A compartment model of Tc-99m-DTPA-galactosyl-human serum albumin for evaluating liver function]

Technetium-99m-diethylenetriaminepentaacetic acid-galactosyl-human serum albumin (99mTc-GSA) is a new liver scintigraphy agent which binds to asialoglycoprotein receptor in hepatocyte. Studies were performed in three normal volunteers and 11 patients with liver cirrhosis. Time-activity curves for the heart and liver were obtained for 60 min following an i.v. injection of 99mTc-GSA (1 mg/185 MBq). We introduced five compartments to describe 99mTc-GSA: 1) extrahepatic blood, 2) hepatic blood, 3) receptor, 4) interstitial fluid and 5) urine. The %ID of 99mTc-GSA in blood and the hepatic blood volume were obtained from the extrapolation of the biexponential fitting for the heart and liver curves. Michaelis-Menten type saturation kinetics was applied to the process of receptor-ligand binding. Numerical analysis solved the simultaneous differential equations that were introduced from the compartment model. Hepatic blood flow was 1,651 +/- 131 ml/min, maximal removal rate for the ligand was 0.547 +/- 0.069 mg/min in normal controls. Both results were significantly decreased in patients with liver cirrhosis compared with normal controls. Present study may provide a novel method for the diagnosis of liver function that allows independent quantification of the hepatic blood flow and the receptor population.     

Inhibitory Effect of Cryptoporic Acid E, a Product from Fungus Cryptoporus volvatus, on Colon Carcinogenesis Induced with N-Methyl-N-Nitrosourea in Rats and with 1,2-Dimethylhydrazine in Mice

The antitumorigenic effect of cryptoporic acid E (CPA-E), a dimeric drimane sesquiterpenoid isolated from the fungus Cryptoporus volvatus , on colon carcinogenesis was investigated. Female F344 rats given an intrarectal instillation of 2 mg of N-methyl-N-nitrosourea 3 times weekly in weeks 1 and 2 were fed diet containing 0.2% CPA-E from week 3. Femal ICR mice given 15 weekly intraperitoneal injections of 10 mg of 1,2-dimethylhydrazine/kg body weight during weeks 1 to 15 were fed diet containing 0.06% CPA-E from week 1. The experiment was terminated at week 35 for rats and at week 25 for mice. The incidence and the number of tumors per animal were reduced in CPA-E-fed animals compared to the controls: 31% vs. 75% (P<0.05) and 0.4±0.2 (SEM) vs. 0.9 ± 0.2 (0.1> P >0.05) in rats, and 31% vs. 63% (0.1>P>0.05) and 0.4±0.2 vs. 2.4 ± 0.8 (P<0.05) in mice (16 animals in each group). Intrarectal deoxycholic acid-induced colonic mucosal ornithine decarboxylase activity was significantly lowered in CPA-E-fed animals compared to controls. This shows an antipromoting activity of CPA-E against colon carcinogenesis. Thus, it was concluded that CPA-E inhibits colon cancer development in both rats and mice treated with 2 different colon carcinogens.     

Extracellular or ghost Pick bodies and their lack of tau immunoreactivity: a histological,immunohistochemical and electron microscopic study

Histological, immunohistochemical, and electron microscopic evidence of an extracellular, or ghost Pick body has been found in the granular cell layer and, rarely, in the pyramidal cell layer of the hippocampus of an autopsy case of Pick's disease. The ghost Pick body appeared as a blurred, weak argyrophilic mass in the neuropil, and it was composed of accumulated fibrillary structures, 13 nm in diameter, intermingled with glial filament bundles. These ghost Pick bodies did not react with anti-tau and antiubiquitin antibodies, but did react weakly with antiglial fibrillary acidic protein antibody, whereas intracytoplasmic Pick bodies were strongly immunolabeled with anti-tau but only weakly with anti-ubiquitin anti-bodies. These results suggest that the Pick body is discharged into the neuropil after destruction of the mother neuron, loses its immunoreactivity to certain tau and ubiquitin antibodies during this process (thereby inducing a glial reaction) and remains in the neuropil as a ghost Pick body.     

Increased delivery of gallium-67 to tumors using serum-stable liposomes

Gallium-67 chelated to nitrilotriacetic acid was encapsulated in liposomes composed of various phospholipids, and 67Ga delivery potential to the tumor after intravenous injection of these liposomes was examined. Tumor uptake of the liposomes themselves and their stability in the serum were also studied. It was found that liposomes composed of distearoylphosphatidylcholine, diarachidoylphosphatidylcholine, or sphingomyelin with cholesterol (molar ratio of phospholipid:cholesterol, 2:1) could be taken by the tumor effectively and could deliver large amounts of 67Ga to the tumor. They could also give high 67Ga accumulation ratios (tumor to the other tissues). The study of liposomal stability in the serum suggested that the marked 67Ga accumulation in the tumor resulted from the serum stability of the liposomal bilayer, i.e., the stable liposomes in the blood circulation could reach the tumor in large quantities after i.v. injection. These observations indicate that liposomes with an appropriate lipid composition may be an excellent tool to accumulate 67Ga in tumors.     

Evaluation of water-electrolyte metabolism in patients with upper GI tract cancer--the dynamic status of secretion of alpha-hANP levels

For the purpose of evaluation of the water-electrolyte metabolism in upper GI tract surgery, I measured alpha-human atrial natriuretic polypeptide (alpha-hANP) and other parameters of twenty-eight patients daily for seven days after operation. The subjects were divided in four groups as follows; 6 r-thoracal and abdominal esophagectomy (r-TA group); 4 l-thoracoabdominal total gastrectomy (1-TA group), 8 abdominal total gastrectomy (TMR group) and 10 partial gastrectomy (PMR group). Plasma alpha hANP levels in r-TA group were significantly higher than those in PMR group on the first, second, third and seventh postoperative days (p less than 0.05). Furthermore, those in 1-TA group were also significantly higher compared to those in PMR group on the second and seventh postoperative days (p less than 0.05). Significant correlation between plasma alpha hANP level and water balance was detected in transabdominal groups (TMR, PMR). However, this correlation was not found in thoracoabdominal groups (r-TA, l-TA). There was no correlation among alpha hANP level, heart rate and blood pressure. Serum and urinary Na/K ratio was lower in r-TA group, l-TA group, TMR group, and PMR group in descending order. Consequently, plasma alpha hANP level plays an important role in water-electrolyte metabolism during the perioperative period. A good group of the dynamic status of the secretion of alpha hANP levels might be a very useful index for the evaluation of the magnitude of surgical stress.     

Enhancement of the intrinsic defecation reflex by mosapride, a 5-HT4 agonist, in chronically lumbosacral denervated guinea pigs.

The defecation reflex is composed of rectal distension-evoked rectal (R-R) reflex contractions and synchronous internal anal sphincter (R-IAS) reflex relaxations in guinea pigs. These R-R and R-IAS reflexes are controlled via extrinsic sacral excitatory nerve pathway (pelvic nerves), lumbar inhibitory nerve pathways (colonic nerves) and by intrinsic cholinergic excitatory and nitrergic inhibitory nerve pathways. The effect of mosapride (a prokinetic benzamide) on the intrinsic reflexes, mediated via enteric 5-HT(4) receptors, was evaluated by measuring the mechanical activity of the rectum and IAS in anesthetized guinea pigs using an intrinsic R-R and R-IAS reflex model resulting from chronic (two to nine days) lumbosacral denervation (PITH). In this model, the myenteric plexus remains undamaged and the distribution of myenteric and intramuscular interstitial cells of Cajal is unchanged. Although R-R and R-IAS reflex patterns markedly changed, the reflex indices (reflex pressure or force curve-time integral) of both the R-R contractions and the synchronous R-IAS relaxations were unchanged. The frequency of the spontaneous R and IAS motility was also unchanged. Mosapride (0.1-1.0 mg/kg) dose-dependently increased both intrinsic R-R (maximum: 1.82) and R-IAS reflex indices (maximum: 2.76) from that of the control (1.0) 6-9 days following chronic PITH. The dose-response curve was similar to that in the intact guinea pig, and had shifted to the left from that in the guinea pig after acute PITH. A specific 5-HT(4) receptor antagonist, GR 113808 (1.0 mg/kg), decreased both reflex indices by approximately 50% and antagonized the effect of mosapride 1.0 mg/kg. This was quite different from the result in the intact guinea pig where GR 113808 (1.0 mg/kg) did not affect either of the reflex indices. The present results indicate that mosapride enhanced the intrinsic R-R and R-IAS reflexes and functionally compensated for the deprivation of extrinsic innervation. The actions of mosapride were mediated through endogenously active, intrinsic 5-HT(4) receptors which may be post-synaptically located in the myenteric plexus of the anorectum.     

Clinical characteristics of thrombotic microangiopathy following ABO incompatible living donor liver transplantation.

Thrombotic microangiopathy (TMA) may develop after living donor liver transplantation (LDLT), but the mechanism is not fully understood. We retrospectively analyzed all patients undergoing LDLT at our center, including TMA patients, to elucidate the clinical characteristics and presentation and to determine which patients have a higher risk of occurrence of TMA. In all, 57 adult patients were reviewed after LDLT at our institution. TMA was diagnosed by sudden and severe thrombocytopenia, followed by hemolytic anemia with fractionated erythrocytes in the blood smear. Clinical features were compared between the TMA group and the non-TMA group. Of the 57 patients, 4 were diagnosed with posttransplantation TMA. ABO blood group (ABO)-incompatibility, cyclophosphamide (CPA), and recipient blood group (type O) were closely correlated with the occurrence of TMA. Thrombocytopenia appeared 1 to 5 days before hemolytic anemia. Coagulative function markers stayed at the same level after TMA, while marked elevation was shown in fibrinolytic function markers such as plasminogen activator inhibitor type 1 (PAI-1). TMA occurred at a higher prevalence in ABO-incompatible graft recipients. Additional factors associated with ABO-incompatible transplantation, such as an overdose of immunosuppressants, may affect the likelihood of TMA. Sudden and severe thrombocytopenia presented before hemolytic anemia and the serum levels of PAI-1 correlated well with the clinical course of TMA. In conclusion, early recognition of thrombocytopenia and elevation of PAI-1 is crucial to diagnose TMA especially in ABO-incompatible LDLT.     

Enhancing effect of combining two pyrrolidone vehicles on transdermal drug delivery

The enhancing effect of combining 1-methyl-2-pyrrolidone (MP) and 1-lauryl-2-pyrrolidone (LP) as the vehicles for transdermal penetration of phenolsulphonphthalein (phenol red) has been investigated by using an in-vitro technique with excised rat skin. LP had a higher enhancing effect on the penetration of phenol red than MP, but there was a long lag time before steady-state penetration was attained. A potent effect with a shorter lag time was obtained when MP and LP were used together. This potentiation was maintained when the concentration of MP was decreased by 95%. The combined vehicle also enhanced the skin accumulation of phenol red. MP promoted the rapid penetration of LP into the skin and potentiated the enhancing effect of LP on the penetration of phenol red and thereby shortened the lag time. The combined vehicle also enhanced the penetration of the hydrophilic anticancer agent, 5-fluorouracil.