Up-regulation of VGLUT2 expression in hypothalamic-neurohypophysial neurons of the rat following osmotic challenge

A second vesicular glutamate transporter (VGLUT2) has been reported to be expressed in neurosecretory neurons of the hypothalamic-neurohypophysial system. To study its role in the neurosecretory neurons, we evaluated the expression of the VGLUT2 gene in the paraventricular (PVN) and supraoptic (SON) nuclei as well as the immunoreactivity in the neurohypophysis under euhydrated and chronic hyperosmotic conditions with in situ hybridization and immunohistochemistry. The intensity of hybridization signals in the PVN, SON and thalamus of rats subjected to water deprivation for 7 days, or drinking 2% NaCl for 4 or 7 days, was compared with that of euhydrated rats (control). The overall intensity in the entire PVN or SON, but not the thalamus, was higher in osmotically stimulated rats than in controls. Within the PVN, a significantly higher intensity of signals than that of controls was found only in the dorsolateral posterior magnocellular region in 4-day salt-loaded rats and in all subregions in water-deprived or 7-day salt-loaded rats. The intensity in the SON was higher in the stimulated rats than in controls, regardless of subregions. In the neurohypophysis, VGLUT2 staining was frequently localized in vasopressin terminals of control rats and was apparently reduced in stimulated rats. These results indicate that VGLUT2 is principally expressed in magnocellular vasopressin neurons, suggesting some local effect of intrinsic glutamate on neurohypophysial hormone secretion.     

Oxygen-enhanced MR imaging: correlation with postsurgical lung function in patients with lung cancer

PURPOSE: To prospectively determine if lung function as assessed with oxygen-enhanced magnetic resonance (MR) imaging correlates with postsurgical lung function in patients with lung cancer, as compared with quantitative and qualitative findings of computed tomography (CT) and scintigraphy. MATERIALS AND METHODS: Study received institutional review board approval, and informed patient consent was obtained. Thirty consecutive patients (16 men and 14 women, aged 44-81 years; mean age, 65 years) considered candidates for lung resection underwent oxygen-enhanced MR imaging, CT, perfusion scintigraphy, and measurement of forced expiratory volume in 1 second (FEV1). A respiratory-synchronized inversion-recovery half-Fourier single-shot turbo spin-echo MR sequence was used for data acquisition. Correlation of postsurgical lung function (postsurgical FEV1) as determined with oxygen-enhanced MR imaging (FEV1MR), quantitative assessment with CT (FEV1Quant), qualitative assessment with CT (FEV1Qual), and perfusion scintigraphy (FEV1PS) was conducted with actual postsurgical FEV1, and the limits of agreement of each were determined with Bland-Altman analysis. RESULTS: Correlation between postsurgical FEV1MR and actual postsurgical FEV1 values was excellent (r2= 0.81, P < .001); it was better than that of FEV1Qual (r2= 0.76) and FEV1PS (r2= 0.77) and similar to that of FEV1Quant (r2= 0.81) values. The limits of agreement of FEV1MR were between -9.9% and 10.9%. CONCLUSION: Oxygen-enhanced MR imaging can be used to predict posturgical lung function in patients with lung cancer, similar to quantitative CT.     

Peripheral anatomic evaluation using 3D CT hepatic venography in donors: significance of peripheral venous visualization in living-donor liver transplantation

OBJECTIVE: The purpose of this study was to determine clinical roles for 3D CT hepatic venography in the evaluation of peripheral hepatic venous anatomy during living-donor liver transplantation. MATERIALS AND METHODS: Subjects comprised 54 donors (age range, 20-60 years) who had undergone surgery to donate a liver for transplantation. Visualization of each hepatic venous branch and total visualization using 3D CT hepatic venography were evaluated. Maximum venous branch order visualized was graded as nil, first branch, second branch, or third branch or more. The distance between the hepatic surface and the tip of each hepatic venous branch was classified as 0-5 mm, 6-10 mm, 11-15 mm, 16-20 mm, or 21-25 mm. Quality of total 3D CT hepatic venography was evaluated subjectively as poor, good, fair, or excellent. Dominance of large hepatic veins in the right lobe, peripheral branching pattern of the middle hepatic vein, and branching pattern of the vein draining segment IVb were also assessed. RESULTS: Most hepatic venous branches (96.2% [275/286]) were visualized up to at least the second-order branches, and 93.7% (268/286) of branches were within 10 mm of the hepatic surface. As for total visualization, 98% (53/54) of cases were regarded as excellent. The dominant vein in the right lobe was the right hepatic vein in 27 cases, inferior hepatic vein in 25, and middle hepatic vein in one. The branching pattern of the middle hepatic vein was type 1 in 36 cases, type 2 in nine, and type 3 in eight. Segment IVb vein branched from the middle hepatic vein in 20 patients, and from the left hepatic vein in 34. CONCLUSION: Because 3D CT hepatic venography visualizes peripheral hepatic venous branches in detail, the technique is useful for determining operative indications in living-donor liver transplantation.     

Combination phase I study of nedaplatin and gemcitabine for advanced non-small-cell lung cancer

To establish the toxicities and maximum tolerated dose (MTD) of nedaplatin with gemcitabine, and to observe their antitumour activity, we conducted a combination phase I study in advanced non-small-cell lung cancer (NSCLC). Patients received nedaplatin (60-100 mg m(-2) given intravenously over 90 min) on day 1, and gemcitabine (800-1000 mg m(-2) given intravenously over 30 min) on days 1, 8, every 3 weeks. In total, 20 patients with locally advanced or metastatic NSCLC who received no prior chemotherapy or one previous chemotherapy regimen were enrolled. The most frequent toxicities were neutropenia and thrombocytopenia; nonhaematological toxicities were generally mild. Three out of six patients experienced dose-limiting toxicities (neutropenia, thrombocytopenia and delayed anaemia) at dose level 4, 100 mg m(-2) nedaplatin with 1000 mg m(-2) gemcitabine, which was regarded as the MTD. There were three partial responses, for an overall response rate of 16.7%. The median survival time and 1-year survival rate were 9.1 months and 34.1%, respectively. This combination is well tolerated and active for advanced NSCLC. The recommended dose is 80 mg m(-2) nedaplatin with 1000 mg m(-2) gemcitabine. This combination chemotherapy warrants a phase II study and further evaluation in prospective randomised trials with cisplatin- or carboplatin-based combinations as first-line chemotherapy for advanced NSCLC.     

Short report: Lethal malaria in cytosolic phospholipase A2- and phospholipase A2IIA-deficient mice

Lipid mediators play important roles in the pathogenesis of malaria. Phospholipase A2s are enzymes involved in the production of these mediators, and they function in inflammation. Among them, cytosolic phospholipase A2 (cPLA2) is a key enzyme in the metabolism of arachidonic acid, the first intermediate in the production of lipid mediators. Plasmodium berghei ANKA causes cerebral malaria in CL57B/6 mice, and we recently produced cPLA2-deficient mice with this background. With the expectation of reduced pathogenicity, we performed experimental infection in these mice. Unexpectedly, the infected mice developed cerebral malaria and died at the same time as the control mice, while the parasitemia progressed similarly in both groups. These observations suggest that secretory PLA2s rather than cPLA2 may be involved in the aggravation, although possible compensation by the induction of other enzymes has not been excluded. The present findings are expected to help clarify the involvement of various phospholipase A2s in malaria.     

The effects of cholesterol-3-sulfate (CH-3S) on the phosphorylation of human C3a (hC3a) in vitro and on the ability of hC3a to induce vascular permeability in rats

The phosphorylation of human C3a (hC3a, anaphylatoxin) by two distinct protein kinases (PKA and CK-I) and the effect of cholesterol-3-sulfate (CH-3S) on this phosphorylation were biochemically investigated in vitro. It was found that (i) hC3a functions as a phosphate acceptor for PKA and CK-I, but not for CK-II; (ii) the CK-I-mediated phosphorylation of hC3a requires the presence of 3 microM CH-3S in a manner similar to the phosphorylation of HMG1 (CH-3S-binding protein) by CK-I; and (iii) CH-3S inhibits the PKA-mediated phosphorylation of hC3a in a dose-dependent manner (ID50=approximately 2 microM). As expected, hC3a containing high levels of Arg- and Lys-residues stimulated approx. 3-fold CK-II activity (phosphorylation of alpha-casein) in vitro. However, no significant effect of hC3a on CK-II activity was observed when hC3a was preincubated with CH-3S or fully phosphorylated by PKA in vitro. Furthermore, preincubation of hC3a with CH-3S diminished the ability of hC3a to induce vascular permeability in rats. The results provided here suggest that (i) hC3a is a CH-3S-binding protein; and (ii) CH-3S functions as a potent inhibitor for its physiological activities, including phosphorylation by PKA and CK-I, in vitro.