Intrathecal Injection of Spironolactone Attenuates Radicular Pain by Inhibition of Spinal Microglia Activation in a Rat Model

Microglia might play an important role in nociceptive processing and hyperalgesia by neuroinflammatory process. Mineralocorticoid receptor (MR) expressed on microglia might play a central role in the modulation of microglia activity. However the roles of microglia and MR in radicular pain were not well understood. This study sought to investigate whether selective MR antagonist spironolactone develop antinociceptive effects on radicular pain by inhibition neuroinflammation induced by spinal microglia activation.Radicular pain was produced by chronic compression of the dorsal root ganglia with SURGIFLO™. The expression of microglia, interleukin beta (IL-1β), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), NR1 subunit of the NMDA receptor (t-NR1), and NR1 subunit phosphorylated at Ser896 (p-NR1) were also markedly up-regulated. Intrathecal injection of spironolactone significantly attenuated pain behaviors as well as the expression of microglia, IL-1β, TNF-α, t-NR1, and p-NR1, whereas the production of IL-6 wasn't affected.These results suggest that intrathecal delivery spironolactone has therapeutic effects on radicular pain in rats. Decreasing the activation of glial cells, the production of proinflammatory cytokines and down-regulating the expression and phosphorylation of NMDA receptors in the spinal dorsal horn and dorsal root ganglia are the main mechanisms contributing to its beneficial effects

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Intake of high fructose corn syrup sweetened soft drinks, fruit drinks and apple juice is associated with prevalent coronary heart disease, in U.S. adults, ages 45–59 y

BACKGROUND: Intake of high excess free fructose (EFF) beverages, including high fructose corn syrup (HFCS), sweetened soft drinks, fruit drinks, and apple juice, may be associated with childhood asthma, adult idiopathic chronic bronchitis/ COPD, and autoimmune arthritis, possibly due to underlying fructose malabsorption. Fructose malabsorption may contribute to the intestinal in situ formation of advanced glycation end-products (enFruAGEs) that travel to other tissues and promote inflammation. Chronic respiratory conditions and arthritis are comorbidities of coronary heart disease (CHD). The objective of this study was to investigate the association between intake of high EFF beverages and CHD. METHODS: In this cross sectional study (NHANES 2003–2006) of adults, aged 45–59 y, n = 1230, the exposure variables were non-diet soft drinks, and any combination of high EFF beverages including non-diet soft drinks, fruit drinks, and apple juice. Analyses of diet soft drinks, diet fruit drinks, and orange juice (non/low EFF beverages) were included for comparison. The outcome was self-reported history of coronary heart disease and/or angina (CHD). Rao Scott Ҳ2 was used for prevalence differences and logistic regression for associations, adjusted for age, sex, race-ethnicity, BMI, socio-economic status, health insurance coverage, smoking, physical activity level, hypertension, energy intake, fruit and vegetable intake, glycated hemoglobin, pre-diabetes, and diabetes. RESULTS: Intake of any combination of HFCS sweetened soft drinks, fruit drinks, and apple juice (tEFF) was significantly associated with CHD in adults aged 45–59 y. Adults consuming tEFF ≥5 times/wk. were 2.8 times more likely to report CHD than ≤3 times/mo consumers (OR 2.82; 95% CI 1.16–6.84; P = 0.023), independent of all covariates. CONCLUSION: HFCS sweetened soft drinks, fruit drinks, and apple juice may contribute to CHD, a common comorbidity of chronic respiratory conditions and autoimmune arthritis, possibly due to the high ratio of fructose to glucose in these beverages. Underlying fructose malabsorption may contribute to the intestinal in situ formation of pro-inflammatory enFruAGEs, that are eventually absorbed and induce inflammation of the coronary arteries. Additional research is needed