Reproducibility of tract‐specific magnetization transfer and diffusion tensor imaging in the cervical spinal cord at 3 tesla

Damage to specific white matter tracts within the spinal cord can often result in the particular neurological syndromes that characterize myelopathies such as traumatic spinal cord injury. Noninvasive visualization of these tracts with imaging techniques that are sensitive to microstructural integrity is an important clinical goal. Diffusion tensor imaging (DTI)‐ and magnetization transfer (MT)‐derived quantities have shown promise in assessing tissue health in the central nervous system. In this paper, we demonstrate that DTI of the cervical spinal cord can reliably discriminate sensory (dorsal) and motor (lateral) columns. From data derived from nine healthy volunteers, two raters quantified column‐specific parallel (λ_||) and perpendicular (λ_?) diffusivity, fractional anisotropy (FA), mean diffusivity (MD), and MT‐weighted signal intensity relative to cerebrospinal fluid (MTCSF) over two time‐points separated by more than 1 week. Cross‐sectional means and standard deviations of these measures in the lateral and dorsal columns were as follows: λ_||: 2.13 ± 0.14 and 2.14 ± 0.11 μm²/ms; λ_?: 0.67 ± 0.16 and 0.61 ± 0.09 μm²/ms; MD: 1.15 ± 0.15 and 1.12 ± 0.08 μm²/ms; FA: 0.68 ± 0.06 and 0.68 ± 0.05; MTCSF: 0.52 ± 0.05 and 0.50 ± 0.05. We examined the variability and interrater and test‐retest reliability for each metric. These column‐specific MR measurements are expected to enhance understanding of the intimate structure‐function relationship in the cervical spinal cord and may be useful for the assessment of disease progression. Copyright © 2009 John Wiley & Sons, Ltd.     

High‐resolution imaging of magnetisation transfer and nuclear Overhauser effect in the human visual cortex at 7 T

The aim of this study was to optimise a pulse sequence for high‐resolution imaging sensitive to the effects of conventional macromolecular magnetisation transfer (MT^m) and nuclear Overhauser enhancement (NOE), and to use it to investigate variations in these parameters across the cerebral cortex. A high‐spatial‐resolution magnetisation transfer‐prepared turbo field echo (MT‐TFE) sequence was designed to have high sensitivity to MT^m and NOE effects, whilst being robust to B₀ and B₁ inhomogeneities, and producing a good point spread function across the cortex. This was achieved by optimising the saturation and imaging components of the sequence using simulations based on the Bloch equations, including exchange and an image simulator. This was used to study variations in these parameters across the cortex. Using the sequence designed to be sensitive to NOE and MT^m, a variation in signals corresponding to a variation in MT^m and NOE across the cortex, consistent with a reduction in myelination from the white matter surface to the pial surface of the cortex, was observed. In regions in which the stria was visible on T₂*‐weighted images, it could also be detected in signals sensitive to MT^m and NOE. There was greater variation in signals sensitive to NOE, suggesting that the NOE signal is more sensitive to myelination. A sequence has been designed to image variations in MT^m and NOE at high spatial resolution and has been used to investigate variations in contrast in these parameters across the cortex. Copyright © 2013 John Wiley & Sons, Ltd.     

Inverse Z‐spectrum analysis for spillover‐, MT‐, and T1‐corrected steady‐state pulsed CEST‐MRI – application to pH‐weighted MRI of acute stroke

Endogenous chemical exchange saturation transfer (CEST) effects are always diluted by competing effects, such as direct water proton saturation (spillover) and semi‐solid macromolecular magnetization transfer (MT). This leads to unwanted T₂ and MT signal contributions that lessen the CEST signal specificity to the underlying biochemical exchange processes. A spillover correction is of special interest for clinical static field strengths and protons resonating near the water peak. This is the case for all endogenous CEST agents, such as amide proton transfer, –OH‐CEST of glycosaminoglycans, glucose or myo‐inositol, and amine exchange of creatine or glutamate. All CEST effects also appear to be scaled by the T₁ relaxation time of water, as they are mediated by the water pool. This forms the motivation for simple metrics that correct the CEST signal. Based on eigenspace theory, we propose a novel magnetization transfer ratio (MTR_Rex), employing the inverse Z‐spectrum, which eliminates spillover and semi‐solid MT effects. This metric can be simply related to R_ex, the exchange‐dependent relaxation rate in the rotating frame, and k_a, the inherent exchange rate. Furthermore, it can be scaled by the duty cycle, allowing for simple translation to clinical protocols. For verification, the amine proton exchange of creatine in solutions with different agar concentrations was studied experimentally at a clinical field strength of 3 T, where spillover effects are large. We demonstrate that spillover can be properly corrected and that quantitative evaluation of pH and creatine concentration is possible. This proves that MTR_Rex is a quantitative and biophysically specific CEST‐MRI metric. Applied to acute stroke induced in rat brain, the corrected CEST signal shows significantly higher contrast between the stroke area and normal tissue, as well as less B₁ dependence, than conventional approaches. Copyright © 2014 John Wiley & Sons, Ltd.     

Collagen proton fraction from ultrashort echo time magnetization transfer (UTE‐MT) MRI modelling correlates significantly with cortical bone porosity measured with micro‐computed tomography (μCT)

Intracortical bone porosity is a key microstructural parameter that determines bone mechanical properties. While clinical MRI visualizes the cortical bone with a signal void, ultrashort echo time (UTE) MRI can acquire high signal from cortical bone, thus enabling quantitative assessments. Magnetization transfer (MT) imaging combined with UTE‐MRI can indirectly assess protons in the bone collagenous matrix, which are inversely related to porosity. This study aimed to examine UTE‐MT MRI techniques to evaluate intracortical bone porosity. Eighteen human cortical bone specimens from the tibial and fibular midshafts were scanned using UTE‐MT sequences on a clinical 3 T MRI scanner and on a high‐resolution micro‐computed tomography (μCT) scanner. A series of MT pulse saturation powers (500°, 1000°, 1500°) and frequency offsets (2, 5, 10, 20, 50 kHz) were used to measure the macromolecular fraction (MMF) and macromolecular T₂ (T_2MM) using a two‐pool MT model. The measurements were made on 136 different regions of interest (ROIs). ROIs were selected at three cortical bone layers (from endosteum to periosteum) and four anatomical sites (anterior, mid‐medial, mid‐lateral, and posterior) to provide a wide range of porosity. MMF showed moderate to strong correlations with intracortical bone porosity (R = ?0.67 to ?0.73, p < 0.01) and bone mineral density (BMD) (R = +0.46 to +0.70, p < 0.01). Comparing the average MMF between cortical bone layers revealed a significant increase from the endosteum towards the periosteum. Such a pattern was in agreement with porosity reduction and BMD increase towards the periosteum. These results suggest that the two‐pool UTE‐MT technique can potentially serve as a novel and accurate tool to assess intracortical bone porosity.     

Optimization of saturation‐recovery dynamic contrast‐enhanced MRI acquisition protocol: monte carlo simulation approach demonstrated with gadolinium MR renography

Dynamic contrast‐enhanced (DCE) MRI is widely used for the measurement of tissue perfusion and to assess organ function. MR renography, which is acquired using a DCE sequence, can measure renal perfusion, filtration and concentrating ability. Optimization of the DCE acquisition protocol is important for the minimization of the error propagation from the acquired signals to the estimated parameters, thus improving the precision of the parameters. Critical to the optimization of contrast‐enhanced T₁‐weighted protocols is the balance of the T₁‐shortening effect across the range of gadolinium (Gd) contrast concentration in the tissue of interest. In this study, we demonstrate a Monte Carlo simulation approach for the optimization of DCE MRI, in which a saturation‐recovery T₁‐weighted gradient echo sequence is simulated and the impact of injected dose (D) and time delay (TD, for saturation recovery) is tested. The results show that high D and/or high TD cause saturation of the peak arterial signals and lead to an overestimation of renal plasma flow (RPF) and glomerular filtration rate (GFR). However, the use of low TD (e.g. 100 ms) and low D leads to similar errors in RPF and GFR, because of the Rician bias in the pre‐contrast arterial signals. Our patient study including 22 human subjects compared TD values of 100 and 300 ms after the injection of 4 mL of Gd contrast for MR renography. At TD = 100 ms, we computed an RPF value of 157.2 ± 51.7 mL/min and a GFR of 33.3 ± 11.6 mL/min. These results were all significantly higher than the parameter estimates at TD = 300 ms: RPF = 143.4 ± 48.8 mL/min (p = 0.0006) and GFR = 30.2 ± 11.5 mL/min (p = 0.0015). In conclusion, appropriate optimization of the DCE MRI protocol using simulation can effectively improve the precision and, potentially, the accuracy of the measured parameters. Copyright © 2016 John Wiley & Sons, Ltd.     

Detection of cancer in cervical tissue biopsies using mobile lipid resonances measured with diffusion‐weighted 1H magnetic resonance spectroscopy

The purpose of this study was to implement a diffusion‐weighted sequence for visualisation of mobile lipid resonances (MLR) using high resolution magic angle spinning (HR‐MAS) ¹H MRS and to evaluate its use in establishing differences between tissues from patients with cervical carcinoma that contain cancer from those that do not. A stimulated echo sequence with bipolar gradients was modified to allow T₁ and T₂ measurements and optimised by recording signal loss in HR‐MAS spectra as a function of gradient strength in model lipids and tissues. Diffusion coefficients, T₁ and apparent T₂ relaxation times were measured in model lipid systems. MLR profiles were characterised in relation to T₁ and apparent T₂ relaxation in human cervical cancer tissue samples. Diffusion‐weighted (DW) spectra of cervical biopsies were quantified and peak areas analysed using linear discriminant analysis (LDA). The optimised sequence reduced spectral overlap by suppressing signals originating from low molecular weight metabolites and non‐lipid contributions. Significantly improved MLR visualisation allowed visualisation of peaks at 0.9, 1.3, 1.6, 2.0, 2.3, 2.8, 4.3 and 5.3 ppm. MLR analysis of DW spectra showed at least six peaks arising from saturated and unsaturated lipids and those arising from triglycerides. Significant differences in samples containing histologically confirmed cancer were seen for peaks at 0.9 (p < 0.006), 1.3 (p < 0.04), 2.0 (p < 0.03), 2.8 (p < 0.003) and 4.3 ppm (p < 0.0002). LDA analysis of MLR peaks from DW spectra almost completely separated two clusters of cervical biopsies (cancer, ‘no‐cancer’), reflecting underlying differences in MLR composition. Generated Receiver Operating Characteristic (ROC) curves and calculated area under the curve (0.962) validated high sensitivity and specificity of the technique. Diffusion‐weighting of HR‐MAS spectroscopic sequences is a useful method for characterising MLR in cancer tissues and displays an accumulation of lipids arising during tumourigenesis and an increase in the unsaturated lipid and triglyceride peaks with respect to saturated MLR. Copyright © 2009 John Wiley & Sons, Ltd.     

Three‐dimensional whole‐brain perfusion quantification using pseudo‐continuous arterial spin labeling MRI at multiple post‐labeling delays: accounting for both arterial transit time and impulse response function

Measurement of the cerebral blood flow (CBF) with whole‐brain coverage is challenging in terms of both acquisition and quantitative analysis. In order to fit arterial spin labeling‐based perfusion kinetic curves, an empirical three‐parameter model which characterizes the effective impulse response function (IRF) is introduced, which allows the determination of CBF, the arterial transit time (ATT) and T_1,eff. The accuracy and precision of the proposed model were compared with those of more complicated models with four or five parameters through Monte Carlo simulations. Pseudo‐continuous arterial spin labeling images were acquired on a clinical 3‐T scanner in 10 normal volunteers using a three‐dimensional multi‐shot gradient and spin echo scheme at multiple post‐labeling delays to sample the kinetic curves. Voxel‐wise fitting was performed using the three‐parameter model and other models that contain two, four or five unknown parameters. For the two‐parameter model, T_1,eff values close to tissue and blood were assumed separately. Standard statistical analysis was conducted to compare these fitting models in various brain regions. The fitted results indicated that: (i) the estimated CBF values using the two‐parameter model show appreciable dependence on the assumed T_1,eff values; (ii) the proposed three‐parameter model achieves the optimal balance between the goodness of fit and model complexity when compared among the models with explicit IRF fitting; (iii) both the two‐parameter model using fixed blood T₁ values for T_1,eff and the three‐parameter model provide reasonable fitting results. Using the proposed three‐parameter model, the estimated CBF (46 ± 14 mL/100 g/min) and ATT (1.4 ± 0.3 s) values averaged from different brain regions are close to the literature reports; the estimated T_1,eff values (1.9 ± 0.4 s) are higher than the tissue T₁ values, possibly reflecting a contribution from the microvascular arterial blood compartment.     

Diagnostic Yield of Heat Shock Protein 70 (HSP‐70) and Anti‐HSP‐70 in Behcet‐Induced Uveitis

Heat shock proteins (HSPs) are intracellular proteins with pro‐ and anti‐inflammatory actions, playing an important role in the pathogenesis of Behcet's disease (BD). Diagnosis of BD uveitis in early stages is still problematic, thus this study was undertaken to determine diagnostic values of serum HSP‐ and anti‐HSP‐70 in BD uveitis. Serum levels of HSP‐ and anti‐HSP‐70 were measured in 53 patients with BD (26 with and 27 without uveitis). In control group, 25 age‐ and sex‐matched idiopathic uveitis patients were enrolled consecutively. Both groups had no medical problems save uveitis at the time of sampling. Confounders like medications were analysed subsequently. HSP‐ and anti‐HSP‐70 values were measured by commercial ELISA kits. Data were analysed by spss 11.5 and medcalc 11.5.1 software. The Mean HSP‐70 serum levels were different among aforementioned subgroups (P = 0.001, anova ). They were elevated in BD uveitis compared with BD without uveitis (4.84 ± 4.21 versus 2.24 ± 2.08 ng/ml; P = 0.045). HSP‐70 in sera of BD uveitis was also higher than that parameter in patients with idiopathic uveitis (4.84 ± 4.21 versus 2.37 ± 3.30 ng/ml; P = 0.001; cut‐off point value 1.0 9 ng/ml, 95% CI 0.61–0.86, P = 0.0002, ß = 0.06). However, there was not any statistical difference among those groups in the serum anti‐HSP‐70 levels (P = 0.63, anova ). Multiple regression analysis demonstrated that among different confounders, only prednisolone increases and BD uveitis decreases HSP‐70 levels independently. This prospective cross‐sectional study suggested that HSP‐70 serum level is impressed over the course of BD uveitis, and it could be utilized to diagnose or predict developing it.     

Ultrashort echo time magnetization transfer (UTE‐MT) imaging of cortical bone

Magnetization transfer (MT) imaging is one way to indirectly assess pools of protons with fast transverse relaxation. However, conventional MT imaging sequences are not applicable to short T₂ tissues such as cortical bone. Ultrashort echo time (UTE) sequences with T_E values as low as 8 µs can detect signals from different water components in cortical bone. In this study we aim to evaluate two‐dimensional UTE‐MT imaging of cortical bone and its application in assessing cortical bone porosity as measured by micro‐computed tomography (μCT) and biomechanical properties. In total, 38 human cadaveric distal femur and proximal tibia bones were sectioned to produce 122 rectangular pieces of cortical bone for quantitative UTE‐MT MR imaging, μCT, and biomechanical testing. Off‐resonance saturation ratios (OSRs) with a series of MT pulse frequency offsets (Δf) were calculated and compared with porosity assessed with μCT, as well as elastic (modulus, yield stress, and strain) and failure (ultimate stress, failure strain, and energy) properties, using Pearson correlation and linear regression. A moderately strong negative correlation was observed between OSR and μCT porosity (R² = 0.46–0.51), while a moderate positive correlation was observed between OSR and yield stress (R² = 0.25–0.30) and failure stress (R² = 0.31–0.35), and a weak positive correlation (R² = 0.09–0.12) between OSR and Young's modulus at all off‐resonance saturation frequencies. OSR determined with the UTE‐MT sequence provides quantitative information on cortical bone and is sensitive to μCT porosity and biomechanical function. Copyright © 2015 John Wiley & Sons, Ltd.     

Over‐expression of metallothionein predicts chemoresistance in breast cancer

Metallothionein (MT) plays a role in fundamental cellular processes such as proliferation, apoptosis and differentiation. We examined MT expression in women with invasive breast ductal carcinoma who underwent mastectomy/lumpectomy without neo‐adjuvant treatment. We showed that MT was over‐expressed in 87.9% of breast cancer tissues examined, with the mean percentage of positive cells at 30%. There were two patterns of MT expression: predominantly cytoplasmic in 75.9% and nuclear in 24.1% of MT‐positive cases. Higher MT scores were associated with poorer histological grade (p = 0.009) but were independent of age, tumour size and oestrogen receptor status. For patients who were treated with adjuvant chemotherapy (cyclophosphamide/methotrexate/5 fluorouracil‐ or doxorubicin‐based regimes), those with high MT expression had a significantly lower recurrence‐free survival (p = 0.048), suggesting a role of MT in predicting disease recurrence. Down‐regulation of MT in MCF‐7 cells by silencing the MT‐2A gene (the most abundantly expressed of the 10 known functional MT isoforms) increased chemosensitivity of the cells to doxorubicin. To examine the mechanisms underlying these clinical data, we used siRNAs to decrease MT‐2A mRNA expression and protein expression. In MT down‐regulated cells challenged with the IC₅₀ concentration of doxorubicin, we observed a significant reduction in cell viability. Cell cycle analysis also revealed a corresponding increase in apoptosis in the MT down‐regulated cells following doxorubicin exposure, showing that down‐regulation of MT increased susceptibility to doxorubicin cytotoxicity. The data suggest that MT could be a potential marker of chemoresistance and a molecular therapeutic target. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Correction of B1‐inhomogeneities for relaxation‐compensated CEST imaging at 7 T

Chemical exchange saturation transfer (CEST) imaging of endogenous agents in vivo is influenced by direct water proton saturation (spillover) and semi‐solid macromolecular magnetization transfer (MT). Lorentzian fit isolation and application of the inverse metric yields the pure CEST contrast AREX, which is less affected by these processes, but still depends on the measurement technique, in particular on the irradiation amplitude B₁ of the saturation pulses. This study focuses on two well‐known CEST effects in the slow exchange regime originating from amide and aliphatic protons resonating at 3.5 ppm or ?3.5 ppm from water protons, respectively. A B₁‐correction of CEST contrasts is crucial for the evaluation of data obtained in clinical studies at high field strengths with strong B₁‐inhomogeneities. Herein two approaches for B₁‐inhomogeneity correction, based on either CEST contrasts or Z‐spectra, are investigated. Both rely on multiple acquisitions with different B₁‐values. One volunteer was examined with eight different B₁‐values to optimize the saturation field strength and the correction algorithm. Histogram evaluation allowed quantification of the quality of the B₁‐correction. Finally, the correction was applied to CEST images of a patient with oligodendroglioma WHO grade 2, and showed improvement of the image quality compared with the non‐corrected CEST images, especially in the tumor region. Copyright © 2015 John Wiley & Sons, Ltd.     

Low‐volume muscle endurance training prevents decrease in muscle oxidative and endurance function during 21‐day forearm immobilization

Aim: To examine the effects of low‐volume muscle endurance training on muscle oxidative capacity, endurance and strength of the forearm muscle during 21‐day forearm immobilization (IMM‐21d). Methods: The non‐dominant arm (n = 15) was immobilized for 21 days with a cast and assigned to an immobilization‐only group (Imm‐group; n = 7) or an immobilization with training group (Imm+Tr‐group; n = 8). Training comprised dynamic handgrip exercise at 30% of pre‐intervention maximal voluntary contraction (MVC) at 1 Hz until exhaustion, twice a week during the immobilization period. The duration of each exercise session was 51.7 ± 3.4 s (mean ± SE). Muscle oxidative capacity was evaluated by the time constant for phosphocreatine recovery (τ_offPCr) after a submaximal handgrip exercise using ³¹phosphorus‐magnetic resonance spectroscopy. An endurance test was performed at 30% of pre‐intervention MVC, at 1 Hz, until exhaustion. Results: τ _offPCr was significantly prolonged in the Imm‐group after 21 days (42.0 ± 2.8 and 64.2 ± 5.1 s, pre‐ and post‐intervention respectively; P < 0.01) but did not change for the Imm+Tr‐group (50.3 ± 3.0 and 48.8 ± 5.0 s, ns). Endurance decreased significantly for the Imm‐group (55.1 ± 5.1 and 44.7 ± 4.6 s, P < 0.05) but did not change for the Imm+Tr‐group (47.9 ± 3.0 and 51.7 ± 4.0 s, ns). MVC decreased similarly in both groups (P < 0.01). Conclusions: Twice‐weekly muscle endurance training sessions, each lasting approx. 50 s, effectively prevented a decrease in muscle oxidative capacity and endurance; however, there was no effect on MVC decline with IMM‐21d.     

Quantitative susceptibility mapping and 23Na imaging‐based in vitro characterization of blood clotting kinetics

Blood clotting is a fundamental biochemical process in post‐hemorrhagic hemostasis. Although the varying appearance of coagulating blood in T₁‐ and T₂‐weighted images is widely used to qualitatively determine bleeding age, the technique permits only a rough discrimination of coagulation stages, and it remains difficult to distinguish acute and chronic hemorrhagic stages because of low T₁‐ and T₂‐weighted signal intensities in both instances. To investigate new biomedical parameters for magnetic resonance imaging‐based characterization of blood clotting kinetics, sodium imaging and quantitative susceptibility mapping (QSM) were compared with conventional T₁‐ and T₂‐weighted imaging, as well as with biochemical hemolysis parameters. For this purpose, a blood‐filled spherical agar phantom was investigated daily for 14 days, as well as after 24 days at 7 T after initial preparation with fresh blood. T₁‐ and T₂‐weighted sequences, a three‐dimensional (3D) gradient echo sequence and a density‐adapted 3D radial projection reconstruction pulse sequence for ²³Na imaging were applied. For hemolysis estimations, free hemoglobin and free potassium concentrations were measured photometrically and with the direct ion‐selective electrode method, respectively, in separate heparinized whole‐blood samples along the same timeline. Initial mean susceptibility was low (0.154 ± 0.020 ppm) and increased steadily during the course of coagulation to reach up to 0.570 ± 0.165 ppm. The highest total sodium (NaT) values (1.02 ± 0.06 arbitrary units) in the clot were observed initially, dropped to 0.69 ± 0.13 arbitrary units after one day and increased again to initial values. Compartmentalized sodium (NaS) showed a similar signal evolution, and the NaS/NaT ratio steadily increased over clot evolution. QSM depicts clot evolution in vitro as a process associated with hemoglobin accumulation and transformation, and enables the differentiation of the acute and chronic coagulation stages. Sodium imaging visualizes clotting independent of susceptibility and seems to correspond to clot integrity. A combination of QSM and sodium imaging may enhance the characterization of hemorrhage.     

Chain‐Length‐Dependent Termination of Vinyl Acetate and Vinyl Pivalate Bulk Homopolymerizations Studied by SP‐PLP‐EPR

Bulk homopolymerizations of vinyl acetate and vinyl pivalate are studied by EPR experiments between ?65 °C and 60 °C with dicumyl peroxide acting as the photoinitiator. No mid‐chain radicals are seen, which demonstrates that backbiting plays no role. The chain‐length dependence of the termination rate coefficients measured up to 13% monomer conversion is adequately represented by the composite model. The power‐law exponents α_s and α_l for short‐chain and long‐chain radicals are: α_s(VAc) = 0.57 ± 0.05, α_s(VPi) = 0.67 ± 0.15, α_l(VAc) = 0.16 ± 0.07, and α_l(VPi) = 0.16 ± 0.07. The crossover chain lengths differ largely: i_c(VAc) = 20 ± 10 and i_c(VPi) = 110 ± 30. The rate coefficient for termination of two radicals of chain length unity, , which is the fourth composite‐model parameter, depends on temperature, as does the monomer fluidity.

     

Effect of natural full weight‐bearing during standing on the rotation of the first metatarsal bone

To evaluate the rotational change in the first metatarsal bone (1MT) of the foot during natural standing using an upright computed tomography (CT) scanner with 320‐detector rows. A total of 52 feet of 28 asymptomatic subjects (aged 23–39 years) were evaluated in the natural standing position with or without weight‐bearing. A foot pressure plate was used to determine the non‐weight‐bearing (NWB) or single leg full‐weight‐bearing (s‐FWB) conditions. CT examinations were performed using a noise index of 15 for a slice thickness of 5 mm, rotation speed of 0.5 sec, and slice thickness of 0.5 mm. The rotation of the 1MT was measured on the coronal CT image, which cut the sesamoids' bellies in the frontal slide of the first metatarsal and sesamoids perpendicular to the longitudinal bisection of the third metatarsal, and compared between the weight‐bearing conditions. Intra‐ and inter‐observer reliabilities of the rotation angle were also evaluated. The intra‐ and inter‐observer correlation coefficients were 0.961 and 0.934, respectively. The 1MT pronation angle was significantly greater in the s‐FWB condition than in the NWB condition (15.2° ± 5.4° vs. 12.5° ± 5.3°, P < 0.01). No sex difference was found in the magnitude of the 1MT pronation angle as a result of weight‐bearing. This study first demonstrated that pronation of 1MT occurs due to natural full‐weight‐bearing in asymptomatic feet. The 1MT's rotational movement under weight‐bearing conditions may relate to the onset and pathogenesis of the hallux valgus. Clin. Anat. 32:715–721, 2019. © 2019 Wiley Periodicals, Inc.     

Poly(phenylnorbornene) from Ring‐Opening Metathesis and Its Hydrogenated Derivatives

Novel polymers are synthesized from 5‐phenyl‐2‐norbornene (PhNb) and its saturated side group analog, 5‐cyclohexyl‐2‐norbornene, using ring‐opening metathesis polymerization (ROMP). Polymers of both endo‐rich and all‐exo PhNb show glass transition temperatures (T_g) = 88 ± 1 °C, indicating a negligible effect of monomer stereoisomerism on segmental packing or the energy barriers to motion at the glass transition, despite the substantial size of the side group. Post‐polymerization hydrogenation of the PhNb polymers using catalysts with different selectivities reveals that saturation of the backbone produces a 17 °C decrease in T_g (for both aromatic and cycloaliphatic side groups), whereas saturation of the side groups produces a 14 °C increase in T_g (for both saturated and unsaturated backbones).     

Response of HT29 colorectal xenograft model to cediranib assessed with 18F‐fluoromisonidazole positron emission tomography,dynamic contrast‐enhanced and diffusion‐weighted MRI

Cediranib is a small‐molecule pan‐vascular endothelial growth factor receptor inhibitor. The tumor response to short‐term cediranib treatment was studied using dynamic contrast‐enhanced and diffusion‐weighted MRI at 7 T, as well as ¹⁸F‐fluoromisonidazole positron emission tomography and histological markers. Rats bearing subcutaneous HT29 human colorectal tumors were imaged at baseline; they then received three doses of cediranib (3 mg/kg per dose daily) or vehicle (dosed daily), with follow‐up imaging performed 2 h after the final cediranib or vehicle dose. Tumors were excised and evaluated for the perfusion marker Hoechst 33342, the endothelial cell marker CD31, smooth muscle actin, intercapillary distance and tumor necrosis. Dynamic contrast‐enhanced MRI‐derived parameters decreased significantly in cediranib‐treated tumors relative to pretreatment values [the muscle‐normalized initial area under the gadolinium concentration curve decreased by 48% (p = 0.002), the enhancing fraction by 43% (p = 0.003) and K^trans by 57% (p = 0.003)], but remained unchanged in controls. No change between the pre‐ and post‐treatment tumor apparent diffusion coefficients in either the cediranib‐ or vehicle‐treated group was observed over the course of this study. The ¹⁸F‐fluoromisonidazole mean standardized uptake value decreased by 33% (p = 0.008) in the cediranib group, but showed no significant change in the control group. Histological analysis showed that the number of CD31‐positive vessels (59 per mm²), the fraction of smooth muscle actin‐positive vessels (80–87%) and the intercapillary distance (0.17 mm) were similar in cediranib‐ and vehicle‐treated groups. The fraction of perfused blood vessels in cediranib‐treated tumors (81 ± 7%) was lower than that in vehicle controls (91 ± 3%, p = 0.02). The necrotic fraction was slightly higher in cediranib‐treated rats (34 ± 12%) than in controls (26 ± 10%, p = 0.23). These findings suggest that short‐term treatment with cediranib causes a decrease in tumor perfusion/permeability across the tumor cross‐section, but changes in vascular morphology, vessel density or tumor cellularity are not manifested at this early time point. Copyright © 2012 John Wiley & Sons, Ltd.     

31P‐MRS of healthy human brain: ATP synthesis,metabolite concentrations,pH, and T1 relaxation times

The conventional method for measuring brain ATP synthesis is ³¹P saturation transfer (ST), a technique typically dependent on prolonged pre‐saturation with γ‐ATP. In this study, ATP synthesis rate in resting human brain is evaluated using EBIT (exchange kinetics by band inversion transfer), a technique based on slow recovery of γ‐ATP magnetization in the absence of B₁ field following co‐inversion of PCr and ATP resonances with a short adiabatic pulse. The unidirectional rate constant for the P_i → γ‐ATP reaction is 0.21 ± 0.04 s^?1 and the ATP synthesis rate is 9.9 ± 2.1 mmol min^?1 kg^?1 in human brain (n = 12 subjects), consistent with the results by ST. Therefore, EBIT could be a useful alternative to ST in studying brain energy metabolism in normal physiology and under pathological conditions. In addition to ATP synthesis, all detectable ³¹P signals are analyzed to determine the brain concentration of phosphorus metabolites, including UDPG at around 10 ppm, a previously reported resonance in liver tissues and now confirmed in human brain. Inversion recovery measurements indicate that UDPG, like its diphosphate analogue NAD, has apparent T₁ shorter than that of monophosphates (P_i, PMEs, and PDEs) but longer than that of triphosphate ATP, highlighting the significance of the ³¹P–³¹P dipolar mechanism in T₁ relaxation of polyphosphates. Another interesting finding is the observation of approximately 40% shorter T₁ for intracellular P_i relative to extracellular P_i, attributed to the modulation by the intracellular phosphoryl exchange reaction P_i ? γ‐ATP. The sufficiently separated intra‐ and extracellular P_i signals also permit the distinction of pH between intra‐ and extracellular environments (pH 7.0 versus pH 7.4). In summary, quantitative ³¹P MRS in combination with ATP synthesis, pH, and T₁ relaxation measurements may offer a promising tool to detect biochemical alterations at early stages of brain dysfunctions and diseases. Copyright © 2015 John Wiley & Sons, Ltd.     

Feasibility of quantitative ultrashort echo time (UTE)‐based methods for MRI of peripheral nerve

Peripheral nerves are a composite tissue consisting of neurovascular elements packaged within a well‐organized extracellular matrix. Their composition, size, and anatomy render nerves a challenging medical imaging target. In contrast to morphological MRI, which represents the predominant approach to nerve imaging, quantitative MRI sequences can provide information regarding tissue composition. Here, we applied standard clinical Carr‐Purcell‐Meiboom‐Gill (CPMG) and experimental three‐dimensional (3D) ultrashort echo time (UTE) Cones sequences for quantitative nerve imaging including T₂ measurement with single‐component analysis, T₂* measurement with single‐component and bi‐component analyses, and magnetization transfer ratio (MTR) analysis. We demonstrated the feasibility and the high quality of single‐component T₂*, bi‐component T₂*, and MTR approaches to analyze nerves imaged with clinically deployed 3D UTE Cones pulse sequences. For 24 single fascicles from eight nerves, we measured a mean single‐component T₂* of 22.6 ±8.9 ms, and a short T₂* component (STC) with a mean T₂* of 1.7 ±1.0 ms and a mean fraction of (6.74 ±4.31)% in bi‐component analysis. For eight whole nerves, we measured a mean single‐component T₂* of 16.7 ±2.2 ms, and an STC with a mean T₂* of 3.0 ±1.0 ms and a mean fraction of (15.56 ±7.07)% in bi‐component analysis. For nine fascicles from three healthy nerves, we measured a mean MTR of (25.2 ±1.9)% for single fascicles and a mean MTR of (23.6 ±0.9)% for whole nerves. No statistically significant correlation was observed between any MRI parameter and routine histological outcomes, perhaps due to the small sample size and lack of apparent sample pathology. Overall, we have successfully demonstrated the feasibility of measuring quantitative MR outcomes ex vivo, which might reflect features of nerve structure and macromolecular content. These methods should be validated comprehensively on a larger and more diverse set of nerve samples, towards the interpretation of in vivo outcomes. These approaches have new and broad implications for the management of nerve disease, injury, and repair.     

Adenosine induces prolonged anti‐β‐adrenergic effects in guinea‐pig papillary muscle

A sustained anti‐β‐adrenergic effect of adenosine has been reported. This study was initiated to investigate this topic and especially elucidate the role of protein kinase C (PKC). Contractile force amplitude and action potential duration at 90% repolarization (APD₉₀) were measured in guinea‐pig papillary muscles before and after 5 min challenge with 5 nm isoproterenol. Protocols contained 30 min exposure to the test agents adenosine 33 μm (ado), adenosine + PKC‐inhibitor bisindolylmaleimide 20 nM (ado + BIM), PKC‐activator 1,2‐dioctanoyl‐sn‐glycerol 10 μm (DOG) and α‐agonist phenylephrine 5 μm (phe). Isoproterenol was given at the end of test exposure and after 15 min washout. Results are mean ± SEM of percentage‐change, P ≤ 0.05 considered significant and labelled *. The first isoproterenol challenge significantly increased contractile force (27 ± 7%*) in the control group. Responses in the test groups were 2 ± 4 (ado), 1 ± 5 (ado + BIM), 14 ± 4* (DOG), 0 ± 2% (phe). After washout of adenosine, DOG and phenylephrine, isoproterenol induced 3 ± 8 (ado), 23 ± 5* (ado + BIM), 13 ± 5* (DOG), 15 ± 7% (phe) increase in test groups compared with 22 ± 5%* increase in contractile force in the control group. After 45 min washout of adenosine the inotropic response was still significantly reduced compared with control (29 ± 4 vs. 79 ± 8%*). Isoproterenol stimulation shortened APD₉₀ in controls at both time points (5 ± 1%* and 4 ± 1%*), with no significant shortening in test groups. Adenosine induces sustained anti‐β‐adrenergic effects on contractile force as well as APD₉₀. A role for PKC in signal transduction is supported with respect to contractile force.