Background In several tumours the endogenous activity of histidine decarboxylase (HDC), the enzyme stimulating histamine synthesis, sustains the autocrine trophic effect of histamine on cancer progression. Cholangiocarcinoma is a biliary cancer with limited treatment options. Histamine interacts with four G-protein coupled receptors, H1–H4 histamine receptors (HRs). Objective To determine the effects of histamine stimulation and inhibition of histamine synthesis (by modulation of HDC) on cholangiocarcinoma growth. Methods In vitro studies were performed using multiple human cholangiocarcinoma lines. The expression levels of the histamine synthetic machinery and HRs were evaluated along with the effects of histamine stimulation and inhibition on cholangiocarcinoma proliferation. A xenograft tumour model was used to measure tumour volume after treatment with histamine or inhibition of histamine synthesis by manipulation of HDC. Vascular endothelial growth factor (VEGF) expression was measured in cholangiocarcinoma cells concomitant with the evaluation of the expression of CD31 in endothelial cells in the tumour microenvironment. Results Cholangiocarcinoma cells display (1) enhanced HDC and decreased monoamine oxidase B expression resulting in increased histamine secretion; and (2) increased expression of H1–H4 HRs. Inhibition of HDC and antagonising H1HR decreased histamine secretion in Mz-ChA-1 cells. Long-term treatment with histamine increased proliferation and VEGF expression in cholangiocarcinoma that was blocked by HDC inhibitor and the H1HR antagonist. In nude mice, histamine increased tumour growth (up to 25%) and VEGF expression whereas inhibition of histamine synthesis (by reduction of HDC) ablated the autocrine stimulation of histamine on tumour growth (~80%) and VEGF expression. No changes in angiogenesis (evaluated by changes in CD31 immunoreactivity) were detected in the in vivo treatment groups. Conclusion The novel concept that an autocrine loop (consisting of enhanced histamine synthesis by HDC) sustains cholangiocarcinoma growth is proposed. Drug targeting of HDC may be important for treatment of patients with cholangiocarcinoma.

A growing body of evidence suggests glutamate excess in schizophrenia and that N-methyl-d-aspartate receptor (NMDAR) hypofunction on γ-aminobutyric acid (GABA) interneurons disinhibiting pyramidal cells may be relevant to this hyperglutamatergic state. To better understand how NMDAR hypofunction affects the brain, we used Magnetic Resonance Spectroscopy and resting state functional MRI to study the effects of ketamine on hippocampal neurometabolite levels and functional connectivity in 15 healthy human subjects. We observed a ketamine induced increase of hippocampal Glx (glutamate+glutamine; F= 3.76; p= 0.04), a decrease in fronto-temporal (t=4.92, pFDR< .05, kE= 2198, x= -30, y= 52, z= 14) and temporo-parietal functional connectivity (t=5.07, pFDR< .05, kE= 6094, x= -28, y= -36, z= -2), and a possible link between connectivity changes and elevated Glx. Our data empirically support that hippocampal glutamatergic elevation and resting state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia.

We observed a mnemonic discrimination deficit but intact recognition in both datasets. Our findings suggest a tentative mechanistic link between dentate gyrus dysfunction in first-episode psychosis and N-methyl-D-aspartate receptor hypofunction.

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Background Context-No clinical trial of spinal manipulation for chronic neck pain, either for single or multiple intervention session(s), has employed an effective sham-manipulation control group. Purpose-Validate a practical sham cervical high velocity, low amplitude (HVLA) spinal manipulation. Study design/Setting-Randomized, experimental validation study in an institutional clinical research laboratory Patient Sample-Eligible subjects were males and females, 18-60 years of age with mechanical neck pain (as defined by the International Association for the Study of Pain Classification) of at least 3 months duration. Subjects with arm pain, any pathologic cause of neck pain or any contraindication to spinal manipulation were excluded. Outcome Measures-The primary outcome was the patient's self-report or "registration" of group allocation following treatment. Secondary outcomes were NRS-101 for neck pain, range of motion (by goniometer), tenderness (by pressure algometry). Methods-Eligible subjects were randomly allocated to one of two groups: "real" or sham cervical manipulation (RM or SM). All subjects were given two procedures in sequence, either RM+SM or SM+SM. Immediately following the two procedures, subjects were asked to register any pain experienced during the procedures and to identify their treatment group allocation. Forcetime profiles were recorded during all procedures. Secondary clinical outcome measures were obtained at baseline, 5 and 15 minutes after the intervention including range of motion, self-report of pain and local spinous process tenderness. Data for each variable were summarized and tested for normality in distribution. Summary statistics were obtained for each variable and statistically tested. Funding for this study was obtained from the National Institutes of Health (NCCAM: R21 AT004396-01A1) and the Canadian Institutes of Health Research (BMT91926). No conflicts of interest exist in this study. Results-Sixty-seven subjects were randomized. Data from 64 subjects (32 per group) were available for analysis. There were no significant differences between the groups at baseline. One adverse event occurred in the "real" group which was a mild post-treatment pain reaction lasting < 24 hours. In the RM group, 50% of subjects incorrectly registered their treatment allocation; in