A randomized controlled trial comparing a prepackaged low-residue diet with a restricted diet for colonoscopy preparation: the impact on the results of colonoscopy in adenoma detection.

AIM: This study aimed to investigate the clinical utility of a prepackaged low-residue diet (PLD) compared with a restricted diet (RD) for colonoscopic bowel preparation. METHOD: A prospective randomized controlled trial was carried out with patients undergoing colonoscopy. One hundred patients were randomly assigned to PLD and RD groups. In the RD group, the patients received an information sheet containing acceptable low-residue options and instructions from the medical staff. All patients received 10 ml sodium picosulphate the day before colonoscopy and 1 l of polyethylene glycol with ascorbic acid (PEG-A) on the day of the colonoscopy. If the bowel preparation was not adequate, an additional PEG-A solution was given. The primary outcome was the efficacy of colonic cleansing as rated by the Boston Bowel Preparation Scale (BBPS). The additional amount of PEG-A solution, adenoma detection rate and patient tolerance were assessed as secondary outcomes. RESULTS: The BBPS score in the PLD group was 7.3 ± 1.7 compared with 6.5 ± 1.7 in the RD group. The quality of bowel preparation was significantly better in the PLD group (P < 0.05). The mean amount of additional PEG-A solution in the PLD group was smaller than in the RD group (293.8 ± 474.8 vs 444.1 ± 625.0 ml), but there was no statistical difference between the two groups. Adenoma detection rates and patient tolerance were similar in the two groups. CONCLUSION: Prepackaged low-residue diets PLD is superior to RD for bowel preparation for colonoscopy.

Clinical outcomes of endoscopic resection for nonampullary duodenal high-grade dysplasia and intramucosal carcinoma.

This study retrospectively analyzed the clinical outcomes of endoscopic resection of 26 sporadic (i. e., not associated with polyposis syndrome) nonampullary duodenal lesions representing high-grade dysplasia or intramucosal carcinoma (duodenal HGD/IMC) in 23 patients. No severe complications such as perforation were observed, but three cases of delayed bleeding were seen. The use of endoscopic clips significantly decreased the delayed bleeding rate (0/19, 0%) compared with cases in which clips were not used (3/7, 42.9%; P = 0.013, χ2 test). Eighteen lesions (69.2%) were removed by en bloc resection. The follow-up period after resection was 25.5 ± 23.3 months. Two lesions (7.7%) that recurred locally were detected at the first surveillance endoscopy 3 months after resection. These lesions were 22 and 15 mm in size respectively and were resected piecemeal. Endoscopic resection is an effective and safe procedure for treating duodenal HGD/IMC. En bloc resection and prophylactic clip usage are encouraged.

Pleiotropic effects of mitiglinide in type 2 diabetes mellitus.

This study investigated the effects of mitiglinide in 16 patients with type 2 diabetes mellitus treated with 30 mg/day mitiglinide, divided into three doses given just before each meal, for approximately 12 months. A 450 kcal meal tolerance test was performed at baseline and after 3, 6 and 12 months, and levels of plasma glucose and immunoreactive insulin were measured. Various parameters of glucose metabolism and lipid metabolism, urinary albumin and markers of atherosclerosis, coagulation and fibrinolysis were also determined. Mitiglinide showed a rapid stimulatory effect on insulin secretion and reduced the levels of plasma glucose. The free fatty acid level significantly decreased at 60 min after the meal tolerance test. Mitiglinide also significantly lowered glycosylated haemoglobin and raised 1,5-anhydroglucitol after 6 months, and significantly decreased urinary albumin after 12 months. These data indicate that mitiglinide may have beneficial effects not only on glycaemic control but also on lipid metabolism and urinary albumin excretion, and may have a role in the prevention of the vascular complications of diabetes.

Calcineurin Inhibitor-Induced Pain Syndrome in ABO-Incompatible Living Kidney Transplantation: A Case Report.

BACKGROUND: Calcineurin-inhibitor-induced pain syndrome (CIPS) was used as a reference in the literature as reflex sympathetic dystrophy syndrome related to calcineurin inhibitors. Much of the literature describes CIPS that occurred after kidney and bone marrow transplantation. We describe a rare case of CIPS in induction immunosuppression before kidney transplantation, under administration of an anti-rheumatoid drug. METHODS: A 53-year-old woman had pre-status of ABO-incompatible living kidney transplantation. The patient had rheumatoid arthritis, but that was well-controlled with salazosulfapyridine as an anti-rheumatoid drug. Fourteen days before transplantation, she received induction immunosuppressive therapy consisting of tacrolimus (TAC) and mycophenolate mofetil (MMF) and she stopped taking salazosulfapyridine. The third day after that treatment, she had a high fever, fatigue, and joint pains of the knees, elbows, and wrists. RESULTS: When the patient stopped taking TAC and MMF and started taking salazosulfapyridine again, she soon recovered. Next, we challenged same induction immunosuppression therapy with administration of salazosulfapyridine; however, the patient had the same symptom. We considered that the symptom was caused by TAC or MMF, and we did not challenge-test each drug. We found that taking only TAC caused the same symptom for the patient. Also, we challenged cyclosporine (CsA) with MMF and confirmed that she did not have the symptom. CONCLUSIONS: We decided that drugs of the induction immunosuppression therapy were CsA, MMF, prednisolone, and basiliximab. The patient received induction therapy with plasmapheresis and rituximab in addition to the above-mentioned drugs, and we performed ABO-incompatible kidney transplantation for her. The post-surgical course was good, without acute rejection, and she had no pain.

Evaluating the performance of a hybrid artificial liver support system with a recoverable hepatic failure rat model.

To evaluate the performance of an artificial liver, we created a recoverable hepatic failure rat model. This involves a 30-60 minute warm ischemia, via clamping, of one-third of the liver with a partial (two-thirds) hepatectomy. Variations on this method provide for the possibility of several modes of hepatic failure. Survival time of the rats was prolonged (35%) by applying our hybrid artificial liver. However, the extracorporeal circulation is a considerable burden to the rat. Therefore, we need to apply the hybrid artificial liver intermittently and repeatedly.

Identification of a unique ligand which has high affinity for all four bombesin receptor subtypes.

Four subtypes of bombesin receptors are identified (gastrin-releasing peptide receptor, neuromedin B receptor, the orphan receptor bombesin receptor subtype 3 (BB3 or BRS-3) and bombesin receptor subtype 4 (BB4)), however, only the pharmacology of the gastrin-releasing peptide receptor has been well studied. This lack of data is due in part to the absence of a general ligand. Recently we have discovered a ligand, 125I-[D-Tyr6,betaAla11,Phe13,Nle14]bombesin-(6-1 4) that binds to BRS-3 receptors. In this study we investigate its ability to interact with all four bombesin receptor subtypes. In rat pancreatic acini containing only gastrin-releasing peptide receptor and in BB4 transfected BALB cells, this ligand and 125I-[Tyr4]bombesin, the conventional gastrin-releasing peptide receptor ligand, gave similar results for receptor number, affinity for bombesin and affinity for the unlabeled ligand. In neuromedin B receptor transfected BALB cells, this ligand and 125I-[D-Tyr0]neuromedin B, the generally used neuromedin B receptor ligand, gave similar results for receptor number, neuromedin B affinity or the unlabeled ligand affinity. Lastly, in BRS-3 transfected BALB cells, only this ligand had high affinity. For all four bombesin receptors this ligand had an affinity of 1-8 nM and was equal or greater in affinity than any other specific ligands for any receptor. The unlabeled ligand is specific for gastrin-releasing peptide receptors on rat pancreatic acini and did not inhibit binding of 125I-cholecystokinin octapeptide (125I-CCK-8), 125I-vasoactive intestinal peptide (125I-VIP) or 125I-endothelin to their receptors. The unlabeled ligand was an agonist only at the gastrin-releasing peptide receptor in rat acini and did not interact with CCK(A) receptors or muscarinic M3 acetylcholine receptors to increase [3H]inositol phosphates. These results demonstrate 125I-[D-Tyr6,betaAla11,Phe13,Nle14]bombesin-(6-1 4) is a unique ligand with high affinity for all subtypes of bombesin receptors. Because of the specificity for bombesin receptors, this ligand will be a valuable addition for such pharmacological studies as screening for bombesin receptor agonists or antagonists and, in particular, for investigating BRS-3 cell biology, a receptor for which no ligand currently exists.

Scrotal ulcer occurring in patients with acute promyelocytic leukemia during treatment with all-trans retinoic acid.

Although all-trans retinoic acid (ATRA) has been shown to improve the outcome of patients with acute promyelocytic leukemia (APL) compared with chemotherapy alone, various adverse effects have been reported. We report here the development of scrotal ulcer in four patients with APL during ATRA treatment. ATRA 45 mg/m2 was administered orally to four patients with newly diagnosed APL, two of whom also received chemotherapy. Scrotal ulcers appeared in all four patients after a median of 22 days (range: 17-29 days) of ATRA treatment. ATRA was discontinued in only one patient, who was then treated with methylprednisolone pulse therapy. The fever resolved, and scrotal ulcer improved after this treatment. The other three patients were treated with steroid or antibiotic ointment for scrotal ulcers. ATRA was re-administered 2 years later in one patient who had relapse of APL. Ulcers appeared again on the scrotal and lower abdominal skin on day 27 of ATRA treatment. These findings strongly suggest that scrotal ulcer is a potential adverse effect of ATRA.

[Effect of intensive vacuum cleaning in reducing house dust mite antigen in bed rooms of asthmatic children].

House dust mite (Dermatophagoides farinae) antigen was measured by enzyme-linked immunosorbent assay in house dust samples obtained from the bed rooms of asthmatic children and normal controls. In 37 rooms where regular vacuum cleaning was performed, the mean of D.f. antigen was 4.42 +/- 7.55 micrograms/m2. In the 24 bed rooms of asthmatic children, mean levels of D.f. antigen decreased significantly (p less than 0.05) after intensive cleaning (systematic cleaning) was continued for 4 weeks (0.78 +/- 0.93 micrograms/m2) compared to prior to initiation of systematic cleaning (4.12 +/- 6.31 micrograms/m2). Symptom scores decreased in 65% of the asthmatic children. In 8 bed rooms of normal controls, mean levels of D.f. antigen also showed a decrease after systematic cleaning (0.43 +/- 0.62 micrograms/m2) compared to before (5.59 +/- 12.46 micrograms/m2). However there was no significant difference in D.f. antigen between the bed rooms of asthmatic children and normal controls. Intensive cleaning markedly decreased the allergen in both groups, clearly suggesting effectiveness in the reduction of asthmatic attacks in patients and perhaps also in preventing sensitization of healthy children.

Predictive factors of response to intravenous ciclosporin in severe ulcerative colitis: the development of a novel prediction formula.

BACKGROUND: When treating patients with severe ulcerative colitis (UC), accurate prediction of drug efficacy contributes to early clinical decision-making. AIM: To identify predictive factors and to develop a reliable prediction formula and a decision tree of response to intravenous ciclosporin treatment for severe UC. METHODS: Patients included in this study were those diagnosed with refractory severe UC who had undergone ciclosporin treatment between December 2004 and March 2011 at a tertiary referral centre in Japan. Demographic and clinical parameters from all patients were analysed by multivariate statistics. RESULTS: Fifty-two patients were included in this study (36.5% men with an average age of ciclosporin initiation of 40.2 ± 15.6 years). Thirty-four patients (65.4%) were responders to the treatment with ciclosporin and avoided colectomy, 18 patients (34.6%) were nonresponders and underwent colectomy. Stepwise multiple logistic regression analysis identified four independent predictive factors of response to intravenous ciclosporin: age at hospitalisation (AGE), platelet count (×10(4) /µL) on the first day (PLA), Lichtiger score on the third day (LIC) and total protein (g/dL) on the third day minus total protein on the first day (ΔTP). The calculation formula (8.5 - 0.16 × AGE + 0.21 × PLA - 0.61 × LIC + 2.3 × ΔTP < 0) predicted colectomy with an accuracy of 88.5% and the decision tree predicted colectomy with an accuracy of 90.4%. CONCLUSION: The novel calculation formula and the decision tree effectively predict the clinical outcome of ciclosporin treatment for severe ulcerative colitis as early as on day 3 after starting ciclosporin treatment.

Concomitant use of enteral nutrition therapy is associated with sustained response to infliximab in patients with Crohn's disease.

BACKGROUND/OBJECTIVES: A significant proportion of Crohn's disease (CD) patients receiving infliximab (IFX) maintenance therapy show loss of responsiveness despite a good initial response. The factors other than immunomodulators that prevent IFX dose escalation have yet to be fully elucidated. This study was performed to identify clinical factors or concomitant therapies associated with sustained response to IFX. SUBJECTS/METHODS: Seventy-four consecutive CD patients who had successful IFX induction therapy between 2002 and 2010 underwent IFX maintenance therapy. Patients showing loss of response to IFX were treated with IFX intensification therapy. Factors involved in the sustained response to IFX were investigated retrospectively. RESULTS: After a median follow-up of 85 weeks, loss of response to IFX was observed in 30 (40.5%) cases. On logistic regression analysis, concomitant use of enteral nutrition (EN) therapy (elemental and/or polymeric formulas) was identified as an independent factor associated with sustained response to IFX. Receiver operating characteristic curve analysis indicated a cutoff value of 600 kcal/day. We divided the patients into the 'EN group' (≥ 600 kcal/day) and 'control group' (<600 kcal/day). The cumulative number of loss of response was significantly lower in the EN group (odds ratio: 0.23, P = 0.0043). Kaplan-Meier analysis confirmed the significantly lower rate of loss of response in the EN group (P = 0.013). Multivariate hazard ratio was 0.37 (P = 0.025). Type of EN formula did not affect the results. CONCLUSIONS: Concomitant use of EN ≥ 600 kcal/day is likely to yield a sustained response to IFX in CD patients.

Tight junction-based epithelial microenvironment and cell proliferation.

Belt-like tight junctions (TJs), referred to as zonula occludens, have long been regarded as a specialized differentiation of epithelial cell membranes. They are required for cell adhesion and paracellular barrier functions, and are now thought to be partly involved in fence functions and in cell polarization. Recently, the molecular bases of TJs have gradually been unveiled. TJs are constructed by TJ strands, whose basic frameworks are composed of integral membrane proteins with four transmembrane domains, designated claudins. The claudin family is supposedly composed of at least 24 members in mice and humans. Other types of integral membrane proteins with four transmembrane domains, namely occludin and tricellulin, as well as the single transmembrane proteins, JAMs (junctional adhesion molecules) and CAR (coxsackie and adenovirus receptor), are associated with TJ strands, and the high-level organization of TJ strands is likely to be established by membrane-anchored scaffolding proteins, such as ZO-1/2. Recent functional analyses of claudins in cell cultures and in mice have suggested that claudin-based TJs may have pivotal functions in the regulation of the epithelial microenvironment, which is critical for various biological functions such as control of cell proliferation. These represent the dawn of 'Barriology' (defined by Shoichiro Tsukita as the science of barriers in multicellular organisms). Taken together with recent reports regarding changes in claudin expression levels, understanding the regulation of the TJ-based microenvironment system will provide new insights into the regulation of polarization in the respect of epithelial microenvironment system and new viewpoints for developing anticancer strategies.

Clinical significance of circulating hepatocyte growth factor, a new risk marker of carotid atherosclerosis in patients with Type 2 diabetes.

AIMS: Recent studies have provided increasing evidence that hepatocyte growth factor (HGF) has a pathophysiological role in the development of diabetic complications. We set out to determine the relationship between serum HGF and risk factors for macroangiopathy including carotid atherosclerosis. Carotid atherosclerosis is an established and important risk factor for both cerebral and coronary artery diseases. METHODS: We studied 89 patients (48 males, 41 females, mean age 62.5 +/- 10.3 years) with Type 2 diabetes (DM). RESULTS: Serum levels of HGF correlated positively with both intimal-media thickness (IMT) (r = 0.24, P = 0.0248) and plaque score (r = 0.27, P = 0.0126). In multiple regression analysis, serum HGF was associated independently with IMT (standardized beta = 0.28, P = 0.0499). We also found that both IMT and plaque score were higher in patients with ischaemic heart disease (IHD) than in patients without IHD, and that plaque score in patients with lacunar infarcts was higher than in patients without lacunar infarcts. CONCLUSIONS: Serum HGF concentration may be a new marker of atherosclerotic complications in patients with Type 2 DM.

Independent accumulations of tau and amyloid beta-protein in the human entorhinal cortex.

BACKGROUND: Previous studies have repeatedly described that neurofibrillary tangles arise earlier than senile plaques (SPs) in the entorhinal cortex, but one study suggested that SPs, if present, enhance the former lesions. All of these studies were performed at the histologic or immunocytochemical level, which may not accurately reflect the actual levels of amyloid beta-protein (Abeta) and tau. OBJECTIVE: To determine whether there is significant interaction between Abeta and tau in the human entorhinal cortex with regard to the Braak stage. METHODS: Biochemical studies were conducted on 50 brains from elderly people, who were mainly at Braak stages I to III. All the cases were examined neuropathologically and staged according to Braak and Braak. A small piece of brain tissue for each case was dissected from the anterior portion of the right entorhinal cortex. The amounts of tau and Abeta in the insoluble fraction of the tissue were quantified using western blotting. RESULTS: The levels of tau and possibly Abeta42 in the entorhinal cortex appeared to rise steeply at approximately age 75. The levels of insoluble tau increased as the Braak stage increased from I to II; however, it had a tendency to remain between stages II and III. The levels of Abeta42 showed a small increase, whereas those of Abeta40 increased continuously as the Braak stage advanced. In contrast, the extent of Abeta42 accumulation increased with increasing Braak stage for SPs. There was no significant correlation between the levels of insoluble tau and Abeta42 in the entorhinal cortex. Even if Abeta did not accumulate to significant extents, substantial accumulation of insoluble tau occurred. CONCLUSION: Accumulations of tau and amyloid beta-protein occur independently in the human entorhinal cortex.

A role of PKC in the improvement of energy metabolism in preconditioned heart.

OBJECTIVE: A possible link between activation of PKC and improvement of energy metabolism during reperfusion in ischemic preconditioning hearts was examined. METHODS: Isolated perfused rat hearts were preconditioned by 5-min ischemia and 5-min reperfusion in the presence and absence of a PKC inhibitor polymyxin B (50 microM) and then subjected to 40-min sustained ischemia and subsequent 30-min reperfusion. In another set of experiments, the hearts pretreated with and without a PKC activator PMA (15 pmol/5 min) were subjected to the sustained ischemia and reperfusion. Myocardial high-energy phosphates, glycolytic intermediates and mitochondrial oxygen consumption capacity were determined at appropriate experimental sequences. RESULTS: Preconditioning enhanced the recovery of cardiac function such as left ventricular developed pressure, heart rate and rate-pressure product of the reperfused heart, suppressed the release of creatine kinase, enhanced the reperfusion-induced restoration of myocardial high-energy phosphates, attenuated the reperfusion-induced accumulation in glucose 6-phosphate and fructose 6-phosphate contents, abolished the ischemia-induced increase in tissue lactate content and prevented the ischemia-induced decrease in mitochondrial oxygen consumption capacity. Treatment of the perfused heart with PMA mimicked the effects of preconditioning on post-ischemic contractile function, enzyme release, levels of myocardial energy store, glycolytic intermediates and lactate, and mitochondrial function. Polymyxin B-treatment abolished the preconditioning-induced recovery of post-ischemic contractile function, the suppression of the release of CK, the restoration of myocardial energy store, and the preservation of mitochondrial function, whereas it did not cancel the improvement of glycolytic intermediate levels and the reduction in tissue lactate accumulation. Post-ischemic contractile function was closely related to restoration of high-energy phosphates and mitochondrial oxygen consumption capacity in all hearts subjected to ischemia/reperfusion. CONCLUSION: The results suggest that activation of PKC and preservation of mitochondrial function are closely linked with each other in the preconditioned heart, which may lead to the improvement of post-ischemic contractile function.

Changes of cytokines during the course of graft-versus-host disease following bone marrow transplantation: a case report.

Allogeneic bone marrow transplantation was performed in a 24-year-old woman with acute myelogenous leukemia in the first remission (FAB classification: M4). Graft-versus-host disease occurred from around day 150 after bone marrow transplantation. The levels of tumour necrosis factor-alpha, interleukin 12, and intercellular adhesion molecule-1 were elevated in the early stage of graft-versus-host disease, followed by elevation of interleukin 10 and interleukin 8. Her symptoms subsequently improved and all of these parameters became normal. The levels of thrombomodulin and plasminogen activator inhibitor type 1 showed changes that were in parallel with the clinical course. Interleukin 1beta, interleukin 6, interleukin 2, and interferon-gamma showed no changes throughout the course of her graft-versus-host disease. These findings suggested the possibility that release of inflammatory molecules occurred at the onset of graft-versus-host disease and caused vascular endothelial damage, which led to the exacerbation of her disease.

Tyrosine 220 in the 5th transmembrane domain of the neuromedin B receptor is critical for the high selectivity of the peptoid antagonist PD168368.

Peptoid antagonists are increasingly being described for G protein-coupled receptors; however, little is known about the molecular basis of their binding. Recently, the peptoid PD168368 was found to be a potent selective neuromedin B receptor (NMBR) antagonist. To investigate the molecular basis for its selectivity for the NMBR over the closely related receptor for gastrin-releasing peptide (GRPR), we used a chimeric receptor approach and a site-directed mutagenesis approach. Mutated receptors were transiently expressed in Balb 3T3. The extracellular domains of the NMBR were not important for the selectivity of PD168368. However, substitution of the 5th upper transmembrane domain (uTM5) of the NMBR by the comparable GRPR domains decreased the affinity 16-fold. When the reverse study was performed by substituting the uTM5 of NMBR into the GRPR, a 9-fold increase in affinity occurred. Each of the 4 amino acids that differed between NMBR and GRPR in the uTM5 region were exchanged, but only the substitution of Phe(220) for Tyr in the NMBR caused a decrease in affinity. When the reverse study was performed to attempt to demonstrate a gain of affinity in the GRPR, the substitution of Tyr(219) for Phe caused an increase in affinity. These results suggest that the hydroxyl group of Tyr(220) in uTM5 of NMBR plays a critical role for high selectivity of PD168368 for NMBR over GRPR. Receptor and ligand modeling suggests that the hydroxyl of the Tyr(220) interacts with nitrophenyl group of PD168368 likely primarily by hydrogen bonding. This result shows the selectivity of the peptoid PD168368, similar to that reported for numerous non-peptide analogues with other G protein-coupled receptors, is primarily dependent on interaction with transmembrane amino acids.

Glycosylation of the gastrin-releasing peptide receptor and its effect on expression, G protein coupling, and receptor modulatory processes.

Many gastrointestinal G protein-coupled receptors are glycosylated; however, which potential glycosylation sites are actually glycosylated and their role in receptor transduction or receptor modulation (internalization, down-regulation, desensitization) is largely unknown. We used site-directed mutagenesis to address these issues with the gastrin-releasing peptide receptor (GRP-R). Each of the four potential glycosylation sites was mutated by converting the Asn (N) to Gln (Q). Transient expression in CHOP cells demonstrated that changing Asn(24) or Asn(191) inhibited GRP-R cell surface expression, whereas elimination of Asn(5) and Asn(20) had no effect. Using ligand cross-linking studies in stable mutants expressed in Balb 3T3 cells, all four potential extracellular sites were glycosylated with carbohydrate residues of approximately 13 kDa on Asn(5), 10 kDa on Asn(20), 5 kDa on Asn(24), and 9 kDa on Asn(191). Removal of three glycosylation sites (N5,20,24,Q mutant) did not alter receptor affinity or G protein coupling; therefore, it could be speculated that deglycosylation at Asn(191) might be responsible for the altered G protein coupling seen with complete enzymatic deglycosylation of the native receptor previously reported. Removal of any single glycosylation site did not interfere with GRP-R induced chronic desensitization or down-regulation. However, elimination of all three NH(2)-terminal sites (N5,20,24) markedly attenuated both processes, with no effect on acute homologous desensitization and with only a minimal alteration of GRP-R internalization, supporting the findings of other studies that suggest that chronic desensitization and down-regulation are functionally coupled, distinct from acute desensitization and distinct from internalization. These data show that separate and specific glycosylation sites are important for GRP-R trafficking to the cell surface, ligand binding, G protein coupling, chronic desensitization, and down-regulation.