Relationship between Pulmonary Gas Exchange Function and Brain Uptake Dynamics Investigated with Hyperpolarized 129Xe MR Imaging and Spectroscopy in a Murine Model of Chronic Obstructive Pulmonary Disease.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is a complex multisystem disease associated with comorbidities outside the lungs. The aim of this study was to measure changes in metrics of pulmonary gas exchange function and brain tissue metabolism in a mouse model of COPD using hyperpolarized 129Xe (HP 129Xe) MRI/MR spectroscopy (MRS) and investigate the relationship between the metrics of lung and brain. METHODS: COPD phenotypes were induced in 15 mice by 6-week administration of cigarette smoke extract (CSE) and lipopolysaccharide (LPS). A separate negative control (NC) group was formed of 6 mice administered with saline for 6 weeks. After these 6-week administrations, the pulmonary gas exchange function parameter fD (%) and the rate constant, α (s-1), which are composed of the cerebral blood flow Fi and the longitudinal relaxation rate 1/T1i in brain tissue, were evaluated by HP 129Xe MRI/MRS. RESULTS: The fD of CSE-LPS mice was significantly lower than that of NC mice, which was in parallel with an increase in bronchial wall thickness. The α in the CSE-LPS mice decreased with the decrease of fD in contrast to the trend in the NC mice. To further elucidate the opposed trend, the contribution of T1i was separately determined by measuring Fi. The T1i in the CSE-LPS mice was found to correlate negatively with fD as opposed to the positive trend in the NC mice. The opposite trend in T1i between CSE-LPS and NC mice suggests hypoxia in the brain, which is induced by the impaired oxygen uptake as indicated by the reduced fD. CONCLUSION: This study demonstrates the feasibility of using HP 129Xe MRI/MRS to study pathological mechanisms of brain dysfunction in comorbidities with COPD.

Sexual dimorphism of the human fetal pelvis exists at the onset of primary ossification.

Human adolescent and adult skeletons exhibit sexual dimorphism in the pelvis. However, the degree of sexual dimorphism of the human pelvis during prenatal development remains unclear. Here, we performed high-resolution magnetic resonance imaging-assisted pelvimetry on 72 human fetuses (males [M]: females [F], 34:38; 21 sites) with crown-rump lengths (CRL) of 50-225 mm (the onset of primary ossification). We used multiple regression analysis to examine sexual dimorphism with CRL as a covariate. Females exhibit significantly smaller pelvic inlet anteroposterior diameters (least squares mean, [F] 8.4 mm vs. [M] 8.8 mm, P = 0.036), larger subpubic angle ([F] 68.1° vs. [M] 64.0°, P = 0.034), and larger distance between the ischial spines relative to the transverse diameters of the greater pelvis than males. Furthermore, the sacral measurements indicate significant sex-CRL interactions. Our study suggests that sexual dimorphism of the human fetal pelvis is already apparent at the onset of primary ossification.

In Vivo and Post-mortem Comparisons of IVIM/Time-dependent Diffusion MR Imaging Parameters in Melanoma and Breast Cancer Xenograft Models.

PURPOSE: We aimed to investigate the changes in intravoxel incoherent motion (IVIM) and diffusion parameters between in vivo and post-mortem conditions and the time dependency of these parameters using two different mouse tumor models with different vessel lumen sizes. METHODS: Six B16 and six MDA-MB-231 xenograft mice were scanned using 7 Tesla MRI under both in vivo/post-mortem conditions. Diffusion weighted imaging with 17 b-values (0-3000 s/mm2) were obtained at two diffusion times (9 and 27.6 ms). The shifted apparent diffusion coefficient (sADC) using 2 b-values (200 and 1500 s/mm2), non-Gaussian diffusion and IVIM parameters (ADC0, K, fIVIM) were estimated at each of the diffusion times. The results were evaluated by repeated measures two-way analysis of variance and post hoc Bonferroni test. RESULTS: In B16 tumors, fIVIM significantly decreased with post-mortem conditions (from 12.6 ± 6.5% to 5.2 ± 1.9%, P < 0.05 at long diffusion time; from 11.0 ± 2.4% to 4.6 ± 2.7%, P < 0.05 at short diffusion time). In MDA-MB-231 tumors, fIVIM also significantly decreased (from 8.8 ± 3.8% to 2.6 ± 1.1%, P < 0.05 at long; from 7.9 ± 5.4% to 2.9 ± 1.1%, P < 0.05 at short). No diffusion time dependency was observed (P = 0.59 in B16 and P = 0.77 in MDA-MB-231). The sADC and ADC0 values tended to decrease and the K value tended to increase after sacrificing and when increasing the diffusion time. CONCLUSION: The fIVIM values dropped after sacrificing, confirming that IVIM MRI is a promising quantitative parameter to evaluate blood microcirculation. The presence of residual post-mortem fIVIM values suggested that the influence of water molecule diffusion in the blood lumen may contribute to the IVIM effect. Diffusion MRI parameter's time dependency and those changes after sacrificing could possibly provide additional insights into diffusion hindrance mechanisms.

Formation of tendinous intersections in the human fetal rectus abdominis.

Previous studies have poorly described the initial development process of the tendinous intersections of the rectus abdominis muscle (RAM). The present study aimed to observe the formation of tendinous intersections in the RAM during the early fetal period using diffusion tensor imaging (DTI). Fifteen human fetal specimens (crown-rump length [CRL]: 39.5-93.7 mm) were selected. Three-dimensional measurements revealed that Zone-4 (i.e., the zone between the pubic symphysis and the caudal base of the umbilical ring in the RAM) had a smaller width and was thicker than Zone-1 and Zone-2 (i.e., the zones between the costal arch and the cranial base of the umbilical ring) and Zone-3 (i.e., the zone at the umbilical ring). Characteristics of tendinous intersections in the RAM during the early fetal period were assessed according to number, size, type, laterality, and sex. The mean number of tendinous intersections on both sides was 3.1 (range: 2.0-4.0), and 21% of specimens had only two tendinous intersections, which was higher than that reported in previous adult studies. The present data suggest that the formation of tendinous intersections was still in progress in specimens with two tendinous intersections in the RAM and that the third tendinous intersection was formed in Zone-2. Ordinal logistic regression via generalized estimating equations revealed that the odds for a higher type of tendinous intersections in Zone-1 and Zone-2 were significantly higher than those in Zone-4 (adjusted odds ratio: 14.85, 8.84). The odds for the presence of incomplete types (tendinous intersections that could not completely transverse the RAM) in Zone-3 were significantly higher than those in Zone-1 (adjusted odds ratio: 7.4). The odds for missing tendinous intersections in Zone-4 were significantly higher than those in Zone-1 (adjusted odds ratio: 20.5). These zonal differences in the formation of tendinous intersections were consistent with those observed in previous adult studies. In this study, DTI detected tendinous intersections in a sample with a CRL of 45.8 mm (approximately 11 weeks of gestation), which is earlier than that in previous histological findings, indicating that the RAM does not have mature tendinous intersections until the 17th week of gestation. In conclusion, DTI could detect the premature differentiation of tendinous intersection formation. Our data may aid in elucidating the developmental processes of tendinous intersections in the RAM.

Regional differences in the umbilical vein and ductus venosus at different stages of normal human development.

During the fetal period, oxygenated blood from the placenta flows through the umbilical vein (UV), portal sinus, ductus venosus (DV), and inferior vena cava (IVC) to the heart. This venous route varies regionally in many aspects. Herein, we sought to characterize the venous route's morphological features and regional differences during embryonic and early-fetal periods. Twenty-nine specimens were selected for high-resolution digitized imaging; 18 embryos were chosen for histological analysis. The venous route showed a primitive, large, S-shaped curved morphology with regional narrowing and dilation at Carnegie stage (CS) 15. Regional differences in vessel-wall differentiation became apparent from approximately CS20. The vessel wall was poorly developed in most DV parts; local vessel-wall thickness at the inlet was first detected at CS20. The lumen of the venous route changed from a nonuniform shape to a relatively round and uniform morphology after CS21. During the early-fetal period, two large bends were observed around the passage of the umbilical ring and at the inlet of the liver. The length ratio of the extrahepatic UV to the total venous route increased. The sectional area gradually increased during embryonic development, whereas differences in sectional area between the DV, UV, and IVC became more pronounced in the early-fetal period. Furthermore, differences in the sectional area between the narrowest part of the DV and other hepatic veins and the transverse sinus became more pronounced. In summary, the present study described morphological, morphometric, and histological changes in the venous route throughout embryonic and early-fetal development, clarifying regional characteristics.

Pyramidalis muscle formation during human embryonic and early fetal periods.

The pyramidalis muscle (PM) is a paired small triangular muscle of the anterior abdominal wall; however, its physiological significance is unclear. Recent studies have failed to detect this muscle during embryonic period. Hence, the present study aimed to determine the time when PM is emerging and reveal its features using high-resolution magnetic resonance imaging. Fourteen embryos between Carnegie stage (CS)18 and CS23 and 59 fetuses (crown-rump length: 39.5-185.0 mm) were selected for this study. The PM was first detected in one of the three samples at CS20. It was detected in five of the seven samples (71.4%) between CS21 and CS23. Forty-eight samples (81.4%) at early fetal period had PMs on both the right and left sides, and 3 (5.1%) had it only on the right side. Eight samples (13.6%) had no PMs. No side-differences or sexual dimorphisms were detected. The PM length was larger than the width in most samples, although the length/width ratio varied among the samples. The PM/rectus abdominis muscle length and PM/umbilicus-pubic symphysis length ratios were almost constant, irrespective of the crown-rump length. The PM was located ventrally inferior to the rectus abdominis and closer to the medial muscle groups of the lower limb than the rectus abdominis. The present study demonstrated that PM formation occurred in the late embryonic period, and that the frequency, side differences, sex dimorphism, and spatial position of the PM in the early fetal period were similar to those in adults.

Morphogenesis of the pulmonary vein and left atrial appendage in human embryos and early fetuses.

The left atrium wall has several origins, including the body, appendage, septum, atrial-ventricular canal, posterior wall, and venous component. Here, we describe the morphogenesis of left atrium based on high-resolution imaging (phase-contrast X-ray computed tomography and magnetic resonance imaging). Twenty-three human embryos and 19 fetuses were selected for this study. Three-dimensional cardiac images were reconstructed, and the pulmonary veins and left atrium, including the left atrial appendage, were evaluated morphologically and quantitatively. The positions of the pericardial reflections were used as landmarks for the border of the pericardial cavity. The common pulmonary vein was observed in three specimens at Carnegie stages 17-18. The pericardium was detected at the four pulmonary veins (left superior, left inferior, right superior, and right inferior pulmonary veins) at one specimen at Carnegie stage 18 and all larger specimens, except the four samples. Our results suggest that the position of the pericardial reflections was determined at two pulmonary veins (right and left pulmonary vein) and four pulmonary veins almost simultaneously when the dorsal mesocardial connection between the embryo and heart regressed. The magnetic resonance images and reconstructed heart cavity images confirmed that the left atrium folds were present at the junction between the body and venous component. Three-dimensional reconstruction showed that the four pulmonary veins entered the dorsal left atrium tangentially from the lateral to the medial direction. More specifically, the right pulmonary veins entered at a greater angle than the left pulmonary veins. The distance between the superior and inferior pulmonary veins was shorter than that between the left and right pulmonary veins. Three-dimensional reconstruction showed that the venous component increased proportionally with growth. No noticeable differences in discrimination between the right and left parts of the venous component emerged, while the junction between the venous component and body gradually became inconspicuous but was still recognizable by the end of the observed early fetal period. The left superior pulmonary vein had the smallest cross-sectional area and most flattened shape, whereas the other three were similar in area and shape. The left atrial appendage had a large volume in the center and extended to the periphery as a lobe-like structure. The left atrial appendage orifice increased in the area and tended to become flatter with growth. The whole left atrium volume^(1/3) increased almost proportionally with growth, parallel to the whole heart volume. This study provided a three-dimensional and quantitative description of the developmental process of the left atrium, comprising the venous component and left atrial appendage formation, from the late embryonic to the early fetal stages.

Quantification of Cerebral Glucose Concentrations via Detection of the H1-α-Glucose Peak in 1 H MRS at 7 T.

BACKGROUND: Sensitive detection and quantification of cerebral glucose is desired. PURPOSE: To quantify cerebral glucose by detecting the H1-α-glucose peak at 5.23 ppm in 1 H magnetic resonance spectroscopy at 7 T. STUDY TYPE: Prospective. SUBJECTS: Twenty-eight non-fasted healthy subjects (aged 20-28 years). FIELD STRENGTH/SEQUENCE: Short echo time stimulated echo acquisition mode (short-TE STEAM) and semi-localized by adiabatic selective refocusing (semi-LASER) at 7 T. ASSESSMENT: Single voxel spectra were obtained from the posterior cingulate cortex (27-mL) using a 32-channel head coil. The H1-α-glucose peak in the spectrum with retrospective removal of the residual water peak was fitted using LCModel with a glucose basis set of only the H1-α-glucose peak. Conventional spectral analysis was performed with a glucose basis set of a full spectral pattern of glucose, also. Fitting precision was evaluated with Cramér-Rao lower bounds (CRLBs). The repeatability of glucose quantification via the semi-LASER sequence was tested. STATISTICAL TESTS: Paired or Welch's t-test were used for normally distributed values. A P value of <0.05 was considered significant. The repeatability of measures was analyzed using coefficient of variation (CV). RESULTS: Removal of the residual water peak improved the flatness and stability of baselines around the H1-α-glucose peak and reduced CRLBs for fitting the H1-α-glucose peak. The semi-LASER sequence was superior to the short-TE STEAM in the higher signal-to-noise ratio of the H1-α-glucose peak (mean ± SD 7.9 ± 2.5, P < 0.001). The conventional analysis overfitted the H1-α-glucose peak. The individual CVs of glucose quantification by detecting the H1-α-glucose peak were smaller than the corresponding CRLBs. DATA CONCLUSION: Cerebral glucose concentration is quantitated to be 1.07 mM by detecting the H1-α-glucose peak in the semi-LASER spectra. Despite requiring long scan times, detecting the H1-α-glucose peak allows true glucose quantification free from the influence of overlapping taurine and macromolecule signals. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY STAGE: 1.

KUS121, a VCP modulator, has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular ATP levels.

AIMS: As heart failure (HF) progresses, ATP levels in myocardial cells decrease, and myocardial contractility also decreases. Inotropic drugs improve myocardial contractility but increase ATP consumption, leading to poor prognosis. Kyoto University Substance 121 (KUS121) is known to selectively inhibit the ATPase activity of valosin-containing protein, maintain cellular ATP levels, and manifest cytoprotective effects in several pathological conditions. The aim of this study is to determine the therapeutic effect of KUS121 on HF models. METHODS AND RESULTS: Cultured cell, mouse, and canine models of HF were used to examine the therapeutic effects of KUS121. The mechanism of action of KUS121 was also examined. Administration of KUS121 to a transverse aortic constriction (TAC)-induced mouse model of HF rapidly improved the left ventricular ejection fraction and improved the creatine phosphate/ATP ratio. In a canine model of high frequency-paced HF, administration of KUS121 also improved left ventricular contractility and decreased left ventricular end-diastolic pressure without increasing the heart rate. Long-term administration of KUS121 to a TAC-induced mouse model of HF suppressed cardiac hypertrophy and fibrosis. In H9C2 cells, KUS121 reduced ER stress. Finally, in experiments using primary cultured cardiomyocytes, KUS121 improved contractility and diastolic capacity without changing peak Ca2+ levels or contraction time. These effects were not accompanied by an increase in cyclic adenosine monophosphate or phosphorylation of phospholamban and ryanodine receptors. CONCLUSIONS: KUS121 ameliorated HF by a mechanism totally different from that of conventional catecholamines. We propose that KUS121 is a promising new option for the treatment of HF.

Femoral posture during embryonic and early fetal development: An analysis using landmarks on the cartilaginous skeletons of ex vivo human specimens.

The pre-axial border medially moves between the fetal and early postnatal periods, and the foot sole can be placed on the ground. Nonetheless, the precise timeline when this posture is achieved remains poorly understood. The hip joint is the most freely movable joint in the lower limbs and largely determines the lower-limb posture. The present study aimed to establish a timeline of lower-limb development using a precise measurement of femoral posture. Magnetic resonance images of 157 human embryonic samples (Carnegie stages [CS] 19-23) and 18 fetal samples (crown rump length: 37.2-225 mm) from the Kyoto Collection were obtained. Three-dimensional coordinates of eight selected landmarks in the lower limbs and pelvis were used to calculate the femoral posture. Hip flexion was approximately 14° at CS19 and gradually increased to approximately 65° at CS23; the flexion angle ranged from 90° to 120° during the fetal period. Hip joint abduction was approximately 78° at CS19 and gradually decreased to approximately 27° at CS23; the average angle was approximately 13° during the fetal period. Lateral rotation was greater than 90° at CS19 and CS21 and decreased to approximately 65° at CS23; the average angle was approximately 43° during the fetal period. During the embryonic period, three posture parameters (namely, flexion, abduction, and lateral rotation of the hip) were linearly correlated with each other, suggesting that the femoral posture at each stage was three-dimensionally constant and exhibited gradual and smooth change according to growth. During the fetal period, these parameters varied among individuals, with no obvious trend. Our study has merits in that lengths and angles were measured on anatomical landmarks of the skeletal system. Our obtained data may contribute to understanding development from anatomical aspects and provide valuable insights for clinical application.

Three-dimensional morphogenesis of the human diaphragm during the late embryonic and early fetal period: Analysis using T1-weighted and diffusion tensor imaging.

A precise understanding of human diaphragm development is essential in fetal medicine. To our knowledge, no previous study has attempted a three-dimensional (3-D) analysis and evaluation of diaphragmatic morphogenesis and development from the embryonic to the early fetal period. This study aimed to evaluate the morphogenesis and fibrous architecture of the developing human diaphragm during the late embryonic and early fetal periods. Fifty-seven human embryos and fetuses (crown-rump length [CRL] = 8-88 mm) preserved at the Congenital Anomaly Research Center of Kyoto University and Shimane University were analyzed. 3-D morphogenesis and fiber orientation of the diaphragm were assessed using phase-contrast X-ray computed tomography, T1-weighted magnetic resonance imaging (T1W MRI), and diffusion tensor imaging (DTI). T1W MR images and DTI scans were obtained using a 7-T MR system. The diaphragm was completely closed at Carnegie stage (CS) 20 and gradually developed a dome-like shape. The diaphragm was already in contact with the heart and liver ventrally in the earliest CS16 specimen observed, and the adrenal glands dorsally at CS19 or later. In the fetal period, the diaphragm contacted the gastric fundus in samples with a CRL ≥41 mm, and the spleen in samples with a CRL ≥70 mm. The relative position of the diaphragm with reference to the vertebrae changed rapidly from CS16 to CS19. The most cranial point of the diaphragm was located between the 4th and 8th thoracic vertebrae, regardless of fetal growth, in samples with a CRL of ≥16 mm. Diaphragmatic thickness was nearly uniform (0.15-0.2 mm) across samples with a CRL of 8-41 mm. The sternal, costal, lumbar parts, and the area surrounding the esophageal hiatus thickened with growth in samples with a CRL of ≥46 mm. The thickness at the center of the diaphragm and the left and right hemidiaphragmatic domes did not increase with growth. Tractography showed that the fiber orientation of the sternal, costal, and lumbar parts became more distinct as growth progressed in CS19 or later. All fibers in the costal and lumbar regions ran toward the left and right hemidiaphragmatic domes, except for those running to the caval opening and esophageal hiatus. The fiber orientation patterns from the right and left crura surrounding the esophageal hiatus were classified into three types. Distinct fiber directions between the costal and sternal and between the costal and lumbar diaphragmatic parts were observable in samples with a CRL of ≥46 mm. Anterior costal and sternal fibers ran toward the center. Fiber tracts around the center and the left and right hemidiaphragmatic domes; between the costal and lumbar orientations; and between the costal and sternal orientations showed a tendency for decreasing fractional anisotropy values with fetal growth and showed less density than other areas. In conclusion, we used 3-D thickness assessment and DTI tractography to identify qualitative changes in the muscular and tendonous regions of the diaphragm during the embryonic and early fetal periods. This study provides information on normal human diaphragm development for the progression of fetal medicine and furthering the understanding of congenital anomalies.

Tentorium cerebelli formation during human embryonic and early fetal development.

The morphologies of the fetal tentorium cerebelli (TC) and brain influence each other during development. This study aimed to analyze and more comprehensively understand the three-dimensional morphogenesis of the TC and fetal brain. We examined magnetic resonance imaging from 64 embryonic and fetal specimens (crown-rump length range, 9.2-225 mm). During the embryonic period, the lateral folds of the TC elongated to traverse the middle part of the midbrain. The TC and falx cerebri appeared separated, and no invaginations at the parieto-occipital region were observed. In the early fetal period, the cerebrum covered approximately half of the midbrain. The separation of the dural limiting layer at the parieto-occipital region widened from the posterior cerebrum to the cranial cerebellum. The lateral folds of the TC were spread between its tip, continuous with the falx cerebri, and its base plane, located between the midbrain and rostral hindbrain. Differences in the TC components' growth directions gradually diminished as the cerebrum covered the midbrain. We observed rotation of the TC at its median section according to its growth, which ceased in the middle fetal period. The brainstem and cerebellum extended inferiorly via differential growth, with the cerebrum covering them superiorly. The morphology of the TC curved to conform to the cerebellar and cerebral surfaces. Our present study suggests that factors affecting TC morphology differ between the early and middle fetal periods. Present data provided a more comprehensive view of TC formation according to developmental stage.

Targeted Imaging of Lung Cancer with Hyperpolarized 129Xe MRI Using Surface-Modified Iron Oxide Nanoparticles as Molecular Contrast Agents.

Hyperpolarized 129Xe (HP 129Xe) MRI enables functional imaging of various lung diseases but has been scarcely applied to lung cancer imaging. The aim of this study is to investigate the feasibility of targeted imaging of lung cancer with HP 129Xe MRI using surface-modified iron oxide nanoparticles (IONPs) as molecular targeting contrast agents. A mouse model of lung cancer (LC) was induced in nine mice by intra-peritoneal injection of urethane. Three months after the urethane administration, the mice underwent lung imaging with HP 129Xe MRI at baseline (0 h). Subsequently, the LC group was divided into two sub-groups: mice administered with polyethylene glycol-coated IONPs (PEG-IONPs, n = 4) and folate-conjugated dextran-coated IONPs (FA@Dex-IONPs, n = 5). The mice were imaged at 3, 6, and 24 h after the intravenous injection of IONPs. FA@Dex-IONPs mice showed a 25% reduction in average signal intensity at cancer sites at 3 h post injection, and a 24% reduction at 24 h post injection. On the other hand, in PEG-IONPs mice, while a signal reduction of approximately 28% was observed at cancer sites at 3 to 6 h post injection, the signal intensity was unchanged from that of the baseline at 24 h. Proton MRI of LC mice (n = 3) was able to detect cancer five months after urethane administration, i.e., later than HP 129Xe MRI (3 months). Furthermore, a significant decrease in averaged 1H T2 values at cancer sites was observed at only 6 h post injection of FA@Dex-IONPs (p < 0.05). As such, the targeted delivery of IONPs to cancer tissue was successfully imaged with HP 129Xe MRI, and their surface modification with folate likely has a high affinity with LC, which causes overexpression of folate receptors.

Thioredoxin deficiency increases oxidative stress and causes bilateral symmetrical degeneration in rat midbrain.

Thioredoxin, encoded by Txn1, acts as a critical antioxidant in the defense against oxidative stress by regulating the dithiol/disulfide balance of interacting proteins. The role of thioredoxin in the central nervous system (CNS) is largely unknown. A phenotype-driven study of N-ethyl-N-nitrosourea-mutated rats with wild-running seizures revealed the importance of Txn1 mutations in CNS degeneration. Genetic mapping identified Txn1-F54L in the epileptic rats. The insulin-reducing activity of Txn1-F54L was approximately one-third of that of the wild-type (WT). Bilateral symmetrical vacuolar degeneration in the midbrain, mainly in the thalamus and the inferior colliculus, was observed in the Txn1-F54L rats. The lesions displayed neuronal and oligodendrocytic cell death. Neurons in Txn1-F54L rats showed morphological changes in the mitochondria. Vacuolar degeneration peaked at five weeks of age, and spontaneous repair began at seven weeks. The TUNEL assay showed that fibroblasts derived from homozygotes were susceptible to cell death under oxidative stress. In five-week-old WT rats, energy metabolism in the thalamus was significantly higher than that in the cerebral cortex. In conclusion, in juvenile rats, Txn1 seems to play an essential role in reducing oxidative stress in the midbrains with high energy metabolism.

Three-dimensional visualization and quantitative analysis of embryonic and fetal thigh muscles using magnetic resonance and phase-contrast X-ray imaging.

The musculoskeletal system around the human hip joint has acquired a suitable structure for erect bipedal walking. However, little is known about the process of separation and maturation of individual muscles during the prenatal period, when muscle composition is acquired. Understanding the maturation process of the normal musculoskeletal system contributes to elucidating the acquisition of bipedal walking in humans and to predicting normal growth and detecting congenital muscle disorders and anomalies. In this study, we clarify the process of thigh muscle maturation from the embryonic stage to the mid-fetal stage using serial sections, phase-contrast X-ray computed tomography, and magnetic resonance imaging. We also provide a 4D atlas of human thigh muscles between 8 and 23 weeks of gestation. As a result, we first show that muscle separation in the lower thigh tends to progress from the superficial to the deep layers and that all musculoskeletal components are formed by Carnegie Stage 22. Next, we show that femur and muscle volume grow in correlation with crown-rump length. Finally, we show that the anterior, abductor, and posterior muscle groups in the thigh contain a high percentage of monoarticular muscle volume by the end of the embryonic period. This ratio approaches that of adult muscle composition during normal early fetal development and is typical of bipedal walking. This study of fetal muscle composition suggests that preparation for postnatal walking may begin in early fetal period.

Morphometric analysis of secondary palate development in human embryos.

Rapid shelf elevation and contact of the secondary palate and fusion reportedly occur due to a growth-related equilibrium change in the structures within the oro-nasal cavity. This study aimed to quantitatively evaluate complex three-dimensional morphological changes and their effects on rapid movements, such as shelf elevation and contact, and fusion. Morphological changes during secondary palate formation were analyzed using high-resolution digitalized imaging data (phase-contrast X-ray computed tomography and magnetic resonance images) obtained from 22 human embryonic and fetal samples. The three-dimensional images of the oro-nasal structures, including the maxilla, palate, pterygoid hamulus, tongue, Meckel's cartilage, nasal cavity, pharyngeal cavity, and nasal septum, were reconstructed manually. The palatal shelves were not elevated in all the samples at Carnegie stage (CS)21 and CS22 and in three samples at CS23. In contrast, the palatal shelves were elevated but not in contact in one sample at CS23. Further, the palatal shelves were elevated and fused in the remaining four samples at CS23 and all three samples from the early fetal period. For each sample, 70 landmarks were subjected to Procrustes and principal component (PC) analysis. PC-1 accounted for 67.4% of the extracted gross changes before and after shelf elevations. Notably, the PC-1 values of the negative and positive value groups differed significantly. The PC-2 value changed during the phases in which the change in the PC-1 value was unnaturally slow and stopped at CS22 and the first half of CS23. This period, defined as the "approach period", corresponds to the time before dynamic changes occur as the palatal shelves elevate, the tongue and mandibular tip change their position and shape, and secondary palatal shelves contact and fuse. During the "approach period", measurements of PC-2 changes showed that structures on the mandible (Meckel's cartilage and tongue) and maxilla (palate and nasal cavity) did not change positions, albeit both groups of structures appeared to be compressed anterior-posteriorly. However, during and after shelf elevation, measurements of PC-1 changes showed significant changes between maxillary and mandibular structures, particularly positioning of the shelves above the tongue and protrusion of the tongue and mandible. These results suggest an active role for Meckel's cartilage growth in repositioning the tongue to facilitate shelf elevation. The present data representing three distinct phases of secondary palate closure in humans can advance the understanding of morphological growth changes occurring before and after the horizontal positioning of palatal shelves and their fusion to close the secondary palate in humans successfully.

Excess intracellular ATP causes neuropathic pain following spinal cord injury.

Intractable neuropathic pain following spinal cord injury (NP-SCI) reduces a patient's quality of life. Excessive release of ATP into the extracellular space evokes neuroinflammation via purinergic receptor. Neuroinflammation plays an important role in the initiation and maintenance of NP. However, little is known about whether or not extracellular ATP cause NP-SCI. We found in the present study that excess of intracellular ATP at the lesion site evokes at-level NP-SCI. No significant differences in the body weight, locomotor function, or motor behaviors were found in groups that were negative and positive for at-level allodynia. The intracellular ATP level at the lesion site was significantly higher in the allodynia-positive mice than in the allodynia-negative mice. A metabolome analysis revealed that there were no significant differences in the ATP production or degradation between allodynia-negative and allodynia-positive mice. Dorsal horn neurons in allodynia mice were found to be inactivated in the resting state, suggesting that decreased ATP consumption due to neural inactivity leads to a build-up of intracellular ATP. In contrast to the findings in the resting state, mechanical stimulation increased the neural activity of dorsal horn and extracellular ATP release at lesion site. The forced production of intracellular ATP at the lesion site in non-allodynia mice induced allodynia. The inhibition of P2X4 receptors in allodynia mice reduced allodynia. These results suggest that an excess buildup of intracellular ATP in the resting state causes at-level NP-SCI as a result of the extracellular release of ATP with mechanical stimulation.

Evolutionary loss of complexity in human vocal anatomy as an adaptation for speech.

Human speech production obeys the same acoustic principles as vocal production in other animals but has distinctive features: A stable vocal source is filtered by rapidly changing formant frequencies. To understand speech evolution, we examined a wide range of primates, combining observations of phonation with mathematical modeling. We found that source stability relies upon simplifications in laryngeal anatomy, specifically the loss of air sacs and vocal membranes. We conclude that the evolutionary loss of vocal membranes allows human speech to mostly avoid the spontaneous nonlinear phenomena and acoustic chaos common in other primate vocalizations. This loss allows our larynx to produce stable, harmonic-rich phonation, ideally highlighting formant changes that convey most phonetic information. Paradoxically, the increased complexity of human spoken language thus followed simplification of our laryngeal anatomy.

The bifurcation angle is associated with the progression of saccular aneurysms.

The role of the bifurcation angle in progression of saccular intracranial aneurysms (sIAs) has been undetermined. We, therefore, assessed the association of bifurcation angles with aneurysm progression using a bifurcation-type aneurysm model in rats and anterior communicating artery aneurysms in a multicenter case-control study. Aneurysm progression was defined as growth by ≥ 1 mm or rupture during observation, and controls as progression-free for 30 days in rats and ≥ 36 months in humans. In the rat model, baseline bifurcation angles were significantly wider in progressive aneurysms than in stable ones. In the case-control study, 27 and 65 patients were enrolled in the progression and control groups. Inter-observer agreement for the presence or absence of the growth was excellent (κ coefficient, 0.82; 95% CI, 0.61-1.0). Multivariate logistic regression analysis showed that wider baseline bifurcation angles were significantly associated with subsequent progressions. The odds ratio for the progression of the second (145°-179°) or third (180°-274°) tertiles compared to the first tertile (46°-143°) were 5.5 (95% CI, 1.3-35). Besides, the bifurcation angle was positively correlated with the size of aneurysms (Spearman's rho, 0.39; P = 0.00014). The present study suggests the usefulness of the bifurcation angle for predicting the progression of sIAs.

Investigation of breast cancer microstructure and microvasculature from time-dependent DWI and CEST in correlation with histological biomarkers.

We investigated the associations of time-dependent DWI, non-Gaussian DWI, and CEST parameters with histological biomarkers in a breast cancer xenograft model. 22 xenograft mice (7 MCF-7 and 15 MDA-MB-231) were scanned at 4 diffusion times [Td = 2.5/5 ms with 11 b-values (0-600 s/mm2) and Td = 9/27.6 ms with 17 b-values (0-3000 s/mm2), respectively]. The apparent diffusion coefficient (ADC) was estimated using 2 b-values in different combinations (ADC0-600 using b = 0 and 600 s/mm2 and shifted ADC [sADC200-1500] using b = 200 and 1500 s/mm2) at each of those diffusion times. Then the change (Δ) in ADC/sADC between diffusion times was evaluated. Non-Gaussian diffusion and intravoxel incoherent motion (IVIM) parameters (ADC0, the virtual ADC at b = 0; K, Kurtosis from non-Gaussian diffusion; f, the IVIM perfusion fraction) were estimated. CEST images were acquired and the amide proton transfer signal intensity (APT SI) were measured. The ΔsADC9-27.6 (between [Formula: see text] and [Formula: see text] and ΔADC2.5_sADC27.6 (between [Formula: see text] and [Formula: see text]) was significantly larger for MCF-7 groups, and ΔADC2.5_sADC27.6 was positively correlated with Ki67max and APT SI. ADC0 decreased significantly in MDA-MB-231 group and K increased significantly with Td in MCF-7 group. APT SI and cellular area had a moderately strong positive correlation in MDA-MB-231 and MCF-7 tumors combined, and there was a positive correlation in MDA-MB-231 tumors. There was a significant negative correlation between APT SI and the Ki-67-positive ratio in MDA-MB-231 tumors and when combined with MCF-7 tumors. The associations of ΔADC2.5_sADC27.6 and API SI with Ki-67 parameters indicate that the Td-dependent DW and CEST parameters are useful to predict the histological markers of breast cancers.