Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats

Background  Branched-chain amino acids (BCAAs) reportedly inhibit the incidence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and obesity that is frequently associated with insulin resistance (IR). However, the possible mechanism is still obscure. The aim of the present study was to examine the effect of BCAAs, especially in conjunction with angiogenesis, on hepatocarcinogenesis under the condition of IR. Methods  The effect of BCAAs on the development of liver enzyme-altered preneoplastic lesions and angiogenesis was examined in obese diabetic Otsuka Long-Evans Tokushima Fatty rats. We also performed an in vitro study to elucidate the possible mechanisms involved. Results  Treatment with BCAAs markedly inhibited glutathione-S-transferase placental form (GST-P)-positive preneoplastic lesions along with suppression of neovascularization in the liver. The hepatic expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, was also attenuated. BCAA treatment significantly suppressed glucose- and insulin-induced in vitro angiogenesis in the presence of VEGF. Conclusions  In obese diabetic rats BCAAs exerted a chemopreventive effect against HCC, associated with the suppression of VEGF expression and hepatic neovascularization. Since BCAA preparations are widely used in clinical practice for patients with chronic liver diseases, this agent may represent a new strategy for chemoprevention against HCC in the future.     

Comparative analysis of systolic and isolated diastolic dysfunction: Sado heart failure study

Determining the type of cardiac dysfunction is important for implementing therapeutic strategies and for prognostic insights. We characterized systolic dysfunction (SD) and isolated diastolic dysfunction (IDD) in adults referred for echocardiographic evaluation, and compared their clinical and other characteristics. In the present work, we studied 218 patients (137 males) with cardiac dysfunction (mean age, 66.3 +/- 8.3 years). SD was defined as a left ventricular ejection fraction (LVEF) of < 45%, whereas IDD was defined as a LVEF >or= 45% in addition to the standard Doppler-echocardiography diagnostic criteria for IDD. Approximately 68% of subjects had SD (70% males). The proportions of hypertension, diabetes, and dyslipidemia were 44%, 26%, and 22%, respectively, without significant association with the type of dysfunction. Myocardial infarction (MI) was found in 31% of patients, and was significantly (P < 0.001) more prevalent among SD compared with IDD cases. Cerebral stroke (18%) and malignancy (16%) were significantly associated with IDD (29% versus 13% for SD in the case of stroke, and 26% versus 11% for SD in the case of malignancy; P = 0.008 for each). In multivariately-adjusted logistic regression analysis, the following variables were found to be significantly (P < 0.05) and independently associated with IDD: female gender (odds ratio [OR] = 2.207 [95% CI = 1.302-4.608]), stroke (OR = 2.009 [1.119-3.980]), and malignancy (OR = 2.016 [1.230-4.010]). On the other hand, previous MI (OR = 2.075 [1.769-4.808]) was independently associated with SD. In conclusion, some factors/comorbidities were more likely to associate with IDD (female gender, stroke, and malignancy) or SD (previous MI) when IDD and SD were compared with each other.     

Regulation of macrophage phagocytosis of syngeneic erythrocytes by T-cell subsets from NZB mice: differential effects of T cells from young and old mice.

The regulation of syngeneic erythrophagocytosis (EP) by macrophages (M phi) harvested from young and old NZB mice was examined by spectrophotometric assay and morphological observation. Peritoneal exudate M phi from young NZB mice weakly ingested syngeneic red blood cells (RBC). T cells derived from old NZB mice accelerated ingestion of RBC by young M phi. On the contrary, T cells from young NZB mice suppressed EP by young T cells appeared clearly when they were added to M phi derived from old mice, which ingested syngeneic RBC actively without help by old NZB T cells. Namely, such an active EP by old M phi was completely suppressed when they were incubated with young T cells. Simultaneous addition of both young and old T cells to either young or old NZB M phi with RBC suppressed the EP. Pretreatment of young T cells with anti-Lyt 1.2 antibody and complement (C) made the suppressive activity prominent, and preincubation with anti-Lyt 2.2 and C eliminated the suppressive activity, but gave rise to the enhancing activity. Young T-cell homogenates added to younger or old M phi together with RBC did not reveal suppressive activity for EP, and on the contrary facilitating activity appeared predominantly. Young and old T-cell homogenates added together to young M phi did not suppress EP. The largest of T-cell-factor accelerating EP was M phi, but not RBC. M phi with active EP belong to Ia-bearing subpopulations.     

Involvement of Nax sodium channel in peripheral nerve regeneration via lactate signaling

Na_x, a sodium concentration‐sensitive sodium channel, is expressed in non‐myelinating Schwann cells of the adult peripheral nervous system, but the pathophysiological role remains unclear. We found that functional recovery of the hind paw responses from the sciatic nerve transection was delayed in Na_x knockout ( ) mice. Histological analyses showed a decrease in the number of regenerated myelinated axons in sciatic nerves. The delay in the recovery in mice was improved by lactate and inhibited by a monocarboxylate transporter inhibitor. In vitro experiments using cultured Schwann cells showed that lactate release was enhanced by endothelin (ET)‐1 and blocked by an ET receptor type B antagonist. Here, it is conceivable that Na_x was activated by ET‐1. The amount of lactate release by ET‐1 was lower in mice than in wild‐type mice. These results indicated that Na_x is functionally coupled to ET for lactate release via ET receptor type B and is involved in peripheral nerve regeneration.     

Aortic atresia with Ebstein's and Uhl's anomaly in corrected transposition of the great arteries: clinicopathologic findings

The common form of aortic atresia is associated with atrioventricular and ventriculoarterial concordant connections, but it has been very rarely found in "discordant connection" in the literature. In a 6-day-old male infant, clinical and postmortem pathologic features of this rare lesion, associated with Ebstein's and Uhl's anomaly in "congenitally corrected transposition" in situs solitus, are described. A possible pathogenesis is suggested for the concomitant presence of aortic atresia and poor-functioning, morphologic right ventricle.     

Identification of a novel tobacco DnaJ-like protein that interacts with the movement protein of tobacco mosaic virus

The movement protein (MP) of tobacco mosaic virus (TMV) mediates the transport of viral RNA from infected cells to neighboring uninfected cells via plasmodesmata by interacting with putative host factors. To find such host factors, we screened tobacco proteins using the yeast two-hybrid system. NtMPIP1, a novel subset of DnaJ-like proteins, was identified from a tobacco cDNA library, and its specific interaction with TMV MP was confirmed with an in vitro filter-binding assay. In a deletion analysis, using a series of truncated TMV MPs and NtMPIP1s, at least two regions of TMV MP, amino acid residues 65–86 and 120–185, conferred the ability to interact with the C-terminal domain of NtMPIP1, which is thought to be involved in substrate binding. Virus-induced gene silencing of NtMPIP1 significantly inhibited the spread of TMV. Therefore, it is reasonable to consider that endogenous NtMPIP1 is a host factor involved in virus cell-to-cell spread by interacting with TMV MP. Nucleotide sequence data reported are available in the DDBJ/EMBL/GenBank databases under accession number AB092334.     

Levels and expressions of orotate phosphoribosyltransferase in gastric carcinoma and normal gastric mucosa tissues

Background Orotate phosphoribosyltransferase (OPRT; EC 2.4.2.10), a key enzyme that catalyzes one of the primary steps in the phosphorylation of fluoropyrimidine, was recently recognized as an important enzyme that determines the anticancer effects of the dihydropyrimidine dehydrogenase-inhibitory fluoropyrimidine, S-1. Methods Levels of OPRT were examined in 97 gastric carcinoma tissues and 65 normal gastric mucosa tissues obtained from patients with gastric carcinoma. The relation between OPRT levels and clinicopathological variables was evaluated, and correlations of OPRT with thymidylate synthase and dihydropyrimidine dehydrogenase levels in gastric carcinoma tissues were evaluated. Results Although OPRT levels were high in well-differentiated and localized carcinomas, they were not correlated with other clinicopathological variables or with the pathological stage of gastric carcinoma. Levels of OPRT were significantly higher in gastric carcinoma tissue than in normal gastric mucosa. OPRT levels were not correlated with levels of either thymidylate synthase or dihydropyrimidine dehydrogenase. In samples of gastric carcinoma tissues and normal gastric mucosa tissues obtained simultaneously from 24 patients, no correlation was found between OPRT levels in gastric carcinoma and levels in normal gastric mucosa. Conclusion These results suggest that the OPRT level is significantly higher in gastric carcinoma tissue than in normal gastric mucosa and that the OPRT level in gastric carcinoma is a novel variable that is independent of the levels of other previously known enzymes related to 5-fluorouracil (FU) metabolism.     

Criteria revision and performance comparison of three methods of signal detection applied to the spontaneous reporting database of a pharmaceutical manufacturer.

BACKGROUND AND OBJECTIVE: Several statistical methods exist for detecting signals of potential adverse drug reactions in spontaneous reporting databases. However, these signal-detection methods were developed using regulatory databases, which contain a far larger number of adverse event reports than the databases maintained by individual pharmaceutical manufacturers. Furthermore, the composition and quality of the spontaneous reporting databases differ between regulatory agencies and pharmaceutical companies. Thus, the signal-detection criteria proposed for regulatory use are considered to be inappropriate for pharmaceutical industry use without modification. The objective of this study was to revise the criteria for signal detection to make them suitable for use by pharmaceutical manufacturers. METHODS: A model comprising 40 drugs and 1000 adverse events was constructed based on a spontaneous reporting database provided by a pharmaceutical company and used in a simulation to investigate appropriate criteria for signal detection. In total, 1000 pseudo datasets were generated with this model, and three statistical methods (proportional reporting ratio [PRR], Bayesian Confidence Propagation Neural Network [BCPNN] and multi-item gamma Poisson shrinker [MGPS]) for signal detection were applied to each dataset. The sensitivity and specificity of each method were evaluated using these pseudo datasets. The optimum critical value for signal detection (i.e. the value that achieved the highest sensitivity with 95% specificity) was identified for each method. The optimum values were also examined with the adverse events classified into two categories according to frequency. The three original detection methods and their revised versions were applied to a real pharmaceutical company database to detect 173 known adverse reactions of four drugs. RESULTS: The 1000 pseudo datasets consisted of an average of 81 862 reports and 11,407 drug-event pairs, including 1192 adverse drug reactions. The sensitivities of PRR, BCPNN and MGPS methods were 49%, 45% and 26%, respectively, whereas their specificities were 95%, 99.6% and 99.99%, respectively; these sensitivities were unacceptably low for pharmaceutical manufacturers, whereas the specificities were acceptable. The highest sensitivity for each method, obtained by changing critical values and maintaining specificity at 95%, was 44%, 62% and 62%, respectively. When adverse events were classified into two categories, sensitivities as high as 75% for regular events and 39% for rare events were achieved with the revised BCPNN method. The critical values of the information component minus two standard deviations (IC - 2SD) index of the revised BCPNN method were greater than -0.7 for regular events and greater than -0.6 for rare events. The revised BCPNN method yielded 51% sensitivity and 89% specificity for the real dataset. CONCLUSION: A lower critical value may be needed when signal-detection methodology is applied to the spontaneous reporting databases of pharmaceutical manufacturers. For example, it is recommended that pharmaceutical manufacturers use the BCPNN method with IC - 2SD criteria of greater than -0.7 for regular events and greater than -0.6 for rare events.