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Background: Although proton pump inhibitors (PPI) and H2-receptor antagonists (H2-RA) are routinely used in the treatment of reflux esophagitis (RE), no consensus has been reached yet as to whether the first-choice drug should be PPI or H2-RA. In this study, the effects of omeprazole (OMP) and famotidine (FAM) on RE have been examined in a randomized comparative study., Methods: Protocols of OMP 20 mg once daily or FAM 20 mg twice daily for 8 weeks were allocated to 56 cases with RE at random, using an envelope randomization method. Their efficacy in achieving healing was examined endoscopically and a relief from subjective symptoms was compared., Results: Patient's background such as sex, age, recurrence, hiatal hernia, smoking and drinking habits, and complications, and the severity of esophagitis at the time of enrolment were not significantly different between the two groups. Healing in the OMP group and the FAM group was observed in 72 and 32% (P = 0.025) of patients at week 4 and 95 and 53% (P = 0.003) of patients at week 8, respectively. Subjective symptoms were relieved more frequently in the OMP group (at week 2, 67% compared with 29%, P = 0.005; at week 4, 95% compared with 55%, P = 0.009), but this superiority was not significant at week 8 (94% compared with 65%, P = 0.085). No serious adverse events occurred., Conclusions: Omeprazole provided quicker healing and a greater relief from subjective symptoms than did FAM in the treatment of RE, and was considered more suitable as a first-choice drug., (Copyright 2002 Blackwell Publishing Asia Pty Ltd)

We have already reported that the ratio of portal venous flow 30 min after oral intake of glucose 75 g to that before intake (PVFR30), measured using pulsed-Doppler ultrasonography (US), correlated significantly with other indicators of liver function and that it could be used to estimate hepatic function before surgery, including liver resection. In this study, to assess the disadvantages of pulsed-Doppler ultrasonography, PVFR30 was measured using two-dimensional (2D) phase-shift (PS) magnetic resonance imaging (MRI). PVFR30 was measured in 17 patients and 7 volunteers: 13 with liver cirrhosis (LC) and 11 without LC (non-LC). Portal venous flow could be measured in all patients without any disturbance of intestinal gas or patient fat, or the high degree of technical skill that Doppler US requires. PVFR30 was significantly lower in the LC group than in the non-LC group. In addition, it correlated significantly with other indicators of liver function, including the indocyanine green clearance test, prothrombin time, hepaplastin test, and cholinesterase activity. These results suggest that PVFR30 measured by 2D PS MRI can be used to estimate liver function, and that this MRI method can be performed more easily than pulsed-Doppler US.

Background & Aims: Indomethacin impairs liver microsomal monooxygenase activities mediated by cytochrome P450 (CYP). We investigated the inhibition mechanism and the isoform selectivity in vitro and in vivo., Methods: In an in vitro study, liver microsomes from male Wistar rats were preincubated with indomethacin and a reduced nicotinamide adenine dinucleotide phosphate-generating system, followed by assay of monooxygenase activities indicative of several CYP isoforms. In an in vivo study, rats were intraperitoneally treated with indomethacin, followed by preparation of microsomes and the enzyme assays., Results: The preincubation of microsomes with indomethacin and reduced nicotinamide adenine dinucleotide phosphate decreased CYP3A2 activity but not any other isoforms. Kinetic analysis showed the mechanism-based inactivation of CYP3A2. The metabolism of [14C]indomethacin resulted in covalent binding to microsomal protein, which was diminished by inhibiting CYP3A enzyme. Administration of indomethacin caused impairment of not only CYP3A2 but also other CYP isoforms. Rats were protected from the impairment of the CYP enzymes except CYP3A2 by depleting macrophages and inhibiting inducible nitric oxide synthase., Conclusions: Metabolism of indomethacin causes inactivation of CYP3A2, which is the result of the covalent binding of its metabolite, whereas partially selective in vivo impairment of CYP isoforms is suggested to be indirect inhibition by inflammatory mediators probably released from Kupffer cells.

Nuclear Factor of Activated T cell (NFAT) is a family of transcription factors that are important for the coordinate expression of various cytokines and immunoregulatory cell surface molecules in T cells and other types of cells in the immune system. In addition, analysis of gene disrupted mice revealed that some members of NFAT family are important for the development of myocardium, myocardial hypertrophy, and mesenchymal stem cells. NFAT family proteins have two conserved domains, the NFAT Homology Domain (NHD) and the Rel Similarity Domain (RSD). The RSD is DNA binding and AP-1 interacting domain which has structural similarity to the Rel Homology Region, the DNA binding domain of Rel family proteins. The NHD is a regulatory domain required for the Ca regulated translocation of NFAT. We report here the isolation and initial characterization of a novel RSD containing protein designated NFATz. NFATz has a RSD but no NHD. NFATz protein is localized in the nucleus without Ca signal. There is no detectable binding to a typical NFAT site even in the presence of AP-1, and it is not capable of activating transcription through the NFAT site. The chromosomal location determined by FISH revealed that NFATz and NFATx genes are in the same region., (Copyright 2000 Academic Press.)

The goals of treatment of acute iliofemoral DVT should be prevention of fatal PE, reduction of pain and swelling of the involved leg, trying to stop the development of phlegmasia cerulea dolens and venous gangrene, prevention of disabling PTS by early removal of the blood clot, avoiding proximal venous obstruction, preserving normal, functioning valves in the leg veins, and preventing reflux. The authors recommend an aggressive approach with rapid removal of the occluding thrombus in the leg veins extending up into the iliac veins in active patients with a short history of symptomatic DVT, usually less than 7 days. This approach is not justified in chronically ill, bedridden, high-risk, or aged patients, or those with serious intercurrent disease or limited life expectancy. In these patients, such interventions can only be indicated for limb salvage in phlegmasia cerulea dolens when conservative treatment does not prevent the development of an acute compartment syndrome with venous gangrene. The preferred means of accomplishing early and quick removal of the thrombus is CDITT. Most of the authors' positive experience with thrombolysis is based on the use of urokinase. The Food and Drug Administration (FDA) has put this drug on temporary hold for almost 1 year. The alternative drugs (e.g., tissue plasminogen activator [tPA]) have not been tested for CDITT of DVT, and tPA is not FDA-approved for this indication. When there are contraindications or failure of thrombolysis, TE with a temporary AVF is a valid alternative.

Venous thromboembolism (VTE) in legs and lungs is a potentially life-threatening condition. The incidence of VTE associated with air travel is still unknown, but it may have increased. Most travelers who develop symptoms do so within 24 hours after their flight takes off. Predisposing risk factors may be divided into patient-related and cabin-related factors, both of which are described. It is emphasized that better information and better inflight precautions can minimize these risk factors.

Acinic cell carcinoma of the salivary glands is a rare cancer representing a low grade malignancy. The recurrence of a tumor is sometimes encountered, usually within 5 years of initial operation. We describe an unusual recurrence after a long interval following primary surgery. In 1987, a 60-year-old woman underwent excision of a mass in the superficial lobe of the right parotid gland under the preoperative diagnosis of a benign tumor. A histologic diagnosis of acinic cell carcinoma was made by examining sections from the resected mass. The patient noted several small nodules in the right parotid region in 1995, but she did not visit our clinic until 1998 when tenderness developed. A locally recurrent tumor and cervical lymph nodes containing metastases were resected and postoperative radiotherapy was given 11 years after the first operation. At least 10 years of follow-up may be necessary for patients with acinic cell carcinoma because of slow-tumor growth.

Background and Objectives: The exact role of ret/PTC in the development of papillary carcinoma remains unclear. Expression of the ret/PTC oncogene was examined immunohistochemically to address its role in the progression of thyroid carcinomas., Methods: Paraffin-embedded samples from 34 clinically evident thyroid papillary carcinomas and 19 occult papillary carcinomas were analyzed using an antibody raised against the ret tyrosine kinase domain., Results: Expression of ret/PTC was demonstrated in 6/19 (32%) occult carcinomas. The frequency of expression of ret/PTC in clinically evident carcinomas in 16/34 (47%) was significantly higher than in normal tissues (0%) and follicular adenomas (1/14, 7%, P < 0.01).ret/PTC expression was observed more frequently in the peripheral areas of clinically evident carcinomas (P < 0.01). Although there was no correlation of ret/PTC expression with tumor size, lymph node metastasis, or distant metastasis, the incidence of ret/PTC expression in tumors with extrathyroidal invasion (13/19, 68%) was significantly higher than those without extrathyroidal invasion (3/15, 20%, P < 0.01). Local invasion was found in none of the occult carcinomas. The frequency of expression in occult carcinomas was significantly lower than in clinically evident carcinomas with extrathyroidal invasion (P < 0.05)., Conclusions: The ret/PTC oncogene may be involved in the local invasion of thyroid papillary carcinomas.

Intracellular calcium regulates events controlling nuclear translocation of nuclear factor of activated T cells (NF-AT). Calcium-dependent phosphatase calcineurin (CN) plays a central role in this process. Structural and functional analyses of the N-terminal domain of murine NF-ATx1, a member of the NF-AT family, have defined two distinct CN binding regions (CNBRs), CNBR1 and CNBR2, which are located in the region preceding the SP boxes of serine/proline-rich sequences and the region between the SP boxes and Rel similarity domain, respectively. The binding of murine NF-ATx1 (mNF-ATx1) to CN was abolished by deletion of these two regions, yet was unaffected by the individual deletion. In contrast, the nuclear translocation of mNF-ATx1 was much reduced when only CNBR2 was removed. Luciferase assay revealed that both regions are required for mNF-ATx1-dependent activation of the murine IL-2 promoter. Most importantly, recombinant CNBR2 bound CN with a higher affinity, and when expressed in Jurkat cells, it functioned as a dominant negative mutant that prevented the transcription driven by exogenous mNF-ATx1, probably by interfering with the function of CN. We propose that activation of mNF-ATx1 can be modulated through two distinct CN target regions. Our findings provide a new opportunity for pharmacological intervention with Ca2+-dependent signaling events.

NFAT regulates transcription of a number of cytokine and other immunoregulatory genes. We have isolated NFATx, which is one of four members of the NFAT family of transcription factors and is preferentially expressed in the thymus and peripheral blood leukocytes, and an isoform of NFATx, NFATx1. Here we provide evidence showing that 15 amino acids in the carboxyl-terminal end of NFATx1 are required for its maximum transactivation activity in Jurkat T cells. A fusion between these 15 amino acids and the GAL4 DNA binding domain was capable of transactivating reporters driven by the GAL4 DNA binding site. Interestingly, this 15-amino acid transactivation sequence is well conserved in NFAT family proteins, although the sequences contiguous to the carboxyl-terminal regions of the NFAT family are much less conserved. We also report three additional isoforms of NFATx, designated NFATx2, NFATx3, and NFATx4. This transactivation sequence is altered by tissue-specific alternative splicing in newly isolated NFATx isoforms, resulting in lower transactivation activity in Jurkat T cells. NFATx1 is expressed predominantly in the thymus and peripheral blood leukocyte, while the skeletal muscle expressed primarily NFATx2. In Jurkat cells, transcription from the NFAT site of the IL-2 promoter is activated strongly by NFATx1 but only weakly by NFATx2. These data demonstrate that the 15-amino acid sequence of NFATx1 is a major transactivation sequence required for induction of genes by NFATx1 in T cells and possibly regulates NFAT activity through tissue-specific alternative splicing.

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.

Purpose: Although the fact is well accepted that deep venous thrombosis (DVT) of the iliac, femoral, and popliteal veins can lead to the post-thrombotic (postphlebitic) syndrome, the significance of isolated calf DVT on the development of late venous sequelae and physiologic calf dysfunction is unknown. The purpose of this study was to review the outcome of 58 limbs with isolated calf DVT and report the clinical, physiologic, and imaging results up to 6 years after the onset of DVT., Methods: The study consisted of 58 limbs of 54 patients in whom isolated calf vein DVT was diagnosed between 1990 and 1995. Proximal propagation of clot, lysis of thrombi, and development of symptomatic pulmonary emboli were examined. Of the patients, 28 received anticoagulation therapy, and 26 did not, but they had follow-up with serial duplex scans. At late follow-up 1 to 6 years later (median, 3 years), 23 patients were examined for the post-thrombotic syndrome, and all 23 underwent clinical examination, color-flow duplex scanning, and air plethysmography., Results: Proximal propagation of DVT from the calf veins into the popliteal or thigh veins occurred in 2 of 49 cases (4%) within 2 weeks of diagnosis. No patient had clinically overt pulmonary emboli develop regardless of whether anticoagulation therapy was received or not. The most common site for calf DVT was the peroneal vein (71%). Complete lysis of calf thrombi was found in 88% of the cases by 3 months. At 3 years, 95% of the patients were either asymptomatic or mildly symptomatic, and 5% had discoloration of the limb. No ulcers occurred. By air plethysmography, physiologic abnormalities were found in 27% of the cases, which was not significantly different from normal controls. Valvular reflux by duplex scanning of the calf vein segment with DVT was found in 2 of 23 cases (9%). However, reflux in at least one venous segment not involved with DVT was found in 7 of 23 cases (30%), which was higher than, but not statistically different from, normal controls, with reflux occurring in 5 of 26 cases (19%)., Conclusions: Isolated calf vein DVT leads to few early complications (ie, clot propagation, pulmonary emboli) and few adverse sequelae at 3 years. The peroneal vein is most commonly involved and should be a part of the routine screening for DVT. Lysis of clot usually occurs by 3 months. Although valvular reflux rarely is found in the affected calf vein at 3 years, reflux may be found in adjacent uninvolved veins in approximately 30% of the cases. The question of whether this will lead to future sequelae, such as ulceration, will require longer follow-up.

Cell proliferation in the gastroduodenal mucosa of patients with duodenal ulcers was evaluated using flow cytometry. Forty patients with duodenal ulcers and 12 normal subjects were investigated. Biopsy samples were obtained during endoscopic examination and subjected to DNA analysis by flow cytometry. Thirty patients with duodenal ulcers were healed within 3 months with H2 blockers (tractable or responsive ulcers), whereas 10 patients did not respond to treatment (intractable ulcers). The percentage of cells at the DNA-synthetic phase, an index of cell proliferation, was constant in the adjacent duodenal mucosa 2 cm from ulcer margin and antral mucosa during duodenal ulcer healing. The index at the margin of tractable ulcers was elevated during the active stage (12.9 +/- 1.3), peaked during the healing stage (15.4 +/- 2.8) and returned to the same level at the scarring stage (10.9 +/- 2.0) as normal controls (10.3 +/- 1.7). However, the index was not elevated in intractable ulcers (10.3 +/- 1.7 in the healing stage) and was smaller than in tractable ulcers. These data indicate that augmented mucosal cell proliferation at the ulcer margin plays an important role in duodenal ulcer healing and intractable ulcers are characterized by an abnormal failure to accelerate DNA synthesis to achieve ulcer repair.

The nuclear factor of activated T cells (NFAT) is involved in the transcriptional induction of cytokine and other immunoregulatory genes during an immune response. Among four distinct NFAT family members identified to date, mRNAs of NFAT1, NFATc, and NFATx are expressed in the thymus. Here, we report the distribution of these three NFAT family members in human fetal thymocyte subsets and in peripheral mature T cells. We show that NFATx mRNA was expressed in all T lymphocyte subsets tested and was highest in CD4+CD8+ double positive (DP) thymocytes. Conversely, NFAT1 mRNA was preferentially expressed in the mature CD4+ single positive (SP) populations. NFATc mRNA was present at low levels in all subsets but strongly induced upon treatment with phorbol ester and calcium ionophore. Interestingly, we detected NFAT-DNA binding complexes in DP thymocytes, albeit at lower levels than in CD4 SP cells. Corresponding to the mRNA expression, we observed that NFATx was responsible for the NFAT-DNA binding in DP thymocytes. Moreover, this DNA binding was inhibited by cyclosporin A, indicating that NFATx nuclear translocation was regulated by the calcineurin phosphatase in DP thymocytes. For the CD4 SP populations, NFAT1 and NFATc, and to some extent NFATx, were responsible for the NFAT-DNA binding complexes. These results indicate that NFAT family members are differentially regulated during the development of T cells, and that NFATx may play a distinct role in calcineurin-dependent signaling in DP thymocytes.

Purpose: To determine the feasibility and safety of a new endovascular technique for creating an arteriovenous (AV) fistula utilizing catheter-directed techniques and stents., Methods: Stent-graft AV fistulas were offered on an experimental basis to 8 patients who had a history of multiple failed access procedures or very small arm veins unsuitable for standard vascular access techniques. The device consisted of a balloon-expandable Palmaz stent attached to the designated venous end of a polytetrafluoroethylene graft. The balloon-mounted stent-graft was inserted into the brachial vein through an arteriotomy and advanced over a guidewire into the axillary vein. After the stent-graft was deployed, the arterial anastomosis was completed in standard surgical fashion using an end-to-side anastomosis of the graft to the brachial artery., Results: The stent-graft was inserted successfully in all patients, but there were two early failures. The first resulted from a steal phenomenon secondary to high flows through the stent-graft, necessitating ligation of the fistula. Another stent-graft was placed too peripherally in the upper arm, and the stainless steel stent was crushed by external compression. Three of the 6 remaining grafts were patent for over 1 year, and 2 grafts are still functioning at 22 and 13 months., Conclusions: Endoluminal stent-grafts can be successfully inserted into the axillary vein for creation of an AV fistula and remain patent for 2 years or more. This method may be most useful in patients with very small, unusable arm veins or multiple failed AV grafts.

Palma and Esperon described the first femoro-femoral cross-over bypass for iliac vein obstruction in 1958, and Kistner performed the first valve reconstruction for deep vein reflux in 1968. Such surgical development has stimulated better diagnostic methods that now form the foundation for a classification of chronic venous disease, and surgery has been supported by, and sometimes replaced by, the rapid progress in endovascular procedures with angioplasty and stenting. The ability now exists to relieve obstruction and repair reflux in the deep veins, and the results in the successful cases demonstrate the improvement that follows correction of the physiologic abnormalities. The detail in workup required to achieve an accurate diagnosis that is adequate enough to guide surgical treatment in these cases has set a new standard for the diagnosis of chronic venous disease that incorporates the clinical state, etiology, pathophysiology and anatomic distribution of the venous problem, and is incorporated in the CEAP (clinical, etiologic, anatomic, pathophysiologic) classification. The challenge at this time is to produce a reliable set of data that demonstrate the results of treatment in patients with chronic venous disease by conventional methods of bandaging, rest and elevation as well as specific surgical correction of venous obstruction and reflux and to follow these cases over a significant period of time.

We previously reported that tumor eradication was induced by a single injection of neocarzinostatin (NCS) between 1 day and 4 weeks before Meth A transplantation in Balb/c mice via augmenting host-mediated antitumor activity. In order to elucidate the mechanism of this tumor eradication, the cellular components of spleen and regional lymph nodes, tumor infiltrating cells and antitumor effector cells were investigated. Pretreatment with NCS on day -3 caused an increase in the percentage of T-cell subsets, a decrease in the percentage of B-cells, Mac-1+ cells and asialo GM1+ cells and a decrease of the total cell number in the spleen. These changes were observed before but not during the period of tumor regression and were also observed in non-transplanted mice with NCS treatment. In the lymph nodes, while B-cells increased on Meth A transplantation, this was suppressed by NCS pretreatment. Although histological examination of tumor nodules showed the presence of only a few host immune cells in the tumor tissue, the area of necrosis was already extensive on day 7 and expanded thereafter. In vivo depletion of whole T-cells, T-cell subsets or asialo GM1+ cells by antibody treatment suggests that the antitumor effector cells in tumor eradication were Thy1,2+/Lyt2+, and at least some of which also express asialo GM1 antigen and that L3T4+ T-cells were also involved in tumor eradication.

Total calcium is routinely measured after thyroidectomy in a clinical setting, while the measurement or calculation of the free calcium level is not generally performed. We reviewed total and free calcium levels in patients who underwent lobectomy (n = 15), subtotal thyroidectomy (n = 15) and total thyroidectomy (n = 15). Postoperative total calcium levels decreased significantly in comparison to preoperative levels in all thyroidectomies (p < 0.01), and this fall was significantly related to the extent of surgery (p < 0.01). In contrast, there was no significant difference between preoperative and postoperative free calcium levels in patients undergoing lobectomy, although we found a decrease in free calcium levels after both subtotal and total thyroidectomy. Total protein levels decreased regardless of the type of operation. Serum total calcium levels were thought to be altered by serum protein levels through the change of protein-bound calcium levels. When examined for free calcium levels, some patients were administered unnecessary calcium supplementation because hypocalcemia had been judged from the total calcium level. Since the wrong diagnosis may be given with regard to hypoparathyroidism by measurement of total calcium levels alone, we propose that free calcium levels should be routinely measured or calculated after thyroidectomy.

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.

Objective: To study risk factors for the development of air travel-related acute venous thromboembolism., Methods: A retrospective study of 254 patients admitted from 1988 to 1993 under the diagnosis of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) identified 44 patients who developed symptoms during or after air flight., Results: There were 24 males and 20 females with a mean age of 63 years. Flight times were 5-17 hours. Twenty-eight patients (63.6%) had DVT only, five patients (11.4%) PE only, and 11 patients (25%) DVT and PE. Ninety-five percent had extension of the thrombus above the calf: popliteal vein, 10 patients; superficial femoral vein, 13 patients; common femoral vein, six patients; and iliac vein, eight patients. Five patient-related risk factors were identified: history of previous DVT (34%), presence of chronic disease or malignancy (25%), hormone therapy (16%), recent lower limb injury (11%), and recent surgery or femoral catheterization (9%)., Conclusions: We can speculate about the role of seven cabin-related risk factors: low humidity, hypoxia, diuretic effect of alcohol, insufficient fluid intake, smoking, "coach" position, and immobilization. In travelers with patient-related risk factors, the cabin-related risk factors are superimposed and may increase the risks for air travel-related acute venous thromboembolism. Active prophylaxis is recommended.

We reported previously that pretreatment with zinostatin stimalamer (ZSS) eradicated Meth A tumors in BALB/c mice. We herein investigated cellular components of spleen and lymph node cells of Meth A-bearing ZSS-pretreated mice by flow cytometry; the antitumor effector cells by in vivo depletion of T cells, NK cells, or macrophages; and host-mediated antitumor activity associated with ZSS treatment after tumor transplantation. ZSS given on day-3 transiently decreased the number of spleen cells. The percentage of T cells increased, but B cells and macrophages decreased. B cells decreased in inguinal lymph nodes in Meth A-bearing ZSS-pretreated mice, but increased in Meth A-bearing control mice. In vivo depletion experiments using antibodies or carrageenan showed that antitumor effector cells for tumor eradication are Thy1.2+/Lyt2.2+ and that at least a part of them are asialo GM1+. Thy1.2+/Lyt2.2+/asialoGM1- cells are important in generation of the antitumor activity of ZSS; however, L3T4+ T cells are also involved in initiation of tumor eradication. The result of ZSS treatment after tumor transplantation suggests that ZSS might exhibit antitumor activity by augementating host-mediated antitumor resistance, as well as its intrinsic cytocidal activity.

Objective: To test a new classification of chronic venous disease (CVD)--based on clinical, etiologic, anatomic, and pathophysiologic data (the CEAP system)--in a series of patients by using objective tests to establish all diagnoses., Material and Methods: The CEAP classification was applied to 102 extremities in 70 consecutive patients with CVD. Diagnoses were based on objective testing with continuous-wave Doppler studies, duplex scanning, plethysmography, venous pressure, and phlebography, which were applied selectively (the more invasive methods were reserved for cases of greater severity)., Results: Use of this classification provided an organized categorization of the key elements of the venous abnormalities in each case and clarified the interrelationships among the clinical manifestations, cause of the process, and anatomic distribution of involvement. For example, in this series of 102 extremities, 79% had primary venous disease, 18% had secondary disease, and 3% had congenital abnormalities. Ulcers were found in 7% of extremities with primary CVD and 44% with secondary CVD. Of the cases with ulceration, 43% were due to primary incompetence and 57% to postthrombotic disease. Reflux was the pathophysiologic problem in 86% of the total series and in 80% of ulcer cases. Similar relationships can be delineated for cases with varicose veins, edema, or skin changes. Study of the specific facets of the CEAP classification provided precise information about the cause and the effect of venous abnormalities that could be compared with cases in other series., Conclusion: Use of the CEAP classification with diagnoses determined by objective testing accurately identifies categories of CVD. The objective date provide a clear description of the abnormalities in each case and may be used for analyses of meaningful relationships between categories of CVD. Adoption of this objective method of classifying CVD will facilitate interinstitutional studies.

The place of deep venous valve reconstruction in the surgical management of the patient with chronic venous insufficiency has become clearer with collected experience over the past 25 years. The reasons to perform surgery in chronic venous disease and the specific rationale for deep venous repair are contrasted with the management of the same patient by medical means. A new classification of chronic venous disease has been developed and provides the basis for a more objective understanding of specific entities in the entire field of chronic venous symptoms. The requirements for diagnosis before reconstructive surgery are stringent and a diagnostic algorithm is discussed in the selection of candidates for deep venous reconstruction. The multiple surgical techniques for deep venous reconstruction include internal intravenous direct valve repair and extravenous tightening of the vein wall around the valve cusp. The results of valve repair for primary valve incompetence are discussed in terms of long-term clinical results, long-term imaging results and long-term physiologic results as reflected by venous pressure examinations. It is becoming increasingly clear with the passage of time and the sharpening of our diagnostic skills that reflux is the dominant cause of chronic venous insufficiency. The ability of surgical procedures to decrease reflux in a diseased extremity can be used to restore patients to their normal way of life free of pain, swelling and ulceration and, in the ideal case, free of the need for elastic support.

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.

The cis-acting region, GM-kappa B/GC-box (positions -95 and -73), within the murine GM-CSF gene promoter is required for maximal induction by stimulation with phorbol-12-myristate acetate (PMA) and calcium ionophore (A23187) in T cells. GM-kappa B defines a binding site for NF-kappa B, and GC-box defines a binding site for three (A1, A2, B) constitutive proteins. We report here that three copies of the GC-box can functionally compensate for the GM-kappa B/GC-box region, suggesting that the GC-motif can function independently of the GM-kappa B motif. The major GC-box binding activity A1 was purified and identified as the transcription factor Sp1. We show that depletion of Sp1 (A1) from nuclear extracts specifically decreases in vitro transcription activity on GM-CSF templates. Since the human GM-CSF promoter has a base difference within the GC-box, we speculate that this may explain why the human promoter is weak and that an upstream enhancer is required for the induction of the human GM-CSF gene.

Purpose: To achieve uniform testing of venous reflux between institutions, comparable methods of testing by duplex scanning are desired. This study directly examines differences of testing by two techniques, Valsalva and rapid cuff deflation, performed in two positions: 15-degree reverse Trendelenburg (RT-15) and standing., Methods: Duplex examination of 22 extremities in 19 patients with moderate to severe, class 2 and 3 chronic venous insufficiency symptoms were compared with duplex scanning of 21 limbs in 11 normal, healthy volunteers. Duration of retrograde flow and peak velocity were measured in 247 venous segments. All extremities were studied in four ways: RT-15 Valsalva, standing Valsalva, RT-15 cuff, and standing cuff. Reflux was defined as duration of retrograde flow or reflux time greater than 0.5 seconds. Six venous segments were examined: common femoral, superficial femoral, deep femoral, and greater saphenous in the upper thigh, popliteal, and posterior tibial (at the ankle)., Results: The results of testing the Valsalva technique and the cuff in both the RT-15 and standing non-weight bearing positions indicate that the Valsalva method is best performed in the RT-15 position as opposed to standing, whereas the cuff technique is more effective in the standing position. In symptomatic limbs, the RT-15 Valsalva method showed similar proportion of reflux in the upper thigh when compared with the standing cuff method: common femoral (90% vs 67%), superficial femoral (81% vs 71%), greater saphenous (88% vs 59%), and deep femoral veins (30% vs 15%). In the popliteal vein the standing cuff test showed similar proportion of reflux (77%) as compared with the RT-15 Valsalva test (68%); however, a case-by-case analysis identified a large amount of variability between techniques, and inconsistencies could not be used to identify one technique as better than the other. Examination of the posterior tibial veins by all methods produced inconsistencies and a low yield of reflux in symptomatic limbs. In the common femoral vein, RT-15 Valsalva testing produced reflux times of up to 1.5 seconds in normal limbs, and represented "physiologic reflux." There was no recognizable effect of iliac vein valves on testing distal venous segments by Valsalva maneuver., Conclusions: Reflux in the upper thigh veins--common femoral, superficial femoral, deep femoral, and greater saphenous-is similarly demonstrated in both normal and symptomatic states by cuff deflation and RT-15 Valsalva techniques. In the popliteal vein, discrepancies between these two techniques are identified in patients with chronic venous insufficiency, and tibial vein reflux is not well demonstrated by either technique. Further investigation is needed to determine ideal techniques for identifying popliteal and tibial vein reflux.

Bacterial translocation across the gut wall may be associated with insult to the latter. In this situation, intestinal flora can enter the blood stream and lymph nodes and be transported to other organs. Glutamine is a nonessential amino acid not presently included in total parenteral nutrition (TPN) preparations. The use of glutamine-enriched TPN in the rat has resulted in a significant reduction in bacterial translocation. This study attempted to evaluate the role of glutamine in preventing bacterial translocation following hemorrhagic shock in a rat model. Forty Sprague-Dawley rats were equally divided into two groups. The controls were given TPN solution, while the treated group had glutamine instead of the standard alanine present in TPN. Hemorrhagic shock was induced in both groups and blood cultures were performed. Glutamine-treated rats did not show a significant difference in survival suggesting that it is of no particular value in severe hemorrhagic shock in rats.

The purpose of this study was to clarify the role of endogenous nitric oxide in ethanol-induced perturbation of microcirculation and hepatic injury in perfused rat liver. Infusion of ethanol into the portal vein at 25 and 100 mmol/L increased portal pressure, which is an indicator of hepatic vasoconstriction, in a concentration-dependent fashion. Portal pressure started to rise immediately after ethanol load, then decreased gradually and remained at higher than basal levels throughout the period of ethanol infusion. Release of lactate dehydrogenase into the effluent perfusate began to increase after 30 min of ethanol infusion and continued to increase during the 60-min period of ethanol infusion. The lactate dehydrogenase level in the effluent perfusate at 60 min was dependent on the ethanol concentration (0 mmol/L, 8 +/- 3 IU/L; 25 mmol/L, 16 +/- 2 IU/L; 100 mmol/L, 52 +/- 6 IU/L). Simultaneous infusion of NG-monomethyl-L-arginine, a nitric oxide synthesis inhibitor, enhanced significantly the ethanol-induced increase in portal pressure by 100% to 400% and increased lactate dehydrogenase release by 40% to 80%. The effect of NG-monomethyl-L-arginine on the ethanol-induced increase in portal pressure was completely reversed by the co-infusion of an excess dose of L-arginine. Change in portal pressure averaged over 60 min of ethanol infusion correlated with levels of lactate dehydrogenase release 60 min after the initiation of ethanol infusion (r = 0.77, p < 0.01). In conclusion, inhibition of the action of endogenous nitric oxide was associated with an increase in hepatic vasoconstriction and hepatocellular damage.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

The P sequence of the human interleukin-4 (IL-4) gene, which was defined as a responsive element for phorbol 12-myristate 13-acetate and calcium ionophore (A23187) in Jurkat T cells, shares sequence similarity with the NF-kappa B and the NF-AT binding sites. We examined whether NF(P), a nuclear factor specific for the P sequence, is related to NF-kappa B and NF-AT. NF-kappa B (P65 or P65/P50 heterodimer) bound to the P sequence in electrophoretic mobility shift assays (EMSA) and activated transcription through the P sequence when expression plasmids were cotransfected with P sequence-driven reporter plasmids in Jurkat T cells. In EMSAs, NF(P) binding was inhibited by the unlabeled NF-AT binding site but not by the unlabeled AP1 binding site and purified NF-AT contained an activity that bound to the P sequence. Both mobility shift and sequence specificity of NF-AT were similar to those of NF(P) and only a small amount of P65 was detected in NF(P) in crude nuclear extracts. These results indicate that the component(s) of NF-AT has the potential to reconstitute NF(P) whereas NF-kappa B alone cannot account for NF(P) in crude extracts. Unlike NF-AT, NF(P) does not contain AP1 as its DNA binding component.

Purpose: The purpose of this study is to describe the very long-term clinical, hemodynamic, and imaging results of venous valve reconstruction for reflux disease in patients with chronic venous insufficiency., Methods: There were 51 extremities (48 patients) with follow-up of 4 to 21 years with a mean of 10.6 years. Clinical severity was graded as asymptomatic (class 0), mildly symptomatic (class 1), moderately symptomatic but without ulceration (class 2), or severely symptomatic with or without ulceration (class 3). Preoperative and postoperative evaluation consisted of history and physical examination, ascending venography (preoperative only), ambulatory venous pressures or photoplethysmography, and descending venography or duplex scanning., Results: Before surgery, 49 (96%) of 51 limbs demonstrated severe, class 3 disease, and two limbs were classified as class 2 disease. After venous valve reconstruction by either direct femoral vein valve repair, transposition, or transplantation, long-term clinical success of achieving a class 0 or 1 result (by life-table analysis) was 60% at 10 years. Thirty-three percent demonstrated a class 0 result in which the limbs were free from symptoms and had no need for long-term elastic support. After 6 years clinical results were stable and did not deteriorate. Incompetent perforators were identified in 31 cases and were treated selectively. Three disease patterns of chronic venous insufficiency were identified: primary valve insufficiency 43%, postthrombotic syndrome 31%, and a group consisting of both primary valve insufficiency of the superficial femoral vein and postthrombotic syndrome of the calf veins (primary valve insufficiency-postthrombotic syndrome) 26%. Ten-year cumulative clinical success was clearly superior in limbs with primary valve insufficiency corrected by valve repair (73%) as opposed to those with postthrombotic syndrome treated by either valve transposition or transplantation (43%) (p = 0.029). Clinical outcome correlated strongly with postoperative imaging results, and durability of valve repair was confirmed by demonstrating competence up to 16 years after the operation. Significant improvement in ambulatory venous pressure (mean percentage of pressure fall and refill time) was found in limbs with class 0 or 1 outcome; however, values did not reach "normal" levels in all cases. Recurrent ulcerations after the operation were attributed to failed reconstructions (10), incompetent profunda femoris veins (three), incompetent perforators (three), and concomitant lymphedema (one)., Conclusions: This report highlights a difference found in very long-term prognosis of surgical treatment of primary valve insufficiency as opposed to postthrombotic syndrome. Long-term elimination of symptoms of chronic venous insufficiency is achieved by valve repair for primary valve insufficiency beyond 10 years, whereas late results of treatment of postthrombotic syndrome in this study was accompanied by high recurrence rates and warrants further investigation.

Hepatic microcirculatory perturbation is observed after ischemia/reperfusion. Endothelin-1, a potent vasoconstrictive peptide, is known to modulate local circulation. This study was designed to examine whether endothelin-1 participates in the mechanism of microcirculatory disturbance and damage of the liver after ischemia/reperfusion. Ischemia in the median and left lateral lobes of the liver was induced for 60 min; it was followed by reperfusion for 24 hr. In some rats, endothelin-1 antiserum or control serum without endothelin-1-blocking activity was administered intravenously just before reperfusion. Rats were divided into three groups: an ischemia/reperfusion group that was injected with control serum, an endothelin-1 antiserum-treated group and a sham-operated group. Endothelin-1 concentrations in blood collected from the suprahepatic vena cava were measured before and after ischemia/reperfusion by use of a sandwich enzyme immunoassay. Index of blood volume in regional hepatic tissue and index of blood oxygenation in regional hepatic tissue were assessed with an organ reflectance spectrophotometry system before and at 5 min and 1, 2, and 24 hr after reperfusion. The endothelin-1 concentration in the ischemia/reperfusion group started to rise immediately at onset of reperfusion from basal values around 1 pg/ml and reached a value of 5 to 6 pg/ml 5 min after reperfusion; it was maintained at significantly high levels during the reperfusion period compared with the sham-operated group. Hepatic microcirculatory disturbance indicated by lowered index of blood volume in regional hepatic tissue and index of blood oxygenation in regional hepatic tissue levels was observed in the early phase of reperfusion in the ischemia/reperfusion group.(ABSTRACT TRUNCATED AT 250 WORDS)

Microcirculatory disturbance is one of the main pathogenetic features of alcoholic liver damage. We have demonstrated that ethanol increased portal pressure, leading to hepatic hypoxia and hepatocellular necrosis. In this ethanol-induced hepatic vasoconstriction, nitric oxide, an endothelial derived relaxing factor, dilated constrictive hepatic vasculature and reduced liver injury by improving the microcirculatory disturbance.

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.

Several valvulotomes are currently available to achieve valvular disruption; however, studies comparing the efficacy of these endoluminal instruments are lacking. This prospective study evaluates the efficacy and safety of the three most commonly employed valve cutters: the Hall, LeMaitre, and Mills valvulotomes. A total of 30 in situ greater saphenous vein bypass grafts were included in this investigation. Valvular disruption was attempted with either the LeMaitre (11 cases), Hall (12 cases), or Mills (7 cases) valvulotomes. Subsequently, angioscopy was employed to assess the completeness of valvulotomy and to identify vein wall injury. Incomplete disruption of one or more valve complexes was identified in 2 of 12 (17%) grafts in the Hall group, 10 of 11 (91%) grafts in the LeMaitre group, and 0 of 7 grafts in the Mills group (p < 0.01). Intact valve cusps were noted in 2 of 36 (5.5%) valves, 31 of 42 (74%) valves, and 0 of 38 valves after valvulotomy with the Hall, LeMaitre, and Mills instruments, respectively (p < 0.01). A total of three valvulotome-related injuries occurred; two injuries were noted in conjunction with the Hall instrument, one was associated with the Mills valvulotome, and no injuries were detected after use of the LeMaitre instrument (p = 0.33). These data demonstrated a significantly increased incidence of retained valve cusps when the LeMaitre valvulotome was used. No significant difference in the rate of vein wall injury was noted in the three groups. Thus this study suggests that the LeMaitre instrument is not as effective as either the Hall or Mills valvulotomes for achieving valvular disruption.

The cis-acting element of the granulocyte-macrophage colony-stimulating factor (GM-CSF) promoter, CLE0, is required for stimulation dependent expression of the GM-CSF gene by phorbol ester (PMA) and calcium ionophore (A23187) in T cells. We recently obtained evidence that NF-CLE0 gamma, one of the CLE0-binding factors, is similar to the nuclear factor of activated T cells, NF-AT. In the present study, we show that the affinity-purified NF-AT from nuclear extracts of human Jurkat T cells stimulated with both PMA and A23187 bound strongly to the CLE0 element and formed a NF-CLE0 gamma complex. This DNA-protein complex was competitively inhibited by oligonucleotides containing NF-AT and AP-1 binding sites, suggesting that the CLE0 gamma complex is identical to NF-AT and contains AP-1 proteins. Here, one component of NF-AT with an apparent molecular mass of 120 kDa on SDS-polyacrylamide gel electrophoresis was purified to near homogeneity by Mono Q chromatography. The purified 120 kDa protein reconstitutes NF-AT binding in combination with recombinant cJun/cFos heterodimer. Furthermore, we demonstrate that binding of this 120 kDa protein to both the NF-AT and the CLE0 sequences can be reconstituted with the addition of affinity-purified Jurkat AP-1 proteins. These results indicate that NF-AT (NF-CLE0 gamma), which is composed of the 120 kDa nuclear protein and AP-1 proteins, regulates the stimulation-dependent expression of the GM-CSF gene as it does the IL-2 gene.

This study examines the late clinical, hemodynamic, and anatomic results of superficial femoral vein ligation performed in 35 extremities that were followed an average of 13 1/2 years (range, 5 to 22 years). Indications for interruption were to prevent recurrent embolization from distal deep venous thrombosis (14 cases), to prevent emboli in patients with contraindication to anticoagulants (eight cases), to prevent distal reflux in selected patients undergoing iliofemoral thrombectomy (11 cases), and to control reflux in failed venous reconstruction (two cases). Ligation was effective in the prevention of pulmonary emboli as indicated by no significant clinical events and 15 negative postligation ventilation-perfusion scans. Long-term clinical follow-up showed normal (class 0) or near-normal (class 1) extremities in 83%. Fourteen percent developed mild to moderate symptoms of pain or swelling but without ulceration (class 2), and only one case (3%) had ulcerative sequelae (class 3). The only two findings that correlated with worse clinical outcome were the presence of an incompetent profunda femoris or an obstructed greater saphenous vein. Profunda femoris reflux was found in 60% (3/5) of patients with class 2 or 3 sequelae, which was significantly higher than the 14% (3/22) found in those patients with class 0 or 1 results (p < 0.05). Obstruction of the greater saphenous vein was found in 50% of those patients with class 2 or 3 results as opposed to 9% with class 0 or 1 results (p = 0.05). A large collateral vessel between the profunda femoris and the distal superficial femoral or popliteal vein was associated with poor long-term results.(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective study comparing duplex scanning and descending venography was applied to 143 venous segments in 25 extremities with moderate to severe manifestations of chronic venous insufficiency (class 2 or 3). Duplex scanning was performed with the patient in the 15 degree reverse Trendelenburg position, and descending venography with the patient in the 60 degrees semi-erect position; the Valsalva maneuver was used to elicit reflux in both tests. The duplex parameter of reflux duration greater than 0.5 second correlated with venographic reflux in 94 of 105 segments (sensitivity of 90%). Conversely, reflux time less than or equal to 0.5 second correlated with venographic competence in 32 of 38 segments (specificity of 84%). A total of 17 discrepancies were identified among the 143 total segments studied, for an accuracy of 88%. The largest proportion of discrepancies was identified in the group with venographic competence and reflux duration greater than 0.5 second and less than or equal to 2.0 seconds; this was designated a gray zone. Mean peak velocities were significantly higher in the reflux group when compared with the competence group in the profunda femoris vein (p = 0.047), greater saphenous vein (p less than 0.001), popliteal vein (p less than 0.001), and tibial vein (p = 0.005). We conclude that venographic reflux correlates best with duplex scan findings of reflux duration greater than 0.5 second. Duration of reflux greater than 0.5 second and less than or equal to 2.0 seconds, however, represents a gray zone and should be interpreted with caution since this could lead to over-reading of reflux disease, in which case verification of incompetence by descending venography may be indicated.

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.

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.

Zinostatin stimalamer (YM881) is an antitumor agent, chemically synthesized by coupling one molecule of neocarzinostatin (NCS), with 2 molecules of styrene maleic acid half-butylester copolymer. YM881 showed strong cytotoxicity to human (KB, ST4 and others) and mouse (P388, L1210) tumor cell lines and also drug-resistant tumor cell lines. The antitumor effects were observed in murine MM46, colon 26 and other tumor models. The antitumor activity was as effective as NCS or better than NCS at the effective dose ranges.

The effects of ethanol on gastric vasculature in isolated vascularly perfused rabbit stomach was investigated. The isolated stomach was perfused with Krebs-Henseleit solution containing 3% dextran bubbled with 95% O2 and 5% CO2 at a rate of 12 ml/min. After mixture and perfusion of 10 mM to 400 mM of ethanol, perfusion pressure and endothelin-1 concentration in effluent from gastric vasculature were measured. Perfusion pressure and endothelin-1 concentration in effluent increased in a dose-dependent manner with increasing ethanol concentrations. In conclusion, the data suggest that ethanol may stimulate the release of endothelin from gastric vasculature and may cause gastric ischemia due to vasoconstriction resulting in acute gastric mucosal injury.

The present series of studies were performed to test the hypothesis that ethanol in the blood may play a role in the pathogenesis of gastric mucosal injury. Another hypothesis to be examined was that endothelin may be involved in ethanol-induced gastric mucosal injury. Elevated levels of blood ethanol induced by intraperitoneal infusion of ethanol increased vulnerability of the stomach to hydrochloric acid in a dose-dependent manner in rats. This may be due to impaired gastric mucosal hemodynamics and oxygenation as demonstrated by the results obtained by organ reflectance spectrophotometry (decreases in indices of mucosal hemoglobin contents and hemoglobin oxygen saturation). Ethanol infusion caused a dose-dependent increase in gastric vascular resistance in perfused rabbit stomach, which was accompanied by an increased production of endothelin-1. The results suggest that endothelin may be involved in the pathogenesis of ethanol-induced gastric mucosal injury.

Although acute gastric mucosal lesions (AGMLs) develop after the mucosal ischemia and reperfusion, precise intracellular mechanism for the development of AGMLs remains unclear. In the present paper, we investigated intracellular calcium level, lipid peroxidation, and gastric mucosal lesion in rat hemorrhagic shock model. We estimated intracellular calcium by measuring phosphorylase a activity in the gastric mucosa. The mucosal phosphorylase a increased during hemorrhagic shock, while it returned to be normal after the reinfusion of shed blood. Although mucosal lipid peroxide and area of AGMLs did not increase significantly during hemorrhagic shock, they increased significantly after the reinfusion. Diltiazem, a calcium antagonist, prohibited both of the increase in mucosal phosphorylase a activity during hemorrhagic shock and the increase in lipid peroxide content and area of AGMLs after the reinfusion of the shed blood. Organ reflectance spectrophotometry revealed that the gastric corpus suffered mucosal ischemia and hypoxia during the hemorrhagic shock. The are of AGMLs had a good correlation with a level of lipid peroxidation in the gastric mucosa. These results suggest 1) that intracellular free calcium in gastric mucosa increases during the mucosal ischemia; 2) that a calcium antagonist prohibits the increased intracellular free calcium during mucosal ischemia; and 3) that a calcium antagonist prohibits the increased mucosal lipid peroxide and the development of AGMLs after the mucosal reperfusion. Thus it is concluded that the increased intracellular free calcium during ischemia plays a key role in the mucosal tissue injury in the ischemia-reperfusion state.