Genotypic and phenotypic spectrum of CADASIL in Japan: the experience at a referral center in Kumamoto University from 1997 to 2014

This study elucidates the genotypic and phenotypic spectrum and histopathological findings related to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in Japan. For this single-center retrospective observational study, we enrolled 215 patients who were clinically suspected of having CADASIL and were examined at Kumamoto University from 1997 to 2014, and we diagnosed CADASIL in 70 patients. We found 19 different NOTCH3 mutations in the patients, with the NOTCH3 Arg133Cys mutation being found most frequently. We also found the Arg75Pro mutation, a cysteine-sparing NOTCH3 mutation. CADASIL patients with this Arg75Pro mutation were frequently found throughout Japan, and fewer patients with the Arg75Pro mutation showed MRI hyperintensity in the anterior temporal pole compared with patients with other NOTCH3 mutations. Significantly more CADASIL patients with the NOTCH3 Arg133Cys mutation had hyperintensity in the external capsule compared with CADASIL patients with the other mutations not including the NOTCH3 Arg75Pro mutation. We also showed postmortem pathological findings of the first Japanese CADASIL case with the NOTCH3 Arg133Cys mutation, and histopathological findings of fresh frozen skin biopsy specimens of CADASIL patients. In conclusions, the spectrum of NOTCH3 mutations in Japanese CADASIL patients may be partially explained by founder effects. Genotype–phenotype correlations may exist in CADASIL, which should be considered so as to make an accurate diagnosis of CADASIL in each population. Fresh frozen skin biopsy specimens may aid detection of Notch3 deposits on vascular walls for an improved diagnosis of CADASIL.     

Simple self‐reported behavioral or psychological characteristics as risk factors for future type 2 diabetes in Japanese individuals: Toranomon Hospital Health Management Center Study 14

Aims/Introduction

Depression, anger, sleep disorders and cognitive impairment are regarded as presenting a high risk for diabetes. We investigated whether responses to single statements on a self-report questionnaire on the presence of each of these four factors were associated with the development of type 2 diabetes.

Materials and Methods

We investigated 3,211 Japanese individuals without diabetes. Cumulative incidence rate and hazard ratios (HRs) for future type 2 diabetes over 7–13 years were evaluated according to the presence of lack of perseverance, anger, memory loss or sleep disorders.

Results

Results of Cox regression analysis showed that lack of perseverance (age- and sex-adjusted HR 1.41, 95% confidence interval 1.07–1.84), anger, (HR 1.51, 95% confidence interval 1.07–2.12) or memory loss (HR 1.47, 95% confidence interval 1.14–1.90) was predictive of the development of diabetes. Even after adjustment for metabolic factors including glycemic measurements, anger was significantly associated with an increased risk of future diabetes. Individuals with both anger and memory loss had a 1.94-fold (95% confidence interval 1.19–3.15) increased risk of type 2 diabetes than those without those two symptoms.

Conclusions

Responses to a simple self-report questionnaire as to whether individuals were aware of anger or memory loss were associated with the development of type 2 diabetes independent of traditional risk factors for diabetes in this cohort of Japanese individuals.     

ASXL2 mutations are frequently found in pediatric AML patients with t(8;21)/ RUNX1‐RUNX1T1 and associated with a better prognosis

ASXL2 is an epigenetic regulator involved in polycomb repressive complex regulation or recruitment. Clinical features of pediatric acute myeloid leukemia (AML) patients with ASXL2 mutations remain unclear. Thus, we investigated frequencies of ASXL1 and ASXL2 mutations, clinical features of patients with these mutations, correlations of these mutations with other genetic alterations including BCOR/BCORL1 and cohesin complex component genes, and prognostic impact of these mutations in 369 pediatric patients with de novo AML (0–17 years). We identified 9 (2.4%) ASXL1 and 17 (4.6%) ASXL2 mutations in 25 patients. These mutations were more common in patients with t(8;21)(q22;q22)/RUNX1‐RUNX1T1 (ASXL1, 6/9, 67%, P = 0.02; ASXL2, 10/17, 59%, P = 0.01). Among these 25 patients, 4 (27%) of 15 patients with t(8;21) and 6 (60%) of 10 patients without t(8;21) relapsed. However, most patients with relapse were rescued using stem cell transplantation irrespective of t(8;21). The overall survival (OS) and event‐free survival (EFS) rates showed no differences among pediatric AML patients with t(8;21) and ASXL1 or ASXL2 mutations and ASXL wild‐type (5‐year OS, 75% vs. 100% vs. 91% and 5‐year EFS, 67% vs. 80% vs. 67%). In 106 patients with t(8;21) AML, the coexistence of mutations in tyrosine kinase pathways and chromatin modifiers and/or cohesin complex component genes had no effect on prognosis. These results suggest that ASXL1 and ASXL2 mutations play key roles as cooperating mutations that induce leukemogenesis, particularly in pediatric AML patients with t(8;21), and these mutations might be associated with a better prognosis than that reported previously.     

Histological study of the developing pterygoid process of the fetal mouse sphenoid

The pterygoid process undergoes ossification of both the cartilage and membrane. However, few studies have attempted to explore the sequential development of the pterygoid process. Using histological examination, we performed morphological observations of the pterygoid process and surrounding tissue. ICR mice at embryonic days 13.5–18.0 and postnatal day 0 were used for morphological observations of the pterygoid process. By embryonic day 14.5, a mesenchymal cell condensation forming the anlage of the future medial pterygoid process differentiated into osteoid-like tissue and cartilage. At embryonic days 15.5–16.5, cartilage cells were clearly evident in the medial pterygoid process. In the medial pterygoid process, a bone collar was evident and calcified bone tissue surrounded the cartilage. At this point, a mesenchymal cell condensation formed the anlage of the pterygoid hamulus. At embryonic days 17.0–18.0, the cartilages were located along the lower and posterior border of the medial pterygoid process. A metachromatically stained matrix first became detectable around cells located in the pterygoid hamulus. On the other hand, at embryonic day 13.5, a metachromatically stained matrix was already evident in the space between the flattened cells in the lateral pterygoid process. At embryonic day 17.0, a hypertrophic cell zone had clearly formed in the diaphysis. On the basis of our present investigation, the lateral pterygoid process can be classified as primary cartilage, whereas the medial pterygoid process can be classified as secondary cartilage. Furthermore, it was found that the pterygoid hamulus is formed latest in the medial pterygoid process.     

Changing pulsatility by delaying the rotational speed phasing of a rotary left ventricular assist device

Continuous-flow left ventricular assist devices (LVADs) have improved the prognosis of end-stage heart failure. However, continuous-flow LVADs diminish pulsatility, which possibly result in bleeding, aortic insufficiency, and other adverse effects. We previously developed a novel control system for a continuous-flow LVAD (EVAHEART^®; Sun Medical), and demonstrated that we could create sufficient pulsatility by increasing its rotational speed (RS) in the systolic phase (Pulsatile Mode) in the normal heart model. Here, we aimed to evaluate differences between systolic assist with advanced and delayed loads by shifting the timing of increased RS. We implanted EVAHEART in six goats (55.3 ± 4.3 kg) with normal hearts. We reduced their heart rates to <60 bpm using propranolol and controlled the heart rates at 80 and 120 bpm using ventricular pacing. We shifted the timing of increasing RS from ?60 to +60 ms in the systolic phase. We found significant increases in all the following parameters when assessments of delayed timing (+60 ms) were compared with assessments of advanced timing (?60 ms): pulse pressure, mean dP/dt max of aortic pressure, and energy-equivalent pulse pressure. During continuous-flow LVAD support, pulsatility can be controlled using a rotary pump. In particular, pulsatility can be shifted by delaying increased RS.