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Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP–CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.

BackgroundWith increasing use of EMR for early stage esophageal carcinoma, the number of cases of iatrogenic esophageal perforation is likely to increase. This study evaluated the results of endoscopic clip application for treatment of perforations caused by EMR in patients with esophageal carcinoma.MethodsAmong 185 patients who underwent EMR for esophageal carcinoma, esophageal perforation occurred in 3 patients (1.6%). Metallic clips were immediately applied endoscopically to close the perforations.ObservationsAll 3 patients were observed closely and were managed conservatively (intravenous hyperalimentation, antibiotics) after closure of the perforation. They were discharged without any further serious complication.ConclusionsWhen esophageal perforation caused by EMR is immediately recognized, endoscopic application of metallic clips is appropriate therapy. However, patients must be carefully monitored for the development of generalized mediastinitis.

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is related to Helicobacter pylori infection. Specifically, it has been pointed out that pathogenesis of MALT lymphoma involves the 60-kDa heat shock protein (hsp60). To investigate humoral immune responses to the H. pylori hsp60 in patients with gastroduodenal diseases and patients with MALT lymphoma, the hsp60 of H. pylori was expressed with a glutathione S-transferase fusion protein and was purified (recombinant hsp60). Sera were obtained from H. pylori-positive patients with gastroduodenal diseases (MALT lymphoma, n = 13; gastric ulcer, n = 20; duodenal ulcer, n = 20; gastritis, n = 20) and from H. pylori-negative healthy volunteers (n = 9). Sera from patients with MALT lymphoma were also obtained at two times: before and after eradication therapy. Antibodies to hsp60 and H. pylori were assessed by enzyme-linked immunosorbent assay. The levels of immunoglobulin G (IgG) antibodies to the hsp60 of H. pylori-positive patients with gastroduodenal diseases were significantly elevated compared to those in the controls. The levels of IgG1 antibodies to hsp60 were elevated and correlated with the levels of anti-H. pylori antibodies in patients with MALT lymphoma. Humarol immunity against hsp60 may be important and relevant to gastroduodenal diseases induced by H. pylori infection.

Background: Although early diagnosis of esophageal carcinoma is an important determinant of outcome, early stage carcinomas are rarely detected on routine endoscopic examination. Iodine staining may be useful in the detection of early stage esophageal carcinoma, especially in high-risk populations. In a prior study, 29.2% (68/233) patients with superficial esophageal carcinoma (SEC) undergoing resection at our hospital had other nonesophageal primary carcinomas, suggesting that patients with nonesophageal primary cancers are at increased risk for the development of esophageal cancer. The aim of the current study was to determine whether endoscopic screening with iodine staining is useful for the detection of SEC in patients with a history of none-sophageal cancers. Patients and Methods: In a prospective study, 331 patients with nonesophageal primary cancers were screened for esophageal cancer by endoscopic examination with iodine staining. All patients were men 55 years of age or older. Results: Nine patients (2.7%) with SEC were identified. Among these patients, 7 with mucosal cancer were treated by endoscopic mucosal resection, and 2 with submucosal cancer were treated by surgical resection or radiation therapy. Five patients (1.5%) were found to have cancer confined to the epithelium or the lamina propria. These lesions were difficult to detect by conventional endoscopic screening and were cured by endoscopic mucosal resection. After exclusion of 51 patients with head and neck cancer, the incidence of SEC was still 2.1% (6/280), higher than reported in prior screening studies. Conclusions: All men with a history of nonesophageal primary cancers should undergo endoscopic screening for esophageal cancer. Endoscopic iodine staining in such patients may be useful in screening for early stage esophageal carcinoma. (Gastrointest Endosc 2001;53:1-5.)

Shales often show strong elastic anisotropy that originate from the alignment and platy nature of its constituent minerals. Despite its impact on amplitude variation with offset response and seismic time‐shifts, elastic anisotropy of shales is, however, often ignored since it is difficult to measure enough parameters in the field. Being able to correctly estimate anisotropy parameters of shales can therefore significantly improve seismic reservoir characterization. A predictive model is developed by combining existing theories. Properties of locally aligned clay platelets, called domains, are calculated using a rock physics model based on the anisotropic Hashin‐Shtrikman estimates. The effect of domain orientation is then accounted for by the orientation distribution function of domains. The applicability of the model was investigated using existing core measurements. Interesting findings include: (a) most of modeled anisotropy parameters are consistent with the measured values even though only limited information was used for the model parameters optimization, and (b) most of optimized interplatelet medium properties are consistent with the saturated fluid and small interplatelet medium shear modulus suggested by existing studies. These findings imply that the model can be used to predict anisotropy parameters from limited information. Shales often show strong elastic anisotropy and it has certain impact on amplitude variation with offset response and seismic time‐shifts. Elastic anisotropy of shales is, however, often ignored since it is difficult to measure enough parameters in the field. A predictive rock physics model is developed based on the recently published Sayers‐den Boer approach. We show how the model can be used to make realistic estimates of anisotropy parameters based on limited data. A predictive rock model is developed based on the recently published Sayers‐den Boer approach and compaction‐dependent domain orientationAnisotropy parameters delta and epsilon can be reasonably estimated from limited information using the modelOptimized parameters based on measured data, interplatelet medium properties, are consistent with the saturated fluid and existing studies A predictive rock model is developed based on the recently published Sayers‐den Boer approach and compaction‐dependent domain orientation Anisotropy parameters delta and epsilon can be reasonably estimated from limited information using the model Optimized parameters based on measured data, interplatelet medium properties, are consistent with the saturated fluid and existing studies

Abstract: Foetal magnetocardiograms (FMCGs) were measured using a ninechannel SQUID system equipped with first-order gradiometers (60 mm baseline, 20 mm diameter). The system was installed in a magnetically shielded room in a hospital. The white noise level was less than$$10 fT/\sqrt {Hz} $$, and FMCGs above 1 pT were detected. These results and the depth to the foetal heart were used to estimate the current dipole. The relationship between the current dipole (Q) and the gestation week (G) was calculated and the average performance was determined as Q=18G −295. By using the estimated foetal current dipole, the measurement limit (average value) between depth and gestation weeks was determined. When the depth from the pickup coil to the foetal heart is 50, 60, 70 and 80 mm, the first detectable gestation weeks of FMCGs above 1 pT measured by a first-order gradiometer with 60 mm baseline were determined at 21, 23, 26, and 30 weeks respectively, and the detectable gestation weeks in the case of a 30 mm baseline were determined at 22, 26, 30 and 36 weeks respectively.

Itraconazole is a triazole antifungal agent that inhibits cell membrane serol biosynthesis. Currently, itraconazole is a potent candidate for in vivouse to revert multidrug resistance in acute leukemias, with the added benefit of its antifungal effect. As previously reported, itraconazole, as well as verapamil, reversed adriamycin-resistant K562 cells (K562/ADR) and HL60 cells (HL60/ADR) in dosages compatible to the plasma levels achieved by the therapeutic dosages used for the treatment of fungal infections. By RT-PCR analysis of mdr1, mdr3, and mrp mRNA, these adriamycin-resistant cells showed a higher expression of the transcript of these genes than those of the parent cells. By FACS analysis, both the adriamycin-resistant cells showed a higher expression of P-glycoprotein on their cell surfaces. These results suggested the involvement of itraconazole in the mdr gene and/or mrp gene product-associated resistance. Furthermore, itraconazole partially reversed etoposide resistance in both the K562 and K562/ADR cells. The present study suggests that itraconazole may reverse multidrug resistance, at least in part, via a classical MDR-associated mechanism.

Recombinant human granulocyte colonystimulating factor (rhG-CSF)-mobilized peripheral blood stem cells (PBSC) are now widely used for autologous transplantation to provide hematopoietic stem cells after intensive chemoradiotherapy. However, PBSC which contain a large number of T cells represent a potential risk for graft-versus-host disease (GVHD) in allogeneic (allo) transplantation. There are about 50 case reports of clinical trials of rhG-CSF-mobilized allo PBSC transplantation (PBSCT) with relatively rapid hematological recovery, without severe acute GVHD except in a few cases. Therefore, the risk of inducing severe acute GVHD is not as high as was expected when allo PBSCT began. However, whether allo PBSCT will increase the risk of chronic GVHD is not clear, because the period of observation has been too short. Also, it will be of interest to determine the clinical effect of allo PBSCT on relapse of hematological malignancy post-transplant. Whether allo PBSCT will increase life-threatening acute and chronic GVHD, and whether PBSC allografting will result in permanent hematological and immunological reconstitution has to be determined by prospective randomized clinical trials.

Immunosuppressants cyclosporin A (CsA), FK506, and KM2210 modulated colony formations of murine hematopoietic progenitor cells. In a 4-h treatment with CsA, 10 µg/ml increased the formation of colony-forming units of mixed lineages (CFU-Mix) but decreased the formation of highly proliferative potential colony-forming units (CFU-HPP); 1 µg/ml of CsA increased the formations of CFU-HPP, CFU-Mix, and colony-forming units of granulocytes/macrophages (CFU-GM); 0.1 µg of CsA increased the formation of CFU-Mix and burst-forming units of erythroid lineage (BFU-E). Lower doses of CsA appeared to induce an increase in various colony formations. FK506 increased CFU-HPP and CFU-Mix formations at lower doses. Another immunosuppressant, KM2210, increased CFU-HPP and CFU-GM formations but decreased CFU-Mix and BFU-E formations. In a 24-h treatment, 10 µg/ml and 1 µg/ml of CsA inhibited all the colony formations, but 0.1 µg/ml of CsA increased CFU-Mix, CFU-GM, and BFU-E formations. Similarly, 100 ng/ml and 10 ng/ml of FK506 decreased all the colony formations but 1 ng/ml of FK506 increased CFU-HPP and CFU-GM formations. KM2210 inhibited all the colony formations. These findings showed that lower doses of CsA and FK506 appeared to increase the colony formations, although higher doses of these drugs decreased the colony formations, similar to the findings in a 4-h treatment. On the other hand, KM2210 showed opposing effects on colony formation with 4-h and 24-h treatments.

In order to determine the relevance of the p53 tumor suppressor gene mutations in acute myelogenous leukemia (AML), we analyzed the p53 gene in genomic DNA of 18 unselected cases of AML by polymerase chain reaction–single-strand conformation polymorphism (PCR–SSCP) and direct sequencing. We detected three cases (16.7%) with the p53 gene mutations showing only the mutant alleles; the high incidence in cases with loss of a whole chromosome 17 (two of three) contrasted with the low incidence in cases without abnormalities of chromosome 17 (one of 15). These cases containing the mutations of the p53 gene showed a poor prognosis. Although we analyzed a rather small series of patients, these findings suggest that the p53 gene mutations might be involved in the progression and prognosis of at least some cases of AML.

Hepatitis C virus (HCV) appears to circulate in various forms such as native virion, immune complexes, and nucleocapsids during chronic infections. To determine the association of the physicochemical properties of HCV and its response to interferon therapy in patients with chronic hepatitis C, we examined pretreatment serum samples from 43 patients with HCV RNA who had received interferon therapy, using differential flotation centrifugation in a NaCl solution with a density of 1.063 g/ml. After centrifugation, the ratio of HCV RNA in the top and bottom fractions was determined by the polymerase chain reaction and expressed as T/B. Patients with a sustained response to IFN therapy were found to have higher T/B ratios than transient responders who relapsed after treatment (P< 0.01) and nonresponders (P< 0.01). With regards to HCV genotypes, patients with genotype 1b had higher T/B ratios in the sustained response group than in the nonsustained response group (P= 0.001), but patients with genotype 2 had a similar distribution of T/B among the 3 response groups (not significant). These findings indicate that the physicochemical properties of HCV affect the effectiveness of interferon therapy, particularly in patients with genotype 1b. J. Med. Virol. 52:190–194, 1997. © 1997 Wiley‐Liss, Inc.

Helicobacter pylori is a major etiologic agent in gastroduodenal disorders. In this study, immunoglobulin A (IgA) antibodies to H. pylori antigens were evaluated in serum and gastric juice specimens obtained from patients with gastritis or peptic ulcers by utilizing antibody capture enzyme-linked immunosorbent assays (ACELISAs). Urease alpha subunit (UA), urease beta subunit (UB), the 66-kDa heat shock protein (HSP), and the 25-kDa protein (25K) were used as antigens for the ACELISAs. The antibody titers of the ACELISAs reflect the ratio of H. pylori-specific IgA to total IgA. The ratio is stable, although the antibody concentration fluctuates in gastric juice. By using ACELISAs it was possible to evaluate quantitatively not only serum IgA antibodies but also gastric juice secretory IgA (S-IgA) antibodies. In both serum IgA and gastric juice S-IgA ACELISAs, the titers of antibody to HSP and 25K were remarkably correlated with the histologic grade of gastritis, whereas those to UA and UB were not strongly correlated with histologic grade. Thus, it is useful for estimating the histologic grade of gastritis to quantify serum IgA and gastric juice S-IgA antibodies to HSP and 25K.

The cause of gastric cell injury induced by Helicobacter pyloriwas investigated in vitro using gastric mucosal cells derived from male Japanese white rabbits. To evaluate the contribution of the potent urease activity of H. pylorito gastric mucosal cell injury, the supernatant of the H. pyloribacterial pellet, solubilized with N-octyl-glucoside, was added to the gastric mucosal cell suspension. Cell injury was assessed by lactate dehydrogenase (LDH) release into the extracellular fluid. Treatment of cells withH. pyloriextracts together with urea resulted in high levels of LDH release, suggesting definite gastric mucosal cell injury, and elevation of ammonia concentration was also observed. In contrast, incubation with H. pyloriextracts alone or urea solution alone did not result in increased LDH release or elevated ammonia concentrations. The degree of LDH release from gastric mucosal cells due to H. pyloriextracts in the presence of urea was similar to that induced by administration of the same amount of exogenous ammonia. The addition of acetohydroxamic acid, a potent specific urease inhibitor, remarkably inhibited ammonia production, the elevation of pH of extracellular fluid, and LDH release in a dose-dependent manner. These results suggest that ammonia produced by potent urease activity ofH. pyloriin the presence of urea plays an important role in the pathogenesis of gastric mucosal cell injury.

A decision circuit IC applicable to 10 Gbit/s optical communication systems has been implemented with AlGaAs/GaAs heterojunction bipolar transistors (HBTs). A 10Gbit/s operation of the D-type M/S flip-flop decision circuit was observed with a clear eye diagram. A good sensitivity of 13mVpp and a wide phase margin of 300 degrees at 5 Gbit/s were also obtained.

A cytogenetically normal man with severe aplastic anemia was treated with granulocyte colonystimulating factor (G-CSF), erythropoietin (EPO), cyclosporin A, anti-thymocyte globulin, and interleukin-6 (IL-6), which resulted in a gradual improvement in his neutrophil count and hemoglobin level. After 2 years of the therapy, monosomy 7 was detected during cytogenetic analysis of his bone marrow, which evolved during a period of 5 months into acute myeloblastic leukemia. An in vitro proliferation assay of cytokine responses showed that leukemic blasts were sensitive only to G-CSF, and not to EPO or IL-6. Although allogeneic bone marrow transplantation from an HLA-matched unrelated donor was carried out in the non-remission stage, the patient died of systemic fungal infection on day 25, without any evidence of hematological engraftment. As long-term use of cytokines and immunomo-suppressants in patients with severe aplastic anemia may induce or hasten the onset of a malignant transformation, careful attention must be paid to clonal evolution. Due to the poor prognosis of secondary myelodysplasia and leukemia, allogeneic bone marrow transplantation for such patients must be carried out early in the course of the disease.

An ultrahigh-speed multiplexer (MUX) circuit has been developed for future optical transmission systems. The IC was fabricated with 160 GHz fmax AlGaAs/GaAs HBTs. Error-free 40 Gbit/s operation with an 0.8 V peak-to-peak output voltage swing was confirmed. Its 50 Gbit/s operation with an output voltage swing of 0.3 V peak-to-peak was also verified. These are, to the authors' knowledge, the fastest operation speeds ever reported for a MUX IC implemented with any type of device.