Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy.

BACKGROUND: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. PATIENTS AND METHODS: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. RESULTS: No SNPs exceeded the genome-wide significance (P < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. CONCLUSION: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.

Minimally invasive esophagectomy may contribute to long-term respiratory function after esophagectomy for esophageal cancer.

Evidence suggests that minimally invasive esophagectomy has several advantages with regard to short-term outcomes, compared to open esophagectomy in esophageal cancer patients. However, the impact of minimally invasive esophagectomy on long-term respiratory function remains unknown. The objective of this study is to assess the association between use of the minimally invasive esophagectomy and long-term respiratory dysfunction in esophageal cancer patients after esophagectomy. This retrospective single institution study using prospectively collected data included 87 consecutive esophageal cancer patients who had undergone esophagectomy. All patients underwent a respiratory function test before, and one year after esophagectomy. Logistic regression analysis was used to compute the hazard ratio for long-term respiratory dysfunction. Minimally invasive esophagectomies were performed in 53 patients, and open esophagectomies in 34 patients. The two groups showed no significant differences in terms of postoperative complications and postoperative course. Nor were any differences observed between the two groups in terms of volume capacity (L) and forced expiratory volume 1.0 (L) before esophagectomy (P > 0.34). However, one year after esophagectomy, the decreases in volume capacity and forced expiratory volume 1.0 were significantly less in the minimally invasive esophagectomy group than in the open esophagectomy group (P = 0.04 and P = 0.007, respectively). Multivariate analyses revealed that minimally invasive esophagectomy was an independent favorable factor for maintenance of forced expiratory volume 1.0 (hazard ratio = 0.17, 95% confidence interval 0.04-0.71; P = 0.01). Minimally invasive esophagectomy may be an independent favorable factor for maintenance of long-term respiratory function in esophageal cancer patients after esophagectomy.

Single-dose new insulin glargine 300 U/ml provides prolonged, stable glycaemic control in Japanese and European people with type 1 diabetes.

AIMS: Two single-dose studies were conducted in Japan and Europe to compare the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of new insulin glargine 300 U/ml (Gla-300) and insulin glargine 100 U/ml (Gla-100) in people with type 1 diabetes mellitus. METHODS: In two double-blind, randomized, crossover studies, 18 Japanese participants (aged 20-65 years) and 24 European participants (aged 18-65 years) with glycated haemoglobin levels ≤9.0% (≤75 mmol/mol) received single subcutaneous doses of Gla-300, 0.4, 0.6 and 0.9 U/kg (0.9 U/kg in the European study only), and Gla-100, 0.4 U/kg. A 36-h euglycaemic clamp procedure was performed after each dosing. RESULTS: The serum insulin glargine concentration (INS) and glucose infusion rate (GIR) developed more gradually into more constant and prolonged profiles with Gla-300 than with Gla-100. In support of this, the times to 50% of glargine exposure and insulin activity were longer for all Gla-300 doses than for Gla-100 during the 36-h clamp period, indicating a more evenly distributed exposure and metabolic effect beyond 24 h. Exposure to insulin glargine and glucose utilization were lower with the 0.4 and 0.6 U/ml Gla-300 doses in both studies compared with the 0.4 U/ml Gla-100 dose. Glucose-lowering activity was detected for up to 36 h with all doses of Gla-300. CONCLUSIONS: Single-dose injections of Gla-300 present more constant and prolonged PK and PD profiles compared with Gla-100, maintaining blood glucose control for up to 36 h in euglycaemic clamp settings in Japanese and European participants with type 1 diabetes.

Effects of once-daily teneligliptin on 24-h blood glucose control and safety in Japanese patients with type 2 diabetes mellitus: a 4-week, randomized, double-blind, placebo-controlled trial.

AIM: To assess blood glucose control over 24 h and the safety of teneligliptin 10 and 20 mg, a novel dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus inadequately controlled with diet and exercise. METHODS: Ninety-nine patients were administered teneligliptin 10 or 20 mg or placebo before breakfast for 4 weeks in a randomized, double-blind, placebo-controlled, parallel-group study. RESULTS: Both teneligliptin-treated groups showed significantly smaller 2-h postprandial glucose (2-h PPG), 24-h mean glucose and fasting plasma glucose values than the placebo group. The differences between the teneligliptin 10 mg and placebo groups in changes in 2-h PPG after each meal were -50.7 ± 7.8, -34.8 ± 9.2 and -37.5 ± 7.5 mg/dl at breakfast, lunch and dinner, respectively [least-squares (LS) means ± standard error (s.e.), all, p < 0.001]. The corresponding LS means ± s.e. for teneligliptin 20 mg versus placebo were -38.1 ± 7.8, -28.6 ± 9.2 and -36.1 ± 7.5 mg/dl, respectively (p < 0.001, p < 0.01, p < 0.001, respectively). Both doses of teneligliptin increased postprandial plasma active glucagon-like peptide-1 concentrations compared with placebo. The incidence of adverse events and drug-related adverse events was similar among groups. There were no hypoglycaemic symptoms or serious adverse events. CONCLUSIONS: Once-daily teneligliptin improved blood glucose levels over 24 h without hypoglycaemia.

Enhanced inhibition of hepatitis B virus production by asialoglycoprotein receptor-directed interferon.

Most chronic carriers of hepatitis B virus (HBV) do not respond to interferon (IFN) treatment. This limitation of IFN therapy may be due in part to scant expression of IFN receptor in the liver. Because the asialoglycoprotein (ASGP) receptor is specifically expressed in the liver at high density, the ASGP receptor-binding domain was generated within an N-glycosylated human IFN-beta molecule by the removal of sialic acid to direct this cytokine to the liver. This modified IFN (asialo-IFN-beta) demonstrated greater inhibition of HBV production in ASGP receptor-positive human liver cells transfected with a replication-competent HBV construct than did conventional IFN-alpha or IFN-beta. Furthermore, the enhanced antiviral effect of asialo-IFN-beta was supported by induction of the 2'-5' oligoadenylate synthetase, an indicator of IFN activity, at a level significantly higher than that produced by conventional IFN-beta. Moreover, mouse asialo-IFN-beta profoundly reduced viremia in vivo in HBV-transfected athymic nude mice, in contrast to conventional IFN-beta, which had no substantial effect. These experiments demonstrate that directing IFN to ASGP receptor facilitates its signaling in the liver and augments its antiviral effect, and is therefore useful in overcoming the limited antiviral effect of conventional IFNs.

Prognostic significance of S-phase kinase-associated protein 2 and p27kip1 in patients with diffuse large B-cell lymphoma: effects of rituximab.

BACKGROUND: The F-box protein S-phase kinase-associated protein 2 (Skp2) positively regulates the G1-S transition by promoting degradation of the cyclin-dependent kinase inhibitor p27(kip1) (p27). Recent evidence has indicated an oncogenic role of Skp2 in not only carcinogenesis but also lymphomagenesis. MATERIALS AND METHODS: Clinicopathologic features and immunohistochemical expression of Skp2 and p27 were studied retrospectively in 671 patients treated with cyclophosphamide, vincristine, doxorubicin and prednisolone (CHOP) or cyclophosphamide, vincristine, doxorubicin and prednisolone plus rituximab (R-CHOP). The median follow-up periods were 43.2 months in the CHOP group (n = 425) and 24.0 months in the R-CHOP group (n = 246). RESULTS: High Skp2 or low p27 expression correlated significantly with poor overall survival (OS) and progression-free survival (P < 0.001) in both treatment groups. The prognostic value of Skp2 or p27 expression was independent of the parameters included in the International Prognostic Index by multivariate analysis. Patients with high Skp2 expression in combination with low p27 expression showed the worst survival. CONCLUSIONS: Addition of rituximab to the CHOP regimen did not provide a beneficial outcome to patients with diffuse large B-cell lymphoma with high Skp2 expression and low p27 expression. Skp2 and p27 may be useful prognostic markers in the rituximab era.

Clock gene expression in peripheral leucocytes of patients with type 2 diabetes.

AIM/HYPOTHESIS: Recent studies have demonstrated relationships between circadian clock function and the development of metabolic diseases such as type 2 diabetes. We investigated whether the peripheral circadian clock is impaired in patients with type 2 diabetes. METHODS: Peripheral leucocytes were obtained from eight patients with diabetes and six comparatively young non-diabetic volunteers at 09:00, 15:00, 21:00 and 03:00 hours (study 1) and from 12 male patients with diabetes and 14 age-matched men at 09:00 hours (study 2). Transcript levels of clock genes (CLOCK, BMAL1 [also known as ARNTL], PER1, PER2, PER3 and CRY1) were determined by real-time quantitative PCR. RESULTS: In study 1, mRNA expression patterns of BMAL1, PER1, PER2 and PER3 exhibited 24 h rhythmicity in the leucocytes of all 14 individuals. The expression levels of these mRNAs were significantly (p < 0.05) lower in patients with diabetes than in non-diabetic individuals at one or more time points. Moreover, the amplitudes of mRNA expression rhythms of PER1 and PER3 genes tended to diminish in patients with diabetes. In study 2, leucocytes obtained from patients with diabetes expressed significantly (p < 0.05) lower transcript levels of BMAL1, PER1 and PER3 compared with leucocytes from control individuals, and transcript expression was inversely correlated with HbA(1c) levels (rho = -0.47 to -0.55, p < 0.05). CONCLUSIONS/INTERPRETATION: These results suggest that rhythmic mRNA expression of clock genes is dampened in peripheral leucocytes of patients with type 2 diabetes. The impairment of the circadian clock appears to be closely associated with the pathophysiology of type 2 diabetes in humans.

Visceral fat accumulation is a significant risk factor for white matter lesions in Japanese type 2 diabetic patients.

BACKGROUND: The presence of white matter lesions (WML) is an important prognostic factor for the development of stroke. The elevated visceral fat accumulation (VFA) has been reported to be closely related to the development of atherosclerosis. This preliminary study was therefore designed to test the hypothesis that the presence of WML correlates with VFA and insulin resistance in type 2 diabetic patients not receiving insulin treatment. MATERIAL AND METHODS: Based on brain magnetic resonance imaging (MRI), 95 type 2 diabetic patients were divided into two groups: WML-positive group (aged 59 +/- 7 years, mean +/- SD n = 37) and WML-negative group (aged 58 +/- 5, years, n = 58). The level of blood glucose was assessed by fasting plasma glucose (FPG), fasting immunoreactive insulin, homeostasis model assessment (HOMA) index, and haemoglobin A1c. The fat distribution was evaluated by measuring the visceral fat accumulation by abdominal computerized tomography at the umbilical level. RESULTS: The body mass index was higher in the WML-positive group than in the WML-negative group (P < 0.005). Plasma levels of triglycerides were higher while high-density lipoprotein cholesterol was lower in the WML-positive group than in the WML-negative group (P < 0.05 and P < 0.01, respectively). FPG (P < 0.01), insulin concentrations (P < 0.0001), HOMA index (P < 0.0001) and VFA (<0.0001) levels were higher in the WML-positive group than in the WML-negative group. Multivariate logistic analysis revealed that WML was independently predicted by the high VFA and insulin resistance (P < 0.001, P < 0.0001, respectively). CONCLUSIONS: The results of this preliminary study indicate that the presence of WML was associated with the high VFA and insulin resistance in Japanese patients with type 2 diabetes mellitus. Further larger cohort studies are warranted to confirm these findings.

Effect of pressure on the self-hole-doped superconductor RbGd2Fe4As4O2.

RbGd2Fe4As4O2 is a newly discovered self-hole-doped stoichiometric superconductor, which has a hybrid structure with separated double FeAs layers and exhibits a high superconducting transition temperature T c = 35 K. Here, we report the effect of pressure (P) on its T c and normal-state transport properties by measuring the temperature dependence of resistivity ρ(T) under various pressures up to 14 GPa with a cubic anvil cell apparatus. We found that the T c is suppressed monotonically to ca. 12.5 K upon increasing pressure to 14 GPa with a slope change of T c(P) at around 4 GPa. In addition, the low-temperature normal-state ρ(T), which is proportional to T n , also evolves gradually from a non-Fermi-liquid with n = 1 at ambient pressure to a Fermi liquid with n = 2 at P ⩾ 4 GPa. Accompanying with the non-Fermi-liquid to Fermi-liquid crossover, the quadratic temperature coefficient of resistivity, which reflects the effective mass of charge carriers, also experiences a significant reduction as commonly observed in the vicinity of a magnetic quantum critical point (QCP). Our results indicate that the stoichiometric RbGd2Fe4As4O2 at ambient pressure might be located near a QCP such that the enhanced critical spin fluctuations lead to high-T c superconductivity. The application of pressure should broaden the electronic bandwidth and weaken the spin fluctuations, and then restore a Fermi-liquid ground state with lower T c.

Useful laboratory markers for the diagnosis of bone marrow involvement by malignant lymphoma.

INTRODUCTION: This study aimed to investigate the effect of bone marrow involvement by malignant lymphoma (BMI) on laboratory data and to determine the useful laboratory markers for diagnosing BMI. METHODS: We compared laboratory data between patients with and without BMI. We performed multivariate logistic regression and receiver operating characteristic (ROC) analyses to evaluate the diagnostic values of independent predictors. RESULTS: In the BMI group, platelets in peripheral blood (PLT) and megakaryocyte count in bone marrow (MgK) were significantly lower than those in the non-BMI group (PLT, P < .0001; MgK, P = .0384). The rate of peripheral blood involvement by malignant lymphoma (PBI), red blood cell distribution width (RDW), D-dimer (DD), soluble interleukin-2 receptor (sIL2R), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) was significantly higher in the BMI group than in the non-BMI group (PBI, P < .0001; RDW, P = .0190; DD, P = .0006; sIL2R, P < .0001; AST, P = .0256; LDH, P = .0002). In multivariate analysis, PBI, PLT, sIL2R, and MgK levels were independent predictors of BMI. CONCLUSION: PBI, PLT, sIL2R, and MgK may be the useful laboratory markers for BMI diagnosis.

Plasma levels of adrenomedullin, a newly identified hypotensive peptide, in patients with hypertension and renal failure.

Adrenomedullin is a potent hypotensive peptide newly discovered in pheochromocytoma tissue by monitoring its elevating activity on platelet cAMP. We measured plasma concentration of adrenomedullin in patients with essential hypertension and chronic renal failure. As compared with normal subjects, plasma adrenomedullin was increased by 26% (P < 0.05) in hypertensives without organ damage and by 45% (P < 0.005) in those with organ damage. The increase in plasma adrenomedullin was more prominent in renal failure than in hypertension. Renal failure patients with plasma creatinine of 1.5-3, 3-6, and > 6 mg/dl had higher plasma adrenomedullin levels than healthy subjects by 78% (P < 0.05), 131% (P < 0.001), and 214% (P < 0.001), respectively. Moreover, adrenomedullin showed intimate correlations with norepinephrine, atrial natriuretic peptide, and cAMP in plasma (r = 0.625, P < 0.001; r = 0.656, P < 0.001; and r = 0.462, P < 0.001; respectively). Thus, plasma adrenomedullin is supposed to increase in association with changes in sympathetic nervous activity and body fluid volume in hypertension and renal failure. Considering its potent vasodilator effect, adrenomedullin may be involved in the defense mechanism preserving the integrity of the cardiovascular system in these disorders.

Interleukin 4 suppresses the spontaneous growth of chronic myelomonocytic leukemia cells.

We studied the effects of IL-4 on the spontaneous proliferation of chronic myelomonocytic leukemia (CMMoL) cells in vitro. IL-4 (100 U/ml) suppressed the spontaneous DNA synthesis by approximately 50% in 5 of 8 cases examined. IL-4 (100 U/ml) also inhibited the spontaneous colony formation by CMMoL cells in a methylcellulose culture by 50-97% in all of the 10 cases in which spontaneous colonies were formed. This IL-4-mediated suppression of the growth of CMMoL cells was completely abolished by the addition of anti-IL-4 neutralizing antibodies. The spontaneous CMMoL colonies were substantially suppressed by the addition of either anti-IL-6 or anti-granulocyte/macrophage colony-stimulating factor (GM-CSF) antibodies to the colony assay system: the addition of both anti-IL-6 and anti-GM-CSF antibodies resulted in greater than 80% inhibition of the colony formation by CMMoL cells. On the other hand, none of anti-IL-1-beta, anti-granulocyte-CSF, anti-macrophage-CSF, or anti-tumor necrosis factor-alpha antibodies affected the CMMoL colony formation. In the supernatants from 24-h cultures of CMMoL cells, high levels of IL-6 and GM-CSF were demonstrated in 9 of 9 and 2 of 9 cases examined, respectively. IL-4 (100 U/ml) almost completely inhibited the secretion of IL-6 and GM-CSF by CMMoL cells. These observations suggest that IL-4 suppresses the spontaneous proliferation of CMMoL cells by inhibiting their production of IL-6 and/or GM-CSF, both of which could act in vitro as an autocrine growth factor for CMMoL cells.

Rituximab does not compromise the mobilization and engraftment of autologous peripheral blood stem cells in diffuse-large B-cell lymphoma.

To investigate effects of the preautografting administration of rituximab on the mobilization and engraftment of peripheral blood stem cells (PBSC), we retrospectively analyzed the outcomes of 43 newly diagnosed diffuse-large B-cell lymphoma patients who received CHOP chemotherapy with or without rituximab as a first-line treatment before autologous PBSC transplantation (PBSCT). There was no difference in the number of CD34(+) cells among PBSC between the non-rituximab and the rituximab groups. Although B-cells were completely depleted from PBSC in the rituximab group, we found no difference in the expression of CXCR-4, VLA-4 and c-Kit on PBSC, indicating that rituximab did not affect the expression of these adhesion molecules, which might be involved in the mechanism of mobilization. There was no significant difference in the recovery of neutrophils and platelets, transplant-related toxicity and post-transplant complications between the two groups. Despite the short follow-up, there was no significant difference in progression-free survival between the two groups. These results indicated no adverse effect of rituximab on the mobilization and engraftment of PBSC. Larger studies are required to determine the impact of rituximab on the mobilization and function of PBSC as well as whether a survival advantage exists in patients who undergo auto-PBSCT with rituximab.

Role of intraoperative enteroscopy for surgical decision making with Crohn's disease.

BACKGROUND: This study aimed to assess the role of intraoperative enteroscopy (IOE) in determining surgical treatment. METHODS: The IOE procedure was performed for 30 patients with Crohn's disease. The degree of stricture and the presence of active ulcer were examined. Preoperative diagnoses and intraoperative findings obtained by inspection and palpation were noted and compared with the IOE findings. RESULTS: Of the 78 intestinal strictures observed by IOE (42%), 33 were not found by preoperative examination. Of the 45 strictures confirmed by IOE to be severe (<15 mm in diameter), 8 were judged to be mild (15-25 mm in diameter) or were not even identified by intraoperative inspection and palpation. Active ulcer was found at 12 of 33 mild strictures, and all 12 strictures were surgically corrected. Of 11 severe strictures detected by IOE at previous surgical sites, 9 were found preoperatively, and 4 were judged to be mild on the basis of inspection and palpation. Stricture was found at the ileocecal valve by IOE in seven patients, but was not diagnosed preoperatively in two of these patients. CONCLUSION: Intraoperative enteroscopy provides useful information regarding the status of the lumen in patients with Crohn's disease.

Clinical characteristics and outcome of human herpesvirus-6 encephalitis after allogeneic hematopoietic stem cell transplantation.

In this retrospective analysis using the Transplant Registry Unified Management Program, we identified 145 patients with human herpesvirus (HHV)-6 encephalitis among 6593 recipients. The cumulative incidences of HHV-6 encephalitis at 100 days after transplantation in all patients, recipients of bone marrow or PBSCs and recipients of cord blood were 2.3%, 1.6% and 5.0%, respectively. Risk factors identified in multivariate analysis were male sex, type of transplanted cells (relative risk in cord blood transplantation, 11.09, P<0.001; relative risk in transplantation from HLA-mismatched unrelated donor, 9.48, P<0.001; vs transplantation from HLA-matched related donor) and GvHD prophylaxis by calcineurin inhibitor alone. At 100 days after transplantation, the overall survival rate was 58.3% and 80.5% among patients with and without HHV-6 encephalitis, respectively (P<0.001). Neuropsychological sequelae remained in 57% of 121 evaluated patients. With both foscarnet and ganciclovir, full-dose therapy (foscarnet ⩾180 mg/kg, ganciclovir ⩾10 mg/kg) was associated with better response rate (foscarnet, 93% vs 74%, P=0.044; ganciclovir, 84% vs 58%, P=0.047). HHV-6 encephalitis is not rare not only in cord blood transplant recipients but also in recipients of HLA-mismatched unrelated donors. In this study, development of HHV-6 encephalitis was associated with a poor survival rate, and neurological sequelae remained in many patients.

Low-dose thymoglobulin as second-line treatment for steroid-resistant acute GvHD: an analysis of the JSHCT.

A nationwide retrospective study for the clinical outcomes of 99 patients who had received thymoglobulin at a median total dose of 2.5 mg/kg (range, 0.5-18.5 mg/kg) as a second-line treatment for steroid-resistant acute GvHD was conducted. Of the 92 evaluable patients, improvement (complete or partial response) was observed in 55 patients (60%). Multivariate analysis demonstrated that male sex and grade III and IV acute GvHD were associated with a lower improvement rate, whereas thymoglobulin dose (<2.0, 2.0-3.9 and ⩾4.0 mg/kg) was NS. Factors associated with significantly higher nonrelapse mortality included higher patient age (⩾50 years), grade IV acute GvHD, no improvement of GvHD and higher dose of thymoglobulin (hazard ratio, 2.55; 95% confidence interval, 1.34-4.85; P=0.004 for 2.0-3.9 mg/kg group and 1.79; 0.91-3.55; P=0.093 for ⩾4.0 mg/kg group). Higher dose of thymoglobulin was associated with a higher incidence of bacterial infections, CMV antigenemia and any additional infection. Taken together, low-dose thymoglobulin at a median total dose of 2.5 mg/kg provides a comparable response rate to standard-dose thymoglobulin reported previously, and <2.0 mg/kg thymoglobulin is recommended in terms of the balance between efficacy and adverse effects.

Inhibition of 5-hydroxytryptamine receptor prevents occlusive thrombus formation on neointima of the rabbit femoral artery.

BACKGROUND: Thrombus propagation on disrupted plaque is a major cause of acute coronary events and serious complication after coronary intervention. 5-Hydroxytryptamine (5-HT) is a potent vasoactive and platelet-aggregating substance that is predominantly mediated by 5-HT2A receptor. However, the roles of 5-HT2A receptor in occlusive thrombus formation on disrupted plaque remain obscure. OBJECTIVE: We investigated the role of 5-HT2A receptor in thrombus formation using a rabbit model of repeated balloon-injury. METHODS: Three weeks after a first balloon-injury of the femoral arteries, luminal diameter, neointimal growth, and vasoconstriction by 5-HT in vitro were examined. Thrombus propagation and the role of 5-HT2A receptor after a second balloon-injury were evaluated using sarpogrelate, a selective 5-HT2A receptor antagonist. RESULTS: Three weeks after the first balloon-injury, luminal stenosis was evident in the femoral arteries, where the neointima expressed tissue factor and 5-HT2A receptor. The hypercontractile response of the stenotic arteries to 5-HT was significantly reduced by sarpogrelate. Balloon-injury of the neointima with substantially reduced blood flow promoted the formation of occlusive thrombus that was immunoreactive against glycoprotein IIb-IIIa, 5-HT2A receptor and fibrin. Intravenous injection of sarpogrelate significantly inhibited ex vivo platelet aggregation induced by adenosine 5'-diphosphate, thrombin and collagen alone as well as with 5-HT, and significantly prevented occlusive thrombus formation in vivo. CONCLUSIONS: The 5-HT2A receptor appears to play a crucial role in occlusive thrombus formation in diseased arteries via platelet aggregation and vasoconstriction. Inhibition of 5-HT2A receptor might help reduce the onset of acute coronary events and of acute coronary occlusion after the intervention.

Plasma adrenomedullin level and development of hypertension.

The hypotensive peptide adrenomedullin (AM) is assumed to act as a factor inhibitory on elevation of blood pressure and on progression of the hypertensive organ damage, and plasma AM levels are elevated in patients with hypertension. The aim of the present study is to explore whether or not a rise in plasma AM levels precedes the development of hypertension. Normotensive local residents without apparent cardiovascular or renal disease (n = 177) were divided into low and high AM groups based on the median concentration of AM in plasma (11.9 fmol/ml), and followed up for 3 years for development of hypertension. The incidence of hypertension was higher in the residents with high AM than low AM levels (27.8 vs 11.5%, P < 0.01), whereas a similar analysis of plasma levels of atrial or brain natriuretic peptides revealed no such difference. The plasma AM level was found to be a significant parameter for the development of hypertension in a univariate analysis (P < 0.01), but not in a multivariate analysis. Meanwhile, the plasma AM level was significantly (P < 0.01) correlated with age and body mass index (BMI), two variables independently significant for the development of hypertension. The present findings suggest that an elevation of the plasma AM level associated with aging and increased BMI precedes the development of hypertension in the normotensive subjects.

Risk factors and prognosis of hepatic acute GvHD after allogeneic hematopoietic cell transplantation.

Hepatic acute GvHD (aGvHD) is associated with high mortality owing to poor response to immunosuppressive therapy. The pathogenesis of hepatic aGvHD differs from that of other lesions, and specific risk factors related to pre-transplant liver conditions should be determined. We conducted a cohort study by using a Japanese transplant registry database (N=8378). Of these subjects, 1.5% had hepatitis C virus Ab (HCV-Ab) and 9.4% had liver dysfunction (elevated transaminase or bilirubin levels) before hematopoietic cell transplantation (HCT). After HCT, the cumulative incidence of hepatic aGvHD was 6.7%. On multivariate analyses, HCV-Ab positivity (hazard ratio (HR), 1.93; P=0.02) and pre-transplant liver dysfunction (HR, 1.85; P<0.01), as well as advanced HCT risk, unrelated donors, HLA mismatch and cyclosporine as GvHD prophylaxis, were significant risk factors for hepatic aGvHD, whereas hepatitis B virus surface Ag was not. Hepatic aGvHD was a significant risk factor for low overall survival and high transplant-related mortality in all aGvHD grades (P<0.01). This study is the first to show the relationship between pre-transplant liver conditions and hepatic aGvHD. A prospective study is awaited to validate the results of this study and establish a new strategy especially for high-risk patients.

Early application of related SCT might improve clinical outcome in adult T-cell leukemia/lymphoma.

Allogeneic hematopoietic SCT (allo-HSCT) is a curative treatment for aggressive adult T-cell leukemia/lymphoma (ATLL). Considering the dismal prognosis associated with conventional chemotherapies, early application of allo-HSCT might be beneficial for patients with ATLL. However, no previous study has addressed the optimal timing of allo-HSCT from related donors. Hence, to evaluate the impact of timing of allo-HSCT for patients with ATLL, we retrospectively analyzed data from patients with ATLL who received an allo-HSCT from a related donor. The median age was 52 years. Patients were grouped according to the interval from diagnosis to allo-HSCT: early transplant group, <100 days, n=72; late transplant group, ⩾100 days, n=428. The corresponding constituents of disease status were not statistically different between the two groups (P=0.11). The probability of OS in the early transplant group was significantly higher than that in the late transplant group (4-year OS, 49.3% vs 31.2%). Multivariate analysis revealed that late allo-HSCT was an unfavorable prognostic factor for OS (hazard ratio, 1.46; 95% confidence interval (CI), 1.01-2.11; P=0.04). Despite the limitations of a retrospective study, it might be acceptable to consider early application of allo-HSCT for ATLL.