Lidocaine‐Propitocain Cream,a Eutectic Mixture of Local Anesthetics,Effectively Relieves Pain Associated With Vascular Access Intervention Therapy in Patients Undergoing Hemodialysis: A Placebo‐Controlled,Double‐Blind,Crossover Study

Vascular access intervention therapy (VAIVT) is necessary to maintain vascular access in patients undergoing hemodialysis. VAIVT‐associated vasodilatation is painful. However, few reports have focused on effective pain relief at the time of VAIVT. The present study was performed to determine whether lidocaine‐propitocain cream, a eutectic mixture of local anesthetics (EMLA), effectively reduces VAIVT‐associated pain in patients undergoing hemodialysis. This placebo‐controlled, double‐blind, crossover study was conducted in a single center. Among 210 patients who underwent a total of 437 VAIVT procedures from August 2017 to June 2018, 30 patients were randomly allocated to either the EMLA–placebo arm or placebo–EMLA arm at the time of VAIVT. EMLA application significantly reduced the visual analog scale score compared with placebo (47.0 ± 21.1 vs. 68.6 ± 20.7 mm, respectively; P < 0.05). EMLA is a safe and effective treatment for relief of VAIVT‐associated pain in patients undergoing hemodialysis.     

Octacalcium phosphate collagen composites with titanium mesh facilitate alveolar augmentation in canine mandibular bone defects

This study was designed to investigate whether bone regeneration by implantation of octacalcium phosphate and porcine atelocollagen composite (OCP/Col) would be enhanced if mechanical stress to the implanted OCP/Col were alleviated. OCP/Col discs were implanted into an arc-shaped mandibular defect in male adult beagle dogs divided into untreated, OCP/Col, and OCP/Col/Mesh groups. In the OCP/Col/Mesh group, mechanical stress towards the implanted OCP/Col was alleviated by a titanium mesh. Bone regeneration in the three groups was compared after 6 months. Macroscopically, the alveolus in the OCP/Col/Mesh group was augmented vertically more than in the other two groups. Morphometric analysis by micro-CT showed the bone volume in the OCP/Col/Mesh group was significantly greater than in the other two groups. The augmented alveolus in the OCP/Col/Mesh group consisted of outer cortical and inner cancellous structure. Histologically, the OCP/Col/Mesh-treated alveolus was augmented by matured bone tissue along the inside of the titanium mesh. The implanted OCP/Col in the OCP/Col/Mesh and OCP/Col groups had almost disappeared. These results indicated that vertical bone regeneration by OCP/Col was efficient and successful when the mechanical stress to the implanted OCP/Col was alleviated. OCP/Col should be a useful bone substitute with active structural reconstitution.     

Extensive gene deletions in Japanese patients with Diamond-Blackfan anemia

Fifty percent of Diamond-Blackfan anemia (DBA) patients possess mutations in genes coding for ribosomal proteins (RPs). To identify new mutations, we investigated large deletions in the RP genes RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24, and RPS26. We developed an easy method based on quantitative-PCR in which the threshold cycle correlates to gene copy number. Using this approach, we were able to diagnose 7 of 27 Japanese patients (25.9%) possessing mutations that were not detected by sequencing. Among these large deletions, similar results were obtained with 6 of 7 patients screened with a single nucleotide polymorphism array. We found an extensive intragenic deletion in RPS19, including exons 1-3. We also found 1 proband with an RPL5 deletion, 1 patient with an RPL35A deletion, 3 with RPS17 deletions, and 1 with an RPS19 deletion. In particular, the large deletions in the RPL5 and RPS17 alleles are novel. All patients with a large deletion had a growth retardation phenotype. Our data suggest that large deletions in RP genes comprise a sizable fraction of DBA patients in Japan. In addition, our novel approach may become a useful tool for screening gene copy numbers of known DBA genes.     

Long-Term Safety of Living Kidney Donors Aged 60 and Older

In Japan, kidney transplantation procedures are usually dependent upon live donors. As the recipient ages have been increasing, so has there been a corollary increase in the age of the live donors. Despite this being controversial, the use of older donors is becoming increasingly common. The purpose of our study was to evaluate the long-term safety of accepting older living kidney donors and graft survival rates. We retrospectively analyzed long-term donor outcomes for consecutive patients at our institution between January 1990 and December 2011. Older live kidney donors were defined as ≥60 years and younger live kidney donors were defined as <60 years old. Thirty-three were ≥60 years and 55 donors were <60 years. The mean follow-up term was 7 years and 4 months. Predonation, older donors had a lower estimated glomerular filtration rate (eGFR) level (77.1 ± 9.5 mL/min/1.73 m²) than younger donors (85.8 ± 14.6 mL/min/1.73 m²; P < .01). More older donors had a history of hypertension (42.4% vs 9.1%; P < .01). In both groups, eGFR levels decreased about 40% immediately after nephrectomy. Residual renal function though was stable on long-term follow-up. The incidence of de novo hypertension and proteinuria after nephrectomy was not different between the 2 groups. In older donors, there were no perioperative complications that required extended hospital stays. Graft survival over a period of 10 years was similar in both groups. In our study, donor age had no influence on the deterioration of renal function after nephrectomy. Regardless of age, careful evaluation and follow-up are important for the donor's long-term safety after donation.     

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.