Successful haploidentical hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria with severe pancytopenia developed after long-term aplastic anemia treatment.

Haploidentical hematopoietic stem cell transplantation (HSCT) with posttransplant cyclophosphamide is an alternative treatment for aplastic anemia-paroxysmal nocturnal hemoglobinuria (PNH) syndrome with poor prognostic factors. Ravulizumab treatment for PNH before HSCT might have a beneficial effect.

Outcomes of adult patients with early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) and non-ETP T-ALL.

Early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) is generally considered to be a high-risk subtype. We retrospectively analyzed the clinical outcomes of adult patients diagnosed with ETP-ALL or other T-cell ALL (non-ETP T-ALL). The subjects were 82 patients (ETP-ALL: n = 18, non-ETP T-ALL: n = 64) for whom relevant immunophenotype data needed for classification were available. ETP-ALL patients were older (median age, 50.5 vs. 33.5 years, P = 0.042) and had less mediastinal involvement (27.8 vs. 73.4%, P < 0.001). The rate of complete remission (CR) with the first induction therapy was significantly lower in the ETP group (33.3 vs. 64.0%, P = 0.03), but the CR rate within 2 cycles of chemotherapy did not differ significantly (61.1 vs. 76.6%, P = 0.232). The 3-year overall survival (OS) rate was also similar in both groups (43.2 vs. 45.8%, P = 0.992). The ETP phenotype had no impact on survival in the transplant group or the non-transplant group. A multivariate analysis identified the male sex as a poor prognostic factor (HR: 4.43, P < 0.01), but not the immunophenotype of ETP. The prognosis for adult patients with ETP-ALL was comparable to that of non-ETP T-ALL patients. However, further studies aimed at improving the remission rate for ETP-ALL are needed.

The Diverse Efficacy of Food-Derived Proanthocyanidins for Middle-Aged and Elderly Women.

Middle-aged and elderly women are affected by various symptoms and diseases induced by estrogen deficiency. Proanthocyanidins, widely present in many kinds of fruits and berries, have many beneficial effects, such as antioxidative, anti-inflammatory, and antimicrobial activities. We researched the effects of proanthocyanidins for middle-aged and elderly women, finding that it has been revealed in many clinical trials and cohort studies that proanthocyanidins contribute to the prevention of cardiovascular disease, hypertension, obesity, cancer, osteoporosis, and urinary tract infection, as well as the improvement of menopausal symptoms, renal function, and skin damage. Thus, proanthocyanidins can be considered one of the potent representatives of complementary alternative therapy.

Cancer association as a risk factor for anti-HMGCR antibody-positive myopathy.

OBJECTIVE: To show cancer association is a risk factor other than statin exposure for anti-3-hydroxy-3-methylglutaryl coenzyme A reductase autoantibody-positive (anti-HMGCR Ab+) myopathy. METHODS: We analyzed the clinical features and courses of 33 patients (23 female and 10 male) with anti-HMGCR Ab+ myopathy among 621 consecutive patients with idiopathic inflammatory myopathies. RESULTS: Among the 33 patients, 7 (21%) were statin-exposed and 26 were statin-naive. In relation with cancer, there were 12 patients (statin-exposed, n = 4) with cancers detected within 3 years of myopathy diagnosis (cancer association), 3 patients (all statin-naive) with cancers detected more than 3 years before myopathy diagnosis (cancer history), 10 cancer-free patients followed up for more than 3 years (all statin-naive), and 8 patients without cancer detection but followed up for less than 3 years (statin-exposed, n = 3). Therefore, 12 patients with cancer association (36%) formed a larger group than that of 7 statin-exposed patients (21%). Among 12 patients with cancer association, 92% had cancer detection within 1 year of myopathy diagnosis (after 1.3 years in the remaining patient), 83% had advanced cancers, and 75% died of cancers within 2.7 years. Of interest, 1 patient with cancer history had sustained increase in creatine kinase level over 12 years from cancer removal to the development of weakness. CONCLUSIONS: Patients with cancer association formed a large group with poor prognosis in our series of patients with anti-HMGCR Ab+ myopathy. The close synchronous occurrence of cancers and myopathies suggested that cancer association is one of the risk factors for developing anti-HMGCR Ab+ myopathy.

Effect of erythropoietin on angiogenesis with the increased adhesion of platelets to the microvessels in the hind-limb ischemia model in mice.

Erythropoietin (EPO) has been shown to enhance angiogenesis, but its precise mechanisms of enhancement during ischemia are not fully elucidated. We examined the effect of EPO on blood flow recovery from acute hind-limb ischemia induced by ligation of the femoral artery in male C57Bl/6 mice. The density of microvessels with platelet adhesion in ischemic tissues was assessed by intravital microscopy. Treatment with EPO (100 and 1000 IU/kg, i.p.) restored blood flow in a dose-dependent manner and increased plasma levels of soluble-P-selectin, vascular endothelial growth factor (VEGF), and stromal cell-derived factor (SDF-1). Flow cytometric analysis revealed increased P-selectin expression on platelets in EPO-treated mice compared to PBS-treated mice. Intravital microscopic studies showed that EPO increased density of microvessels with platelet adhesion selectively in the ischemic tissues. Neutralizing antibody against P-selectin reduced the density of microvessels with platelet adhesion enhanced with EPO and impaired blood flow recovery with reductions in VEGF and SDF-1 levels. These results suggest that EPO administration enhances recovery from hind-limb ischemia, and platelet adhesion to the microvessels is a key event to enhance the angiogenesis in the ischemic tissues.

Megakaryoblastic leukemia factor-1 gene in the susceptibility to coronary artery disease.

Coronary artery disease (CAD) is based on the atherosclerosis of coronary artery and may manifest with myocardial infarction or angina pectoris. Although it is widely accepted that genetic factors are linked to CAD and several disease-related genes have been reported, only a few could be replicated suggesting that there might be some other CAD-related genes. To identify novel susceptibility loci for CAD, we used microsatellite markers in the screening and found six different candidate CAD loci. Subsequent single nucleotide polymorphism (SNP) association studies revealed an association between CAD and megakaryoblastic leukemia factor-1 gene (MKL1). The association with a promoter SNP of MKL1, -184C > T, was found in a Japanese population and the association was replicated in another Japanese population and a Korean population. Functional analysis of the MKL1 promoter SNP suggested that the higher MKL1 expression was associated with CAD. These findings suggest that MKL1 is involved in the pathogenesis of CAD.

Changes in glucagon processing occurring in the intestines of surgically stressed patients.

BACKGROUND/AIMS: The kinetics of the pancreatic hormone glucagon in surgically stressed patients has not been investigated as thoroughly as that of insulin, despite its significant influence on energy metabolism in surgically stressed conditions. In the present study, we examined the kinetics of glucagon and glucagon-related peptides assessed by radioimmunoassay, and the molecular forms of these peptides using gel filtration chromatography, and in addition discuss glucagon processes in the pancreas and intestine in surgically stressed patients. METHODOLOGY: Ten patients who had undergone abdominal surgery for acute abdominal disorders were enrolled in this study (group S). Ten healthy volunteers were also enrolled as normal controls (group C). The serum level of glucagon and glucagon-related peptides were assessed in the early morning fasting state in both groups, on the second postoperative day in group S, using glucagon nonspecific N-terminal (glucagon-like immunoreactivity: GLI) and specific C-terminal (immunoreactive glucagon: IRG) radioimmunoassays. The molecular forms of these peptides were also estimated using the gel filtration chromatography method. RESULTS: Serum IRG in group S was significantly higher than that of group C (P < 0.05). Serum GLI was not significantly different between the two groups. In all patients except one in group S, a peculiar glicentin-like peptide (GLLP: MW about 8000) other than pancreatic glucagon was seen in gel filtration chromatography, which was not seen in group C. CONCLUSIONS: The kinetics and processing of glucagon in surgically stressed patients were quite different from those of healthy subjects. In surgically stressed patients, peculiar processing of glucagon occurred in the intestine, which was quite different from ordinary glucagon processing either in the pancreas or the intestine, generating GLLP.

E-selectin polymorphism associated with myocardial infarction causes enhanced leukocyte-endothelial interactions under flow conditions.

OBJECTIVE: Polymorphisms found in genes encoding adhesion molecules have been reported to be associated with atherosclerosis. We investigated the Ser128Arg polymorphism in the E-selectin gene in Japanese patients with myocardial infarction and its functional significance. METHODS AND RESULTS: Results from 135 patients with myocardial infarction and 327 control subjects revealed that the frequency of Arg128-positive was significantly higher in the patients than in controls (12.6% versus 6.7%; odds ratio, 2.0; 95% CI, 1.04 to 3.85), indicating that the Ser128Arg polymorphism was associated with myocardial infarction. We then generated a recombinant E-selectin adenovirus carrying a mutation (AdS128R-E) and compared it with its wild-type counterpart by evaluating the adhesion characteristics of transduced human umbilical vein endothelial cells under flow. AdS128R-E-transduced human umbilical vein endothelial cells supported significantly more rolling and adhesion of neutrophils and mononuclear cells compared with human umbilical vein endothelial cells transduced with AdWT-E (P<0.001) and also exhibited significantly greater levels of phosphorylation of extracellular signal regulated kinase 1 and 2 and p38 mitogen-activated protein kinase, suggesting that an altered endothelial signaling pathway is associated with this polymorphism. CONCLUSIONS: Our results suggest that the E-selectin Ser128Arg polymorphism can functionally alter leukocyte-endothelial interactions as well as biochemical and biological consequences, which may account for the pathogenesis of myocardial infarction.

[Airway hyperreactivity in patients undergoing hematopoietic stem cell transplantation].

Airway hyperreactivity (AHR) was studied with an astograph for 34 sequential hematopoietic stem cell transplantation (HSCT) patients before and after HSCT. The percentage of Dmin positive patients was 25.0% before HSCT and 25.0-57.1% after HSCT, while all normal subjects were negative for Dmin. The mean Dmin of post HSCT patients was 22.7 u in days 501-1000 and 19.3 u after 1001 days, which was significantly lower than the 45.2 u of normal controls. The patients were divided into two groups according to the treatment before HSCT, strongly treated (S, acute leukemia and non-Hodgikin lymphoma) and weakly treated (W, chronic myelogenous leukemia and aplastic anemia) patients. The ratio of Dmin positive patients and mean Dmin in the W group after HSCT (38.9%, 27.8 u), and the S group before and after HSCT (55.6%, 20.5 u and 45.5%, 23.8 u, respectively), were significantly impaired compared with the findings in the normal controls (0%, 45.2 u). The mean sGrs/Grs count was higher in the W group before HSCT than in the other groups (W before and after HSCT, 0.58 and 0.19, respectively; S before and after HSCT, 0.21 and 0.22, respectively). Taken together, AHR was observed in HSCT patients, particularly for patients in the S group. These data indicate that high dose chemo-radiotherapy including conditioning regimen causes AHR. The mechanisms leading to AHR may be infection, inflammation, and remodeling of the airway.