Genetic susceptibility to autoimmune thyroid diseases in a Chinese Han population: Role of vitamin D receptor gene polymorphisms

Purpose

Previous studies have found that some immune-related genes were associated with autoimmune thyroid diseases (AITDs). A couple of studies have explored the association between vitamin D (1,25-dihydroxyvitamin D3) receptor (VDR) gene polymorphisms and susceptibility to AITDs in different populations and found conflicting results. This case-control study was designed to evaluate the role of polymorphisms of VDR gene in the predisposition of AITDs in a Chinese Han population.

Methods

A total of 417 patients with Graves’ disease (GD), 250 patients with Hashimoto's thyroiditis (HT) and 301 healthy subjects were enrolled. The Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometer (MALDI-TOF-MS) Platform was applied to detect four SNPs (rs1544410, rs2228570, rs731236 and rs7975232) in the VDR gene.

Results

In the rs7975232 allele A frequency showed a significant increase in GD patients (30.34% vs. 25.42% in controls; P = 0.041, OR = 1.278, 95%CI = 1.010–1.617). However, no relationship was found between clinical phenotypes and the four SNPs.

Conclusions

This result suggests that the VDR gene may be one susceptibility gene which contributes to the risk of GD.     

Urinary endometriosis: MR Imaging appearance with surgical and histological correlations

ObjectivesThe goals of the study were to describe the MR imaging features of endometriosis of the urinary tract and identify those that suggest intrinsic involvement of ureteric wall.Materials and methodsThirty-five women with proven urinary tract endometriosis and who had preoperative MR imaging between 2001 and 2011 were included retrospectively. MR images were intrepreted by one junior and one senior radiologists. To characterize the intrinsic parietal involvement, the ureteric circumference involved by the lesion of endometriosis was noted.ResultsThirty-eight ureteric and 13 bladder lesions were analyzed. They were found in association in nine women. Ureteric lesions were bilateral in seven women. Of the 38 ureteric lesions, 27 were extrinsic and 11 intrinsic at histopathological analysis. Sixteen women with extrinsic lesions and 10 with intrinsic ones were correctly identified on MR imaging. When the ureter was included less than 360° in the lesion, extrinsic involvement was confirmed in 80% of cases.ConclusionMR imaging appears to be more sensitive (91%vs 82%) but less specific (59% vs 67%) than surgery for the diagnosis of intrinsic form of ureteric location.     

Central and peripheral serotonergic influences on viscerovisceral inhibitory reflex during duodenal distension in sheep

The effects of duodenal distension on forestomach and abomasal motility were investigated in conscious sheep chronically fitted with intraparietal electrodes, a duodenal cannula, and an intracerebroventricular cannula. Duodenal distensions with a balloon inflated with 40 ml (DD40) of water reduced the frequency of forestomach and abomasal contractions by 45 and 32%, respectively, while distension with 80 ml (DD80) induced a total inhibition. Methysergide, a mixed 5HT₁-5HT₂ antagonist administered intravenously (200 g/kg) or intracerebroventricularly (20 g/kg) suppressed the DD40-induced inhibition and reduced that induced by DD80. Sprioxatrine, a selective 5HT_1A antagonist, intravenously (100 g/kg) or intracerebroventricularly (10 g/kg), suppressed the DD40 and DD80-induced inhibition, which was also attenuated by the 5HT₂ antagonist ritanserin given intravenously (200 g/kg) or intracerebroventricularly (20 g/kg). Granisetron, a 5HT₃ antagonist, injected intravenously (150 g/kg), abolished the effects of DD40 and DD80 while it had no antagonistic action on DD40 and DD80 when given intracerebroventricularly (15 g/kg). It is concluded that in sheep, duodenal distension inhibits forestomach and abomasal motility through 5HT_1A and 5HT₂ receptors at the level of the central nervous system and 5HT₃ receptors located peripherally.This work was presented in part at the First United European Gastroenterology Week, September 25–30, 1992, Athens, Greece.     

The synthetic cathinone psychostimulant α‐PPP antagonizes serotonin 5‐HT2A receptors: In vitro and in vivo evidence

Synthetic cathinones (SCs) are β‐keto analogs of amphetamines. Like amphetamines, SCs target monoamine transporters; however, unusual neuropsychiatric symptoms have been associated with abuse of some SCs, suggesting SCs might possess additional pharmacological properties. We performed radioligand competition binding assays to assess the affinities of nine SCs at human 5‐HT_2A receptors (5‐HT_2AR) and muscarinic M₁ receptors (M₁R) transiently expressed in HEK293 cells. None of the SCs exhibited affinity at M₁R (minimal displacement of [~K_d] [³H]scopolamine up to 10 μM). However, two SCs, α‐pyrrolidinopropiophenone (α‐PPP) and 4‐methyl‐α‐PPP, had low μM K_i values at 5‐HT_2AR. In 5‐HT_2AR–phosphoinositide hydrolysis assays, α‐PPP and 4‐methyl‐α‐PPP displayed inverse agonist activity. We further assessed the 5‐HT_2AR functional activity of α‐PPP, and observed it competitively antagonized 5‐HT_2AR signaling stimulated by the 5‐HT₂R agonist (±)‐2,5‐dimethoxy‐4‐iodoamphetamine (DOI; K_b = 851 nM). To assess in vivo 5‐HT_2AR activity, we examined the effects of α‐PPP on the DOI‐elicited head‐twitch response (HTR) in mice. α‐PPP dose‐dependently blocked the HTR with maximal suppression at 10 mg/kg (P < 0.0001), which is a moderate dose used in studies investigating psychostimulant properties of α‐PPP. To corroborate a 5‐HT_2AR mechanism, we also tested 3,4‐methylenedioxy‐α‐PPP (MDPPP) and 3‐bromomethcathinone (3‐BMC), SCs that we observed had 5‐HT_2AR K_is > 10 μM. Neither MDPPP nor 3‐BMC, at 10 mg/kg doses, attenuated the DOI HTR. Our results suggest α‐PPP has antagonist interactions at 5‐HT_2AR in vitro that may translate at physiologically‐relevant doses in vivo. Considering 5‐HT_2AR antagonism has been shown to mitigate effects of psychostimulants, this property may contribute to α‐PPPs unpopularity compared to other monoamine transporter inhibitors.     

The 5‐HT4 receptor levels in hippocampus correlates inversely with memory test performance in humans

The cerebral serotonin (5‐HT) system is involved in cognitive functions such as memory and learning and animal studies have repeatedly shown that stimulation of the 5‐HT type 4 receptor (5‐HT₄R) facilitates memory and learning and further that the 5‐HT₄R modulates cellular memory processes in hippocampus. However, any associations between memory functions and the expression of the 5‐HT₄R in the human hippocampus have not been investigated. Using positron emission tomography with the tracer [¹¹C]SB207145 and Reys Auditory Verbal Learning Test we aimed to examine the individual variation of the 5‐HT4R binding in hippocampus in relation to memory acquisition and consolidation in healthy young volunteers. We found significant, negative associations between the immediate recall scores and left and right hippocampal BP_ND, (p = 0.009 and p = 0.010 respectively) and between the right hippocampal BP_ND and delayed recall (p = 0.014). These findings provide evidence that the 5‐HT₄R is associated with memory functions in the human hippocampus and potentially pharmacological stimulation of the receptor may improve episodic memory. Hum Brain Mapp 34:3066–3074, 2013. © 2012 Wiley Periodicals, Inc.     

Differentiation renders susceptibility to excitotoxicity in HT22 neurons

HT22 is an immortalized mouse hippocampal neuronal cell line that does not express cholinergic and glutamate receptors like mature hippocampal neurons in vivo.This in part prevents its use as a model for mature hippocampal neurons in memory-related studies.We now report that HT22 cells were appropriately induced to differentiate and possess properties similar to those of mature hippocampal neurons in vivo,such as becoming more glutamate-receptive and excitatory.Results showed that sensitivity of HT22 cells to glutamate-induced toxicity changed dramatically when comparing undifferentiated with differentiated cells,with the half-effective concentration for differentiated cells reducing approximately two orders of magnitude.Moreover,glutamate-induced toxicity in differentiated cells,but not undifferentiated cells,was inhibited by the N-methyl-Daspartate receptor antagonists MK-801 and memantine.Evidently,differentiated HT22 cells expressed N-methyl-D-aspartate receptors,while undifferentiated cells did not.Our experimental findings indicated that differentiation is important for immortalized cell lines to render post-mitotic neuronal properties,and that differentiated HT22 neurons represent a better model of hippocampal neurons than undifferentiated cells.     

Vitamin C modulates DNA damage induced by hydrogen peroxide in human colorectal adenocarcinoma cell lines (HT29) estimated by comet assay in vitro

Introduction

Cancer cells, compared to normal cells, are under increased oxidative stress associated with oncogenic transformation, alterations in metabolic activity, and increased generation of reactive oxygen species.

Material and methods

We investigated the ability of vitamin C to reduce the damage induced by hydrogen peroxide, in human colorectal adenocarcinoma cells in vitro by the comet assay. Additionally, we measured the kinetics and efficacy of the repair of DNA damage after incubation with vitamin C in the presence of H₂O₂.

Results

The obtained results showed that 1 h pre-incubation with vitamin C and exposure to H₂O₂ for the last 10 min of incubation caused a statistically significant (p < 0.05) increase in DNA migration in comet tails in all experimental series. For the 10 µM, 25 µM, 50 µM, 100 µM vitamin C concentrations the levels of DNA damage were as follows: 18.6%, 21.1%, 25.3% and 27.2%, respectively, as compared to the untreated cells (3.26%). However, in comparison with H₂O₂ alone (29.1%), we observed a statistically significant (p < 0.05) decrease of the genotoxic effect in HT29 cells induced by H₂O₂ for the two lowest of concentrations of vitamin C: 10 µM and 25 µM. The HT29 cells were able to achieve effective repair of the damaged DNA within 60 and 120 min after incubation with the tested compounds. All the values obtained in the test were statistically significant (p < 0.05).

Conclusions

Vitamin C caused a weaker DNA damaging effect of hydrogen peroxide and positively influences the level of oxidative DNA damage in HT29 cells (decrease ∼ 30%). We noted that DNA damage was effectively repaired during 120 min postincubation in the tested cells and that oxidative damage was the major type of damage.     

Neonatal lipopolysaccharide treatment has long‐term effects on monoaminergic and cannabinoid receptors in the rat

Brain inflammation in early life has been proposed to play important roles in the development of anxiety and psychosis‐related behaviors in adulthood, behaviors that rely on the integrity of dopamine and/or serotonin systems. Moreover recent behavioral and anatomical evidence suggests involvement of CB1 receptors in the control of emotion and mood. In this study, we determined the effects of neonatal LPS treatment on dopamine, serotonin, and cannabinoid receptor binding in adulthood. Rats were treated with the bacterial endotoxin lipopolysaccharide (LPS) on postnatal day (PND) 3 and 5. Dopamine D1, D2, serotonin 5HT1A, 5HT2A, and serotonin transporter and cannabinoid CB1 receptor binding across several brain regions were measured autoradiographically in adulthood (PND 85). Neonatal LPS treatment caused a significant increase in dopamine D2 in the nucleus accumbens and olfactory tubercle, a decrease in 5HT1A receptor binding in the hippocampus CA1 and ventromedial hypothalamus. A decrease in CB1 receptor binding after neonatal LPS was observed in the amygdala. Neonatal LPS had no significant impact on dopamine D1, serotonin 5HT2A or serotonin transporter binding in any of the brain regions examined. Our results suggest long lasting, region specific effects and differential impact on dopamine, serotonin and cannabinoid receptor systems following neonatal inflammation, that may form the basis for compromised anxiety and psychosis related behaviors. Synapse, 2013. © 2013 Wiley Periodicals, Inc.