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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Oral intake of soy isoflavone aglycone improves the aged skin of adult women.

A double-blind, placebo-controlled trial was conducted to clinically evaluate the effect of soy isoflavone aglycone on the aged skin of middle-aged women. Twenty-six women volunteers in their late 30s and early 40s were randomly assigned to receive either a test food (13 women, the test food group) or a placebo food (13 women, the control group). These groups were given the test food (40 mg of soy isoflavone aglycone per day) and placebo, respectively, for 12 wk. The extent of linear and fine wrinkles at the lateral angle of the eyes was selected as the major evaluation criterion to assess the effects of foods, and the wrinkles' area ratio was used as the evaluation parameter. The extent of skin microrelief at the lateral angle of eyes and that of malar skin elasticity were used as secondary evaluation criteria, and the skin microrelief's area ratio and recovery of skin elasticity were used as the respective evaluation parameters. These parameters were assessed 4, 8, and 12 wk after the start of the test food or placebo intake. The test food group showed a statistically significant improvement of fine wrinkles at week 12 (p<0.05) and of malar skin elasticity at week 8 (p<0.05), compared with the control group. Although there was no significant difference between the test food group and the control group regarding effects on skin microrelief at lateral angle of the eyes, a significant intragroup improvement was observed at week 8 in the test food group (p<0.05). As for the test food safety, none of the subjects presented adverse symptoms during the study period or discontinued the intake of the test food. These data indicate that the oral intake of 40 mg soy isoflavone aglycones per day improves the aged skin of middle-aged women.

Nephrocalcinosis formation by soy isoflavones in male rats.

Isoflavones (IFs), found in the form of both aglycones and glucosides in soybean foods, induce weak estrogenic activities. Although IFs have a number of health benefits, it was previously reported that IFs cause nephrocalcinosis (NC) in the kidney of male Fischer 344 (F344) rats. The present study aims to elucidate the safety of IFs by focusing on IF-induced NC formation in rats. Fermented soybean extract (FSE) containing 420 mg/g isoflavone aglycones was orally administered to male F344 and Sprague-Dawley (SD) rats for 28 days. FSE induced NC formation in the kidney of F344 rats, but not in SD rats. However, absorption of IFs did not differ between F344 and SD rats. NC formation and its severity of FSE were histologically compared with those of soybean extract (SE) containing 518 mg/g isoflavone glucosides in F344 rats. There were no differences in the number of NC formations and the extent of calcium deposit between FSE and SE groups. To examine the dose effect of FSE on NC formation, doses of 20, 140, or 1000 mg/kg FSE were administered to F344 rats for 90 days. NC formation was observed in the 140 and 1000 mg/kg groups. These results indicated that a high dose of oral administration of IFs induced NC formation depending on the strain of rat.

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.

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.