Furan- and Thiophene-2-Carbonyl Amino Acid Derivatives Activate Hypoxia-Inducible Factor via Inhibition of Factor Inhibiting Hypoxia-Inducible Factor-1.

Induction of a series of anti-hypoxic proteins protects cells during exposure to hypoxic conditions. Hypoxia-inducible factor-α (HIF-α) is a major transcription factor that orchestrates this protective effect. To activate HIF exogenously, without exposing cells to hypoxic conditions, many small-molecule inhibitors targeting prolyl hydroxylase domain-containing protein have been developed. In addition, suppression of factor inhibiting HIF-1 (FIH-1) has also been shown to have the potential to activate HIF-α. However, few small-molecule inhibitors of FIH-1 have been developed. In this study, we synthesized a series of furan- and thiophene-2-carbonyl amino acid derivatives having the potential to inhibit FIH-1. The inhibitory activities of these compounds were evaluated in SK-N-BE(2)c cells by measuring HIF response element (HRE) promoter activity. Several furan- and thiophene-2-carbonyl amino acid derivatives inhibited FIH-1 based on correlations among the docking score of the FIH-1 active site, the chemical structure of the compounds, and biological HIF-α/HRE transcriptional activity.

[Evaluation of the Image Registration Program for Portal Images Using CR and DRR Images in Radiation Therapy].

In this study, computer simulations and experiments were used to verify the accuracy of a two-dimensional image registration program (program) for portal images that we previously developed. The program used a computed radiography cassette system and digitally reconstructed radiography images as planning images for external beam radiation therapy. Using this program, we also investigated the reason two-dimensional automatic image registration images experienced large misregistration in clinical practice using commercial image registration systems. Mutual information and normalized mutual information were used as the registration criteria. To investigate the influence of image background with or without a region of interest (ROI), results of image registrations were compared. Parameters of image registration were defined as translation in the horizontal and vertical directions (x and y, respectively) and rotation (θ) around the axis perpendicular to the x-y plane. There was no significant difference in image registration arising from the difference between mutual information and normalized mutual information. Image registration was improved with a ROI. Regardless of the registration criteria, errors in image registration with a ROI in the experimental study were ≤1.2 mm in directions x and y and ≤1.0 degree in rotation θ. We found that image registration required setting up as close to the planned position as possible.

Severe osteogenesis imperfecta caused by double glycine substitutions near the amino-terminal triple helical region in COL1A2.

Most cases of osteogenesis imperfecta (OI) are caused by heterozygous mutations in COL1A1 or COL1A2, the genes encoding the two type I procollagen alpha chains, proα1 (I) and proα2 (I). We report on a unique case of severe OI, a long term survivor of lethal type II OI, rather than progressively deforming type III, due to double substitutions of glycine residues in COL1A2 (p.Gly208Glu and p.Gly235Asp), located on the same allele. To the best of our knowledge, this is the first example of a patient with double COL1A2 glycine substitution mutations on the same allele. We show for the first time that double COL1A2 glycine substitution mutations located near the amino-terminal triple helical region, which individually are likely to result in mild OI, cause severe OI in combination.

Clinical and Microbiological Characteristics of Bacteremia Caused by Carbapenemase-producing Enterobacterales in Minami Ibaraki Area, Japan.

Although recent propagation of carbapenemase-producing Enterobacterales (CPE) has become a problem worldwide, the picture of CPE infection in Japan has not fully been elucidated. In this study, we examined clinical and microbiological characteristics of invasive CPE infection occurring at 8 hospitals in Minami Ibaraki Area between July 2001 to June 2017. Of 7294 Enterobacterales strains isolated from independent cases of bacteremia and/or meningitis, 10 (0.14%) were CPE (8 Enterobacter cloacae-complex, 1 Escherichia coli, and 1 Edwardsiella tarda）, all of which had the blaIMP-1 gene and susceptible to gentamicin and trimethoprim/sulfamethoxazole. These strains were isolated from 7 adult and 2 infant bacteremia (1 infant patient developed CPE bacteremia twice) after 2007. The most common portal of entry was intravenous catheters. All of the adult patients were recovered, while the infant patients eventually died. Genomic analyses showed that the 8 E. cloacae-complex strains were classified into 5 groups, each of which was exclusively detected in specific facilities at intervals of up to 3 years, suggesting persistent colonization in the facilities. This study showed that invasive CPE infection in the area was rare, caused by IMP-1-type CPE having susceptibility to various antibiotics, and nonfatal among adult patients.

Depicting the semicircular canals with inner-ear MRI: a comparison of the SPACE and TrueFISP sequences.

PURPOSE: To assess the ability of magnetic resonance imaging (MRI) to depict the semicircular canals of the inner ear by comparing results from the sampling perfection with application-optimized contrasts by using different flip angle evolutions (SPACE) sequence with those from the true free induction with steady precession (TrueFISP) sequence. MATERIALS AND METHODS: A 1.5-T MRI system was used to perform an in vivo study of 10 healthy volunteers and 17 patients. A three-point visual score was employed for assessing the depiction of the semicircular canals and facial and vestibulocochlear nerves and the contrast-to-noise ratio (CNR) was computed for the vestibule and pons on images with the SPACE and TrueFIPS sequences. RESULTS: There were no susceptibility artifact-related filling defects with the SPACE sequence. However, the TrueFISP sequence showed filling defects for at least one semicircular canal on both sides in seven cases for healthy subjects and in 10 cases for patients. The CNR with the SPACE sequence was significantly higher than with the TrueFISP sequence (P < 0.05). There was no statistically significant difference in depicting the facial and the vestibulocochlear nerves (P = 0.32). CONCLUSION: For the depiction of the semicircular canal, the SPACE sequence is superior to the TrueFISP sequence.

Japanese boy with maturity-onset diabetes of the young type 3 who developed diabetes at 19 months old.

Maturity-onset diabetes of the young type 3 (MODY3) is caused by hepatocyte nuclear factor 1α gene mutation and is clinically characterized by young onset and insufficient insulin secretion. We report a 19-month-old Japanese boy with a family history of young-onset diabetes who was initially diagnosed with type 1 diabetes. Mutational analysis of the hepatocyte nuclear factor 1α gene revealed a novel heterozygous frameshift mutation (c.593delA p.Lys198fs) resulting in a truncated protein in the patient and his father. The patient was diagnosed as having MODY3 and was successfully treated with insulin glargine. We could not determine the genetic or environmental factors to explain the difference in the age of disease onset within the same family. This is the youngest case of a MODY3 child presenting with overt diabetes. Our experience suggests that clinicians should always consider the possible diagnosis of MODY3 in a diabetic child with a family history of young-onset diabetes and should perform molecular investigations.

Deep learning study on the mechanism of edge artifacts in point spread function reconstruction for numerical brain images.

OBJECTIVE: Non-blinded image deblurring with deep learning was performed on blurred numerical brain images without point spread function (PSF) reconstruction to obtain edge artifacts (EA)-free images. This study uses numerical simulation to investigate the mechanism of EA in PSF reconstruction based on the spatial frequency characteristics of EA-free images. METHODS: In 256 × 256 matrix brain images, the signal values of gray matter (GM), white matter, and cerebrospinal fluid were set to 1, 0.25, and 0.05, respectively. We assumed ideal projection data of a two-dimensional (2D) parallel beam with no degradation factors other than detector response blur to precisely grasp EA using the PSF reconstruction algorithm from blurred projection data. The detector response was assumed to be a shift-invariant and one-dimensional (1D) Gaussian function with 2-5 mm full width at half maximum (FWHM). Images without PSF reconstruction (non-PSF), PSF reconstruction without regularization (PSF) and with regularization of relative difference function (PSF-RD) were generated by ordered subset expectation maximization (OSEM). For non-PSF, the image deblurring with a deep image prior (DIP) was applied using a 2D Gaussian function with 2-5 mm FWHM. The 1D object-specific modulation transfer function (1D-OMTF), which is the ratio of 1D amplitude spectrum of the original and reconstructed images, was used as the index of spatial frequency characteristics. RESULTS: When the detector response was greater than 3 mm FWHM, EA in PSF was observed in GM borders and narrow GM. No remarkable EA was observed in the DIP, and the FWHM estimated from the recovery coefficient for the deblurred image of non-PSF at 5 mm FWHM was reduced to 3 mm or less. PSF of 5 mm FWHM showed higher spatial frequency characteristics than that of DIP up to around 2.2 cycles/cm but was lower than the latter after 3 cycles/cm. PSF-RD showed almost the same spatial frequency characteristics as that of DIP above 3 cycles/cm but was inferior below 3 cycles/cm. PSF-RD has a lower spatial resolution than DIP. CONCLUSIONS: Unlike DIP, PSF lacks high-frequency components around the Nyquist frequency, generating EA. PSF-RD mitigates EA while simultaneously suppressing the signal, diminishing spatial resolution.

Diagnostic and prognostic biomarkers for progressive fibrosing interstitial lung disease.

No biomarkers have been identified in bronchoalveolar lavage fluid (BALF) for predicting fibrosis progression or prognosis in progressive fibrosing interstitial lung disease (PF-ILD). We investigated BALF biomarkers for PF-ILD diagnosis and prognosis assessment. Overall, 120 patients with interstitial pneumonia who could be diagnosed with PF-ILD or non PF-ILD were enrolled in this retrospective study. PF-ILD was diagnosed according to Cottin's definition. All patients underwent bronchoscopy and BALF collection. We evaluated blood and BALF parameters, high-resolution computed tomography (HRCT) patterns, and spirometry data to identify factors influencing PF-ILD diagnosis and prognosis. On univariate logistic analysis, age, sex, the BALF white blood cell fraction (neutrophil, lymphocyte, eosinophil, and neutrophil-to-lymphocyte ratio), BALF flow cytometric analysis (CD8), and an idiopathic pulmonary fibrosis/usual interstitial pneumonia pattern on HRCT were correlated with PF-ILD diagnosis. Multivariate logistic regression analysis revealed that sex (male), age (cut-off 62 years, area under the curve [AUC] 0.67; sensitivity 0.80; specificity 0.47), white blood cell fraction in BALF (NLR, neutrophil, and lymphocyte), and CD8 in BALF (cut-off 34.2; AUC 0.66; sensitivity, 0.74; specificity, 0.62) were independent diagnostic predictors for PF-ILD. In BALF, the NLR (cut-off 8.70, AUC 0.62; sensitivity 0.62; specificity 0.70), neutrophil count (cut-off 3.0, AUC 0.59; sensitivity 0.57; specificity 0.63), and lymphocyte count (cut-off 42.0, AUC 0.63; sensitivity 0.77; specificity 0.53) were independent diagnostic predictors. In PF-ILD patients (n = 77), lactate dehydrogenase (cut-off 275, AUC 0.69; sensitivity 0.57; specificity 0.78), Krebs von den Lungen-6 (cut-off 1,140, AUC 0.74; sensitivity 0.71; specificity 0.76), baseline forced vital capacity (FVC) (cut-off 1.75 L, AUC 0.71; sensitivity, 0.93; specificity, 0.46), and BALF neutrophil ratio (cut-off 6.0, AUC 0.72; sensitivity 0.79; specificity 0.80) correlated with death within 3 years. The BALF cellular ratio, particularly the neutrophil ratio, correlated with the diagnosis and prognosis of PF-ILD. These findings may be useful in the management of patients with interstitial pneumonia.

Aliasing artifacts with the BLADE technique: causes and effective suppression.

PURPOSE: To elucidate the causes of aliasing artifacts with the BLADE technique and clarify the effective suppression methods. MATERIALS AND METHODS: We separately observed the aliasing artifacts of BLADE from features inside and then outside the defined field-of-view (FOV) using phantom studies. The effectiveness of suppressing them with phase oversampling (POS) and presaturation pulses (SAT) was evaluated. Finally, our observations were confirmed for a healthy volunteer. RESULTS: Characteristic aliasing artifacts were observed from both inside and outside the FOV. Those from inside the FOV were sufficiently suppressed by using a POS of 25%, considering the acquisition time prolongation. Those from outside the FOV were nearly suppressed using SAT outside the FOV without selecting needless receiver coils. Aliasing artifacts on the coronal images of the head and neck with a healthy volunteer were completely suppressed by a combination of using a POS of 25% and using SAT on all four sides outside the FOV. CONCLUSION: The characteristic aliasing artifacts of BLADE are caused from both inside and outside the defined FOV. They can be effectively suppressed by a combination of using a POS of 25% and using SAT on all four sides outside the FOV.

Multimodal image registration using IECC as the similarity measure.

PURPOSE: The registration of images from positron emission tomography (PET) to those from magnetic resonance imaging (MRI) using mutual information is usually effective, but fails occasionally because of small region of overlap, low-activity defects in the PET image, difference in spatial resolution, etc. In this article, the authors propose the pixel-based individual entropy correlation coefficient (IECC) as a new, more accurate and more robust registration criterion. METHODS: The authors compare it to the current criteria: Mutual information (MI), normalized mutual information (NMI), and the entropy correlation coefficient (ECC). The anatomical region to be registered was the head. A rigid-body registration was used; no deformation was employed. The authors established the effectiveness of IECC by both simulated data and clinical studies using brain fluorodeoxyglucose (FDG) PET and MRI. Both a normal-activity FDG model and a FDG model with a perfusion defect were used for the PET image. Reconstruction by both filtered backprojection and by ordered subset-expectation maximization was investigated. RESULTS: The mean errors and SDs of IECC were 1.17 +/- 0.85 mm for translation and 1.04 +/- 1.28 degrees for rotation in clinical PET. Those of MI, NMI, and ECC were 1.86 +/- 1.22, 1.86 +/- 0.96, and 1.68 +/- 4 1.05 mm for translations and 1.52 +/- 1.84 degrees, 1.74 +/- 1.68 degrees, and 1.70 +/- 1.90 degrees for rotations. The mean errors and SDs of IECC were 1.56 +/- 0.58 mm for translation and 1.46 +/- 1.66 degrees for rotation in clinical PET model with a 30% perfusion defect. Those of MI, NMI, and ECC were 2.81 +/- 1.41, 2.98 +/- 1.80, and 3.29 +/- 2.08 mm for translations and 3.34 +/- 3.800, 2.87 +/- 3.25 degrees, and 3.04 +/- 3.44 degrees for rotations. The mean errors and SDs of IECC were 1.79 +/- 1.04 mm for translation and 1.64 +/- 1.62 degrees for rotation in clinical PET model with a 50% perfusion defect. Those of MI, NMI, and ECC were 3.49 +/- 1.92, 3.57 +/- 2.22, and 3.49 +/- 1.89 mm for translations and 4.12 +/- 4.24 degrees, 3.62 +/- 4.87 degrees, and 3.44 +/- 3.80 degrees for rotations. The significant differences between IECC and each of the other three criteria were found for displacement misregistration in almost all parameters (p < 0.01). CONCLUSIONS: Accuracy of the IECC criterion was higher than that of the other criteria, usually in a statistically significant way.

Conversion of triphenylphosphine oxide to organophosphorus via selective cleavage of C-P, O-P, and C-H bonds with sodium.

For over half a century, thousands of tons of triphenylphosphine oxide Ph3P(O) have been produced every year from the chemical industries as a useless chemical waste. Here we disclose efficient transformations of Ph3P(O) with cheap resource-abundant metallic sodium finely dispersed in paraffin oil. Ph3P(O) can be easily and selectively transformed to three reactive organophosphorus intermediates-sodium diphenylphosphinite, sodium 5H-benzo[b]phosphindol-5-olate and sodium benzo[b]phosphindol-5-ide-that efficiently give the corresponding functional organophosphorus compounds in good yields. These functional organophosphorus compounds are difficult to prepare but highly industrially useful compounds. This may allow Ph3P(O) to be used as a precious starting material for highly valuable phosphorus compounds.

Estimation of cell membrane permeability and intracellular diffusion coefficient of human gray matter.

The signal intensity of diffusion-weighted imaging (DWI) is sensitive to the intra- and extracellular diffusion coefficient of water and cell membrane permeability. We applied a method we proposed in previous papers to estimate noninvasively the membrane permeability and intracellular diffusion coefficient of normal human brain (gray matter) in 3 normal volunteers. We theoretically compared predicted signals and experiment results using a 1.5-tesla magnetic resonance (MR) imaging system. We acquired images using an echo planar imaging (EPI) sequence, applying motion-probing gradient (MPG) pulses in 3 directions. We periodically performed numerical simulations for various combinations of membrane permeability and intracellular diffusion coefficients using the finite-difference method. By minimizing the difference between signals obtained experimentally and those from numerical simulation, we could estimate membrane permeability (76+/-9 mm2/s mum) and intracellular diffusion coefficient (1.0+/-0.0 mm2/s) for the human brain. The estimated membrane permeability was the criterion value for diagnosing disease in gray matter.

[Incident Photon Number and Reconstructed Linear Attenuation Coefficients in Iterative CT Image Reconstruction].

[Purpose] The iterative CT image reconstruction (IR) method has been successfully incorporated into commercial CT scanners as a means to promote low-dose CT with high image quality. However, the algorithm of the IR method has not been made publicly available by scanner manufacturers. Kudo reviewed the fundamentals of IR methods on the basis of the articles published by the joint research group of each manufacture that were released before and during product development (Med Imag Tech 32: 239-248, 2014). According to this review, the object function of the IR method consists of the data fidelity term (likelihood) and the regularization term. The regularization term plays a significant role in the IR method; however, it has not been clarified whether or not the variance of projection data should be included into the likelihood to act the regularization term effectively. Our purpose in this study was to investigate the relationship of the incident photon number and the reconstructed linear attenuation coefficients of the IR method by numerical experiments.[Methods] We assumed the X-ray beam was a pencil beam, and the system matrix was given by the line integral of linear attenuation coefficients because we focused on the accuracy of the reconstructed linear attenuation coefficients in the ideal photon detection system equations given by Kudo. Total variation (TV) and the relative difference function were used for regularization of the IR method. Three kinds of numerical phantoms with 256×256 pixels were used as test images. Poisson noise was added to the projection data with 256 linear sampling and 256 views over 180°. The accuracy of reconstructed linear attenuation coefficients was evaluated by the mean reconstructed value within a region of interest (ROI) and the relative root mean square errors (%RMSEs) to the object image.[Results] The linear attenuation coefficients were reconstructed accurately by the IR method including the variance of projection data into the likelihood in comparison with the IR method without including the variance. When the incident photon number ranged from 100 to 2000 for the object having a mean linear attenuation coefficient of 0.067 to 0.087 cm-1, the reconstructed linear attenuation coefficients in ROI were close to the true values. However, when the incident photon number was 50, both the accuracy and the uniformity of reconstructed images decreased.[Discussion] From the viewpoint of the visual observation, the image quality of the IR method was superior to that of the filtered back-projection (FBP) image processed with the Gaussian filter of FWHM equal to 3 pixels. For the object with a high absorber, the FBP gives linear attenuation coefficients that were lower than the true values. This phenomenon was also observed in the IR method. The projection data of CT were given by the logarithm operation of the ratio between the incident photon and the transmitted photon numbers. If the transmitted photon number happened to be equal to 0 owing to the influence of noise, it was held to a value of 1 to avoid the logarithm of zero. This process caused an error of the linear attenuation coefficients.[Conclusion] The variance of projection data should be included into the likelihood to act the regularization term effectively in the IR method.

An iterative reconstruction using median root prior and anatomical prior from the segmented mu-map for count-limited transmission data in PET imaging.

OBJECTIVE: Recently, whole-body positron emission tomography (PET) examination has greatly developed. To reduce the overall examination time, the transmission scan has been increasingly shortened. Many noise-reduction processes have been developed for count-limited transmission data. Segmented attenuation correction (SAC) is one method by which the pixel values of transmission image are transformed into several groups. The median root prior-ordered subset convex (MRP-OSC) algorithm is another method that is applicable to control the noise level on the basis that the change of the pixel value is locally monotonous. This article presents an alternative approach on the basis of the Bayesian iterative reconstruction technique incorporating a median prior and an anatomical prior from the segmented mu-map for count-limited transmission data. METHODS: The proposed method is based on the Bayesian iterative reconstruction technique. The median prior and the anatomical prior are represented as two Gibbs distributions. The product of these distributions was used as a penalty function. RESULTS: In the thorax simulation study, the mean square error from the true transmission image of the presented method (5.74 x 10(-5)) was lower than MRP-OSC (6.72 x 10(-5)) and SAC (7.08 x 10(-5)). The results indicate that the noise of the image reconstructed from the proposed technique was decreased more than that of MRP-OSC without segmentation error such as that of an SAC image. In the thorax phantom study, the emission image that was corrected using the proposed technique displayed little noise and bias (27.42 +/- 0.96 kBq/ml, calculated from a region of interest drawn on the liver of the phantom); it was very similar to the true value (28.0 kBq/ml). CONCLUSIONS: The proposed method is effective for reducing propagation of noise from transmission data to emission data without loss of the quantitative accuracy of the PET image.

[Influence of count rate on image quality in three-dimensional PET acquisition].

OBJECTIVE: In FDG-PET examinations, optimization of the injected dose and duration of acquisition are important in determining the physical performance of PET or the PET/CT scanner. This study was intended to elucidate the influence of count rate on image quality. METHODS: Three PET/CT scanners (Biograph sensation 16, Discovery ST, and Aquiduo) were used in this study. Body and scatter phantoms (NEMA 2001) and a cylindrical phantom (for QC use) were also used. Data acquisition was performed repeatedly for about 6 h to achieve a fixed 15 million counts of true plus scatter. The count rate performance and image quality (signal-to-noise ratio and contrast) of each frame were analyzed after data acquisition. The relationship between the count rate and image quality was also analyzed. RESULTS: A positive correlation between the random fraction (ratio of random to prompt count rate) and signal-to-noise ratio was found in all PET/CT scanners, but with differing effects of the count rate's influence on image quality. Image contrast was not correlated with count rate. CONCLUSION: Acquisition parameters must be determined by considering each scanner's effect on how count rate influences image quality.