The N-methyl-D-aspartate (NMDA)-subtype of glutamate receptors has been well described as a result of the early appearance of NMDA antagonists, but no potent antagonist for the "non-NMDA" glutamate receptors has been available. Quinoxalinediones have now been found to be potent and competitive antagonists at non-NMDA glutamate receptors. These compounds will be useful in the determination of the structure-activity relations of quisqualate and kainate receptors and the role of such receptors in synaptic transmission in the mammalian brain.

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A comparison of the pharmacological and physiological properties of the metabotropic glutamate 1 alpha and 1 beta receptors (mGluR1 alpha and mGluR1 beta) expressed in baby hamster kidney (BHK 570) cells was performed. The mGluR1 beta receptor is an alternatively spliced form of mGluR1 alpha with a modified carboxy terminus. Immunoblots of membranes from the two cell lines probed with receptor-specific antipeptide antibodies showed that mGluR1 alpha migrated with an M(r) = 154,000, whereas mGluR1 beta migrated with an M(r) = 96,000. Immunofluorescence imaging of receptors expressed in BHK 570 cells revealed that the mGluR1 alpha receptor was localized to patches along the plasmalemma and on intracellular membranes surrounding the nucleus, whereas mGluR1 beta was distributed diffusely throughout the cell. Agonist activation of the mGluR1 alpha and the mGluR1 beta receptors stimulated phosphoinositide hydrolysis. At both receptors, glutamate, quisqualate, and ibotenate were full agonists, whereas trans-(+)-1-aminocyclopentane-1,3-dicarboxylate appeared to act as a partial agonist. The stimulation of phosphoinositide hydrolysis by mGluR1 alpha showed pertussis toxin-sensitive and insensitive components, whereas the mGluR1 beta response displayed only the toxin-insensitive component. The mGluR1 alpha and mGluR1 beta receptors also increased intracellular calcium levels by inducing release from intracellular stores. These results indicate that the different carboxy terminal sequences of the two receptors directly influences G protein coupling and subcellular deposition of the receptor polypeptides and suggest that the two receptors may subserve different roles in the nervous system.

MethodsWe conducted a multicentre, longitudinal, double-blind, doubledummy, add-on, randomized controlled trial. Healthy infants receiving vaccinations in 3 pediatric outpatient clinics, including 7 physician practices in Toronto were eligible. We excluded infants born before 36 weeks' gestation, infants who had stayed in hospital outside of postnatal care, and infants who were allergic to amide ABSTRACT BACKGROUND: Vaccine injections can cause acute pain and distress in infants, which can contribute to dissatisfaction with the vaccination experience and vaccine hesitancy. We sought to compare the effectiveness of additive pain interventions administered consistently during vaccine injections in the first year of life. RESEARCH Relative effectiveness of additive pain interventions during vaccination in infantsAnna METHODS:We conducted a multicentre, longitudinal, double-blind, add-on, randomized controlled trial. Healthy infants were randomly assigned to 1 of 4 levels of pain management for all vaccine injections at 2, 4, 6 and 12 months: (i) placebo control; (ii) parent-directed video education about infant soothing; (iii) the video plus sucrose administered orally or (iv) the video plus sucrose plus liposomal lidocaine applied topically. All infants benefit from injection techniques that minimize pain. We used a doubledummy design; hence all parents watched a video (active psychological intervention or placebo) and all infants received oral solution (sucrose or placebo) and topical cream (lidocaine or placebo). We assessed infant distress during 3 phases -preinjection (baseline), vaccine injection (needle), and 1 minute postinjection (recovery) -using the Modified Behavioural Pain Scale (range 0-10). We compared scores between groups and across infant ages using a mixed-model repeated-measures analysis. RESULTS:A total of 352 infants participated in the study, from Jan. 17, 2012, to Feb. 2, 2016. Demographics did not differ among intervention groups (p > 0.05). Baseline pain scores did not differ among intervention groups (p = 0.4), but did differ across ages (p < 0.001). Needle pain scores differed among groups (p = 0.003) and across ages (p < 0.001). The mean (± standard deviation) needle score was 6.3 (± 0.8) in the video-sucrose-lidocaine group compared with 6.7 (± 0.8) in each of the other groups. There were no other between-group differences. Recovery scores did not differ among groups (p = 0.98), but did differ across ages (p < 0.001). INTERPRETATION:Only liposomal lidocaine provided consistent analgesia within an additive pain intervention regimen during vaccinations in infants. Trial registration: ClinicalTrials.gov, no. NCT01503060 RESEARCH E228CMAJ | FEBRUARY 13, 2017 | VOLUME 189 | ISSUE 6anesthetics or vaccines and for whom mothers planned to use topical anesthetics, sucrose or breast feeding during vaccinations. Infants were randomly assigned to 1 of 4 pain-relieving regimens for all vaccine injections in their first year of life: (i) placebo control; (ii) parent-directed video education about i...

Adiponectin (APN), an adipokine, exerts an anti-inflammatory and anti-cancerous activity with its role in glucose and lipid metabolism and its absence related to several obesity related malignancies including colorectal cancer. The aim of this study is to determine the effect of APN deficiency on the chronic inflammation-induced colon cancer. This was achieved by inducing inflammation and colon cancer in both APN knockout (KO) and C57B1/6 wild type (WT) mice. They were divided into four treatment groups (n=6): 1) control (no treatment); 2) treatment with three cycles of dextran sodium sulfate (DSS); 3) weekly doses of 1,2-dimethylhydrazine (DMH) (20 mg/kg of mouse body weight) for twelve weeks; 4) a single dose of DMH followed by 3 cycles of DSS (DMH+DSS). Mice were observed for diarrhea, stool hemoccult, and weight loss and were sacrificed on day 153. Tumor area and number were counted. Colonic tissues were collected for Western blot and immunohistochemistry analyses. APNKO mice were more protected than WT mice from DSS induced colitis during first DSS cycle, but lost this protection during the second and the third DSS cycles. APNKO mice had significantly severe symptoms and showed greater number and larger area of tumors with higher immune cell infiltration and inflammation than WT mice. This result was further confirmed by proteomic study including pSTAT3, pAMPK and Cox-2 by western blot and Immunohistochemistry. Conclusively, APN deficiency contributes to inflammation-induced colon cancer. Hence, APN may play an important role in colorectal cancer prevention by modulating genes involved in chronic inflammation and tumorigenesis.

1 The effects of a series of structurally-dissimilar ai site ligands were examined on high voltage-activated Ca2`channel activity in two preparations of cultured hippocampal pyramidal neurones. 2 In mouse hippocampal neurones under whole-cell voltage-clamp, voltage-activated Ca2`channel currents carried by barium ions (IB.) were reduced with the rank order (IC" values in (18)>opipramol (32)>carbetapentane (40) (42)>caramiphen (47)>dextromethorphan (73). At the highest concentrations tested, the compounds almost abolished IB. in the absence of any other pharmacological agent.3 The current-voltage characteristics of the whole-cell IB. were unaffected by the test compounds. The drug-induced block was rapid in onset and offset, with the exceptions of carbetapentane and caramiphen where full block was achieved only after two to three voltage-activated currents and was associated with an apparent increase in the rate of inactivation of IB.4 In rat hippocampal neurones loaded with the Ca2"-sensitive dye Fura-2, rises in intracellular free Ca2+ concentration evoked by transient exposure to 50 mM K+-containing medium, either in the absence or in the presence of 10 pM nifedipine (to block L-type high voltage-activated Ca2`channels), were also reversibly attenuated by the ai ligands. The rank order potencies for the compounds in these experimental paradigms were similar to that observed for blockade of IB, in the electrophysiological studies. 5These results indicate that, at micromolar concentrations, the compounds tested block multiple subtypes of high voltage-activated Ca2" channels. These actions, which do not appear to be mediated by high-affinity a binding sites, may play a role in some of the functional effects previously described for the compounds.

BackgroundInflammatory bowel diseases are associated with increased adiponectin (APN) levels, which may exert pro-inflammatory effects in these individuals. Since habitual exercise may increase APN, the aim of this study was to determine how exercise training affects mice with acute colitis.MethodsMale adiponectin knock out (APNKO) and wild type (WT) mice (C57BL/6) were randomly assigned to 4 different groups: 1) Sedentary (SED); 2) Exercise trained (ET); 3) Sedentary with dextran sodium sulfate (DSS) treatment (SED + DSS); and 4) Exercise trained with DSS (ET + DSS). Exercise-trained mice ran at 18 m/min for 60 min, 5d/wk for 4 weeks. Subsequently, the ET + DSS and the SED + DSS mice received 2% DSS in their drinking water for 5 days (d), followed by 5d of regular water.ResultsThe clinical symptoms of acute colitis (diarrhea, stool haemoccult, and weight loss) were unaffected by exercise and there was no difference between the APNKO and WT mice (p > 0.05) except on day 39. However, the clinical symptoms of the DSS-treated APNKO mice were worse than WT mice treated with DSS and had increased susceptibility to intestinal inflammation due to increased local STAT3 activation, higher IL-6, TNF-α, IL-1β and IL-10 levels, and as a result had increased intestinal epithelial cell proliferation (p < 0.05). Exercise training significantly decreased pro-inflammatory cytokines including IL-6, TNF-α and IL-1β (p < 0.05) in the DSS + EX APNKO mice but had no effect on epithelial cell proliferation. Exercise was also found to significantly decrease the phosphorylation expression of STAT3 in both WT and APNKO mice in DSS + EX group when compared to DSS + SED.ConclusionsExercise training may contribute in alleviating the symptoms of acute colitis and APN deficiency may exacerbate the intestinal inflammation in DSS-induced colitis.

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