Clinical pharmacokinetics of oxaliplatin in a hemodialysis patient with advanced gastric cancer

We administered FOLFOX (oxaliplatin (L-OHP) plus infusional 5-fluorouracil (5-FU) and leucovorin) to an hemodialysis (HD) patient with advanced gastric cancer (AGC), and investigated pharmacokinetics (PKs) and dialyzability of L-OHP. The patient was a 54-year-old Japanese man with a diagnosis of inoperable AGC. FOLFOX was instituted 3?h prior to the start of a 4?h HD period with the L-OHP and 5-FU doses reduced by 50% for the first cycle, and 30% reduced dose was administered for the second cycle. We performed an analysis of the PKs of L-OHP during these two cycles. Volume of distribution and area under the curve of the 30% reduced L-OHP dose were 56.7?L and 30.0?μg·h/mL, respectively. A dose reduction of L-OHP by 30%?50% may be advisable for the initial administration, given the need for careful administration of chemotherapy in HD patients, with particular attention to the development of hematological toxicities and neuropathy.     

Localized measurement of atherosclerotic plaque inflammatory burden with dynamic contrast–enhanced MRI

Inflammation plays an important role in progression and rupture of atherosclerotic plaque. Dynamic contrast–enhanced MRI has been proposed as a tool to evaluate inflammation in vivo by measuring the transfer constant and partial plasma volume, which are influenced by inflammation. This study sought to demonstrate the ability of dynamic contrast–enhanced MRI to provide localized measurements of transfer constant and partial plasma volume within plaque regions of different compositions. In order to do that, a highly automatic procedure for localized measurement of dynamic contrast–enhanced MRI parameters was developed. In 47 subjects, the average transfer constant and partial plasma volume were highest in loose matrix and fibrous tissue and substantially lower in intraplaque hemorrhage, lipid rich/necrotic core, and calcification. In addition, except for hemorrhage and calcification, statistically significant differences of transfer constant and partial plasma volume were observed for any pair of these components. This suggests that transfer constant and partial plasma volume could be helpful to differentiate different plaque components and that dynamic contrast–enhanced MRI has the potential to assess inflammatory burden in specific regions. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Mutation (Ser284Leu) of neuronal nicotinic acetylcholine receptor alpha 4 subunit associated with frontal lobe epilepsy causes faster desensitization of the rat receptor expressed in oocytes

To date five mutations in two major constituents of neuronal nicotinic acetylcholine receptor (nAChR) in the brain, i.e. alpha4 and beta2 subunits, have been identified to be associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Among them, only Ser284Leu, a point mutation in alpha4 subunit identified in ADNFLE as well as in a sporadic case with nocturnal frontal lobe epilepsy, remains to be characterized electrophysiologically. We examined the properties of rat nAChR harboring Ser284Leu reconstituted on Xenopus oocytes. Currents elicited in response to application of acetylcholine to oocytes expressing wild type or mutant nAChR were measured by a standard two-microelectrode voltage clamp method. Compared with wild-type nAChR, the mutant nAChR had a comparable EC(50) value for acetylcholine whereas it showed faster desensitization and lower Cs(+)/Na(+) permeability ratio. Ser284Phe, a putative mutation constructed for comparison, exhibited similar properties. These findings indicate that Ser(284) plays an important role in gating of nAChR along with Thr(276) and Ser(280), and suggest that mutation at Ser(284) could reduce nAChR activity similar to other mutations of alpha4 subunit found in ADNFLE.     

Laparoscopically assisted total gastrectomy with sentinel node biopsy for early gastric cancer: preliminary results

This study sought to describe a procedure involving laparoscopically assisted total gastrectomy (LATG) with sentinel node biopsy (SNB) and to evaluate the results of the first three patients. LATG for early gastric cancer was performed with sentinel node (SN) identification using a combined patent blue-violet dye and 99mtechnetium-labeled tin colloid technique. Laparoscopically resected SNs were processed for frozen section examination by routine hematoxylin and eosin (H&E) and immunohistochemical cytokeratin (IHC-CK) stains. LATG consists of a four-surgical port technique, removal of the specimen through a small 5-cm laparotomy, and stapled Roux-en-Y esophagojejunostomy. Five patients were candidates for LATG with SNB between March 2001 and June 2003; two had open surgery because of a tumor extending the serosal surface and peritoneal dissemination, whereas in the remaining three, SNs were successfully identified and evaluated with no evidence of sentinel node (micro) metastases intraoperatively. Based on the results of SNB, three patients underwent LATG with adequate lymphadenectomy. Mean operative time and blood loss were 375 min and 219 mL, respectively. No dissected lymph nodes had evidence of metastasis by H&E and IHC-CK on permanent sections. LATG with SNB followed by adequate lymphadenectomy is technically feasible, and with its acceptable operative time and blood loss, presents an excellent therapeutic option for early gastric cancer; while SNB and subsequent frozen section analysis by H&E and IHC-CK staining is a rapid and reliable diagnostic method for intraoperative detection of SN (micro) metastasis. This combination treatment is a promising alternative to laparoscopic gastrectomy with conventional lymphadenectomy.     

Role of endogenous regucalcin in brain function: suppression of cytosolic nitric oxide synthase and nuclear protein tyrosine phosphatase activities in brain tissue of transgenic rats

The role of regucalcin, a regulatory protein of Ca2+ signaling, in the regulation of brain function was investigated by using regucalcin transgenic (TG) rats. Western blot analysis showed a remarkable expression of regucalcin protein in the cytosol and nucleus of the brain tissue of TG female rats (5-week-old) as compared with that of wild-type (wt) female rats. In TG male rats, the enhancement of regucalcin expression in the brain cytosol and nucleus was only slight. Nitric oxide (NO) synthase activity was significantly decreased in the brain cytosol of TG female rats. Protein tyrosine phosphatase activity was not significantly altered in the brain nucleus of TG female rats. The presence of calcium chloride (10 microM) or anti-regucalcin monoclonal antibody (50 ng/ml) in the enzyme reaction mixture caused a significant increase in cytosolic NO synthase and nuclear protein tyrosine phosphatase activities in the brain tissue of wt rats. The increase was significantly prevented in the brain cytosol and nucleus of TG rats. The present study supports the view that endogenous regucalcin plays a suppressive role in the regulation of brain function in rats.     

Decrease in regucalcin level and enhancement of protein tyrosine phosphatase activity in rat brain microsomes with increasing age

The role of regucalcin, a regulatory protein in Ca2+ signaling, in the microsomes of brain tissue in rats has not been clarified so far. Western blot analysis showed that regucalcin was present in the brain microsomes. Regucalcin levels were significantly decreased in the brain microsomes obtained from 50-week-old rats as compared with that of 5-week-old rats. Meanwhile, protein tyrosine phosphatase activity was seen in the brain microsomes. The enzyme activity was significantly increased with increasing age. The presence of regucalcin (10(-9) M) in the enzyme reaction mixture containing the brain microsomes obtained from 50-week-old rats caused a significant decrease in protein tyrosine phosphatase activity. Such a decrease was not seen in the brain microsomes from 5-week-old rats. Moreover, the presence of anti-regucalcin monoclonal antibody (10 ng/ml) in the enzyme reaction mixture containing the brain microsomes from young and aged rats caused a significant increase in protein tyrosine phosphatase activity, indicating a suppressive role of microsomal endogenous regucalcin. The present study demonstrates that regucalcin is present in the brain microsomes, and that its level is decreased with increasing age. This decrease may be partly involved in the enhancement of protein tyrosine phosphatase activity in the brain mirosomes with increasing age.