in these subjects a median of 10 days after completing treatment. Total plasma cathelicidin (including the protein hCAP18 and its c-terminal peptide, LL37) was measured by ELISA, as described elsewhere.2 Screening 25-hydroxyvitamin D was measured via liquid chromatography-tandem mass spectrometry (LCMS). The study was approved by the institutional review boards at Massachusetts General Hospital and the Massachusetts Institute of Technology and all subjects provided written informed consent. Estimated glomerular filtration rate (eGFR) was calculated using the widely-used Modification of Diet in Renal Disease formula. Spearman correlation was performed to assess the relationship between vitamin D and cathelicidin levels; as vitamin D associated relationships may emerge only below a threshold, levels ≤32 ng/ml and >32 ng/ml were analyzed separately. Multivariate linear spline regression (with an inflection point at 32 ng/ml) was used to confirm this approach and multiple linear regression was used to adjust for potential confounders. Stata 11.1 (StataCorp, College Station, TX) was used for all analysis. Subject characteristics are detailed in table 1. Subjects were predominantly female and white, and all subjects had normal renal function (eGFR > 60 ml/min). Median levels of 25(OH)D and cathelicidin were 30 ng/ml and 698 ng/ml, respectively. A positive correlation between 25(OH)D and cathelicidin was evident at 25(OH)D levels ≤32 ng/ml (r=0.45, P=0.005) but not at higher levels (r=0.12, P=0.58). This relationship was verified using a piecewise polynomial (linear spline) regression with an infection point of 32 ng/ml. The linear relationship was significant at levels ≤32 ng/ml (β=27.8, P=0.003) and remained significant after adjustment for age, sex, race, serum calcium, use of supplements containing vitamin D, and season (p 32 ng/ml (P=0.16). The results are summarized in table E1 in the Online Repository. Table 1 Baseline characteristics of subjects screened (n=60). Continuous variables are reported as median (interquartile range). Based on the presence of a 25(OH)D level ≤ 32 ng/ml, 25 subjects had repeat testing for cathelicidin and 25(OH)D following ergocalciferol treatment. The mean increase in 25(OH)D following treatment was 25 ng/ml. The change in cathelicidin associated with treatment was analyzed by change in 25(OH)D (categorized by tertile; Figure 1). Only in the third tertile (change in 25(OH)D 32–64 ng/ml) was the change in cathelicidin significantly greater than 0 (P=0.04). After adjustment for age, sex, and change in calcium, only change in vitamin D was significantly associated with change in cathelicidin (P=0.03). Furthermore, the change in cathelicidin in tertile 3 was significantly different from that of tertile 1 (P=0.04). When grouped by tertile, subjects with the greatest increase in 25(OH)D had the lowest baseline 25(OH)D levels (p for trend, p=0.048), consistent with prior findings. However, no such relationship was observed with cathelicidin levels (p=0.82), suggesting that changes in cathelicidin levels were driven by the ergocalciferol treatment itself. Figure 1 Change in cathelicidin by change in 25-hydroxyvitamin D following ergocalciferol treatment (n=25). Diamonds represent group means, while black bars represent standard error. *The difference between tertile 1 and 3 was significant (P=0.04), adjusted for ... In recent years, there has been increasing interest in the “non-traditional” effects of vitamin D, actions that are outside the traditional axis of mineral metabolism. With vitamin D receptors identified in many immunologically active cells, data have emerged suggesting an immunologic role for vitamin D. To date, much of this research has been limited to animal studies, in vitro, or ex vivo analysis. Our study of healthy adults demonstrates, for the first time, that 25(OH)D levels correlate with both baseline cathelicidin levels and changes in cathelicidin levels following high-dose ergocalciferol treatment. A recent study by Adams and colleagues did not show a correlation between circulating levels of 25(OH)D and cathelicidin, but this analysis was limited to 50 elderly patients with established bone disease, a group that was considerably older than the current study population.9 It is likely that additional factors confound the relationship between vitamin D and cathelicidin in older individuals. Nevertheless, these authors were able to identify vitamin D-based changes in cathelicidin mRNA production after monocyte stimulation.9 Of note, we found a relationship between baseline cathelicidin and 25(OH)D only at levels ≤32 ng/ml, a relationship analogous to that of 25(OH)D and parathyroid hormone.8 Given the previously observed associations of circulating cathelicidin levels and infection-associated mortality in human studies and animal models of sepsis,3, 4 our findings support the possibility that supplementation with vitamin D may be clinically useful in patients at high risk of infection. However, a treatment-associated increase in cathelicidin was not universal and was statistically significant only in subjects with the greatest increase in 25(OH)D. Given the limited nature of the relationship between cathelicidin and 25(OH)D and the potential for unmeasured confounding variables, randomized controlled trials studying the effect of vitamin D supplementation on clinically relevant infection outcomes (such as infection rates, severity of disease indices, and infection-related mortality) are necessary to definitively establish an immunologic role for vitamin D supplementation.

67 citations

Journal ArticleDOI
TL;DR: It is found that drugs that modulate the two dominant GABA receptor types in the brain, GABAA (clobazam) and GABAB (arbaclofen), increase perceptual suppression during rivalry relative to a placebo, the first causal link between GABAergic inhibition and binocular rivalry in humans.
Abstract: Binocular rivalry is a classic experimental tool to probe the neural machinery of perceptual awareness. During rivalry, perception alternates between the two eyes, and the ebb and flow of perception is modeled to rely on the strength of inhibitory interactions between competitive neuronal populations in visual cortex. As a result, rivalry has been suggested as a noninvasive perceptual marker of inhibitory signaling in visual cortex, and its putative disturbance in psychiatric conditions, including autism. Yet, direct evidence causally implicating inhibitory signaling in the dynamics of binocular rivalry is currently lacking. We previously found that people with higher GABA levels in visual cortex, measured using magnetic resonance spectroscopy, have stronger perceptual suppression during rivalry. Here, we present direct causal tests of the impact of GABAergic inhibition on rivalry dynamics, and the contribution of specific GABA receptors to these dynamics. In a crossover pharmacological design with male and female adult participants, we found that drugs that modulate the two dominant GABA receptor types in the brain, GABAA (clobazam) and GABAB (arbaclofen), increase perceptual suppression during rivalry relative to a placebo. Crucially, these results could not be explained by changes in reaction times or response criteria, as determined through rivalry simulation trials, suggesting a direct and specific influence of GABA on perceptual suppression. A full replication study of the GABAB modulator reinforces these findings. These results provide causal evidence for a link between the strength of inhibition in the brain and perceptual suppression during rivalry and have implications for psychiatric conditions including autism.SIGNIFICANCE STATEMENT How does the brain accomplish perceptual gating? Here we use a direct and causal pharmacological manipulation to present insight into the neural machinery of a classic illusion of perceptual awareness: binocular rivalry. We show that drugs that increase GABAergic inhibition in the brain, clobazam (GABAA modulator) and arbaclofen (GABAB modulator), increase perceptual suppression during rivalry relative to a placebo. These results present the first causal link between GABAergic inhibition and binocular rivalry in humans, complementing classic models of binocular rivalry, and have implications for our understanding of psychiatric conditions, such as autism, where binocular rivalry is posited as a behavioral marker of disruptions in inhibitory signaling in the brain.

40 citations


Cited by
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Journal ArticleDOI
21 Jul 1979-BMJ
TL;DR: It is suggested that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units, outpatients, and referrals to social services, but for house doctors to assess overdoses would provide no economy for the psychiatric or social services.
Abstract: admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

4,497 citations

Journal ArticleDOI
TL;DR: Findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment.
Abstract: Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics) We investigated whether metabolite profiles could predict the development of diabetes Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes Amino acids, amines and other polar metabolites were profiled in baseline specimens by liquid chromatography-tandem mass spectrometry (LC-MS) Cases and controls were matched for age, body mass index and fasting glucose Five branched-chain and aromatic amino acids had highly significant associations with future diabetes: isoleucine, leucine, valine, tyrosine and phenylalanine A combination of three amino acids predicted future diabetes (with a more than fivefold higher risk for individuals in top quartile) The results were replicated in an independent, prospective cohort These findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment

2,487 citations

Journal ArticleDOI
TL;DR: By performing global metabolite profiling, also known as untargeted metabolomics, new discoveries linking cellular pathways to biological mechanism are being revealed and are shaping the understanding of cell biology, physiology and medicine.
Abstract: Metabolites, the chemical entities that are transformed during metabolism, provide a functional readout of cellular biochemistry. With emerging technologies in mass spectrometry, thousands of metabolites can now be quantitatively measured from minimal amounts of biological material, which has thereby enabled systems-level analyses. By performing global metabolite profiling, also known as untargeted metabolomics, new discoveries linking cellular pathways to biological mechanism are being revealed and are shaping our understanding of cell biology, physiology and medicine.

1,900 citations

Journal ArticleDOI
TL;DR: This article conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent, and identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association.
Abstract: To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.

1,899 citations

Journal ArticleDOI
TL;DR: It is shown here that TGR5 signaling induces intestinal glucagon-like peptide-1 (GLP-1) release, leading to improved liver and pancreatic function and enhanced glucose tolerance in obese mice, and suggested that pharmacological targeting of T GR5 may constitute a promising incretin-based strategy for the treatment of diabesity and associated metabolic disorders.

1,412 citations