Hypoglycemic Events in the Emergency Department.

BACKGROUND: In the United States, hypoglycemic events contribute to 100 000 emergency department (ED) visits, costing $120 million annually. Hypoglycemia hinders glycemic management in people living with diabetes. Glucagon is the first line of treatment for severe hypoglycemia that is administrable by a caregiver in a nonclinical setting. However, there is a paucity of evidence on how frequently glucagon is prescribed for the anticipatory management of hypoglycemia, especially in ED. METHODS: A retrospective study of patients seen with hypoglycemic events in an urban ED between 2016 and 2018 was performed to characterize gaps in prescription and use of glucagon for the anticipatory management of severe hypoglycemia. RESULTS: We identified 232 patients with a documented history of type 1 diabetes mellitus or type 2 diabetes mellitus who were seen in the ED with hypoglycemia. The majority of the patients were women (59%), African American (57%), and covered by public insurance (76%). Eighty-four percent of the patients had type 2 diabetes mellitus, 75% were receiving treatment with hypoglycemic medications, and 61% were receiving treatment with insulin. The prevalence of glucagon prescription was only 3% in this sample, and only 12% of the patients had received formal diabetes education in the year before the ED visit. CONCLUSION: Despite its proven efficacy in the management of severe hypoglycemia, glucagon is underused. This may be due to the lack of awareness, education, or training among both providers and patients. ED providers should be educated on prescribing glucagon and its use as a tool for the self-management of hypoglycemia. Patients at risk of hypoglycemia and their families need to be educated on the efficacy and use of glucagon.

Oxytocin alterations and neurocognitive domains in patients with hypopituitarism.

PURPOSE: Oxytocin is a hypothalamus derived, posterior pituitary stored nonapeptide which has gained recent interest as an important neuropsychiatric and metabolic hormone beyond its classic role in lactation and parturition. Hypopituitarism is a heterogenous disorder of derangement in one or more anterior or posterior pituitary hormones. Diagnosis of deficiency and hormone replacement exists to address all relevant axes except for oxytocin. Our study aims to define derangements in oxytocin in a unique population of patients with hypopituitarism and correlate levels with measures of emotional health and quality of life. METHODS: A cross-sectional, single day study was completed to measure plasma oxytocin levels in a diverse population of patients with hypopituitarism compared to controls. Subjects also completed depression, quality of life and stress-related questionnaires, and emotion recognition tasks. RESULTS: Thirty-eight subjects completed the study, 18 with hypopituitarism (9 with diabetes insipidus) and 20 controls. After controlling for differences in age, weight and gender, plasma oxytocin levels were highest in subjects with diabetes insipidus compared to control [mean, IQR: 44.3 pg/ml (29.8-78.2) vs. 20.6 (17-31.3), p = 0.032]. Amongst hypopituitary subjects, those with duration of disease greater than 1 year had higher oxytocin levels. No significant differences were observed for psychosocial measures including emotion recognition tasks. CONCLUSIONS: Plasma oxytocin levels were found higher in patients with hypopituitarism compared to controls and highest in those with diabetes insipidus. Longer duration of hypopituitarism was also associated with higher plasma levels of oxytocin. Further study is needed to better define oxytocin deficiency and investigate response to treatment.

CLINICAL PRACTICE PATTERNS FOR POSTOPERATIVE WATER BALANCE AFTER PITUITARY SURGERY.

Objective: Abnormalities of water and sodium balance, including diabetes insipidus and the syndrome of inappropriate antidiuretic hormone (SIADH), are common complications of transsphenoidal surgery. Postoperative practice patterns vary among clinicians, and no consensus guidelines exist to direct their monitoring and management. We aimed to identify and compare practice patterns regarding the evaluation and management to these postoperative complications. Methods: A questionnaire was utilized to capture demographic data and practice habits in the postoperative setting. Respondents were members of the Pituitary Society, an international organization comprised of clinicians and researchers dedicated to the study of pituitary disease. Results: Eighty-six respondents completed at least part of the survey. The geographic distribution of respondents was roughly even between American and non-American practitioners. The majority of respondents practiced at academic institutions (67.4%), worked in multidisciplinary teams (88.4%), and possessed significantly greater than 10 years of clinical experience (71%). Compared to non-American practitioners, American practitioners described a shorter length of stay postoperatively (P<.001) and prescribed more restrictive volume recommendations for postoperative SIADH (P = .0035). Early career clinicians (less than 10 years in practice) checked first postoperative sodium level earlier than later career clinicians (P = .010). Conclusion: Water and sodium dysregulation are common following transsphenoidal surgery, but their management is not well-standardized in clinical practice. We created a questionnaire to define and compare practice patterns. Most respondents practice in academic settings in multidisciplinary teams. The length of clinical experience did not significantly impact practice habits. Practice location influenced length of stay postoperatively and fluid restriction in SIADH. Abbreviations: AVP = arginine vasopressin; DI = diabetes insipidus; LOS = length of stay; SIADH = syndrome of inappropriate antidiuretic hormone.

ENDOCRINE MANIFESTATIONS OF PRIMARY HYPEROXALURIA.

OBJECTIVE: Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder of oxalate overproduction. It is associated with urolithiasis and nephrocalcinosis, which progress to end-stage renal disease and systemic oxalosis. As oxalate deposits in tissues, non-parathyroid hormone (nonPTH)-mediated hypercalcemia, oxalate osteopathy, primary hypothyroidism, and primary hypogonadism develop. In this review, we will present a case of PH1 and provide an overview of this clinical entity and its endocrine manifestations. METHODS: We conducted a PubMed search for articles related to PH1. The terms "primary hyperoxaluria," "nonPTH mediated hypercalcemia," "hypothyroidism," and "hypogonadism" were used to identify pertinent literature. RESULTS: Given the rarity of PH1, there is scant literature regarding the incidence and clinical significance of endocrine manifestations of this disorder. There are rare reports of hypercalcemia secondary to osteoclast-stimulating activity of macrophages in bone granulomas, which occur in response to oxalate deposits. We report that hypercalcemia may also be mediated by 1,25-dihydroxyvitamin D and PTH-related protein (PTHrP). Primary hypothyroidism and primary hypogonadism are thought to be due partly to calcium oxalate deposition in thyroid and testicular tissue. The presented case is the first to report PTHrP-mediated hypercalcemia and primary hypogonadism in a patient with PH1. CONCLUSION: PH1 is a metabolic disease with significant morbidity and mortality. Owing to its rarity, it is not widely recognized in the field of endocrinology, despite presenting with several endocrinopathies. Recognition of endocrine disturbances can result in early and successful treatment, limiting morbidity and improving quality of life in these challenging patients. ABBREVIATIONS: 1,25(OH)2D= 1,25-dihydoxyvitamin D AGT = alanine:glyoxylate aminotransferase ESRD = end-stage renal disease GRHPR = glyoxylate reductase-hydroxypyruvate reductase nonPTH = non-parathyroid hormone PH = primary hyperoxaluria pQCT = peripheral quantitative computed tomography PTH = parathyroid hormone PTHrP = parathyroid hormone-related protein T4 = thyroxine TSH = thyroid-stimulating hormone.

ADIPSIC DIABETES INSIPIDUS: A REVIEW.

OBJECTIVE: Adipsic diabetes insipidus (ADI) is a rare disorder consisting of central diabetes insipidus (CDI) and a deficient or absent thirst response to hyperosmolality. Patients with ADI experience marked morbidity and mortality. Diagnosis and management of these patients is quite challenging, even in expert hands. In this review, we aim to provide an updated overview of this difficult clinical scenario. METHODS: We conducted a PubMed search for articles related to ADI. The search terms "adipsia," "adipsic," "thirst," and "diabetes insipidus" were used to identify relevant literature. RESULTS: ADI has been described in only approximately 100 patients. This rarity has limited the quality and quantity of literature to case reports, case series, and expert opinion. Diagnosis focuses on confirmation of CDI followed by documenting subnormal or completely absent thirst in response to a hypertonic stimulus. Among the described patients with ADI, the majority experience morbidity (e.g., severe hypernatremia, sleep apnea, venous thromboembolism [VTE], and obesity) and an increased mortality risk. Management focuses on frequent reassessment of daily prescribed water intake with fixed antidiuretic therapy (desmopressin) and comorbidity screening. CONCLUSION: The complexity of patients with ADI provides a difficult challenge for clinicians. Prompt recognition of thirst disorders in patients with CDI should lead to appropriately regimented management strategies and can result in safe outpatient care for these unique patients.

EFFECT OF HIGH-DOSE VITAMIN D REPLETION ON GLYCEMIC CONTROL IN AFRICAN-AMERICAN MALES WITH PREDIABETES AND HYPOVITAMINOSIS D.

OBJECTIVE: This double-blind, randomized, controlled trial evaluated whether 12 months of high-dose vitamin D2 supplementation improved insulin sensitivity and secretion and glycemic status. METHODS: African-American males (AAM) with prediabetes (glycosylated hemoglobin [A1C] 5.7-6.4%), hypovitaminosis D (25-hydroxyvitamin D [25OHD] 5-29 ng/mL), and prevalent medical problems were supplemented with vitamin D3 (400 IU/day) and then randomized to weekly placebo or vitamin D2 (50,000 IU). The primary outcome was the change in oral glucose insulin sensitivity (OGIS, from an oral glucose tolerance test [OGTT]) after 12 months of treatment. Secondary outcomes included other glycemic indices, A1C, and incident diabetes. RESULTS: Baseline characteristics were similar in vitamin D-supplemented (n = 87) and placebo (n = 86) subjects completing the trial with average concentrations 14.4 ng/mL, 362 mL × min(-1) × m(-2), and 6.1% for 25OHD, OGIS and A1C, respectively. After 12 months, the vitamin D-supplemented group had a change in serum 25OHD +35 versus +6 ng/mL for placebo, P<.001; OGIS +7.8 versus -16.0 mL × min(-1) × m(-2) for placebo, P = .026; and A1C -0.01 versus +0.01% for placebo, P = .66. Ten percent of subjects in both groups progressed to diabetes. A posthoc analysis of participants with baseline impaired fasting glucose (IFG) showed that more subjects in the vitamin D subgroup (31.6%) than placebo (8.3%) returned to normal glucose tolerance, but the difference did not reach significance (P = .13). CONCLUSION: The trial does not provide evidence that 12 months of high-dose D2 repletion improves clinically relevant glycemic outcomes in subjects with prediabetes and hypovitaminosis D (NCT01375660).

Pheochromocytoma: Secondary Hypertension in Pregnancy.

Secondary hypertension can occur from a variety of renal and endocrine disorders. Pheochromocytoma, a rare catecholamine-secreting neuroendocrine tumor, is associated with adverse maternal and fetal outcomes in the absence of a timely diagnosis and a coordinated multidisciplinary approach. Clues to diagnosis include resistant hypertension or an adrenal mass on imaging.

Primary Adrenal Insufficiency After COVID-19 Infection.

BACKGROUND/OBJECTIVE: The multisystemic effects of COVID-19 are becoming evident. In the adrenal gland, adrenal hemorrhage and infarction after COVID-19 infection have been reported. Our objective is to present a case of autoimmune adrenal insufficiency diagnosed after COVID-19 infection, without the evidence of a hemorrhage or an infarction. CASE REPORT: A 64-year-old woman with hypothyroidism and type 2 diabetes presented with a 1-week history of abdominal pain, nausea, and vomiting. She had experienced asymptomatic COVID-19 infection 5 months prior and reported an unintentional 30-lb weight loss. The home medications included enalapril, atorvastatin, and levothyroxine. A physical examination was notable for hypotension, epigastric tenderness, and mucocutaneous hyperpigmentation. Laboratory tests revealed a serum sodium level of 117 mmol/L (range, <20 mmol/L), thyroid-stimulating hormone level of 0.33 µIU/mL (range, 0.35-4.00 µIU/mL), free thyroxine level of 1.4 ng/dL (range, 0.6-1.7 ng/dL), serum osmoles of 253 mOsm/kg (range, 279-300 mOsm/kg), urine osmoles of 324 mOsm/kg (range, 300-900 mOsm/kg), and urine sodium level of 104 mmol/L. The morning cortisol level was 2.6 µg/dL (reference [ref], >18 µg/dL). This was followed by a high-dose, 250-µg adrenocorticotropic hormone (ACTH) stimulation test, which revealed that the cortisol level was 2.3, 2.9, and 2.6 µg/dL (ref, >18 µg/dL) at baseline, 30 minutes, and 60 minutes, respectively. The ACTH level was 1944 pg/mL (range, 7.2-63.3 pg/mL), the aldosterone level was <3.0 ng/dL (range, 4.0-31.0 ng/dL), and anti-21-hydroxylase antibody was present (ref, negative). A computed tomography scan of the adrenals was unremarkable. Hypotension and hyponatremia resolved after initiation of intravenous hydrocortisone, and she was discharged on hydrocortisone and fludrocortisone. DISCUSSION: The patient's symptoms, elevated ACTH level, low cortisol level, and presence of 21-hydroxylase antibodies were consistent with Addison disease. COVID-19 might have contributed to rapid, clinically relevant disease progression after the infection. CONCLUSION: The development of autoimmune Addison disease in the patient might be related to the prior COVID-19 infection.

Adipsic diabetes insipidus.

Adipsic diabetes insipidus (ADI) is a rare but devastating disorder of water balance with significant associated morbidity and mortality. Most patients develop the disease as a result of hypothalamic destruction from a variety of underlying etiologies. Damage to osmolar-responsive neuroreceptors, primarily within the supraoptic and paraventricular nuclei, results in impaired production and release of arginine vasopressin (AVP). Important regulating circuits of thirst sense and drive are regionally colocalized with AVP centers and therefore are also injured. Patients with central diabetes insipidus with impaired thirst response, defined as ADI, suffer from wide swings of plasma osmolality resulting in repeated hospitalization, numerous associated comorbidities, and significant mortality. Treatment recommendations are based largely on expert advice from case series owing to the rarity of disease prevalence. Acute disease management focuses on fixed dosing of antidiuretic hormone analogues and calculated prescriptions of obligate daily water intake. Long-term care requires patient/family education, frequent reassessment of clinical and biochemical parameters, as well as screening and treatment of comorbidities.

Predictors of HbA1c among Adipocytokine Biomarkers in African-American Men with Varied Glucose Tolerance.

This study explored adipocytokine associations with acute and chronic hyperglycemia in African-American men (AAM). Fourteen adipocytokines were measured from men with normal glucose tolerance (NGT) or type 2 diabetes (T2D, drug-naïve MF(-) or using metformin MF(+)). Acute and chronic hyperglycemia were evaluated by 120 min oral glucose tolerance test (OGTT) and glycohemoglobin A1c (HbA1c). AAM with T2D (n = 21) compared to NGT (n = 20) were older, had higher BMI and slightly higher glucose and insulin. In the fasted state, TNF-α, IL-6, PAI-1, IL-13, adiponectin, adipsin, and lipocalin were lower in T2D vs. NGT. At 120 min post-glucose load, TNF-α, IL-6, IL-13, IL-8, PAI-1, adiponectin, adipsin, lipocalin, and resistin were lower in T2D vs. NGT. There were no statistical differences for GM-CSF, IL-7, IL-10, IP-10, and MCP-1. Regression analysis showed that fasting IL-8, TNF-α, adiponectin, lipocalin, resistin, adipsin, and PAI-1 were associated with HbA1c. After adjusting for age, BMI, glucose tolerance, and metformin use, only adipsin remained significantly associated with HbA1c (p = 0.021). The model including adipsin, TNF-α, age, BMI, and group designation (i.e., NGT, MF(-), MF(+)) explained 86% of HbA1c variability. The data suggested that adipsin could be associated with HbA1c in AAM with varied glucose tolerance.

Unusual Case of Malignant Struma Ovarii and Cervical Thyroid Cancer Preceded by Ovarian Teratoma: Case Report and Review of the Literature.

OBJECTIVE: To present a rare case of malignant struma ovarii (MSO) and synchronous thyroid cancer, review the medical literature, and present the latest trends in management. METHODS: The case of a woman with MSO and concomitant thyroid cancer is presented, including clinical presentation, treatment, and follow-up care. A search of the English-language literature was conducted using MEDLINE and Google Scholar data bases. RESULTS: We found 10 publications (one abstract) describing 10 patients with MSO and concomitant thyroid cancer. Six additional patients were reported by a study that analyzed the SEER (cancer registry) database. The median age of women was 42 years, with the majority of them presenting with abdominal symptoms. Histologically, most tumors were papillary carcinomas in both organs. In 5 patients, there was extrathyroidal tumor extension at time of surgery. CONCLUSION: MSO can occasionally coexist with highly aggressive eutopic thyroid cancer. Although this concurrence is even rarer than MSO, clinicians should routinely investigate for possible synchronous thyroid cancer in all cases of MSO and also consider aggressive postoperative treatment including thyroidectomy and radioiodine ablation therapy in cases of MSO.

Predictors of Obesity among Gut Microbiota Biomarkers in African American Men with and without Diabetes.

Gut microbiota and their biomarkers may be associated with obesity. This study evaluated associations of body mass index (BMI) with circulating microbiota biomarkers in African American men (AAM) (n = 75). The main outcomes included fecal microbial community structure (16S rRNA), gut permeability biomarkers (ELISA), and short-chain fatty acids (SCFAs, metabolome analysis). These outcomes were compared between obese and non-obese men, after adjusting for age. The results showed that lipopolysaccharide-binding protein (LBP), the ratio of LBP to CD14 (LBP/CD14), and SCFAs (propionic, butyric, isovaleric) were higher in obese (n = 41, age 58 years, BMI 36 kg/m2) versus non-obese (n = 34, age 55 years, BMI 26 kg/m2) men. BMI correlated positively with LBP, LBP/CD14 (p < 0.05 for both) and SCFAs (propionic, butyric, isovaleric, p < 0.01 for all). In the regression analysis, LBP, LBP/CD14, propionic and butyric acids were independent determinants of BMI. The study showed for the first time that selected microbiota biomarkers (LBP, LBP/CD14, propionic and butyric acids) together with several other relevant risks explained 39%-47% of BMI variability, emphasizing that factors other than microbiota-related biomarkers could be important. Further research is needed to provide clinical and mechanistic insight into microbiota biomarkers and their utility for diagnostic and therapeutic purposes.

Prevalence of Undiagnosed Diabetes Identified by a Novel Electronic Medical Record Diabetes Screening Program in an Urban Emergency Department in the US.

This cross-sectional study describes a screening program that was developed to screen for type 2 diabetes in an urban emergency department setting in the US.

Oxytocin is lower in African American men with diabetes and associates with psycho-social and metabolic health factors.

OBJECTIVE: Recently, it has been suggested that oxytocin (OT) has a role in metabolism and neuropsychiatry health and disease, and therefore, it may represent a potential therapeutic target. The current study aimed to investigate relationships between OT and glycemic status along with psycho-social and behavioral factors. DESIGN AND METHODS: A total of 92 obese or overweight, African American, male subjects were enrolled in the study. Biometric and biochemical data were collected including oral glucose tolerance testing and urinary OT (measured by ELISA). Subjects also completed questionnaires on social and lifestyle factors. RESULTS: OT levels were found to be significantly lower in subjects with type 2 diabetes mellitus (T2DM) compared to normal glucose tolerance (p<0.05). When stratified by OT tertiles, subjects with higher OT had lower weight, body mass index (BMI) and hemoglobin A1c, but higher eGFR which remained significant after BMI adjustment. The highest OT tertile also had more smokers and more users of psychiatric medications. A stepwise ordered logistic regression supported these findings and could account for 21% of the variation in OT categories (pseudoR2 = 0.21). CONCLUSIONS: In this unique population, OT was found lower in subjects with diabetes but higher with better renal function, cigarette smoking and use of psychiatric medications. Future studies are needed to confirm these findings and examine the potential therapeutic role of OT.

Gut microbiota varies by opioid use, circulating leptin and oxytocin in African American men with diabetes and high burden of chronic disease.

OBJECTIVE: The gut microbiota is known to be related to type 2 diabetes (T2D), psychiatric conditions, and opioid use. In this study, we tested the hypothesis that variability in gut microbiota in T2D is associated with psycho-metabolic health. METHODS: A cross-sectional study was conducted among African American men (AAM) (n = 99) that were outpatients at a Chicago VA Medical Center. The main outcome measures included fecal microbiota ecology (by 16S rRNA gene sequencing), psychiatric disorders including opioid use, and circulating leptin and oxytocin as representative hormone biomarkers for obesity and psychological pro-social behavior. RESULTS: The study subjects had prevalent overweight/obesity (78%), T2D (50%) and co-morbid psychiatric (65%) and opioid use (45%) disorders. In the analysis of microbiota, the data showed interactions of opioids, T2D and metformin with Bifidobacterium and Prevotella genera. The differential analysis of Bifidobacterium stratified by opioids, T2D and metformin, showed significant interactions among these factors indicating that the effect of one factor was changed by the other (FDR-adjusted p [q] < 0.01). In addition, the pair-wise comparison showed that participants with T2D not taking metformin had a significant 6.74 log2 fold increase in Bifidobacterium in opioid users as compared to non-users (q = 2.2 x 10-8). Since metformin was not included in this pair-wise comparison, the significant 'q' suggested association of opioid use with Bifidobacterium abundance. The differences in Bifidobacterium abundance could possibly be explained by opioids acting as organic cation transporter 1 (OCT1) inhibitors. Analysis stratified by lower and higher leptin and oxytocin (divided by the 50th percentile) in the subgroup without T2D showed lower Dialister in High-Leptin vs. Low-Leptin (p = 0.03). Contrary, the opposite was shown for oxytocin, higher Dialister in High-Oxytocin vs. Low-Oxytocin (p = 0.04). CONCLUSIONS: The study demonstrated for the first time that Bifidobacterium and Prevotella abundance was affected by interactions of T2D, metformin and opioid use. Also, in subjects without T2D Dialister abundance varied according to circulating leptin and oxytocin.

Similarities and differences between patients included and excluded from a randomized clinical trial of vitamin D supplementation for improving glucose tolerance in prediabetes: interpreting broader applicability.

BACKGROUND: Randomized Clinical Trial (RCT) designs range from highly selective resulting in lack of external validity to more inclusive, requiring large sample sizes to observe significant results. Few publications, however, have compared excluded to enrolled participants. We aimed to assess our trial's design based on the effectiveness versus efficacy continuum using the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS) tool and to compare included and excluded patients. METHODS: Fifteen members of endocrinology section completed PRECIS for DIVA (D-Vitamin Intervention in VA) trial; an RCT evaluating vitamin D supplementation in improving dysglycemia in patients with prediabetes. Retrospective chart review compared subjects excluded (OUT) to those included (IN) in RCT. Student's t and Chi-square tests were used to compare continuous and categorical variables. Additionally, multiple logistic regression was completed. RESULTS: PRECIS scores were nearly universally pragmatic. 178 patients enrolled in DIVA trial were compared with 178 randomly selected patients excluded from study involvement. There was no significant difference between IN and OUT for the majority of the continuous and all of the categorical variables. Multivariate logistic regression identified only the A1c, HDL and Charlson Index as significant predictors of a participant's inclusion or exclusion. There was higher HDL (51.3(13.9) versus 44.6(10.1), P = 0.001) and Charlson Index (2.85(1.6) versus 2.2(1.17), P = 0.001) for OUT versus IN groups. Subanalysis of excluded patients in A1c range 5.7 to 6.9, had lower BMI (30.7(3.4) versus 32(2.7), P = 0.002) but higher HDL (mg/l: 49.7(11.8) versus 44.6(10.1), P = 0.001) and Charlson index (2.85(1.6) versus 2.2(1.17), P = 0.001) than included participants. Additionally, there was a trend towards higher rates of cancer (22.9% versus 12.9%, P = 0.033) but less psychiatric problems (56.2% versus 72.5%, P = 0.026) and thiazide diuretic use (18.1% versus 29.8%, P = 0.034). CONCLUSION: DIVA trial design appears to favor broad clinical applicability. The majority of objectively compared variables did not different between patients included and excluded from this RCT. Advice based on the evidence from this RCT may be applicable to a larger group of patients than those fitting inclusion/exclusion criteria alone. TRIAL REGISTRATION: ClinicalTrials.gov NCT01375660 (registered 15 June 2011).

Astroglia-mediated effects of uric acid to protect spinal cord neurons from glutamate toxicity.

Uric acid (UA) has been demonstrated to reduce damage to neurons elicited by oxidative stress. However, our studies utilizing cultures derived from embryonic rat spinal cord indicate that an astroglia-mediated mechanism is involved in the effects of UA to protect neurons from glutamate toxicity. The damage elicted by glutamate to neurons in a mixed culture of spinal cord cells can be reversed by UA. Furthermore, addition of UA after the termination of glutamate exposure suggests that UA plays an active role in mediating neuroprotection rather than purely binding peroxynitrite, as previously thought. Importantly, in pure neuron cultures from the same tissue, UA does not protect against glutamate toxicity. Addition of astroglia to the pure neuron cultures restores the ability of UA to protect the neurons from glutamate-induced toxicity. Our results also suggest that glia provide EAAT-1 and EAAT-2 glutamate transporters to protect neurons from glutamate, that functional EAATs may be necessary to mediate the effects of UA, and that treatment with UA results in upregulation of EAAT-1 protein. Taken together, our data strongly suggest that astroglia in mixed cultures are essential for mediating the effects of UA, revealing a novel mechanism by which UA, a naturally produced substance in the body, may act to protect neurons from damage during insults such as spinal cord injury.