Splenectomy and antiviral treatment for thrombocytopenic patients with chronic hepatitis C virus infection.

Thrombocytopenic patients with chronic hepatitis C virus (HCV) infection are poor candidates for antiviral treatment with interferon (IFN), but no standard treatment for thrombocytopenia has yet been established. We evaluated the safety of splenectomy and its efficacy for the initiation and continuation of antiviral therapy. From March 2003 to April 2006, 10 patients (mean age 62.5 years) with HCV-related cirrhosis, low platelet count (<==106 000/mm(3)) and splenomegaly (spleen size >==10 cm) underwent splenectomy. Platelet counts significantly increased at 4-8 weeks after splenectomy [pre: 64 200 +/- 6900/mm(3)vs post 209 000 +/- 40 600/mm(3) (P = 0.004)]. No severe operative complications were observed. All patients subsequently received antiviral therapy. Of the eight patients who were infected with HCV genotype 1 and had a high viral load (>==100 KIU/mL), four received combination therapy with pegylated IFNalpha-2b plus ribavirin, and the other four received standard IFNalpha-2b plus ribavirin. One patient infected with HCV genotype 2 and another with HCV genotype 1 and a low viral load (<100 KIU/mL) were treated with pegylated IFNalpha-2a. Six patients achieved sustained virologic response (SVR). Among four patients who failed to achieve SVR, one was given retreatment with pegylated IFN plus ribavirin, and the other three received low-dose long-term IFN therapy. Although this study was small, the treatment results were similar to those for patients without thrombocytopenia and suggested that splenectomy would not reduce the antiviral efficacy of IFNalpha-based treatment.

[Full-thickness pleural biopsy using an Insulation-tipped Diathermic Knife in a patient with malignant pleural mesothelioma].

A 72-year-old woman was pointed out a right pleural effusion and thickening pleura on the chest computed tomography. The patient underwent semiflexible thoracoscopy under local anesthesia at the endoscopy room. The patient was placed in the lateral decubitus position, and flexible trocar was inserted with the single puncture technique. At the macroscopic findings, the parietal pleura were thickened prominently, and patchy plaques were occasionally recognized. A standard biopsy forceps hardly grasped pleura because of presence of scar, so we performed pleural biopsy using Insulation-tipped Diathermic (IT) knife. A subpleural injection of saline containing 0.5% lidokine and 0.005% epinephrine was performed for raising the affected parietal pleura with an injection needle. After a pin hole was made, the pleural lesion was incised in a circle by manipulating the IT knife, and the incised pleura were removed. Pathology revealed extensive fibrosis and epithelial mesothelioma by the specimen. This biopsy technique using IT knife through semiflexible thoracoscopy enabled to obtain a full-thickness pleura It is thought to be useful for the diagnosis of malignant pleural mesothelioma (MPM) in which standard forceps are difficult to grasp.

Clinical outcome after endoscopic mucosal resection for esophageal squamous cell carcinoma invading the muscularis mucosae--a multicenter retrospective cohort study.

BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection (EMR) is now commonly indicated for esophageal squamous cell carcinoma (ESCC) within the lamina propria mucosa. However, EMR for ESCC that has invaded the muscularis mucosa is controversial because the risk of lymph node metastasis is not negligible. We conducted a multicenter retrospective cohort study to investigate the incidence of lymph node metastasis and survival after EMR for ESCC invading the muscularis mucosa. PATIENTS AND METHODS: A total of 104 patients with 111 lesions invading the muscularis mucosa, were retrospectively studied at eight institutes. No patients exhibited evidence of metastasis of lymph nodes or distant organs prior to EMR. Overall and cause-specific survival rates were calculated from the date of EMR to the date of death or the most recent follow-up visit. Survival curves were plotted according to the Kaplan-Meier method. RESULTS: In total, 86 patients (82.7%) who did not receive further treatment such as chemotherapy, irradiation therapy, chemoradiotherapy, or esophagectomy after EMR were followed up. Only two patients (1.9%) developed lymph node metastasis after EMR. With a median follow-up period of 43 months (range, 8-134 months), overall and cause-specific survival rates at 5 years after EMR were 79.5% and 95.0%, respectively. CONCLUSIONS: EMR for ESCC that invades the muscularis mucosa has curative potential as a minimally invasive treatment option.

[Formation mechanism of 4,4-methylenebis(N,N-dimethylaniline) by the anodic oxidation of N,N-dimethylaniline].

Preparative constant-current electrolysis of N,N-dimethylaniline(100 mM, DMA) was carried out in dry acetonitrile containing Et4NClO4 to give N,N,N',N'-tetra-methylbenzidine(TMB) and 4,4'-methylenebis(N,N-dimethylaniline) (MDMA). In the presence of HCl, DMA was quantitatively oxidized to TMB. Formation mechanism of MDMA was discussed using the results of semi-empirical calculations that were PM3 and AM1. The proposed mechanism by Hand and coworker was ruled out and an alternative one is suggested as follows. DMA undergoes one-electron oxidation at the anode and gives the corresponding N,N-dimethylaniline cation (A). Aydroxy ion, instead of DMA, abstracts a proton from A and gives H2O and methyl(phenyl)aminomethyl radical (B). B reacts with DMA to give a 1-dimethylamino-4-(N-methyl-N-phenylamino)methyl-2,5-cyclohexadienyl radical (I). The radical I decomposes to N-methylaniline and a 1-dimethylamino-4-methylene-2,5-cyclohexadienyl radical (J). The radical J reacts with DMA to give a 1-dimethylamino-4-(4-dimethylaminobenzyl)-2,5-cyclohexadienyl radical (K), which is oxidized to MDMA by the anode.

Re-examination of the anodic oxidation of N,N-dimethylaniline, using parametric method 3.

A semi-empirical calculation (PM3) was applied to elucidate the anodic oxidation mechanism of N,N-dimethylaniline (DMA) and the dimerization of a cation radical (A) derived from DMA was ruled out. The heat of reaction value of the dimerization of A was 42.43 kcal/mol. We propose the following. Cation radical A reacts with DMA to generate another cation radical (D). This reaction was exothermic and the heat of reaction value and the activation energy were -0.35 kcal/mol and 1.31 kcal/mol, respectively. Deprotonation of D by DMA gives neutral radical (E), which is oxidized to TMB by A. All these reactions were exothermic.

[Biomimetic oxidation of diphenyl sulfide with electrochemical P-450 model system in CH2Cl2 treated with alkaline solution].

Dichloromethane containing metalloporphyrins [meso-tetraphenylporphyrinatomanganese(III) chloride (1) or meso-tetraphenylporphyrinatoiron(III) chloride (2)] and Bu4NClO4 was treated with an aqueous solution of NaOH (5%), and subjected to controlled potential electrolysis at -1.0 V (vs. S.C.E. (saturated calomel electrode)) in a divided cell after addition of diphenyl sulfide (3). Diphenyl sulfoxide (4) and diphenyl sulfone (5) were found in an electrolyzed solution as the reaction products. Results obtained from cyclic voltammetry and visible spectrometry suggested that the treatment of dichloromethane containing metalloporphyrins with the aqueous solution of NaOH did not change the fifth ligand of metalloporphyrins from Cl to OH. On the electrode, dissolved dioxygen was reduced to hydrogen peroxide. Compounds 1 and 2 catalyze the oxidation of 3 by hydrogen peroxide without imidazole. Compound 2 showed higher selectivity than compound 1.

[Mucosal microcirculation and angiogenesis in gastrointestinal tract].

In this review, various aspects of gastrointestinal microcirculation were described. Endothelin-1, vasoconstrictor, is elevated in gastric mucosa, causes gastric ischemia and results in gastric ulceration in human and animals under physical stress. Vasodilators such as NO anticipate the alove actions of endothelin, and thereby protect mucosa from injury. Once ulcer is developed, angiogenesis plays a key role in its healing. Various growth factors, cyclooxygenases-1 and -2, and non-peptide angiogenic factors stimulate this phenomenon and participate in ulcer healing. However, acidic conditions, H. pylori and its product, ammonia, suppress angiogenesis in vitro and in vivo. These evidences may explain why ulcer heals so slowly in gastroduodenal mucosa.

Thrombotic thrombocytopenic purpura developed suddenly during interferon treatment for chronic hepatitis C.

A 57-year-old man had abnormal hepatic function identified in April 1994. In October 1994, chronic hepatitis C was diagnosed. Based on the findings of a liver biopsy, administration of recombinant interferon (rIFN)-alpha2b was begun. In the 16th week of treatment, the patient experienced headache and fever and developed a markedly decreased, platelet count and hemolytic anemia. He was admitted on May 19, 1995 and thrombotic thrombocytopenic purpura (TTP) was diagnosed. He died on the 3rd hospital day. The causes of TTP have yet to be elucidated, but in this patient the occurrence of TTP appeared to be related to the IFN treatment for chronic hepatitis C.

Endoscopic follow-up study of development of gastric antral vascular ectasia associated with liver cirrhosis.

Gastric antral vascular ectasia is an important cause of chronic gastrointestinal blood loss. However, its development and progression have not yet been clarified. We investigated its early lesions and progression by reviewing endoscopic films of five patients with gastric antral vascular ectasia followed for liver cirrhosis. In all patients, early findings were prepyloric red spots. In two patients, anemia due to gastrointestinal bleeding was already observed when vascular lesions were confined to the distal antrum. In the other three patients, anemia was observed 1-2 years after they showed a diagnostic pattern of gastric antral vascular ectasia. The vascular lesions gradually thickened and extended throughout the antrum, with the complete picture shown in 1.5-5 years. The pattern of distribution was classified into three types: diffuse spotty, diffuse confluent, and striped. These types could be predicted before the complete formation. Gastric antral vascular ectasia associated with liver cirrhosis started as prepyloric red spots and extended to the proximal antrum in various ways and varying time courses of less than 5 years; this entity may cause hemorrhage even in the early stage.

Endothelin-1 in the gastric mucosa in stress ulcers of critically ill patients.

OBJECTIVE: Gastric microcirculatory disturbances are involved in the pathogenesis of stress ulcers; however, vasomodulators causing this process are not fully understood. This study was conducted to investigate the role of endothelin 1 (ET-1), a potent vasoconstrictive peptide, in stress ulcers in critically ill patients. METHODS: Using sandwich enzyme immunoassay, we measured ET-1 content in plasma and the gastric mucosa of 16 critically ill patients with traumatic head injury on admission and of 11 healthy subjects. Gastric mucosal samples were obtained endoscopically. When gastric drainage contained occult blood, endoscopic examination was performed again, and ET-1 concentrations in injured and adjacent normal mucosa were compared. RESULTS: Plasma and mucosal ET-1 concentrations were significantly higher in critically ill patients on admission (6.1 +/- 0.6 pg/ml and 13.8 +/- 1.6 ng/g, respectively) compared with values in control subjects (2.7 +/- 0.4 pg/ml and 8.2 +/- 0.5 ng/g, respectively) (p < 0.01). The mucosal ET-1 concentration tended to be elevated in patients who had experienced hypoxia compared with those who had not (p = 0.07). In five patients who were again examined endoscopically, the ET-1 concentration in the injured mucosa was significantly higher than that in adjacent mucosa (19.2 +/- 3.2 and 10.1 +/- 1.6 ng/g, respectively; p < 0.05). CONCLUSIONS: These results suggest that endogenous ET-1 plays an important role in the local pathogenesis of stress ulcers, especially those caused by hypoxia.

Evaluation of combined therapy with chemoembolization and ethanol injection for advanced hepatocellular carcinoma.

To evaluate the therapeutic efficacy of transcatheter arterial chemoembolization (TACE) combined with percutaneous ethanol injection therapy (PEIT) for advanced hepatocellular carcinoma, we studied the effectiveness of TACE therapy combined with PEIT (50 cases) and TACE alone (50 cases). In both groups, patients had multiple lesions, or a single lesion with a diameter exceeding 2 cm or with vascular invasion (stages II, III, and IV in the tumor staging classification of the Liver Cancer Study Group of Japan). The clinical features in the two groups were comparable. The cumulative survival rates with TACE-PEIT were 95.0% for 1 year, 72.5% for 2 years, and 50.0% for 3 years, whereas the rates with TACE alone were 92.5% for 1 year, 57.5% for 2 years, and 20.0% for 3 years. The survival rate in the TACE-PEIT group was significantly higher than that in the TACE alone group. Moreover, the survival rate of patients with stage II or III disease in the TACE-PEIT group was significantly better than that in the TACE alone group, and the survival rate of patients with Child's classification B or C in the TACE-PEIT group was significantly higher than that in the TACE alone group. Multivariate analysis using Cox's proportional hazard regression model showed that the most significant prognostic factors in the TACE-PEIT group were tumor embolus in the portal vein and the number of tumors. These results suggest the effectiveness of combining TACE and PEIT for the treatment of advanced hepatocellular carcinoma.

Plasma and gastric mucosal endothelin-1 concentrations in patients with peptic ulcer.

Peptic ulcer in the human stomach causes localized destruction of the gastric wall, which may be associated with focal vascular insufficiency. Endothelin-1, an extremely potent vasoconstrictor peptide, modulates regional blood flow in the vasculature of stomach, suggesting a role for endothelin-1 in peptic ulcer. We examined the relationship among endogenous plasma and mucosal endothelin-1 concentrations and the severity and area of ulcer in 19 patients with gastric ulcers and eight healthy adults. Endothelin-1 concentrations were measured by enzyme immunoassay in plasma and gastric mucosal specimens from ulcer margins, corpus, and antrum. The severity and area of ulcer were assessed endoscopically. Plasma endothelin-1 concentrations in active (P < 0.01 compared with normal) and healing (P < 0.05) stages of ulcer were significantly greater than those in normal subjects. Plasma endothelin-1 concentrations, but not mucosal endothelin-1 concentrations in the ulcer margin, were significantly associated with the severity of the ulcer. There was a significant positive correlation between plasma endothelin-1 concentrations and area of ulcer (r = 0.70, P < 0.01). In conclusion, locally increased endothelin-1 may be an important mediator contributing to the pathogenesis of peptic ulcer.

An endoscopic follow-up study of the development of diffuse antral vascular ectasia.

No endoscopic follow-up studies are available on the development of diffuse antral vascular ectasia (DAVE). We present here a ten-year follow-up study from discrete initial lesions to the full picture of DAVE. In a 72-year-old female patient with liver cirrhosis, the earliest findings of DAVE were several red spots, with or without a white halo, in the distal antrum. During follow-up, the spots increased in number, coalesced, and extended to the proximal antrum. Three years after the initial findings, latent hemorrhage occurred at a time when confluent lesions were formed. One year later, diffuse distribution of the antral lesions was observed, which led to the diagnosis of DAVE and developed to the full picture within three more years. Two years later, the patient presented with hematemesis, which confirmed the diagnosis of DAVE clinically. Treatment consisted of monopolar electrocoagulation, leading to a stable hemoglobin value for one year. This case study provides some substantial clues to the early detection and treatment of DAVE.

Endogenous nitric oxide modulates ethanol-induced gastric mucosal injury in rats.

BACKGROUND/AIMS: Endothelium-derived relaxing factor regulates vascular tone via vasodilation. The relative contribution of endogenous nitric oxide to the pathophysiology of ethanol-induced gastric mucosal microcirculatory disturbances was investigated in anesthetized rats. METHODS: Macroscopic and microscopic gastric mucosal damage and gastric mucosal hemodynamics including blood flow and hemoglobin oxygen saturation (ISO2) were assessed by pretreatment with a specific NO synthase inhibitor, N omega-nitro-L-arginine (L-NNA), before and after intragastric administration of ethanol. RESULTS: Pretreatment with L-NNA significantly increased macroscopic (7.7-fold) and microscopic damage caused by 30% ethanol. Concurrent administration of L-arginine, but not D-arginine, significantly reduced the increase in mucosal damage. Similar results were obtained with 60% ethanol. Pretreatment with L-NNA decreased both mucosal blood flow and ISO2 in the basal period and enhanced decreases in both mucosal blood flow (2.7-fold) and ISO2 (4.3-fold) induced by 30% ethanol compared with controls. Concurrent administration of L-arginine, but not D-arginine, significantly inhibited the effect of L-NNA on blood flow and ISO2 in the basal period as well as after intragastric administration of 30% ethanol. CONCLUSIONS: Endogenous NO modulates ethanol-induced gastric mucosal injury through the regulation of gastric mucosal microcirculation.

Role of endothelin 1 in hemorrhagic shock-induced gastric mucosal injury in rats.

BACKGROUND/AIMS: Gastric microcirculatory disturbances are involved in the pathogenesis of stress ulcers; however, vasomodulators regulating this process are not fully understood. This study was conducted to investigate the role of endothelin 1 (ET-1) in hemorrhagic shock-induced gastric mucosal damage in rats. METHODS: ET-1 contents in plasma and gastric mucosa were measured and gastric mucosal damage was evaluated during a control period, 60 minutes of ischemia, 15 minutes of reperfusion, and 30 minutes of postreperfusion. Next, effects of BQ-123, an endothelinA receptor antagonist, on the gastric mucosal damage and hemodynamics were studied. RESULTS: Both plasma and mucosal ET-1 significantly increased after ischemia and reperfusion compared with the control values, but only mucosal ET-1 continued to increase after reperfusion, leading to the development of gastric mucosal damage. BQ-123, administered just before reperfusion, reduced mucosal damage in the postreperfusion period dose-dependently and improved mean gastric mucosal blood flow and mucosal hemoglobin oxygen saturation during the 30-minute postreperfusion period. CONCLUSIONS: These results suggest that endogenous ET-1 plays an important role in the pathogenesis of hemorrhage shock-induced gastric mucosal damage through impairment of mucosal microcirculation. Further, endothelinA antagonists may have therapeutic benefits for shock-induced gastric mucosal damage.

Vasoactive effect of endothelin-1 on rat liver in vivo.

The purpose of this study was to evaluate the role of endothelin-1 in modulating hepatic microcirculation and liver damage. Rats were infused with endothelin-1 at doses ranging from 30 to 1,000 pmol/kg over 1 min through an indwelling cannula placed in the portal vein. In control rats, saline solution was infused at the same rate. Alterations in hepatic microcirculation were measured with an in vivo microscopy system. Serum lactate dehydrogenase activity, an indicator of hepatic damage, was measured 1 hr after endothelin-1 infusion. Immediately after infusion of endothelin-1, we noted a rapid increase in portal pressure, which remained increased for up to 30 min after endothelin-1 infusion. In contrast, systemic blood pressure remained unchanged, even at 1,000 pmol/kg of endothelin-1. Sinusoidal width was reduced and sinusoidal erythrocyte velocity was diminished in a dose-dependent manner. Oxygen saturation of blood in sinusoids was decreased in a dose-dependent manner, reaching values around 40% of control with 1,000 pmol/kg endothelin-1. The degree of decrease in oxygen saturation of blood in sinusoids had an excellent correlation with the calculated blood flow in the liver tissue. Serum lactate dehydrogenase levels were three to four times control values when endothelin-1 was administered at 1,000 pmol/kg. Thus endothelin-1 decreased hepatic tissue oxygenation associated with sinusoidal vasoconstriction. At high concentrations of endothelin-1, this decrease results in hepatocellular damage.

Role of endogenous endothelin in pathogenesis of ethanol-induced gastric mucosal injury in rats.

The major objective of this study was to elucidate the role of endogenous endothelin (ET)-1, a potent vasoconstrictor peptide, in the pathogenesis of ethanol (EtOH)-induced gastric mucosal injury. Two series of experiments were performed in anesthetized rats. First, we examined the time course of relationships among changes in ET-1 concentrations in gastric mucosal and portal plasma, gastric mucosal hemodynamics, and mucosal damage produced by EtOH. Intragastric EtOH stimulated release of endogenous ET-1 in gastric mucosal tissue. Plasma ET-1 concentrations in the portal vein also increased after intragastric EtOH administration. ET-1 concentrations in gastric mucosal tissue and portal plasma increased significantly before gastric mucosal hemorrhagic damage occurred. Moreover, 30 min after EtOH administration there were significant correlations between gastric mucosal ET-1 concentrations and both area of gastric hemorrhagic damage as well as concentration of EtOH administered intragastrically. After intragastric EtOH administration, increase in gastric mucosal hemoglobin concentration and decrease in gastric mucosal hemoglobin oxygen saturation, estimated using reflectance spectrophotometry, occurred within 2.5 min and continued throughout the experiments. The time course of microcirculatory changes correlated closely with increases in gastric mucosal ET-1 and portal plasma ET-1 concentrations after intragastric EtOH administration. Gastric microcirculatory disturbances induced by EtOH were associated with significant decreases in gastric mucosal ATP content. Second, we examined whether pretreatment with anti-ET-1 antibody protected against EtOH-induced mucosal injury by improving mucosal microcirculation. Pretreatment with anti-ET-1 antibody microscopically and macroscopically reduced gastric mucosal hemorrhagic damage induced by EtOH and significantly reduced EtOH-induced gastric microcirculatory disturbances and decreases in gastric mucosal ATP.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethanol stimulates immunoreactive endothelin-1 and -2 release from cultured human umbilical vein endothelial cells.

The present study employed enzyme-immunoassay to examine the effect of ethanol on endothelin-1 and/or -2(ET1 + 2) release from human umbilical vein endothelial cells. Thirty minutes of exposure to ethanol increased the release of immunoreactive ET1 + 2 from cultured endothelial cells in a dose-dependent manner. However, ethanol at concentrations of less than 400 mM did not induce any LDH release from the endothelial cells. Trypan blue exclusion test revealed that 400 mM solution of ethanol decreased the cell viability to 7.7%. Thus, ethanol was found to directly stimulate ET1 + 2 release from cultured human umbilical vein endothelial cells. This reaction of vascular endothelial cells against ethanol may be related to ethanol-induced cardiovascular diseases such as hypertension, myocardial infarction and stroke, as well as fatal alcohol syndrome.

[Protective effect of proton pump inhibitor on the gastric mucosa].

Although many authors reported that proton pump inhibitor showed mucosal protective activity, the precise mechanism is still unclear. In this study, we investigated the effect of proton pump inhibit on gastric mucosal hemodynamics, using a reflectance spectrophotometry system. The proton pump inhibitors had no effect on the gastric mucosal hemodynamics prior to the state of hemorrhagic shock state. However, during the hemorrhagic shock, proton pump inhibitors significantly inhibited the decrease in tissue oxygenation and significantly reduced ulcer formation. In conclusion, proton pump inhibitors maintained tissue oxygenation resulting in reduction of ulcer formation.