Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan

Upshaw–Schulman syndrome (USS) is an extremely rare hereditary deficiency of ADAMTS13 activity, termed congenital TTP. The clinical signs are usually mild during childhood, often with isolated thrombocytopenia. But their symptoms become more evident when patients have infections or get pregnant. We identified 43 USS-patients in Japan, who ranged in age from early childhood to 79 years of age. Analysing the natural history of these USS patients based on ADAMTS13 gene mutations may help characterise their clinical phenotypes. Severe neonatal jaundice that requires exchange blood transfusion, a hallmark of USS, was found in 18 of 43 patients (42%). During childhood, 25 of 43 patients were correctly diagnosed with USS without gender disparity. These 25 patients were categorised as having ‘the early-onset phenotype’. Between 15 and 45 years of age, 15 were correctly diagnosed, and, interestingly, they were all female. The remaining three patients were male and were diagnosed when they were older than 45 years of age, suggesting that they were ‘the late-onset phenotype’. Two of these three males developed sudden overt TTP when they were 55 and 63 years old, respectively. These two men had two different homozygous ADAMTS13 gene mutations, p.R193W/p.R193W and p.C1024R/p.C1024R, respectively. Both of which were not discovered in the US or Western countries. In vitro expression studies showed that these two proteins were consistently secreted into the culture medium but to a lesser extent and with reduced activity compared to the wild-type protein. Our results indicate that ‘the late-onset phenotype’ of USS is formed with ethnic specificity.・The definitive version is available at " http://dx.doi.org/10.1111/j.1538-7836.2011.04341.x "・State of the Art 2011 : XXIII Congress of the International Society on Thrombosis and Haemostasis Invited Reviewhttp://dx.doi.org/10.1111/j.1538-7836.2011.04341.

A novel homozygous variant of the thrombomodulin gene causes a hereditary bleeding disorder

ArticleBlood Advances. 5(19): 3830-3838 (2021)journal articl

PO-158 Association Of Glucose Metabolism and Physical Activity By Chronotype in Elderly Japanese Adults: There is no full text article associated with this abstract

Objective Chronotype is a trait determining individual circadian preference in behavioral and biological rhythm relative to external light-dark cycle. Although evening chronotype has been reported to be associated with bad glucose control and low physical activity in middle-aged adults, it is not known whether it is true in elderly people. Therefore, the aim of this study was to investigate the relationship between glucose metabolism and physical activity by chronotype (circadian rhythm) in elderly Japanese adults. Methods A cross-sectional study was conducted in 178 adults (72 men and 106 women), aged 60-79 years, who were classified into three chronotype groups, ”definitely morning type (DMT)”, “moderately morning type (MMT)” and “neither type (NET)”, based on the Morningness/Eveningness Questionnaire scores (MEQ-Score). All participants were required to report their daily rhythms of behavior, such as meal time and sleep-wake cycle. Additionally, their physical activity were measured by an uniaxial accelerometer (Kenz Lifecorder EX, SUZUKEN, Nagoya, Japan). Energy intake was assessed by a brief self-administered diet-history questionnaire. Blood was drawn for biochemical analysis after an overnight fast. Results BMI and serum insulin in the DMT group was significantly higher than MMT and NET groups in male. The DMT group had a significantly shorter time interval between dinner and sleep than the other two groups, both in male and female. After adjustment for covariates (age, smoking and alcohol status, energy intakes, moderate-vigorous physical activity (MVPA) and sleep duration), the BMI, serum insulin, fasting blood glucose (FBG) and HOMA-IR in the DMT group was significantly higher than other groups. However, after adjustment for the time interval between dinner and sleep, the significant difference had disappeared. There was significant difference in terms of low-intensity physical activity between male and female. And MVPA in the DMT group, the subjects with low MVPA (<23Mets·hour/week) had higher FBG, serum insulin and HOMA-IR than the subjects with high MVPA (>23Mets·hour/week) in men, but not in women. Conclusions This study demonstrated that the DMT group with early sleep-wake lifestyle had higher BMI,  FBG, serum insulin and HOMA-IR, specially in elderly Japanese men with low MVPA, but not in women

Antisense RNA transcripts in the blood may be novel diagnostic markers for colorectal cancer

Numerous genetic studies have been conducted regarding the occurrence of colorectal cancer (CRC) and the prognosis using microarrays. However, adequate investigations into the diagnostic application of microarrays have yet to be performed. The simplicity and accuracy of diagnosis and prognosis tracking are important requirements for its processes, and the use of blood cells for diagnosis is considered to be suitable to meet these requirements. The patients involved in the study were 28 preoperative patients with CRC and 6 healthy individuals who served as controls. RNA was extracted from the blood cells of the patients and analyzed using a sense/antisense RNA custom microarray. In the patients with CRC, the expression levels of 20 sense RNA and 20 antisense RNA species were identified as being significantly altered compared with that of the healthy volunteers (P2.0). Cluster analysis of these RNA species revealed that the top 10 antisense RNAs significantly clustered patients with cancer and healthy individuals separately. Patients with stage I or II CRC exhibited significant changes in the expression levels of 33 sense and 39 antisense RNA species, as compared with healthy volunteers (P2.0). Cluster analysis demonstrated that patients with stage I or II CRC and healthy volunteers formed separate clusters only among the top 20 antisense RNA species. A tracking study of expression levels of haloacid dehalogenase‑like hydrolase domain‑containing 1 (HDHD1) antisense RNA was performed and a significant difference was identified between the CRC and healthy groups revealing that the levels at one week and three months following surgical removal of the cancerous tissue, decreased to almost same levels of the healthy individuals. The results of the current study indicate that HDHD1 antisense RNA may serve as a potential biomarker for the prognosis of CRC

Effects of daily aspirin on cancer incidence and mortality in the elderly Japanese

BackgroundLong‐term follow‐up of studies to investigate preventive effects of aspirin on arterial thrombosis indicate that aspirin reduces the incidence and mortality of some cancers in Western populations.ObjectivesTo explore the effects of aspirin on cancer incidence and mortality in the elderly Japanese.Patients/MethodsPatients aged 60 to 85 years, presenting with hypertension, dyslipidemia, or diabetes mellitus (n = 14 601, 7297 in the aspirin group and 7304 in the no‐aspirin group) participated the Japanese Primary Prevention Project (JPPP), a multicenter, open‐label, randomized, parallel‐group trial. A subanalysis of JPPP was performed to analyze the incidence of newly diagnosed cancer and death related to cancer.ResultsThe cumulative incidence of newly diagnosed cancer was 5.60% (4.65‐6.64%) in the aspirin group and 4.14% (3.67‐4.66%) in the no‐aspirin group. The hazard ratio for newly diagnosed cancer was 1.24 (1.06‐1.46), and the cancer incidence was significantly higher in the aspirin group. The cumulative cancer mortality was 1.96% (1.65‐2.31%) in the aspirin group and 1.87% (1.56‐2.22%) in the no‐aspirin group, with no statistically significant difference. The Fine and Gray model suggested that the difference in the incidence of newly diagnosed cancer between the two groups decreased year by year.ConclusionsLow‐dose aspirin use did not reduce the cancer incidence or cancer mortality during a 5‐year‐average study period in the elderly Japanese. The cancer incidence in the aspirin group might decrease, however, to less than that in the no‐aspirin group after the study period. Aspirin use might have led to earlier cancer diagnosis in our study

Initial Surgical Versus Conservative Strategies in Patients With Asymptomatic Severe Aortic Stenosis

AbstractBackgroundCurrent guidelines generally recommend watchful waiting until symptoms emerge for aortic valve replacement (AVR) in asymptomatic patients with severe aortic stenosis (AS).ObjectivesThe study sought to compare the long-term outcomes of initial AVR versus conservative strategies following the diagnosis of asymptomatic severe AS.MethodsWe used data from a large multicenter registry enrolling 3,815 consecutive patients with severe AS (peak aortic jet velocity >4.0 m/s, or mean aortic pressure gradient >40 mm Hg, or aortic valve area <1.0 cm2) between January 2003 and December 2011. Among 1,808 asymptomatic patients, the initial AVR and conservative strategies were chosen in 291 patients, and 1,517 patients, respectively. Median follow-up was 1,361 days with 90% follow-up rate at 2 years. The propensity score–matched cohort of 582 patients (n = 291 in each group) was developed as the main analysis set for the current report.ResultsBaseline characteristics of the propensity score–matched cohort were largely comparable, except for the slightly younger age and the greater AS severity in the initial AVR group. In the conservative group, AVR was performed in 41% of patients during follow-up. The cumulative 5-year incidences of all-cause death and heart failure hospitalization were significantly lower in the initial AVR group than in the conservative group (15.4% vs. 26.4%, p = 0.009; 3.8% vs. 19.9%, p < 0.001, respectively).ConclusionsThe long-term outcome of asymptomatic patients with severe AS was dismal when managed conservatively in this real-world analysis and might be substantially improved by an initial AVR strategy. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140