Clonal leukemic evolution in myelodysplastic syndromes with TET2 and IDH1/2 mutations

Somatic mutations of TET2, IDH1, and IDH2 have been described in myelodysplastic syndrome. The impact of these mutations on outcome of myelodysplastic syndrome and their progression to secondary acute myeloid leukemia remains unclear. Mutation status of TET2, IDH1 and IDH2 was investigated in a cohort of 46 paired myelodysplastic syndrome/acute myeloid leukemia samples and 122 non-paired cases with de novo myelodysplastic syndrome, to clarify their roles in the evolution of myelodysplastic syndrome to acute myeloid leukemia. Among the 168 de novo myelodysplastic syndrome patients, the frequency of TET2, IDH1, and IDH2 mutations was 18.5%, 4.2% and 6.0%, respectively. TET2/IDH mutations had no impact on survivals, while TET2 mutations were significantly associated with rapid progression to acute myeloid leukemia. Seventeen of the 46 paired myelodysplastic syndrome/secondary acute myeloid leukemia samples harbored TET2/IDH mutations; none acquired these mutations in acute myeloid leukemia phase. Progression to acute myeloid leukemia was accompanied by evolution of a novel clone or expansion of a minor pre-existing subclone of one or more distinct mutations in 12 of the 17 cases with TET2/IDH mutations. A minor subclone in 3 cases with biallelic TET2 inactivation subsequently expanded, indicating biallelic TET2 mutations play a role in acute myeloid leukemia progression. Twelve patients acquired other genetic lesions, and/or showed increased relative mutant allelic burden of FLT3-ITD, N/K-RAS, CEBPA or RUNX1 during acute myeloid leukemia progression. Our findings provide a novel insight into the role of TET2/IDH mutation in the pathogenesis of myelodysplastic syndrome and subsequent progression to acute myeloid leukemia.     

Factors associated with development and distribution of granular/fuzzy astrocytes in neurodegenerative diseases

Granular/fuzzy astrocytes (GFAs), a subtype of “aging‐related tau astrogliopathy,” are noted in cases bearing various neurodegenerative diseases. However, the pathogenic significance of GFAs remains unclear. We immunohistochemically examined the frontal cortex, caudate nucleus, putamen and amygdala in 105 cases composed of argyrophilic grain disease cases (AGD, N = 26), and progressive supranuclear palsy (PSP, N = 10), Alzheimer’s disease (AD, N = 20) and primary age‐related tauopathy cases (PART, N = 18) lacking AGD, as well as 31 cases bearing other various neurodegenerative diseases to clarify (i) the distribution patterns of GFAs in AGD, and PSP, AD and PART lacking AGD, (ii) the impacts of major pathological factors and age on GFA formation and (iii) immunohistochemical features useful to understand the formation process of GFAs. In AGD cases, GFAs consistently occurred in the amygdala (100%), followed by the putamen (69.2%) and caudate nucleus and frontal cortex (57.7%, respectively). In PSP cases without AGD, GFAs were almost consistently noted in all regions examined (90–100%). In AD cases without AGD, GFAs were less frequent, developing preferably in the putamen (35.0%) and caudate nucleus (30.0%). PART cases without AGD had GFAs most frequently in the amygdala (35.3%), being more similar to AGD than to AD cases. Ordered logistic regression analyses using all cases demonstrated that the strongest independent factor of GFA formation in the frontal cortex and striatum was the diagnosis of PSP, while that in the amygdala was AGD. The age was not significantly associated with GFA formation in any region. In GFAs in AGD cases, phosphorylation and conformational change of tau, Gallyas‐positive glial threads indistinguishable from those in tufted astrocytes, and the activation of autophagy occurred sequentially. Given these findings, AGD, PSP, AD and PART cases may show distinct distributions of GFAs, which may provide clues to predict the underlying processes of primary tauopathies.     

The impact of cesarean section on neonatal outcome of infants born at 23 weeks of gestation

Objective

Determine the impact of cesarean section (CS) on neonatal outcome of infants born at 23 weeks of gestation.

Methods

A retrospective study was performed involving 34 infants born at 23 weeks and 91 infants born at 24–26 weeks. Indications necessitating delivery were severe pregnancy induced hypertension, non-reassuring fetal heart rate patterns (NRFHRs), or intrauterine infection (IUI). Obstetrical indication for CS included NRFHR and breech presentation. Poor outcome included neonatal death or cerebral palsy. Univariate and multiple logistic analyses were performed to determine the effect of CS for obstetrical indications on poor outcome.

Results

The incidence of poor outcome was significantly higher at 23 weeks (number of poor outcomes/total number: 22/34) compared to that (31/91) at 24–26 weeks (p < 0.01). The incidence of a poor outcome was significantly higher at 23 weeks for infants having NRFHR (11/16) compared to those at 24–26 weeks (15/43, p = 0.02). However, the incidence of a poor outcome was similar in infants with IUI (6/10 at 23 weeks versus 5/11 at 24–26 weeks, p = 0.41). Vaginal birth in cases of obstetrical indication for CS at 23 weeks was associated with higher risk of a poor outcome (odds ratio: 8.2). In contrast, the risk at 24–26 weeks was not higher (OR, 0.8). After adjustment using variables of vaginal birth and IUI, vaginal birth significantly affected poor outcome (OR, 13.0).

Conclusion

Poor neonatal outcome was closely related to the mode of delivery, suggesting that CS for obstetrical indication at 23 weeks may improve neonatal outcome.     

Accelerated Tau Aggregation,Apoptosis and Neurological Dysfunction Caused by Chronic Oral Administration of Aluminum in a Mouse Model of Tauopathies

To clarify whether long‐term oral ingestion of aluminum (Al) can increase tau aggregation in mammals, we examined the effects of oral Al administration on tau accumulation, apoptosis in the central nervous system (CNS) and motor function using tau transgenic (Tg) mice that show very slowly progressive tau accumulation. Al‐treated tau Tg mice had almost twice as many tau‐positive inclusions in the spinal cord as tau Tg mice without Al treatment at 12 months of age, a difference that reached statistical significance, and the development of pretangle‐like tau aggregates in the brain was also significantly advanced from 9 months. Al exposure did not induce any tau pathology in wild‐type (WT) mice. Apoptosis was observed in the hippocampus in Al‐treated tau Tg mice, but was virtually absent in the other experimental groups. Motor function as assessed by the tail suspension test was most severely impaired in Al‐treated tau Tg mice. Given our results, chronic oral ingestion of Al may more strongly promote tau aggregation, apoptosis and neurological dysfunction if individuals already had a pathological process causing tau aggregation. These findings may also implicate chronic Al neurotoxicity in humans, who frequently have had mild tau pathology from a young age.     

Molecular characterization of the recurrent unbalanced translocation der(1;7)(q10;p10)

An unbalanced translocation der(1;7)(q10; p10) is a nonrandom chromosomal aberration commonly observed in myelodysplastic syndrome and acute myeloid leukemia. We molecularly analyzed the breakpoints of der(1;7)(q10;p10) by quantitative fluorescent in situ hybridization (FISH) analyses using centromeric satellite DNAs mapped to chromosomes 1 and 7 as probes. We found that the signal intensities of 2 centromere alphoid probes, D1Z7 on chromosome 1 and D7Z1 on chromosome 7, were almost invariably reduced on the derivative chromosome compared with those on their normal counterparts. These results suggest that this translocation results from the recombination between the 2 alphoids, which was further confirmed by fiber FISH experiments. Because the relative reduction in the intensities of D1Z7 and D7Z1 signals on the derivative chromosomes was highly variable among patients, it was estimated that the breakpoints in these patients were randomly distributed over several megabase pairs within each alphoid cluster except for its extreme end to the short arm. Our results provide a novel insight into the structural basis for generation of this translocation as well as its leukemogenic roles.     

Studies on the polymerization of vinyl compounds in the presence of metal salts, 9. On the initiation mechanism of polymerization of acrylamide by ceric salt

In order to elucidate the initiation mechanism of the polymerization of acrylamide by ceric salt, the complexation of ceric salt with acrylamide and its methylated derivatives was investigated by IR and NMR spectrometry. The decomposition of the complex was also studied by determining the rate of ceric salt consumption. From the results it was concluded that the oxygen of acrylamide coordinates with the ceric ion to form the complex and that a radical is produced by abstraction of a hydrogen atom from the amide group of the molecule to initiate the polymerization.     

Clinical efficacy of 5-fluorouracil (5-FU) topical cream for treatment of cholesteatoma

OBJECTIVE: In order to clarify clinical efficacy of commercially available 5-fluorouracil (5-FU) topical cream, a clinical study was conducted. METHODS: Two to three cubic millimetres of 5-FU topical cream (Kyowa, Roche) was applied on 50 cases of various types of cholesteatoma (50 patients) two to five times with the interval of 2 weeks, and its clinical efficacy was evaluated by the criteria we developed. RESULTS: In total, 59% of the cholesteatomas showed good effect, 29% of them showed fair effect, and the effect was poor in the remaining 12%. It was particularly effective in cholesteatomas in the EAC, attic cholesteatomas with an aerated mastoid, and in recurrent-type cholesteatomas. CONCLUSION: 5-FU topical cream appeared effective for the treatment of cholesteatomas.     

Projections to the alimentary canal from the dopaminergic neurons in the dorsal motor nucleus of the vagus of the rat

The motility of the alimentary canal is regulated not only by neurons that contain acetylcholine or adrenaline, but also by nonadrenergic noncholinergic neurons. There are many neurons containing dopamine in the dorsal motor nucleus of the vagus (DMV). We examined the projections of these dopaminergic neurons to the alimentary canal with double-labeling immunohistochemistry for tyrosine hydroxylase (TH) and the retrograde tracer cholera toxin subunit b following its injection into the subdiaphragmatic esophagus, the cardia, the pylorus, the duodenum, the jejunum, and the ascending colon. Almost all double-labeled neurons were found in the half of the DMV caudal to the area postrema. In the caudal half of the DMV, about 58% of the TH-immunoreactive neurons projected to the cardia, about 36% projected to the pylorus, and about 28% projected to the subdiaphragmatic esophagus. Only a few TH-immunoreactive neurons projected to the duodenum, the jejunum, or the ascending colon. As a whole, less than 10% of the neurons in the DMV that projected to the alimentary canal showed TH-like immunoreactivity. These results suggest that some of the dopaminergic neurons in the DMV might regulate the activities of the stomach and the subdiaphragmatic esophagus.