Parbendazole as a promising drug for inducing differentiation of acute myeloid leukemia cells with various subtypes.

Acute myeloid leukemia (AML) is a malignancy characterized by differentiation arrest of hematopoietic precursor cells. Differentiation therapy is effective for patients with acute promyelocytic leukemia; however, only a few effective differentiation therapies have been established for patients with other AML subtypes. In this study, seven benzimidazole anthelmintics were examined to determine the effects of differentiation on AML cells. The expression of monocyte markers (CD11b and CD14) was elevated after treatment with most benzimidazole anthelmintics. Among these drugs, parbendazole (PBZ) induced AML cell differentiation at low concentration. PBZ induced the monocyte marker expression, KLF4/DPYSL2A gene expression, and apoptosis for 21 AML cell lines with various subtypes and a primary AML sample. Finally, an in vivo analysis using an AML patient-derived xenograft mouse model showed a significant decrease in the chimerism level and prolonged survival in PBZ-treated mice. These findings could lead to a more effective differentiation therapy for AML.

Estimation of Visual Function Using Deep Learning From Ultra-Widefield Fundus Images of Eyes With Retinitis Pigmentosa.

Importance: There is no widespread effective treatment to halt the progression of retinitis pigmentosa. Consequently, adequate assessment and estimation of residual visual function are important clinically. Objective: To examine whether deep learning can accurately estimate the visual function of patients with retinitis pigmentosa by using ultra-widefield fundus images obtained on concurrent visits. Design, Setting, and Participants: Data for this multicenter, retrospective, cross-sectional study were collected between January 1, 2012, and December 31, 2018. This study included 695 consecutive patients with retinitis pigmentosa who were examined at 5 institutions. Each of the 3 types of input images-ultra-widefield pseudocolor images, ultra-widefield fundus autofluorescence images, and both ultra-widefield pseudocolor and fundus autofluorescence images-was paired with 1 of the 31 types of ensemble models constructed from 5 deep learning models (Visual Geometry Group-16, Residual Network-50, InceptionV3, DenseNet121, and EfficientNetB0). We used 848, 212, and 214 images for the training, validation, and testing data, respectively. All data from 1 institution were used for the independent testing data. Data analysis was performed from June 7, 2021, to December 5, 2022. Main Outcomes and Measures: The mean deviation on the Humphrey field analyzer, central retinal sensitivity, and best-corrected visual acuity were estimated. The image type-ensemble model combination that yielded the smallest mean absolute error was defined as the model with the best estimation accuracy. After removal of the bias of including both eyes with the generalized linear mixed model, correlations between the actual values of the testing data and the estimated values by the best accuracy model were examined by calculating standardized regression coefficients and P values. Results: The study included 1274 eyes of 695 patients. A total of 385 patients were female (55.4%), and the mean (SD) age was 53.9 (17.2) years. Among the 3 types of images, the model using ultra-widefield fundus autofluorescence images alone provided the best estimation accuracy for mean deviation, central sensitivity, and visual acuity. Standardized regression coefficients were 0.684 (95% CI, 0.567-0.802) for the mean deviation estimation, 0.697 (95% CI, 0.590-0.804) for the central sensitivity estimation, and 0.309 (95% CI, 0.187-0.430) for the visual acuity estimation (all P < .001). Conclusions and Relevance: Results of this study suggest that the visual function estimation in patients with retinitis pigmentosa from ultra-widefield fundus autofluorescence images using deep learning might help assess disease progression objectively. Findings also suggest that deep learning models might monitor the progression of retinitis pigmentosa efficiently during follow-up.

Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole-exome sequencing.

Inherited retinal diseases (IRDs) comprise a phenotypically and genetically heterogeneous group of ocular disorders that cause visual loss via progressive retinal degeneration. Here, we report the genetic characterization of 1210 IRD pedigrees enrolled through the Japan Eye Genetic Consortium and analyzed by whole exome sequencing. The most common phenotype was retinitis pigmentosa (RP, 43%), followed by macular dystrophy/cone- or cone-rod dystrophy (MD/CORD, 13%). In total, 67 causal genes were identified in 37% (448/1210) of the pedigrees. The first and second most frequently mutated genes were EYS and RP1, associated primarily with autosomal recessive (ar) RP, and RP and arMD/CORD, respectively. Examinations of variant frequency in total and by phenotype showed high accountability of a frequent EYS missense variant (c.2528G>A). In addition to the two known EYS founder mutations (c.4957dupA and c.8805C>G) of arRP, we observed a frequent RP1 variant (c.5797C>T) in patients with arMD/CORD.

Progression Rate of Visual Function and Affecting Factors at Different Stages of Retinitis Pigmentosa.

We reviewed medical records of 121 patients/235 eyes of typical retinitis pigmentosa (RP) patients who could be followed up for at least 5 years with the aim of investigating the long-term course of visual function progression at each RP stage and appropriate assessment methods. Patients were classified into three groups: mild RP (baseline mean deviation (MD) ≥ -5), moderate RP (-25 < baseline MD < -5), and late RP (baseline MD ≤ -25). Linear mixed-effect models were used to follow MD, the average retinal sensitivity of the central four points of the Humphrey field analyzer 10-2 program (S4), and visual acuity (VA) with increasing time. The associations among factors (baseline MD group, sex, hereditary form) and the interaction between each factor and time were also investigated. The mean reduction of the MD, S4, and VA for all patients was -0.37 dB/year, -0.25 dB/year, and 0.018/year, respectively. The moderate RP group had a faster progression than other groups in MD (-0.43 dB/year, p < 0.05). The moderate (-0.31 dB/year, p = 0.01) and late RP groups (-0.25 dB/year, p < 0.01) had faster progression than the mild RP group in S4. The late RP group had faster progression in VA than the other groups (0.03/year, p < 0.05). Females had a slower progression of the S4 (-0.15 dB/year, p = 0.02) and VA (0.01/year, p < 0.001) than males. The autosomal dominant group had a slower progression than the sporadic group in MD (-0.22 dB/year, p = 0.02); the autosomal dominant and autosomal recessive groups had a slower VA decline than the sporadic group (0.01/year, p = 0.03; 0.01/year, p = 0.04). Because the progression rates of VA and visual field test differed as per the RP stage, S4 and VA can also be useful assessment methods depending on the stage. Inheritance form and sex may affect the progression rate.

Triboelectric charging of polytetrafluoroethylene antithrombotic catheters.

This study proposes that a polytetrafluoroethylene (PTFE) electret tube charged by frictional electricity can prevent the solidification of the indwelling catheter in blood vessels. Coagulation in intravascular indwelling catheters may discontinue the treatment because of thrombus-derived bacteria-adhesion infections or poor blood removal. Current commercially available intravascular catheters lack complete antithrombotic measures, even with heparin or urokinase antithrombotic coatings. Herein, we tested the effectiveness of an antithrombotic treatment that prevents coagulation using a static electric charge on the interior of the PTFE tube via the triboelectric effect by rubbing the tube's inner wall with a round glass rod. The anticoagulation properties were evaluated by enclosing a sample of blood in an electret tube and observing the coagulase adhering to the inner wall using a microscope. To confirm the effectiveness of this treatment, the charge-distribution on the inner surface of the electret tube was measured, surface irregularities were observed, and the elements on the surface were analyzed. The surface potential inside the electret tube was - 366.4 V, which proved effective for an antithrombotic treatment, as it discouraged coagulation, and the triboelectric charging process caused neither surface element denaturation nor significant surface irregularities. The nearly uniform negative surface charge on the inside of the tube was responsible for the antithrombotic effect because no surface irregularities or change in the surface element denaturation was observed. Triboelectrically charged PTFE electret tubes are highly useful for intravascular indwelling catheters.

Motor Training Promotes Both Synaptic and Intrinsic Plasticity of Layer II/III Pyramidal Neurons in the Primary Motor Cortex.

Motor skill training induces structural plasticity at dendritic spines in the primary motor cortex (M1). To further analyze both synaptic and intrinsic plasticity in the layer II/III area of M1, we subjected rats to a rotor rod test and then prepared acute brain slices. Motor skill consistently improved within 2 days of training. Voltage clamp analysis showed significantly higher α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-d-aspartate (AMPA/NMDA) ratios and miniature EPSC amplitudes in 1-day trained rats compared with untrained rats, suggesting increased postsynaptic AMPA receptors in the early phase of motor learning. Compared with untrained controls, 2-days trained rats showed significantly higher miniature EPSC amplitude and frequency. Paired-pulse analysis further demonstrated lower rates in 2-days trained rats, suggesting increased presynaptic glutamate release during the late phase of learning. One-day trained rats showed decreased miniature IPSC frequency and increased paired-pulse analysis of evoked IPSC, suggesting a transient decrease in presynaptic γ-aminobutyric acid (GABA) release. Moreover, current clamp analysis revealed lower resting membrane potential, higher spike threshold, and deeper afterhyperpolarization in 1-day trained rats-while 2-days trained rats showed higher membrane potential, suggesting dynamic changes in intrinsic properties. Our present results indicate dynamic changes in glutamatergic, GABAergic, and intrinsic plasticity in M1 layer II/III neurons after the motor training.

Does wearing dentures change sensory nerve responses under the denture base?

BACKGROUND: The standard textbook on complete dentures suggests the necessity of relief for the incisive and posterior palatine foramina of denture wearers to prevent the impingement of the nerves and vessels passing through these foramina. However, concrete evidence of the effect of dentures on the sensory function of the nerves underlying dentures is lacking. OBJECTIVE: The study aim was to investigate the influence of denture-induced compression on sensory nerve responses to stimulations. MATERIALS AND METHODS: Only partially edentulous patients of maxillary Kennedy class II who wear dentures (WD) or who never wear dentures (ND) were recruited as participants. The WD and ND groups had 15 participants with a mean age of 66.9 years and 22 participants with a mean age of 60.2 years, respectively. Current perception thresholds (CPTs) at 2000, 250 and 5 Hz, corresponding to A-beta, A-delta and C fibres, respectively, were measured by the Neurometer(®) NS3000 device and compared between groups. The data were analysed by the t-test, the paired t-test and analysis of covariance adjusted for age, sex and thickness of the mucosa. RESULTS: The CPTs showed large differences at 2000 Hz but no differences at the other frequencies when the WD and ND groups were compared. Only the CPT of the edentulous side at 2000 Hz was significantly different between groups. CONCLUSION: Wearing removable partial dentures contributes to changes of responses to stimulations in the large fibre of the sensory nerve underlying the maxillary alveolar ridge.

Survival analysis of mandibular complete dentures with acrylic-based resilient liners.

OBJECTIVE: The purpose of this long-term randomised controlled trial was to compare the longevity of dentures constructed using a conventional acrylic resin (CAR) to that of dentures constructed using an acrylic-based resilient liner (ARL). MATERIALS AND METHODS: The follow-up study was essentially carried out by annual telephone calls to each of the 67 participants. The Kaplan-Meier method and life-table analysis were used for univariate analyses. The Cox proportional-hazards test was used as a final model for statistically adjusting predictor variables such as sex, clinician type, mandibular denture type and age at denture delivery. RESULTS: The denture type was likely to affect the survival time of the dentures, while the sex and clinician type were not. The group using acrylic-based resilient denture liners had twice the risk of having shorter denture-survival times than those using conventional acrylic resin dentures. Younger participants were likely to have a reduced risk of having shorter denture-survival times than older participants. CONCLUSION: We conclude that mandibular complete dentures constructed using ARL are twice as likely as dentures constructed using CAR to have shorter denture survival times, mainly because of material deterioration.

Maxillary sensory nerve responses induced by different types of dentures.

PURPOSE: The purpose of this study was to investigate whether different types of dentures induced different responses to stimulations in sensory nerve underlying the denture-supporting mucosa using current perception threshold (CPT). MATERIALS AND METHODS: The study population comprised 45 complete denture wearers with a mean age of 69.7 years (CD), 30 partial denture wearers (PD) with a mean age of 67.1 years, and 40 dentulous participants with a mean age of 69.0 years (Dent). Current perception threshold (CPT) on the greater palatine nerve at 2000 Hz, 250 Hz, and 5 Hz, corresponding to A-beta, A-delta, and C fibers respectively, were measured by the Neurometer® NS3000 device. The differences CPTs among CD, PD, and Dent groups were analyzed by Kruskal-Wallis test and Mann-Whitney U test with adjusting the multiple comparisons' inflation of type 1 error rate by a Bonferroni correction. RESULTS: CPTs of CD, PD, and Dent group at 2000 Hz were 61.5±45.8, 53.5±25.3, 33.0±11.4 (10(-2) mA) respectively. CPTs of CD, PD, and Dent group at 250 Hz were 29.2±28.2, 20.1±13.2, 14.3±5.9 (10(-2) mA) respectively. CPTs of CD, PD, and Dent group at 5 Hz were 28.9±23.4, 17.8±12.2, 12.2±5.6 (10(-2) mA) respectively. The CPTs at all frequencies increased in the following order: Dent