Role of NMDA receptors in the increase of glucose metabolism in the rat brain induced by fluorocitrate

The effect of inhibition of glial metabolism by infusion of fluorocitrate (FC, 1 nmol/μl, 2 μl) into the right striatum of the rat brain on the glucose metabolism was studied. Significant increases in [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) uptake (45 min) in the right cerebral cortex and striatum were observed 4 h after the infusion of FC, both as determined by the tissue dissection method and autoradiography. No significant increase in the initial uptake of [¹⁸F]FDG (1 min) was seen in the striatum. Pretreatment with dizocilpine (MK-801), an N-methyl-d-aspartate (NMDA) receptor antagonist, reduced [¹⁸F]FDG uptake in not only FC infused hemisphere but also in the contralateral hemisphere (saline-infused side). The radioactivity concentrations in plasma at 1, 5 and 45 min after the [¹⁸F]FDG injection were not altered by MK-801. This effect of MK-801 on glucose metabolism observed in the rat brain infused with FC was different from previous reports which indicated an increase in glucose metabolism in some areas of normal rat brain. In addition, the enhancement of glucose metabolism in the striatum induced by FC was almost completely abolished by pretreatment with MK-801. In the cerebral cortex, the relative ratio of radioactivity concentration in the right hemisphere to that in the left hemisphere still remained 1.37 (tissue dissection method) or 1.55 (autoradiography), which indicated that MK-801 partially blocked the effect of FC of enhancing glucose metabolism in this region. These results indicate an important role of NMDA-mediated signal transmission on the increase of glucose utilization induced by inhibition of glial metabolism.     

GM-CSF-producing CCR2+CCR6+ Th17 cells are pathogenic in dextran sodium sulfate-induced colitis model in mice

Although excessive immune responses by Th17 cells, a helper T cell subset, are implicated in the pathogenesis of inflammatory bowel disease (IBD), the mechanism by which its localization in an inflamed colon is regulated remains unclear. Chemokines and their receptors are involved in the pathogenesis of IBD, however, the relative significance of each receptor on Th17 cells remains unknown. We generated C–C motif chemokine receptor 2 (CCR2) knockout (KO) and CCR6 KO mice in the syngeneic background using the CRISPR/Cas9 system and found that the phenotypes of experimental colitis worsened in both mutant mice. Surprisingly, the phenotype of colitis in CCR2/CCR6-double knockout (CCR2/6 DKO) mice was opposite to that of the single-deficient mice, with significantly milder experimental colitis (p < .05). The same was true for the symptoms in CCR6 KO mice, but not in wild type mice treated with a CCR2 inhibitor, propagermanium. Colonic CCR2⁺CCR6⁺ Th17 cells produced a potentially pathogenic cytokine GM-CSF whose levels in the gut were significantly reduced in CCR2/6 DKO mice (p < .05). These results suggest that GM-CSF-producing CCR2⁺CCR6⁺ Th17 cells are pathogenic and are attracted to the inflamed colon by either CCR2 or CCR6 gradient, which subsequently exacerbates experimental colitis in mice.     

DIAGNOSIS OF CONGENITAL CYTOMEGALOVIRUS INFECTION BY EXAMINATION OF PLACENTA: Application of Polymerase Chain Reaction and in Situ Hybridization

We examined the placentas of 12 patients in whom congenital cytomegalovirus CMV infection was suspected from serological and or pathological evaluation. Seven patients died including four intrauterine deaths and five survived. On histological examination, the characteristic inclusion bodies were detected in only three placentas, and villitis with plasma cell infiltration was seen in eight placentas. Immunohistochemistry using a specific antibody against CMV improved the sensitivity of CMV detection 10 cases were positive . With the polymerase chain reaction PCR following the extraction of DNA from formaldehyde-fixed placenta samples, CMV DNA was detected in seven cases. All 12 subjects were diagnosed with CMV infection by additional Southern blot analysis after the PCR. CMV DNA was also detected by an in situ hybridization method in all cases. With current molecular biological techniques the placenta can be reliably used for the diagnosis of congenital CMV infection.     

Clinical significance of and future perspectives for hepatic arterial infusion chemotherapy in patients with liver metastases from colorectal cancer

The most common site of metastases in patients with colorectal cancer is the liver. Hepatic resection is considered to be the treatment of choice for liver metastasis from colorectal cancer; however, hepatic resection can be performed in only 20 or 25 % of all patients. Recurrence develops in the remnant liver or other organs after hepatic resection in over half of all patients with liver-only metastasis. Hepatic arterial infusion (HAI) chemotherapy can provide relatively high concentrations of drugs to microscopic or macroscopic metastases in the liver, with less toxicity than systemic administration. Meta-analyses have shown HAI chemotherapy to have a significantly higher response rate than systemic chemotherapy and its effect on extrahepatic metastases is negligible. HAI chemotherapy provides much better local control of liver metastases from colorectal cancer than systemic chemotherapy. However, well-controlled studies are needed to elucidate the optimal treatment strategies for neoadjuvant and postoperative adjuvant chemotherapy that optimally combine HAI chemotherapy, molecular targeted agents, and systemic chemotherapy such as FOLFOX or FOLFIRI.