Sensitivity of a bone-equivalent polymer gel dosimeter for measuring the dose to bone during radiation therapy.

Treatment planning systems that use the Monte Carlo algorithm can calculate the dose to the medium (Dm) in non-water-equivalent tissues such as bones. However, Dm cannot be verified using actual measurements; therefore, it is necessary to develop tissue-equivalent dosimeters. In this study, we developed a bone-equivalent polymer gel dosimeter (BPGD) that can measure the dose absorbed by the bone and investigated its sensitivity. The BPGDs were prepared by adding 3.0 mol of calcium hydrogen phosphate dihydrate as a component of bone to an improved dose-sensitive polyacrylamide gelatin and tetrakis hydroxymethyl phosphonium chloride (iPAGAT). One day after preparation, the BPGDs were irradiated with a field size of 15 × 15 cm2 using a 10 MV X-ray beam to evaluate the dose sensitivity, dose-rate dependence, and dose-integration dependence. One day after dose exposure, the BPGDs were scanned using a 0.4 T MRI APERTO Eterna (Hitachi, Tokyo, Japan) to obtain R2 values. The difference between the R2 values of 6 Gy and 0 Gy was up to 5 s-1, and the R2 curve plateaued in the high-dose region. Moreover, the BPGD did not depend on the integration of the dose and dose rates. Therefore, the BPGDs that we developed can determine the radiation dose to bones.

Pathogenic variants in the survival of motor neurons complex gene GEMIN5 cause cerebellar atrophy.

Cerebellar ataxia is a genetically heterogeneous disorder. GEMIN5 encoding an RNA-binding protein of the survival of motor neuron complex, is essential for small nuclear ribonucleoprotein biogenesis, and it was recently reported that biallelic loss-of-function variants cause neurodevelopmental delay, hypotonia, and cerebellar ataxia. Here, whole-exome analysis revealed compound heterozygous GEMIN5 variants in two individuals from our cohort of 162 patients with cerebellar atrophy/hypoplasia. Three novel truncating variants and one previously reported missense variant were identified: c.2196dupA, p.(Arg733Thrfs*6) and c.1831G > A, p.(Val611Met) in individual 1, and c.3913delG, p.(Ala1305Leufs*14) and c.4496dupA, p.(Tyr1499*) in individual 2. Western blotting analysis using lymphoblastoid cell lines derived from both affected individuals showed significantly reduced levels of GEMIN5 protein. Zebrafish model for null variants p.(Arg733Thrfs*6) and p.(Ala1305Leufs*14) exhibited complete lethality at 2 weeks and recapitulated a distinct dysplastic phenotype. The phenotypes of affected individuals and the zebrafish mutant models strongly suggest that biallelic loss-of-function variants in GEMIN5 cause cerebellar atrophy/hypoplasia.

Evaluation of technical performance of optical surface imaging system using conventional and novel stereotactic radiosurgery algorithms.

The Catalyst HD (C-RAD Positioning AB, Uppsala, Sweden) optical surface imaging (OSI) system is able to manage interfractional patient positioning, intrafractional motion monitoring, and non-contact respiratory gating without x-ray exposure for radiation therapy. In recent years, a novel high-precision surface registration algorithm for stereotactic radiosurgery (SRS algorithm) has been released. This study aimed to evaluate the technical performance of the OSI system using rigid phantoms, by comparing the conventional and SRS algorithms. To determine the system's technical performance, isocenter displacements were calculated by surface image registration via the OSI system using head, thorax, and pelvis rigid phantoms. The reproducibility of positioning was evaluated by the mean value calculated by repeating the registration 10 times, without moving each phantom. The accuracy of positioning was evaluated by the mean value of the residual error, where the 10 offset values given to each phantom were subtracted from the isocenter displacement values. The stability of motion monitoring was evaluated by measuring isocenter drift during 20 min and averaging it over 10 measurements. For the head phantom, all tests were compared with the mask types and algorithms. As a result, for all sites and both algorithms, the reproducibility, accuracy, and stability for translation and rotation were <0.1 mm and <0.1°, <1.0 mm and <1.0°, and <0.1 mm and <0.1°, respectively. In particular, the SRS algorithm had a small absolute error and standard deviation of calculated isocenter displacement, and a significantly higher reproducibility and accuracy than the conventional algorithm (P < 0.01). There was no difference in the stability between the algorithms (P = 0.0280). The SRS algorithm was found to be suitable for the treatment of rigid body sites with less deformation and small area, such as the head and face.

Slowly progressive leukodystrophy in an adolescent male with phosphoglycerate kinase deficiency.

We report the case of an 18-year-old man with a phosphoglycerate kinase (PGK) deficiency who had slowly progressive leukodystrophy during adolescence. The patient had a history of severe neonatal jaundice, hemolytic crisis with rhabdomyolysis triggered by febrile viral infections, dysarthria, and intellectual disability during early childhood. Clumsiness in walking and writing became obvious at ∼10years of age. Evaluations performed by us on the 18-year-old patient confirmed the presence of pyramidal tract signs, increased muscle tone, and generalized dystonia. Brain magnetic resonance (MR) imaging revealed leukodystrophy in the periventricular white matter, posterior limbs of the internal capsule, dorsal pons, and middle cerebellar peduncles. Compared to MR images acquired at 9years of age, MR images acquired at 18years of age showed that the white matter atrophy had progressed. The PGK deficiency was diagnosed by identifying a known missense mutation in PGK1 (c.1060G>C) through comprehensive target capture sequencing and by observing low PGK activity in his red blood cells. The patient underwent a ketogenic diet for 2weeks, which we expected would increase adenosine triphosphate levels through sources other than the PGK-associated glycolytic pathway. The diet was not tolerated owing to the unexpected emergence of hemolysis. Hemolytic anemia, neurological dysfunction, and myopathy are often associated with PGK deficiencies. However, leukodystrophy as a symptom of PGK deficiency has not been reported previously. Our case highlights the progressive nature of the neurological complications related to PGK deficiencies. Therefore, long-term follow-up is recommended, even if neurological impairments are not obvious during childhood.

JunD suppresses bone formation and contributes to low bone mass induced by estrogen depletion.

JunD is an activator protein-1 (AP-1) component though its function in skeletal system is still not fully understood. To elucidate the role of JunD in the regulation of bone metabolism, we analyzed JunD-deficient mice. JunD deficiency significantly increased bone mass and trabecular number. This bone mass enhancement was due to JunD deficiency-induced increase in bone formation activities in vivo. Such augmentation of bone formation was associated with simultaneous increase in bone resorption while the former was dominant over the latter as accumulation of bone mass occurred in JunD-deficient mice. In a pathological condition relevant to postmenopausal osteoporosis, ovariectomy reduced bone mass in wild type (WT) mice as known before. Interestingly, JunD deficiency suppressed ovariectomy-induced increase in bone resorption and kept high bone mass. In addition, JunD deficiency also enhanced new bone formation after bone marrow ablation. Examination of molecular bases for these observations revealed that JunD deficiency enhanced expression levels of c-jun, fra-1, and fra-2 in bone in conjunction with elevated expression levels of runx2, type I collagen, and osteocalcin. Thus, JunD is involved in estrogen depletion-induced osteopenia via its action to suppress bone formation and to enhance bone resorption.