New pharmaceutical treatment of gastric MALT lymphoma: anti-angiogenesis treatment using VEGF receptor antibodies and celecoxib.

In addition to eradication of Helicobacter pylori, chemotherapy with anticancer agents, and radiation therapy, the treatment with molecular target drugs including rituximab, a CD20 antagonist, is one of the promising new regimens. The mucosa-associated lymphoid tissue (MALT) lymphoma is histologically characterized by rich distribution of the microvascular network consisting of the immature capillaries, lymphatics and venules, and this microvascular network could be the target of the new pharmacotherapy in addition to the direct action on the accumulated B lymphocytes. We have established the animal model of the gastric MALT lymphoma by the Helicobacter heilmannii (H. heilmannii) peroral infection of C57BL/6 mice. The disease induced by this model is very similar to the human counterpart, because of the lymphoepithelial lesion characteristic of the human MALT lymphoma as well as the rich vascularization and localization of vascular endothelial growth factor (VEGF) and its receptors, Flt-1, Flk-1 and Flt-4. By administering VEGF receptor antibodies or celecoxib, one of the cyclooxygenase 2 inhibitors, we were able to induce a significant decrease in the size of the tumor and the apoptotic changes of the endothelial cells of the microvascular network. These antiangiogenic strategies were suggested to be candidates for the new pharmacological treatment of gastric MALT lymphoma, when other treatments are not effective.

Musashi-1 post-transcriptionally enhances phosphotyrosine-binding domain-containing m-Numb protein expression in regenerating gastric mucosa.

OBJECTIVE: Upregulation of the RNA-binding protein Musashi-1 (Msi1) has been shown to occur in rat gastric corpus mucosa after ethanol-induced mucosal injury. However, there is no direct evidence linking Msi1 with gastric regeneration. We examined the process of tissue repair after acute gastric mucosal injury with Msi1-knock-out (KO) mice to clarify the role of Msi1 and Msi1-dependent regulation of m-Numb expression in regenerating gastric mucosa. METHODS: Acute gastric injury was induced in Msi1-KO and wild-type ICR mice by administering absolute ethanol. Expression of the splicing variants of m-Numb mRNA and protein in the gastric mucosa were analyzed by quantitative RT-PCR and western blotting, respectively. RESULTS: We demonstrated that phosphotyrosine-binding domain-containing m-Numb expression was significantly upregulated at both the mRNA and protein levels in wild-type mice at 3 h after ethanol-induced acute gastric injury. In contrast, in Msi1-KO mice, the m-Numb protein was expressed weakly, and was associated with delayed regeneration of the injured gastric mucosal epithelium. In the Msi1-KO mouse, the ratio of m-Numb mRNA to total m-Numb mRNA in the heavy polysome fractions was lower than that in the wild-type mouse. Further, we showed that m-Numb-enhancement in gastric mucous cells induced the expression of prostate stem cell antigen and metallothionein-2. Under the m-Numb enhancing condition, the gastric cells exhibited enhanced cell proliferation and were significantly more resistant to H(2)O(2)-induced cell death than control cells. CONCLUSIONS: Msi1-dependent post-transcriptional enhancement of m-Numb is crucial in gastric epithelial regeneration.

[A case of small intestine type steroid-naïve Crohn disease in which osteomalacia was diagnosed by fractures on the transcervical bone].

We present a 35-year-old Japanese man with Crohn disease. He underwent ileocolectomy for ileum perforation when he was 28 years old, Crohn ileitis was diagnosed and medical treatment was commenced. When he was 35 years old, he complained of severe pain of the right upper torso and the left leg with no apparent trigger. A full check-up revealed that he had multiple fractures including a transcervical fracture of the left femur, ribs on both sides, and fracture of the sacroiliac joint. He had no history of prior use of steroids, and the fractures were thought to have been caused by vitamin D deficiency. This case suggests that clinicians should be aware of the possibility of osteomalacia caused by malabsorption of fat-soluble vitamin D when examining patients with ileocolic Crohn disease.

Disadvantages of peginterferon and ribavirin treatment in older patients with chronic hepatitis C: an analysis using the propensity score.

PURPOSE: Peginterferon (PEG-IFN) and ribavirin (RBV) combination treatment for patients with chronic hepatitis C (CHC), infected by genotype-1 hepatitis C virus with high viral loads, results in a sustained viral response (SVR) in ~50%. However, a trend of decreasing SVR in the older patients has been reported. In the present study, we verified this trend of treatment efficacy in older patients using the propensity score (PS). METHODS: We conducted a survey of 327 patients with CHC (genotype 1 and high viral loads) who were treated with PEG-IFN and RBV for 48 weeks. The SVR rate was compared between patients =60 and <60 years of age. Because backgrounds of these patients differed considerably, we verified this efficacy between the older (n = 102) and younger (n = 102) patients matched for gender, body weight, platelets (PLT), and red blood cell (RBC) counts using PS. RESULTS: The total SVR rate was 42.9% (161/327); this rate decreased with increasing age and was lower in the older patients (≥60 years: 41.5%, <60 years: 54.3%, P = 0.0245). Moreover, younger age was a significant factor for SVR. After correction by PS, the SVR in older patients remained significantly lower (≥60 years: 43.1%, <60 years: 57.8%, P = 0.0497). In addition, RBC counts and hemoglobin (Hgb) concentrations, as well as RBV adherence in the older patients, decreased with this treatment, although there were no significant differences in pretreatment RBC and Hgb levels. CONCLUSIONS: The analysis using PS indicated that RBV adherence in the older patients decreased even if they did not have lower pretreatment RBC and Hgb levels.

[A case of pneumatosis cystoides intestinalis induced by steroid pulse therapy for severe acute hepatitis B].

A 26-year-old Japanese woman was admitted to the hospital because of fever and general fatigue. A diagnosis of acute hepatitis B was given because of high levels of transaminase and positivity for HBs-Ag, HBe-Ag and HBc-IgM. On the 2nd day progression to fulminant hepatitis was suspected, and steroid pulse therapy, cyclosporin, entecavir, and interferon-ß were started. Her laboratory data improved until transaminase showed an increase on 18th day, and steroid was once again administered. Abdominal CT scan and plain abdominal X-ray showed pneumatosis cystoides intestinalis (PCI) mainly along the ascending colon without any symptoms. After discontinuation of steroid therapy, abnormal gas gradually disappeared. This is a very rare case of PCI, which may have been caused by short-term steroid pulse therapy.

Dermal mast cells reduce progressive tissue necrosis caused by subcutaneous infection with Streptococcus pyogenes in mice.

A single subcutaneous (s.c.) infection with 1×10(7) c.f.u. GAS472, a group A streptococcus (GAS) serotype M1 strain isolated from the blood of a patient suffering from streptococcal toxic shock syndrome, led to severe damage of striated muscle layers in the feet of mast cell (MC)-deficient WBB6F(1)-Kit(W)/Kit(W-v) (W/W(v)) mice 72 h after infection. In contrast, no damage was recognized in striated muscle layers in the feet of the control WBB6F(1)-Kit(+/+) (+/+) mice 72 h after infection. In addition, adoptively transferred MCs reduced progressive tissue necrosis of the feet of W/W(v) mice after infection. However, there was no significant difference in the mortality rates between the W/W(v) and +/+ mice, or between the human CD46-expressing transgenic (Tg) mouse bone marrow-derived cultured MC-reconstituted W/W(v) and non-Tg mouse bone marrow-derived cultured MC-reconstituted W/W(v) mice after infection. Consequently, although MCs can help to reduce the severity of necrosis of the feet caused by s.c. infection with GAS472, such reduction of tissue necrosis scarcely improves the mortality rates of these mice. Moreover, human CD46 does not play a crucial role in the MC-mediated innate immune defence against GAS infection.

Optimal erythrocyte ribavirin level to reduce the risk of anemia and obtain an early virological response in patients with chronic hepatitis C caused by genotype 1b infection.

Aims. To determine whether the erythrocyte phosphorylated ribavirin (RBV) level might be a useful index of EVR and risk of anemia and to determine the optimal dose of RBV in 24 patients with hepatitis C with pegylated interferon and RBV. Methodology. The RBV level was measured by a high-performance liquid chromatography. Results and Conclusion. In patients aged 50 years or over, a negative correlation (r = -0.548, P < .05) was observed between the RBV level at week 2 and rate of Hb reduction (ΔHb) at week 4. The ΔHb at week 4 was significantly greater in patients with RBV levels of ≥800 µM (-25.5 ± 10.1%) than in patients with RBV levels <800 µM (-15.6 ± 7.7%). None of the patients with RBV levels <600 µM at week 2 achieved EVR and SVR. Thus the optimal levels of erythrocyte phosphorylated RBV at week 2 of therapy in order to achieve EVR without anemia seemed to be 600-800 µM.

Suppression of lymphangiogenesis induced by Flt-4 antibody in gastric low-grade mucosa-associated lymphoid tissue lymphoma by Helicobacter heilmannii infection.

BACKGROUND AND AIMS: Our recent study revealed that per oral infection with Helicobacter heilmannii induced low-grade mucosa-associated lymphoid tissue (MALT) lymphoma in the gastric fundus of C57BL/6 mice after a period of 6 months, although the pathophysiological mechanism of lymphoma expansion remains to be clarified. The present study was undertaken to elucidate the interaction of this tumor with angiogenesis and lymphangiogenesis. In addition, the effect of Flt-4 antibodies on lymphoma expansion was investigated. METHODS: C57BL/6 female mice infected with H. heilmannii for 3 months were used in the experiments. Localization of vascular endothelial growth factor C (VEGF-C) and Flt-4 immunoreactivity were detected by indirect immunohistochemical methods. Localization of lymphatic and vascular endothelial cells was investigated by localization of prox-1. In addition, Flt-4 antibody with and without Flt-1 or Flk-1 antibodies was administered i.p. to clarify their effects on tumor size. RESULTS: MALT lymphoma has a rich microvascular network consisting of immature capillaries, lymphatics and venules. By immunohistochemical analysis, prox-1 immunoreactivity was observed mostly in the marginal area of the lymphoma, where VEGF-C and Flt-4 immunoreactivities were also seen. Stereomicroscopic study revealed that administration of Flt-4 and Flt-1 antibodies significantly reduced the surface area of the lymphoma in the mouse stomach. CONCLUSION: A VEGF-C-mediated mechanism plays an important role in the expansion of MALT lymphoma and the administration of VEGF receptor antibodies had a suppressive effect on tumor growth.

CD46 transgenic mouse model of necrotizing fasciitis caused by Streptococcus pyogenes infection.

We developed a human CD46-expressing transgenic (Tg) mouse model of subcutaneous (s.c.) infection into both hind footpads with clinically isolated 11 group A streptococcus (GAS) serotype M1 strains. When the severity levels of foot lesions at 72 h and the mortality rates by 336 h were compared after s.c. infection with 1x10(7) CFU of each GAS strain, the GAS472 strain, isolated from the blood of a patient suffering from streptococcal toxic shock syndrome (STSS), induced the highest severity levels and mortality rates. GAS472 led to a 100% mortality rate in CD46 Tg mice after only 168 h postinfection through the supervention of severe necrotizing fasciitis (NF) of the feet. In contrast, GAS472 led to a 10% mortality rate in non-Tg mice through the supervention of partial necrotizing cutaneous lesions of the feet. The footpad skin sections of CD46 Tg mice showed hemorrhaging and necrotic striated muscle layers in the dermis, along with the exfoliation of epidermis with intracellular edema until 48 h after s.c. infection with GAS472. Thereafter, the bacteria proliferated, reaching a 90-fold or 7-fold increase in the livers of CD46 Tg mice or non-Tg mice, respectively, for 24 h between 48 and 72 h after s.c. infection with GAS472. As a result, the infected CD46 Tg mice appeared to suffer severe liver injuries. These findings suggest that human CD46 enhanced the progression of NF in the feet and the exponential growth of bacteria in deep tissues, leading to death.

Prediction of survival and complications after percutaneous endoscopic gastrostomy in an individual by using clinical factors with an artificial neural network system.

BACKGROUND: The demand for percutaneous endoscopic gastrostomy (PEG) has increased because it is safe and a technically easy method, but it has risks of severe complications including death and a high mortality rate within 30 days. At present, we cannot predict survival or the incidence of complications before tube placement in an individual. Earlier studies have used traditional statistical analysis by assuming a linear relationship between clinical features, but most phenomena in the clinical situation are not linearly related. AIMS: We predicted the survival and complications before PEG placement in an individual by using artificial neural network (ANN) system, which can assess the nonlinear relationship. METHODS: We studied 100 patients who underwent PEG at the Kitasato Medical Institute Hospital from 1997 to 2005. Clinical data and laboratory data were used as input data. Complications related to PEG placement and survival dates were historically and prospectively measured. From the clinical data and laboratory data, we examined the prediction of outcome in individual patients using multiple logistic regression analysis and an ANN. RESULTS: The correct answer rate of survival by multiple logistic regression analysis was 67.9%. In contrast, using the ANN, we correctly predicted the survival date and aspiration pneumonia in 75 and 89% of patients, respectively. There was a nonlinear relationship among input factors and survival and complications. CONCLUSION: We correctly predicted the outcome and complications of individual patients with PEG with a high correct answer rate. Our data show the potential of an ANN as a powerful tool in daily clinical use to individualize treatment ('tailor-made medicine') for PEG and reduce costs.

Pentoxifylline prevents pig serum-induced rat liver fibrosis by inhibiting interleukin-6 production.

BACKGROUND/AIM: Pig serum-induced rat liver fibrosis is a model of liver fibrosis in the absence of obvious hepatocyte injury. Penoxifylline (PTX), a xanthine derivative, which is a well-known suppressor of tumor necrosis factor-alpha (TNF-alpha) production from inflammatory cells, has also been shown to inhibit the growth of hepatic stellate cells and to inhibit collagen synthesis in these cells in vitro. We investigated the effect of PTX on pig serum-induced liver fibrosis in vivo, and assessed the mechanisms of prevention of fibrogenesis by this drug. METHODS: Male Wistar rats were given intraperitoneal injections of 0.5 ml normal pig serum twice a week for 10 weeks with or without concomitant oral administration of PTX (20 mg/kg). RESULTS: Rats that received pig serum showed significant liver fibrosis, and their serum interleukin-6 (IL-6) and hyaluronic acid levels were significantly increased. The serum levels of IL-6 were well correlated with the serum levels of hyaluronic acid, and increased as the liver fibrosis progressed. Penoxifylline prevented the development of fibrosis in this animal model and reduced the serum levels of IL-6 in a dose-dependent manner. In vitro, by the addition of PTX to the culture medium of the rat hepatic stellate cells (HSCs), the proliferation of the HSCs was significantly inhibited and IL-6 in the culture supernatant was also reduced significantly. Exogenous addition of IL-6 partially restored the proliferation. CONCLUSION: Penoxifylline prevents pig serum-induced rat liver fibrosis by inhibiting the proliferation of HSCs and by inhibiting the production of IL-6 from HSCs.

Polaprezinc attenuates liver fibrosis in a mouse model of non-alcoholic steatohepatitis.

BACKGROUND AND AIM: The effect of polaprezinc, a zinc-carnosine chelate compound, on the development of non-alcoholic steatohepatitis (NASH) was investigated in dietary methionine and choline deficient (MCD) mice. METHODS: Mice were fed the MCD diet with or without polaprezinc (2.2 g/kg diet) for 10 weeks. Liver histopathology, triglyceride and lipid peroxide levels, and the expression of genes linked to fibrosis were then assessed. RESULTS: MCD mice developed steatohepatitis accompanied by mild fibrosis with an increase in lipid peroxidation, hepatic stellate cell (HSC) activation, and the augmented mRNA expression of tumor necrosis factor-alpha, transforming growth factor-beta1 and procollagen alpha1(I). The mRNA expression levels of matrix metalloproteinase (MMP)-2 and tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 were also enhanced. Histopathologically, polaprezinc supplementation did not influence the development of steatosis but it apparently attenuated fibrosis. Polaprezinc slightly reduced lipid peroxidation and suppressed HSC activation as well as the mRNA expression of pro-inflammatory cytokines. Polaprezinc affected the MCD diet-enhanced expression of TIMP-1 even when administered relatively late. CONCLUSION: These results suggest that polaprezinc attenuates fibrosis in NASH by reducing inflammation and lipid peroxidation and, during a later phase, promoting fibrolysis via the inhibition of TIMP expression in the liver. Further investigation is required to clarify the clinical efficacy of polaprezinc in patients with NASH.

Microcirculatory alteration in low-grade gastric mucosa-associated lymphoma by Helicobacter heilmannii infection: its relation to vascular endothelial growth factor and cyclooxygenase-2.

BACKGROUND: There are clinical reports that Helicobacter heilmannii, as well as Helicobacter pylori, has been clinically reported to cause gastric low-grade mucosa-associated lymphoid tissue-type (MALT) lymphoma, although its precise mechanism remains to be clarified. Thus, the present study was undertaken to elucidate the alteration of the microcirculatory structure and the relation to angiogenetic factors in mice infected with H. heilmannii for 3 and 6 months. METHODS: Immunohistochemical studies have been performed by FITC-dextran intra-aortic infusion or CD31, vascular endothelial growth factor-A, cyclooxygenase 2 antibodies using our recently established model of gastric mucosa-associated lymphoid tissue-type gastric B-cell lymphoma in C57BL/6 mice. RESULTS: Increased microcirculatory network was recognized surrounding the MALT lymphoma tissues by both the FITC-dextran infusion method and CD31 immunoreactivity. Vascular endothelial growth factor-A immunoreactivity was recognized within the lymphoma tissues as well as in the marginal area, while cyclooxygenase-2 immunoreactivity was localized in the area surrounding the MALT lymphoma tissues. CONCLUSION: Increased microvascular network as well as enhanced VEGF-A immunoreactivity was shown to be related to expansion of the MALT lymphoma formed by Helicobacter heilmannii infection.

Nonpathogenic Escherichia coli strain Nissle 1917 inhibits signal transduction in intestinal epithelial cells.

Although the probiotic Escherichia coli strain Nissle 1917 has been used for the treatment of inflammatory bowel diseases, the precise mechanisms of action of this strain remain unclear. In the present study, we estimated the anti-inflammatory effect of E. coli Nissle 1917 on inflammatory responses in vitro to determine the suppressive mechanism of Nissle 1917 on the inflammatory process. To determine the effect of E. coli Nissle 1917, the human colonic epithelial cell line HCT15 was incubated with or without E. coli Nissle 1917 or another nonpathogenic E. coli strain, K-12, and then tumor necrosis factor alpha (TNF-alpha)-induced interleukin-8 (IL-8) production from HCT15 cells was assessed. Enzyme-linked immunosorbent assays and real-time quantitative PCR showed that Nissle 1917 treatment suppressed TNF-alpha-induced IL-8 transcription and production. In addition, results from luciferase assays indicated that Nissle 1917 inhibited IL-8 promoter activity. On the other hand, these anti-inflammatory effects were not seen with E. coli K-12. In addition, heat-killed Nissle 1917 or its genomic DNA did not have this anti-inflammatory effect. Surprisingly, Nissle 1917 did not affect IL-8 transactivation pathways, such as NF-kappaB activation, nuclear translocation, and DNA binding, or even activation of other transcriptional factors. Furthermore, it also became evident that Nissle 1917 induced the anti-inflammatory effect without contact to epithelial cells. In conclusion, these data indicate that the nonpathogenic E. coli strain Nissle 1917 expresses a direct anti-inflammatory activity on human epithelial cells via a secreted factor which suppresses TNF-alpha-induced IL-8 transactivation through mechanisms different from NF-kappaB inhibition.

L-lactic acid secreted from gastric mucosal cells enhances growth of Helicobacter pylori.

BACKGROUND: Helicobacter pylori mainly inhabit the mucus layer in the gastric mucosa. However, mechanisms involving H. pylori colonization and proliferation in gastric mucosa are not well established. This study focuses on elucidating the role of gastric mucosal cells on growth of H. pylori. MATERIALS AND METHODS: H. pylori was co-cultured with the murine gastric surface mucosal cells (GSM06), and the growth of H. pylori on the cells was assessed by enumerating the colony-forming units (CFU). The H. pylori growth factor in the culture media conditioned by GSM06 cell was purified by HPLC, and the chemical structure of the growth factor was identified by analyses of (1)H- and (13)C-NMR spectra. RESULTS: A marked increase in the number of CFU of H. pylori was observed in the GSM06 cells. The enhanced H. pylori growth was also observed when indirectly incubated with GSM06 cells through semi-permeable membrane. In addition, culture media conditioned by GSM06 cell stimulated H. pylori growth approximately one thousand-fold. By bioassay-guided purification, the H. pylori growth factor was isolated from the conditioned medium of GSM06 cells and identified as L-lactic acid. The H. pylori growth-enhancing activity under microaerobic condition was well correlated with L-lactic acid concentrations in the conditioned media. CONCLUSIONS: This study demonstrates that L-lactic acid secreted by gastric mucosal cells enhances the growth of H. pylori, and this L-lactic acid-dependent growth of H. pylori may be important to the long-term colonization of H. pylori in the stomach.

Increased apoptosis and angiogenesis in gastric low-grade mucosa-associated lymphoid tissue-type lymphoma by Helicobacter heilmannii infection in C57/BL6 mice.

Helicobacter heilmannii has been reported to cause gastric low-grade mucosa-associated lymphoid tissue-type (MALT) lymphoma, but its precise pathophysiological mechanism remains to be clarified. We recently established a model of gastric B-cell MALT lymphoma in C57BL/6 mice by means of peroral infection of H. heilmannii primarily obtained from cynomolgus monkeys. Using this model, macroscopic, immunohistochemical, and electron microscopic observations of MALT lymphomas were carried out in order to examine the development of apoptosis and angiogenesis. Enhancement of the microvascular network and an increase in vascular endothelial growth factor-A were detected in the central region of the MALT lymphoma tissue in the infected mouse stomach, while vascular endothelial growth factor-C was detected at the margins of the MALT lymphomas. In addition, many H. heilmannii-invaded parietal cells showed caspase-3 immunoreactivity in the fundic mucosal tissue surrounding the MALT lymphoma. In conclusion, in H. heilmannii-induced MALT lymphoma, enhanced immunoreactivity of vascular endothelial growth factor-A and factor-C was observed in areas encircled by increased parietal cell apoptosis, which indicates the pathophysiological relevance of both angiogenesis and apoptosis in MALT lymphoma formation.

"Candidatus Helicobacter heilmannii" from a cynomolgus monkey induces gastric mucosa-associated lymphoid tissue lymphomas in C57BL/6 mice.

Both Helicobacter pylori and "Candidatus Helicobacter heilmannii" infections are associated with peptic ulcers, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue (MALT) lymphomas. However, good animal models of H. pylori clinical diseases are rare. In this study, we aimed to establish an animal model of "Candidatus Helicobacter heilmannii" gastric MALT lymphoma. We used a urease-positive gastric mucosal and mucus homogenate from a cynomolgus monkey maintained in C57BL/6 mouse stomachs. The bacterium in the homogenate was identified as "Candidatus Helicobacter heilmannii" based on a DNA sequence analysis of the 16S rRNA and urease genes. Mucosal and mucus homogenates were used to inoculate C57BL/6 mice, which were then examined for 24 months. We observed a gradual increase in the surface area of protrusive lesions in almost all infected C57BL/6 mouse fundic stomachs 6 months after infection. Light microscopic observations revealed an accumulation of B lymphocytes along with destruction of glandular elements and the presence of lymphoepithelial lesions consistent with low-grade MALT lymphomas. Electron microscopic observation revealed numerous "Candidatus Helicobacter heilmannii" bacilli in the fundic glandular lumen, the intracellular canaliculi, and the cytoplasm of intact cells, as well as damaged parietal cells. In conclusion, "Candidatus Helicobacter heilmannii" induced gastric MALT lymphomas in almost 100% of infected C57BL/6 mice after a 6-month period associated with the destruction of parietal cells.

Lansoprazole Novel Effector Sites Revealed by Autoradiography: Relation to Helicobacter pylori, Colon, Esophagus and Others.

Lansoprazole uptake sites by two kinds of autoradiographic procedures were compared with recent literature. The uptake sites have been seen in the Helicobacter pylori, colonic epithelial cells, inflammatory cells, peripheral autonomic nerves and enterochromaffinlike cells as well as gastric parietal cells. Each uptake sites corresponded to the reported localization of P-type ATPase or acidic compartment.

Efficacy of natural BALL-1 interferon-alpha treatment for patients with chronic hepatitis C and a possible enhancing effect of a twice-daily starting regimen with interferon-beta.

BACKGROUND/AIMS: Two distinct natural interferon-alpha (BALL-1 and Namalwa) are available for patients with chronic hepatitis C in Japan, but the efficacy has not been well documented. We investigated two studies using a natural BALL-1 interferon-alpha treatment for chronic hepatitis C and assessed its efficacy. METHODOLOGY: In interferon-alpha monotherapy (Study I), 42 patients with chronic hepatitis C received 10 mega units of BALL-1 interferon-alpha intramuscularly consecutively for an initial 2 weeks followed by three times a week for 6 months totally. In a combination therapy of natural interferon-alpha and interferon-beta (Study II), 24 patients received intravenous 3 mega units of interferon-beta twice daily for the initial 2 weeks followed by 10 mega units of natural BALL-1 interferon-alpha consecutively for 2 weeks and three times a week for 6 months totally. Efficacy and predictive factors for sustained viral response was investigated. RESULTS: Study II included significant younger patients than study I. Sustained virological response was obtained in 31.0% in Study I and 56.5% in Study II by intention-to-treat analysis. Sustained viral response in the group of genotype 1b and viral load more than 100 KIU/mL was 3/23 (13.0%) and 8/18 (44.4%) in Study I and II, respectively. The response rate in Study II was higher than that of Study I especially among the patients with high pretreatment viral load or genotype 1b (p<0.05). Multivariate analysis showed that pre-treatment HCV-RNA levels, HCV-genotype, and histological staging before the interferon treatment were significant predictive factors of sustained viral response. CONCLUSIONS: These studies suggest that natural BALL-1 interferon-alpha is useful for inducing sustained viral response in patients with chronic hepatitis C, even in those possessing genotype 1b and high viral load. In addition, the combination therapy with a starting regimen with twice-daily interferon-beta administration for 2 weeks may be more effective than monotherapy.

Increased microvascular permeability in early stage of dextran sulfate sodium-induced colitis: its interaction with lansoprazole binding sites.

To clarify the microvascular changes and the effector sites of lansoprazole during the formation of colitis, the dextran sulfate sodium (DSS)-induced colitis was induced by the oral administration for 3 and 7 days. The alteration of the microvascular permeability was estimated by the intraaortic infusion of FITC-dextran. The effector sites of 3H-lansoprazole were examined by the intraaortic infusion of the radiolabelled compound and the autoradiographic procedure of water-soluble compounds. As a result, marked increase of the microvascular permeability was detected three days after DSS treatment near the inflammatory cells in the tip portion of the colonic mucosa. 3H-lansoprazole in the control rat colon was localized in the goblet cells, while in DSS-treated rats, 3H-lansoprazole was accumulated in the cytoplasm of the mesenchymal cells, and most of them coincided with polymorphonuclear leucocytes and macrophages.