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.

Pupillary Light Reflex as a New Prognostic Marker in Patients With Heart Failure.

BACKGROUND: Autonomic function can be evaluated based on the pupillary light reflex (PLR). However, the relationship between PLR and prognosis in patients with heart failure (HF) remains unclear. This study was performed to examine whether PLR could be used as a prognostic indicator in patients with HF. METHODS AND RESULTS: A retrospective review was performed in 535 consecutive Japanese patients hospitalized for acute HF (mean age 66.1 ± 13.7 y). PLR was recorded at least 7 days after hospitalization for HF with the use of a pupilometer. Fifty-three patients died over a median follow-up period of 1.3 years (interquartile range 0.6-2.3 y). After adjustment for several preexisting prognostic factors, including Seattle Heart Failure Score (SHFS), PLR as assessed by recovery time (time to 63% redilation) was independently associated with all-cause mortality (hazard ratio 0.50, 95% confidence interval 0.35-0.73; P < .001). The addition of recovery time to SHFS resulted in a significant increase in the area under the curve on receiver-operating characteristic curve analysis (0.69 vs 0.77; P < .001). CONCLUSIONS: PLR assessed by recovery time was an independent predictor of mortality and added prognostic information to the SHFS in patients with HF. Our results suggest that PLR may be useful as a new prognostic marker in HF patients.

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.

Prevalence and distribution of sarcomeric gene mutations in Japanese patients with familial hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM), which is inherited as an autosomal dominant trait, is the most prevalent hereditary cardiac disease. Although there are several reports on the systematic screening of mutations in the disease-causing genes in European and American populations, only limited information is available for Asian populations, including Japanese. METHODS AND RESULTS: Genetic screening of disease-associated mutations in 8 genes for sarcomeric proteins, MYH7, MYBPC3, MYL2, MYL3, TNNT2, TNNI3, TPM1, and ACTC, was performed by direct sequencing in 112 unrelated Japanese proband patients with familial HCM; 37 different mutations, including 13 novel ones in 5 genes, MYH7, MYBPC3, TNNT2, TNNI3, and TPM1, were identified in 49 (43.8%) patients. Among them, 3 carried compound heterozygous mutations in MYBPC3 or TNNT2. The frequency of patients carrying the MYBPC3, MYH7, and TNNT2 mutations were 19.6%, 10.7%, and 8.9%, respectively, and the most frequently affected genes in the northeastern and southwestern parts of Japan were MYBPC3 and MYH7, respectively. Several mutations were found in multiple unrelated proband patients, for which the geographic distribution suggested founder effects of the mutations. CONCLUSIONS: This study demonstrated the frequency and distribution of mutations in a large cohort of familial HCM in Japan.

Post-discharge depressive symptoms can predict quality of life in AMI survivors: a prospective cohort study in Japan.

BACKGROUND: Reports on health-related quality of life (HRQOL) of Asian populations after acute myocardial infarction (AMI) and its predictors are rare. We describe the longitudinal HRQOL course after AMI, hypothesizing that post-discharge depressive symptoms predict poor recovery of HRQOL in Japan. METHODS: AMI survivors participated in a prospective cohort study of AMI patients admitted to 5 hospitals in Japan. Data from 218 consecutive male patients were analyzed. HRQOL was measured with Short-Form Health Survey-36 at 1, 6, and 12 months post-discharge. Five-question Mental Health Inventory (MHI-5) assessed presence of depressive symptoms. Multiple linear regression analyzed the relationship between depressive symptoms at 1 month and recovery of HRQOL at 6 months. RESULTS: AMI patients at 12 months after discharge had lower HRQOL in physical function (47.8), role-physical (44.1), general health (46.4), social function (47.4), and role-emotional (45.8) than the Japanese national norm. Impairment of each domain of HRQOL was seen in 36%-71% of patients. Multivariate analysis showed that depressive symptoms at 1 month post-discharge adversely affected recovery of physical function (ß = -2.62; CI: -5.00 to -0.23), role-physical (ß = -3.50; CI: -6.94 to -0.06) and bodily pain (ß = -2.92; CI: -5.26 to -0.59) at 6 months. CONCLUSIONS: Despite good prognosis for survival of discharged AMI patients, HRQOL did not recover to the national norm. Post-discharge depressive symptoms were significantly associated with poor recovery of the physical component of HRQOL. Increasing awareness of depressive symptoms in discharged AMI patients may improve survivor HRQOL.

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.

Antihypertensive effect of a gamma-aminobutyric acid rich tomato cultivar 'DG03-9' in spontaneously hypertensive rats.

This study aimed to investigate the effects of a gamma-aminobutyric acid (GABA) rich tomato (Solanum lycopersicum L.) cultivar 'DG03-9' in comparison with 'Momotaro', a commonly consumed tomato cultivar in Japan, on systolic blood pressure (SBP) in spontaneously hypertensive rats (SHR). In a single administration study, treatment with the GABA-rich cultivar elicited a significant decrease in SBP compared to the control group. In a chronic administration study, SHR were fed diets containing one of the tomato cultivars for 4 weeks. Both cultivars significantly reduced the increase in SBP compared to the control. The antihypertensive effect of the GABA-rich cultivar was higher than that of the commonly consumed cultivar in both the single- and chronic-administration studies. Treatment with a comparable amount of GABA elicited a similar response to treatment with the GABA-rich cultivar. These results suggest that the GABA-rich cultivar 'DG03-9' is a potent antihypertensive food and may be useful for treating hypertension effectively.

Validation of the association between AGTRL1 polymorphism and coronary artery disease in the Japanese and Korean populations.

Coronary artery disease (CAD) and stroke are the major health problems in many countries because of their increasing prevalence and high mortality. It is well known that CAD and stroke are based on atherosclerosis and shared environmental and genetic risk factors. Recently, an association of a functional sequence variation -154G>A in the angiotensin receptor-like 1 (AGTRL1) with a susceptibility to stroke was reported. In this study, we investigated a total of 1479 CAD cases and 2062 controls from the Japanese and Korean populations to validate the association of AGTRL1 with CAD. However, we obtained no evidence of the association in both the Japanese (odds ratio (OR)=0.95, 95% confidence interval (CI); 0.82-1.10, P=0.47, allele count model) and Korean (OR=0.90, 95% CI; 0.77-1.05, P=0.18, allele count model) populations. In addition, there was no trend of association between the risk allele and severity of coronary atherosclerosis. These data suggested that AGTRL1 did not contribute much to the atherosclerosis of the coronary artery.

Estimation of damage to cells of Japanese radish induced by high pressure with drying rate as index.

The relative drying rate of samples (RDR), which is the ratio of the drying rate of pretreated samples to that of untreated ones, might be used as a tool to investigate the damage to cells of agroproducts induced by high-pressure treatment. Damage to cells induced by high pressure was estimated by comparing the RDR after high-pressure pretreatment with the RDR after chloroform-vapor, heat, and freeze-thaw pretreatments of Japanese radish samples. The RDR after high-pressure pretreatment was similar to the RDR after chloroform-vapor pretreatment, and was lower than for heat, and for freeze-thaw pretreatment. For agroproducts, high-pressure treatment is thus comparatively moderate.

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.

Replication studies for the association of PSMA6 polymorphism with coronary artery disease in East Asian populations.

Coronary artery disease (CAD) has become a major health problem in many countries because of its increasing prevalence and high mortality. Recently, an association of a functional sequence variation, -8C>G, in the human proteasome subunit alpha type 6 gene (PSMA6) with the susceptibility to CAD was reported. To validate the association, we investigated a total of 1330 cases and 2554 controls from Japanese and Korean populations for PSMA6 genotypes, and no evidence of the association was obtained in both Japanese (odds ratio (OR)=1.03, 95% confidence interval (CI); 0.90-1.19, P=0.66, allele count model) and Korean populations (OR=1.00, 95% CI; 0.86-1.17, P=0.95, allele count model). However, when a meta-analysis of data from this study and previously reported six replication studies was done, OR was 1.08 for the G allele (95% CI; 1.02-1.14, P=0.0057), suggesting that the contribution of PSMA6 to CAD was not large enough to be readily replicated. Further studies are required to establish the contribution of this variant in the susceptibility to CAD.

Beneficial effects of Waon therapy on patients with chronic heart failure: results of a prospective multicenter study.

BACKGROUND: We conducted a prospective multicenter case-control study to confirm the clinical efficacy and safety of Waon therapy on chronic heart failure (CHF). METHODS: Patients (n=188) with CHF were treated with standard therapy for at least 1 week, and then were randomized to Waon therapy (n=112) or a control group (n=76). All patients continued conventional treatment for an additional 2 weeks. The Waon therapy group was treated daily with a far infrared-ray dry sauna at 60 degrees C for 15 min and then kept on bed rest with a blanket for 30 min for 2 weeks. Chest radiography, echocardiography, and plasma levels of brain natriuretic peptide (BNP) were measured before and 2 weeks after treatment. RESULTS: NYHA functional class significantly decreased after 2 weeks of treatment in both groups. Chest radiography also showed a significant decrease of the cardiothoracic ratio in both groups (Waon therapy: 57.2+/-8.0% to 55.2+/-8.0%, p<0.0001; control: 57.0+/-7.7% to 56.0+/-7.1%, p<0.05). Echocardiography demonstrated that left ventricular diastolic dimension (LVDd), left atrial dimension (LAD), and ejection fraction (EF) significantly improved in the Waon therapy group (LVDd: 60.6+/-7.6 to 59.1+/-8.4 mm, p<0.0001; LAD: 45.4+/-9.3 mm to 44.1+/-9.4 mm, p<0.05; EF: 31.6+/-10.4% to 34.6+/-10.6%, p<0.0001), but not in the control group (LVDd: 58.4+/-10.3 mm to 57.9+/-10.4 mm; LAD: 46.3+/-9.7 mm to 46.2+/-10.1 mm; EF: 36.6+/-14.1% to 37.3+/-14.0%). The plasma concentration of BNP significantly decreased with Waon therapy, but not in the control group (Waon: 542+/-508 pg/ml to 394+/-410 pg/ml, p<0.001; control: 440+/-377 pg/ml to 358+/-382 pg/ml). CONCLUSION: Waon therapy is safe, improves clinical symptoms and cardiac function, and decreases cardiac size in CHF patients. Waon therapy is an innovative and promising therapy for patients with CHF.

Replication of the association between a chromosome 9p21 polymorphism and coronary artery disease in Japanese and Korean populations.

Coronary artery disease (CAD) has become a major health problem in many countries. Recent genome-wide association studies have identified the association between rs1333049 on chromosome 9p21 and susceptibility to CAD in Caucasoid populations. In this study, we evaluated the associations of rs1333049 with CAD in Japanese (604 patients and 1,151 controls) and Koreans (679 patients and 706 controls). We found a significant association in both Japanese [odds ratio (OR)=1.30, 95% confidence interval (CI); 1.13-1.49, p=0.00027, allele count model] and Koreans (OR=1.19, 95% CI; 1.02-1.38, p=0.025, allele count model). These observations demonstrated that chromosome 9p21 was the susceptibility locus for CAD also in East Asians.

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.

Changes in glucagon kinetics and processing in patients with acute pancreatitis.

BACKGROUND/AIMS: The kinetics of the pancreatic hormone glucagon in patients with acute pancreatitis have not been investigated as carefully as those of insulin, in spite of its crucial influence on energy metabolism. In the present study, we studied the kinetics of glucagon and glucagon-related peptides assessed by radioimmunoassay. Furthermore, the molecular forms of these peptides were examined using gel filtration chromatography, and the glucagon processes in the pancreas and intestine in the early stage in patients with acute pancreatitis were investigated. METHODOLOGY: Fourteen patients with acute pancreatitis were enrolled in this study. Eight had severe pancreatitis (group S) and six had mild pancreatitis (group M). Ten healthy volunteers were also enrolled as the normal control (group C). Serum levels of glucagon and glucagon-related peptides were assessed on the second admission day in groups S and M, and in an early morning fasting state in group C, using glucagon non-specific N-terminal (glucagon-like immunoreactivity: GLI) and specific C-terminal (immunoreactive glucagon: IRG) radioimmunoassays. The molecular forms of these peptides were also estimated using gel filtration chromatography. We then discuss the glucagon processes based on these findings. RESULTS: Serum GLI and IRG in groups S and M were significantly higher than those of group C (P < 0.01), while those in group S were also significantly higher than those in group M (P < 0.05). In all patients in groups S and M, except for only three in group S, a peculiar glicentin-like peptide (GLLP: MW about 8000) other than pancreatic glucagon was observed in IRG gel filtration chromatography, which was clearly absent from group C. CONCLUSIONS: The kinetics and processing of glucagon in patients with acute pancreatitis were quite different from those of healthy subjects. In patients with acute pancreatitis, the peculiar processing of glucagon proceeded in the intestine quite differently from ordinary glucagon processing either in the pancreas or in the intestine, generating a peculiar GLLP.

The expression of the inducible nitric oxide synthase messenger RNA on monocytes in severe acute pancreatitis.

BACKGROUND/AIMS: Although there have been numerous studies that nitric oxide (NO) is produced in monocytes and macrophages in animal models, it still remains controversial whether NO is produced by human monocytes and macrophages. To clarify whether NO is produced by human monocytes in patients with systemic inflammatory response syndrome (SIRS), we examined the expression of inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) and constitutive nitric oxide synthase (cNOS) mRNA in cultured monocytes derived from severe acute pancreatitis patients complicated with SIRS. METHODOLOGY: Monocytes were harvested from peripheral blood of nine severe acute pancreatitis patients with SIRS (group S) and five mild acute pancreatitis patients with no SIRS (group M). Then we examined the expression of iNOS mRNA and cNOS mRNA in cultured monocytes using the reverse transcription PCR (RT-PCR) method. RESULTS: iNOS mRNA was expressed in the cultured monocytes derived from eight of the nine patients in group S, but not in any of the five patients in group M, while cNOS mRNA was not found in cultured monocytes derived from any patient in either group. CONCLUSIONS: Although it is still not clear whether NO is produced in human monocytes or not, these findings indicate that iNOS is induced in monocytes in severe acute pancreatitis patients with SIRS, but not in mild pancreatitis patients.