Plasma Ratios of Tryptophan and Tyrosine to Other Large Neutral Amino Acids in Manic-Depressive Patients

Abstract: The plasma ratio of each neutral amino acid (tryptophan (TRP), tyrosine (TYR), valine, isoleucine, leucine (LEU) or phenylalanine) to the sum of the other neutral amino acids was measured in 16 : manic and 14 : depressed patients. In the manics, there was a correlation between the psychomotor activity and the plasma TRP and LEU ratios. In the depressives, the depressed mood, retardation and global severity were correlated with the TRP ratio. The zotepine responders showed an increase in the TRP ratio after treatment. In the mianserin responders, the TYR ratio, which was high before the treatment, decreased to the normal range after the treatment. But, the plasma amino acid ratios remained unchanged in the patients treated with lithium carbonate or amitriptyhe. These results suggest that, in manic-depressive illness, there might be abnormalities in the metabolism of neutral amino acids, mainly of TRP and TYR, and that the plasma TRP and TYR ratios might be important indicators for determining the efflcacy of some drugs.     

Anticonvulsant effect of liposome-entrapped superoxide dismutase in amygdaloid-kindled rats.

Amygdaloid-kindled rats received intravenous human copper-zinc superoxide dismutase (CuZn-SOD) either in free form or entrapped within liposomes (SOD-L), at 5, 10 or 20 mg/kg. The animals were stimulated at the generalized seizure-triggering threshold 5 min, 2 h and then every 24 h after the drug was given, until 5 consecutive stage 5 seizures were induced. Free CuZn-SOD had little or no effect. However, SOD-L, particularly at 10 mg/kg, had a prolonged anticonvulsant effect, although there was great individual variation in the onset and duration of seizure suppression. This effect of SOD-L may be due to the ability of liposomes to act as a depot for the sustained release of drugs.     

Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3

The pathogenesis of hepatitis C virus (HCV)-associated insulin resistance remains unclear. Therefore, we investigated mechanisms for HCV-associated insulin resistance. Homeostasis model assessment for insulin resistance was increased in patients with HCV infection. An increase in fasting insulin levels was associated with the presence of serum HCV core, the severity of hepatic fibrosis and a decrease in expression of insulin receptor substrate (IRS) 1 and IRS2, central molecules of the insulin-signaling cascade, in patients with HCV infection. Down-regulation of IRS1 and IRS2 was also seen in HCV core-transgenic mice livers and HCV core-transfected human hepatoma cells. Carbobenzoxy-l-leucyl-l-leucyl-l-leucinal, a potent proteosomal proteolysis inhibitor, blocked down-regulation of IRS1 and IRS2 in HCV core-transfected hepatoma cells. In human hepatoma cells, HCV core up-regulated suppressor of cytokine signaling (SOCS) 3 and caused ubiquitination of IRS1 and IRS2. HCV core-induced down-regulation of IRS1 and IRS2 was not seen in SOCS3(-/-) mouse embryonic fibroblast cells. Furthermore, HCV core suppressed insulin-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase and Akt, activation of 6-phosphofructo-2-kinase, and glucose uptake. In conclusion, HCV infection changes a subset of hepatic molecules regulating glucose metabolism. A possible mechanism is that HCV core-induced SOCS3 promotes proteosomal degradation of IRS1 and IRS2 through ubiquitination.     

Regulation of inflammation-primed activation of macrophages by two serum factors, vitamin D3-binding protein and albumin.

A very small amount (0.0005 to 0.001%) of an ammonium sulfate [50% saturated (NH4)2SO4]-precipitable protein fraction of alpha 2-globulin efficiently supported inflammation-primed activation of macrophages. This fraction contains vitamin D3-binding protein essential for macrophage activation. Comparative macrophage activation studies with fetal calf serum, alpha 2-globulin fraction, 50% (NH4)2SO4 precipitate, and purified bovine vitamin D3-binding protein revealed that fetal calf serum and alpha 2-globulin fraction appear to contain an inhibitor for macrophage activation while ammonium sulfate precipitate contains no inhibitor. This inhibitor was found to be serum albumin. When bovine serum albumin (25 micrograms/ml) was added to a medium supplemented with 0.0005 to 0.05% (NH4)2SO4 precipitate or 1 to 10 ng of vitamin D3-binding protein per ml, activation of macrophages was inhibited.     

Abnormal accumulation in lipopolysaccharide in biliary epithelial cells of rats with self-filling blind loop

Primary sclerosing cholangitis (PSC) is known to be frequently associated with inflammatory bowel diseases. In a rat with self-filling blind loop (SFBL), a proposed animal model for PSC, hepatobiliary inflammation has previously been demonstrated. In this study, we assessed the involvement of lipopolysaccharide (LPS), a bacterial endotoxin, in the pathogenesis of hepatobiliary inflammation of the SFBL model. The hepatic localization of LPS was examined by immunohistochemistry using an anti-lipid A antibody. The portal blood concentration of LPS was measured by an endotoxin-specific chromogenic Limulus test (Endospecy test). LPS was localized in the biliary epithelial cells (BECs) of rats with SFBL, and the portal blood concentration of LPS was significantly higher than that of sham-operated rats. Development of hepatobiliary inflammation, peribiliary fibrosis, and injury to the intestinal mucosa were histologically confirmed. Constriction in the biliary trees was radiologically demonstrated. These findings suggested that abnormal accumulation of LPS, which may be derived from portal blood, in BECs was involved in the pathogenesis of hepatobiliary inflammation with intestinal injury.     

Light and electron microscopic analyses of immediate and late tissue damage caused by radiofrequency ablation in porcine liver

Radiofrequency ablation (RFA) is an effective procedure for localized hepatocellular carcinoma. Contrast-enhanced CT depicts the ablated area as a hypoattenuated area without hepatic blood flow; however, light microscopy does not show obvious necrosis in the ablated area. We evaluated liver tissue changes after RFA by light microscopy and electron microscopy. The normal livers of three anesthetized pigs were coagulated using RFA after laparotomy. The liver was examined immediately, and 1 week after operation by light and electron microscopy. After RFA, the liver parenchyma surrounding the needle electrode was brown in color and surrounded by a red marginal zone separate from the normal liver parenchyma. Hematoxylin-eosin staining of the central area did not show cell necrosis, and the structures of liver sinusoids, liver cell cord and the nuclei of hepatocytes were preserved. However, electron microscopic examination of tissue immediately after RFA showed destruction of mitochondria of hepatocytes and fixation of sinusoidal cells. One week later, there was a large quantity of debris in the enlarged sinusoids, in addition to irreversible destruction of hepatocyte organelles. RFA of the porcine liver causes hepatocyte damage. This damage was not evident by light microscopy but clearly identified by electron microscopy.     

Effect of interferon treatment on serum 2',5'-oligoadenylate synthetase levels in hepatitis C-infected patients

Interferon (IFN) is widely used for patients with hepatitis C. Less than half of treated patients respond to IFN therapy, however, and increased resistance to IFN is particularly observed in genotype 1b patients. Recently, genotype 1b patients with the wild type sequence in the NS5A gene were shown to be resistant to therapy, suggesting that the NS5A protein may be involved to IFN resistance. Thus, we investigated the serum 2',5'-oligoadenylate synthetase (2',5'-OAS) levels before and during IFN treatment. In addition, other biochemical markers and NS5A mutations were also examined in 30 HCV genotype 1b-positive patients. Before IFN treatment, 2',5'-OAS activity in sera was significantly lower in wild type patients than in mutant type patients. All patients were subsequently enrolled in IFN therapy, and 2',5'-OAS activity was elevated both in wild and mutant type patients, irrespective of the number of mutations in NS5A. Logistic regression analysis revealed that clearance of serum HCV RNA was independently related to the pretreatment viral load and NS5A mutations, but not to serum 2',5'-OAS activity. We concluded that the NS5A protein, that is associated with the outcome of IFN therapy, affects the kinetics of IFN-induced molecules, such as 2', 5'-OAS. 2',5'-OAS activity does not, however, seem to be related to long-term virological response to IFN therapy.     

Differences in heart rate variability between young and elderly normal men during graded head up tilt

An autoregressive spectral analysis of heart rate variability (HRV) was used to analyze the differences in autonomic functions during graded head up tilt (HUT) between young and elderly men. After recording at the 0 degree position, the table was rotated to an upright position. The incline of the table was increased progressively to 15 degrees, 30 degrees and 60 degrees. The data obtained from seven young subjects (mean age of 20.0 years) and nine elderly subjects (mean age of 63.3 years) were analyzed. The high frequency components expressed by normalized units (HFnu) were used as the parasympathetic indicators, and HFnu decreased with tilt angle in both age groups. These results suggested that parasympathetic withdrawal have an important role in adaptation to an upright posture in both age groups. However, mean HF amplitude at the 0 degree position in elderly men was not significantly different from that of young men at 60 degrees tilt. A significant interaction effect (age group x tilt angle) was found for mean HF amplitude. The increase of the low frequency components expressed by normalized units (LFnu) and the LF-to-HF ratio in elderly subjects from 0 degree to 15 degrees seemed to be larger than that in young subjects. Sympathetic activities may be sensitive to lower levels of orthostatic stress in the elderly, and the elderly workers are easily affected by a change in workload. Therefore, keeping the workload lower and constant may be recommended to avoid excessive sympathetic activation among the elderly.     

OPC-8212, a quinoline derivative, counteracts the reduction in type III collagen mRNA due to lipopolysaccharides in cultured rat cardiac fibroblasts

Fibrillar collagen plays an essential role in ventricular remodeling, which is a major prognostic factor in various heart diseases. Inflammatory cytokines, including tumor necrosis factor alpha (TNFalpha), have been reported to play a role in various heart diseases and OPC-8212, a quinolinone derivative, has been demonstrated to reduce TNFalpha production. No studies have examined the effects of OPC-8212 on collagen metabolism in connection with inflammatory cytokine and growth factors. Using lipopolysaccharides as a tool to enhance TNFalpha, we examined the effects of OPC-8212 on the expression of type III collagen mRNA [alpha1(III)] in cultured neonatal rat cardiac fibroblasts. We also measured the concentration of TNFalpha and transforming growth factor beta (TGFbeta) in the cultured medium. Northern blot analysis revealed that LPS reduced the expression of alpha1(III) mRNA, and OPC-8212 counteracted this reduction (on average 25% above the reduced level by LPS stimulation). LPS enhanced the TNFalpha concentration in the medium, and OPC-8212 inhibited this enhancement. LPS increased the TGF-beta1 concentration in the cultured medium, while OPC-8212 did not affect this increase. In summary, OPC-8212 counteracted the reduction in type III collagen mRNA expression by LPS accompanied by suppression of the increase in TNFalpha.