Analysis of Factors Related to Variation in Dissolution Profiles Estimated from Continuously Conducted Dissolution Tests of Generic Products.

The development of generic pharmaceuticals involves a bioequivalence study to ensure the therapeutic equivalence of the test formulation to the original innovative product. The formulation characteristics of generic products are expected to be maintained in the long term after approval. This study analyzed the factors contributing to the changes in the dissolution profiles of approved products during their life cycles. Cumulative data on the dissolution similarity of 1675 products of 127 ingredients tested by official laboratories in Japan were assessed according to Japanese bioequivalence guidelines with slight modifications. The products showing dissimilarities in dissolution profiles were analyzed for reporting year, therapeutic category, co-development, physical properties of the active pharmaceutical ingredient (API), and suspected reasons for dissolution change. The increase in the number of dissimilar products is related to the co-development of generic products. Although the solubility of the API was not associated with the dissolution change in the analysis of the total dissolution data, control of the API particle size is suggested to be important for drugs with poorly soluble APIs. Additionally, a risk factor for dissolution changes in the test solutions at a certain pH was the presence of acidic or basic residues. These results indicate the importance of proper development through a thorough evaluation of the formulation and process factors affecting the dissolution properties throughout the product lifecycle.

Superior cerebellar peduncle atrophy of progressive supranuclear palsy on phase difference enhanced imaging: a comparison with Parkinson's disease.

PURPOSE: Phase difference enhanced (PADRE) imaging can enhance myelin density and delineate the superior cerebellar peduncle (SCP). We aimed to determine if SCP atrophy was distinguishable on PADRE imaging and evaluate its diagnostic performance compared with previous MRI progressive supranuclear palsy (PSP) findings. METHODS: Two reviewers measured the SCP widths on PADRE in 20 PSP and 31 Parkinson's disease (PD) patients. The SCP and middle cerebellar peduncle (MCP) widths and the pons and midbrain areas were measured on 3D-T1WI, and the ratio of the area of the pons to the area of the midbrain, the MCP/SCP ratio, and the magnetic resonance parkinsonism index (MRPI) were calculated. We used the Steel-Dwass test to compare PSP, PD, and HS, and receiver operating characteristic curve (ROC) analyses to assess the sensitivity and specificity for diagnosing PSP from PD. A comparison of ROC curves was performed between the SCP on PADRE and these 3D-T1WI parameters. RESULTS: In radiologist 1, the SCP on PADRE in PSP (1.1 ± 0.3 mm) was significantly smaller than those in PD (2.4 ± 0.4 mm) (P < 0.001); the area under the curve (AUC) was 0.97. At a 1.75-mm cutoff value, the diagnostic sensitivity and specificity for differentiating PSP from PD were 93.5% and 100%, respectively. The AUC of the SCP on PADRE was significantly higher than the 3D-T1WI parameters (the SCP, MCP, pons area, MCP/SCP ratio, and MRPI). CONCLUSION: Assessing SCP with PADRE imaging may yield high diagnostic accuracy for discriminating PSP from PD.

Correlation between Phase-difference-enhanced MR Imaging and Amyloid Positron Emission Tomography: A Study on Alzheimer's Disease Patients and Normal Controls.

PURPOSE: While amyloid-ß deposition in the cerebral cortex for Alzheimer's disease (AD) is often evaluated by amyloid positron emission tomography (PET), amyloid-ß-related iron can be detected using phase difference enhanced (PADRE) imaging; however, no study has validated the association between PADRE imaging and amyloid PET. This study investigated whether the degree of hypointense areas on PADRE imaging correlated with the uptake of amyloid PET. METHODS: PADRE imaging and amyloid PET were performed in 8 patients with AD and 10 age-matched normal controls. ROIs in the cuneus, precuneus, superior frontal gyrus (SFG), and superior temporal gyrus (STG) were automatically segmented. The degree of hypointense areas on PADRE imaging in each ROI was evaluated using 4-point scaling of visual assessment or volumetric semiquantitative assessment (the percentage of hypointense volume within each ROI). The mean standardized uptake value ratio (SUVR) of amyloid PET in each ROI was also calculated. The Spearman's correlation coefficient between the 4-point scale of PADRE imaging and SUVR of amyloid PET or between the semiquantitative hypointense volume percentage and SUVR in each ROI was evaluated. RESULTS: In the precuneus, a significant positive correlation was identified between the 4-point scale of PADRE imaging and SUVR of amyloid PET (Rs = 0.5; P = 0.034) in all subjects. In the cuneus, a significant positive correlation was identified between the semiquantitative volume percentage of PADRE imaging and SUVR of amyloid PET (Rs = 0.55; P = 0.02) in all subjects. CONCLUSION: Amyloid-ß-enhancing PADRE imaging can be used to predict the SUVR of amyloid PET, especially in the cuneus and precuneus, and may have the potential to be used for diagnosing AD by detecting amyloid deposition.

Optic radiation atrophy in Lewy body disease with visual hallucination on phase difference enhanced magnetic resonance images.

Visual hallucinations (VH) occur commonly in Lewy body disease (LBD), including Parkinson's disease (PD), PD with dementia, and dementia with Lewy bodies. We aimed to use phase difference enhanced imaging (PADRE) to assess structural abnormalities of optic radiation (OR) in patients with Lewy body disease (LBD) concomitant with VH. Firstly, two radiologists reviewed the OR appearances in healthy subjects (HS) on PADRE. Next, based on the OR abnormalities, two reviewers assessed the PADRE images from 18 HS and 38 and 110 patients with LBD, with and without VH, respectively, in a blinded manner. Finally, all patients with LBD without VH were eventually followed up for at least 5 years after magnetic resonance imaging to determine the appearance of VH. The radiologists identified three layers, namely external sagittal stratum, internal sagittal stratum, and tapetum, in OR on the PADRE in HS. Moreover, they were able to consensually define the OR as abnormal when the layers were obscured and the disappearance of the cranial side. The sensitivity/specificity of abnormal OR for each case was 68%/81% (LBD with VH vs. LBD without VH). Furthermore, VH appeared in 12 of the 21 (57%) patients with LBD and abnormal OR during the follow-up period. However, no patients without abnormal OR reported VH. Patients with LBD and VH demonstrated the abnormal OR. This, in turn, might be a useful marker to distinguish the patients with VH from those without VH and HS. Moreover, abnormal OR on PADRE may precede the appearance of VH in LBD.

Stabilizers for Osmium Isotopes in Microwave-Irradiated Acid Digestion and Inductively Coupled Plasma Mass Spectrometry Analysis.

Osmium is defined in the international council for harmonization (ICH-Q3D) guidelines as an element whose concentration can be determined by validated methods including microwave-assisted nitric acid digestion and inductively coupled plasma mass spectrometry. However, microwave digestion using nitric acid is known to result in osmium recoveries higher than the theoretical values in spiked tests because of the formation of highly volatile osmium tetroxide in an oxidation reaction. To stabilize osmium, the addition of thiourea as a complexing agent has been tested and proved its utility. It remains unclear whether other compounds can prevent the over-recovery of osmium. In this study, we investigated four compounds, thiourea, ascorbic acid, sodium sulfite, and potassium metabisulfite, that could reduce the overestimation of osmium isotopes. The minimum amounts of thiourea, ascorbic acid, sodium sulfite, and potassium metabisulfite required to stabilize 10 ng/mL osmium in blank matrix were 1.0, 1.0, 2.5, and 2.5 g/L, respectively. The relative standard deviations obtained from 12 analyses for each stabilization solution were less than 3.3% in thiourea, 12.7% in ascorbic acid, 9.0% in sodium sulfite, and 10.6% in potassium metabisulfite. The stabilization solutions were investigated in a digested tablet matrix and were found to be effective. The impact of adding stabilization solutions on the determination of all ICH-Q3D element concentrations was also evaluated. As stabilization solutions had a small or significant impact on the determination of some elements, it was concluded that osmium determination should be conducted independently.

Can myocardial susceptibility quantification be an imaging biomarker for cardiac amyloidosis?

PURPOSE: This study aimed to evaluate whether quantification of myocardial susceptibility by cardiac magnetic resonance imaging (CMR) can be an imaging biomarker for cardiac amyloidosis (CA). MATERIALS AND METHODS: Twenty-six patients with CA underwent CMR, including magnetic phase imaging with a 3.0-T magnetic resonance imaging scanner. Myocardial susceptibility was quantified as a phase shift slope value by magnetic phase analysis. Those values from patients with CA were compared with corresponding values from 18 controls and 15 healthy volunteers. A univariate logistic regression analysis was conducted to identify significant parameters related to CA. RESULTS: The phase shift slope, a quantitative parameter of myocardial susceptibility, was significantly lower in the CA group compared with the control group and compared with healthy volunteers (p < 0.01). From a total of 17 tested variables, 6 were considered to be significant predictors of CA (p ≤ 0.05) during the univariate analysis. The phase shift slope yielded the best AUC of 0.89 (95% CI = 0.79-0.98) for the prediction of CA (p < 0.01). The phase shift slope was significantly correlated with the end-diastolic thickness of the interventricular septum (r = - 0.39, p < 0.01) and posterior wall of the left ventricle (r = - 0.35, p = 0.02). CONCLUSION: Myocardial susceptibility analysis by CMR helps in the diagnosis of patients with CA and can be a new quantitative imaging biomarker for CA.

The appearance of magnetic susceptibility objects in SWI phase depends on object size: Comparison with QSM and CT.

PURPOSE: Tissue magnetic susceptibility sign can potentially be detected on susceptibility weighted imaging (SWI) phase (SW-P). This study aims to investigate its performance for depicting brain susceptibility structures. METHODS: A simulation was performed to depict magnetic susceptibility structures of various geometries on SW-P and quantitative susceptibility mapping (QSM). Brain MRI was performed on 25 subjects using SWI on a 3 T MRI system. QSM was generated from the same data. SW-P and QSM were analyzed according to radiological assessment for depicting globus pallidus nuclei, optic radiation white matter tracts, and lateral ventricular choroid plexus calcifications. In 11 of these subjects, CT was available and correlated with SW-P and QSM to assess their performance in quantifying calcifications in the choroid plexus. RESULTS: In simulation, the appearance of a sphere on SW-P ranged from centric nodule to mixed positive and negative values as the diameter increased. Large cylinders also appeared as mixed positive and negative values. In comparison, QSM correctly depicted the susceptibility distribution of all magnetic structures. On human brain images, SW-P depicted the globus pallidus and optic radiation with mixed positive and negative values, consistent with simulation, and small choroid plexus calcifications as either mixed positive and negative values or as centric nodules; QSM depicted all structures as solid structures with the expected signs. For measuring calcification in the choroid plexus, QSM vs CT linear regression had a higher coefficient of determination compared to SW-P vs CT and SW-P vs QSM. CONCLUSION: Appearance of susceptibility sources on SW-P changes with object size. This problem can be overcome using QSM.

Signal intensity of cerebral gyri in corticobasal syndrome on phase difference enhanced magnetic resonance images: Comparison of progressive supranuclear palsy and Parkinson's disease.

We evaluated cerebral gyri (CG) on phase difference enhanced imaging (PADRE) of corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and Parkinson's disease (PD) patients to determine whether it is possible to discriminate among them on an individual basis. Two radiologists reviewed appearance of the normal CG and that of CBS patients on PADRE, and deviations from the appearance of the normal CG were recorded. Next, based on the CG abnormalities, two other reviewers reviewed PADRE images from 12 CBS, 14 PSP, and 30 PD patients. In healthy subjects on the PADRE images, the signal intensity (SI) of the gray matter (GM) was homogeneously, slightly hyperintense to the subcortical white matter (SCWM), and the SI of the SCWM was homogeneously hypointense. In CBS patients, hypointense layer in superficial GM and disappearance of hypointense in SCWM. The frequency of the abnormal findings on PADRE in the blinded manner by two readers was 100% (12/12), 3% (1/30), and 29% (4/14 in Reader 1) or 36% (5/14 in Reader 2) in CBS PD, and PSP patients, respectively. Laterality of the PADRE findings was showed in 12 (100%) CBS patients and 3 (21%) PSP, but not in any PD patients. The previously reported typical findings in CBS on conventional magnetic resonance image (MRIs) were observed in only 42% (5/12) of CBS patients. In conclusion, the abnormal findings in CG on PADRE appears more useful than conventional MRI findings for discriminating CBS from PD on an individual basis.

Evaluation of Analytical Precision of Polychromatic Simultaneous WDXRF Spectrometer and Application to Valence Analysis of Cathode Materials of Lithium-Ion Batteries.

A polychromatic simultaneous wavelength-dispersive X-ray fluorescence (PS-WDXRF) spectrometer can measure the valence changes of 3d transition metals with high precision in the laboratory. Adjustment and maintenance of the drive mechanism are unnecessary, and high-precision measurements are possible in a short time because the optical system has no moving parts and is compact. We have developed a PS-WDXRF spectrometer with improved analytical precision that can measure simultaneously the valence changes of three main elements, Mn, Co, and Ni, which are used as cathode materials in Li-ion batteries (LIBs). In this study, the analytical precision of the spectrometer is evaluated, and its precision is confirmed with actual battery cathodes. The identification precision of the fluorescent X-ray peak energy is <0.015 eV, and the valence identification precision is obtained to be <0.06. LiNi0.5Co0.2Mn0.3O2 (NCM523)-based LIB cathodes are analyzed under conditions maintaining this precision, and the valence changes of the 3d transition metals in NCM523 during charging and discharging are found to be 0.68 for Ni, 0.19 for Co, and 0.08 for Mn. These results indicate that Ni contributes the most to the redox process in NCM523-based LIBs, Co contributes slightly, and Mn does not contribute.

Differentiation of Brain Metastases and Gliomas Based on Color Map of Phase Difference Enhanced Imaging.

Background and objective: Phase difference enhanced imaging (PADRE), a new phase-related MRI technique, can enhance both paramagnetic and diamagnetic substances, and select which phases to be enhanced. Utilizing these characteristics, we developed color map of PADRE (Color PADRE), which enables simultaneous visualization of myelin-rich structures and veins. Our aim was to determine whether Color PADRE is sufficient to delineate the characteristics of non-gadolinium-enhancing T2-hyperintense regions related with metastatic tumors (MTs), diffuse astrocytomas (DAs) and glioblastomas (GBs), and whether it can contribute to the differentiation of MTs from GBs. Methods: Color PADRE images of 11 patients with MTs, nine with DAs and 17 with GBs were created by combining tissue-enhanced, vessel-enhanced and magnitude images of PADRE, and then retrospectively reviewed. First, predominant visibility of superficial white matter and deep medullary veins within non-gadolinium-enhancing T2-hyperintense regions were compared among the three groups. Then, the discriminatory power to differentiate MTs from GBs was assessed using receiver operating characteristic analysis. Results: The degree of visibility of superficial white matter was significantly better in MTs than in GBs (p = 0.017), better in GBs than in DAs (p = 0.014), and better in MTs than in DAs (p = 0.0021). On the contrary, the difference in the visibility of deep medullary veins was not significant (p = 0.065). The area under the receiver operating characteristic curve to discriminate MTs from GBs was 0.76 with a sensitivity of 80% and specificity of 64%. Conclusion: Visibility of superficial white matter on Color PADRE reflects inferred differences in the proportion of vasogenic edema and tumoral infiltration within non-gadolinium-enhancing T2-hyperintense regions of MTs, DAs and GBs. Evaluation of peritumoral areas on Color PADRE can help to distinguish MTs from GBs.

Characteristic phase distribution in the white matter of infants on phase difference enhanced imaging.

BACKGROUND AND PURPOSE: The infantile brain is continuously undergoing development. Non-invasive methods to assess the neurological development of infants are important for the early detection of abnormalities. Some microstructures in the brain have been demonstrated via phase difference-enhanced imaging (PADRE), which may reflect myelin-related microstructures. We aimed to assess the white matter (WM) signal distribution in infants using PADRE and compared it with that using T1-weighted images (T1WI) and diffusion tensor imaging (DTI) on magnetic resonance imaging (MRI). MATERIALS AND METHOD: This study included 18 infants (postmenstrual age at MRI, 37-40 weeks) without abnormal findings on MRI. Signal distribution using T1WI, a fractional anisotropy (FA) map and PADRE was assessed regarding the following intraparenchymal structures: the optic radiation (OR), internal capsule (IC), corpus callosum, corticospinal tract (CST), semiovale center and subcortical regions. RESULTS: We found that the signal distribution was significantly different (P<0.001) with a relatively large signal change found at the IC and CST across the three imaging methods. Signal changes were also greater at the OR and rolandic subcortical WM on PADRE, whereas these were smaller on T1WI and FA. CONCLUSION: PADRE demonstrated a characteristic phase shift distribution in infantile WM, which was different from that observed on T1WI and FA maps, and may demonstrate the developing myelin-related structures. PADRE can be a unique indicator of infantile brain development.

Differentiating between Alzheimer Disease Patients and Controls with Phase-difference-enhanced Imaging at 3T: A Feasibility Study.

PURPOSE: To test the feasibility of the phase difference enhanced (PADRE) imaging for differentiation between Alzheimer disease (AD) patients and control subjects on 3T MR imaging. MATERIALS AND METHODS: Fifteen patients with AD and 10 age-matched control subjects underwent two-dimensional fast field echo imaging to obtain PADRE images on a 3T MR scanner. A double Gaussian distribution model was used to determine the threshold phase value for differentiation between the physiologic and non-physiologic iron in the cerebral cortices, and PADRE images were processed with the threshold. Using a 4-point grading system, two readers independently assessed the signal of the four cerebral cortices on PADRE images: the cuneus, precuneus, superior frontal gyrus, and superior temporal gyrus. The difference in the signals in each cortex between the AD patients and age-matched control subjects was determined by using Mann-Whitney U test. Inter-rater reliability was determined by Kappa analysis. We also evaluated the correlation between Mini-Mental State Examination (MMSE) score and the hypointense grade, and between disease duration and the hypointense grade using the Spearman rank correlation test. RESULTS: The threshold phase value for differentiation between the physiologic and non-physiologic iron was -4.6% π (radian). The mean grades of the cuneus, precuneus, and superior temporal gyrus were significantly higher for the AD patients than for the control subjects (P = 0.002). Excellent inter-rater reliability was seen in the precuneus (kappa = 0.93), superior temporal gyrus (kappa = 0.94), and superior frontal gyrus (kappa = 0.93); good inter-rater reliability was observed in the cuneus (kappa = 0.75). We found a statistical correlation between MMSE score and the hypointense grade in superior temporal gyrus (STG) (P = 0.008), and no correlation between disease duration and the hypointense grade in any gyrus. CONCLUSION: Our results suggest the feasibility of PADRE imaging at 3T for differentiation between AD patients and control subjects.

In vitro Study of Serial Changes to Carmustine Wafers (Gliadel) with MR Imaging and Computed Tomography.

PURPOSE: Implantation of carmustine wafers (Gliadel) in vivo is accompanied by characteristic serial changes on MRI and CT, such as transient hyperintensity of the wafers on T1-weighted images (T1WIs) and considerable gas accumulation in surgical resection cavities. The purpose of this study was to evaluate intrinsic imaging changes to carmustine wafers in vitro. METHODS: Three phantoms simulating a surgical resection cavity were constructed. Each contained either a carmustine wafer fixed with oxidized regenerated cellulose and fibrin sealant, an unfixed carmustine wafer, or a fixed polyethylene control disk, immersed in phosphate-buffered saline. Image acquisition of the phantoms was performed on MRI and CT until 182 days after construction. The radiological appearances of the object in each phantom were assessed by visual evaluation and quantification of the region of interest. The volume of gas around the objects at 24 h after constructing the phantoms was also measured. RESULTS: The carmustine wafers showed low signal intensities on T1WIs and T2-weighted images (T2WIs), and high densities on CT images at 24 h. The signal intensities and CT densities gradually approximated those of saline over a period of months. However, the carmustine wafers never showed hyperintensity on T1WIs in vitro. The fixed carmustine wafer showed slower radiological changes, as compared to the unfixed wafer. The gas volume around the fixed carmustine wafer was greater than that around the fixed control disk. CONCLUSION: Changes to the carmustine wafers probably reflected penetration of fluid inside and degradation of the hydrophobic matrix. Reported transient hyperintensity of wafers on T1WIs in vivo is regarded as the result of biological reactions, whereas the initial production of gas is considered as an intrinsic characteristic of wafers.

Tolvaptan-Type Vasopressin Receptor Ligands: Important Role of Axial Chirality in the Active Form.

The anti and syn isomers of tolvaptan-type compounds, N-benzoyl-5-hydroxy-1-benzazepines (5a-c), were prepared in a stereocontrolled manner by biasing the conformation with a methyl group at C9 and C6, respectively, and the enantiomeric forms were separated. Examination of the affinity at the human vasopressin receptors revealed that the axial chirality (aS) plays a more important role than the central chirality at C5 in receptor recognition, and the most preferable form was shown to be (E,aS,5S).

Improving contrast enhancement in magnetic resonance imaging using 5-aminolevulinic acid-induced protoporphyrin IX for high-grade gliomas.

Magnetic resonance imaging (MRI) with a gadolinium-based contrast agent is the gold standard for high-grade gliomas (HGGs). The compound 5-aminolevulinic acid (5-ALA) undergoes a high rate of cellular uptake, particularly in cancer cells. In addition, fluorescence-guided resection with 5-ALA is widely used for imaging HGGs. 5-ALA is water soluble, while protoporphyrin IX (PpIX) is water insoluble. It was speculated whether converting from 5-ALA to PpIX may relatively increase intracellular water content, and consequently, might enhance the T2 signal intensity in HGG. The aim of the present study was to assess whether 5-ALA-induced PpIX enhances the T2 signal intensity in patients with HGGs. A total of 4 patients who were candidates for HGG surgical treatment were prospectively analyzed with preoperative MRI. Patients received oral doses of 5-ALA (20 mg/kg) 3 h prior to anesthesia. At 2.5 h post-5-ALA administration, T2-weighted images (T2WIs) were obtained from all patients. Subsequently, tumors were evaluated via fluorescence using a modified operating microscope. Fluorescent tumor tissues were obtained to analyze the accumulation of 5-ALA-induced PpIX within the tumors, which was confirmed quantitatively by high-performance liquid chromatography (HPLC) analysis. The MRI T2 signal intensity within the tumors was evaluated prior to and following 5-ALA administration. Three glioblastoma multiformes (GBMs) and 1 anaplastic oligodendroglioma (AO) were included in the analysis. Intraoperatively, all GBMs exhibited strong fluorescence of 5-ALA-induced PpIX, whilst no fluorescence was observed in the AO sample. HPLC analysis indicated a higher accumulation of 5-ALA-induced PpIX in the GBM samples compared with the AO sample. In total, 48 regions of interest were identified within the tumors from T2-WIs. In the GBM group, the relative T2 signal intensity value within the tumors following 5-ALA administration was significantly increased compared with the T2 signal intensity value prior to 5-ALA administration (1.537±0.021 and 1.577±0.023, respectively; P=0.0055). No significant differences were observed in the AO group. These results suggest that the 5-ALA-induced PpIX enhanced the T2 signal intensity in HGG. Therefore, 5-ALA may be a potentially useful MRI contrast reagent for HGG.

Identification of Heschl's gyrus on phase difference enhanced imaging.

Background The white matter in the Heschl's gyrus (HG-WM) may appear differently to the other gyri on phase difference enhanced imaging (PADRE), which can enhance the myelin density. Purpose To evaluate the signal intensity (SI) of HG-WM using the PADRE technique and to compare the images with susceptibility-weighted imaging (SWI)-like images. Material and Methods The participants included 19 normal controls (38 HGs; mean age, 60.1 years; age range, 28-80 years). Coronal PADRE and SWI-like images were acquired using a 3T magnetic resonance (MR) system. The SI of the HG-WM was classified into three grades based on a comparison with the SI of the superior temporal gyrus: Grade 1, isointense; Grade 2, slightly hypointense, and Grade 3, markedly hypointense. Results In the assessment of the SI of the HG-WM, the HG-WM appeared hypointense in all 38 sites of the 19 participants; the hypointensity corresponded to Grade 2 in 13 (34%) images and Grade 3 in 25 (66%) images. On the other hand, the HG-WM was classified as Grade 1 (isointense) in all of the SWI-like images. Conclusion The HG-WM appears hypointense on PADRE, which probably reflects the higher myelin content. PADRE may be useful for identifying the HG through the assessment of the SI of the HG-WM.

Internal Structures of the Globus Pallidus in Patients with Parkinson's Disease: Evaluation with Phase Difference-enhanced Imaging.

PURPOSE: The medial medullary lamina (MML) separates the medial globus pallidus (GPm) from the lateral. The aim of this study was to assess the changes in appearance of MML related to age using the phase difference-enhanced (PADRE) imaging and to determine whether PADRE can depict the MML in the patients with Parkinson's disease (PD). MATERIALS AND METHODS: We enrolled 20 patients with PD and 50 normal control subjects (NC). First, for the visualization of the MML in the NC, we compared the PADRE, susceptibility-weighted imaging (SWI)-like images and T2 weighted imaging (WI) by using multiple comparison. The grading methods are as follows: grade 1; MML was not delineated, grade 2; less than half of MML was delineated, grade 3; more than half of MML was delineated and grade 4; whole MML was clearly delineated. We determined grade 3 and 4 as good depiction, delineating the GPm. Then, we evaluated patients with PD using the same method. RESULTS: In NC, the delineation of MML was good in 84% of cases on PADRE, but only 34% of cases showed a good depiction on SWI-like images (average grading score 3.31 vs 2.11, P < 0.05). No MML was delineated in all cases on T2 WI. Although younger subjects tended to show whole MML clearly, a part of MML tends to be obscured with age on PADRE. In patients with PD the depiction of MML on PADRE was also good in 90% of cases. CONCLUSION: The PADRE technique facilitates the depiction of the MML within globus pallidus (GP) on a broad range of age NC and patients with PD and it is superior to SWI-like images and T2 WI.

Low putamen activity associated with poor reward sensitivity in childhood chronic fatigue syndrome.

Motivational signals influence a wide variety of cognitive processes and components of behavioral performance. Cognitive dysfunction in patients with childhood chronic fatigue syndrome (CCFS) may be closely associated with a low motivation to learn induced by impaired neural reward processing. However, the extent to which reward processing is impaired in CCFS patients is unclear. The aim of the present functional magnetic resonance imaging (fMRI) study was to determine whether brain activity in regions related to reward sensitivity is impaired in CCFS patients. fMRI data were collected from 13 CCFS patients (mean age, 13.6 ± 1.0 years) and 13 healthy children and adolescents (HCA) (mean age, 13.7 ± 1.3 years) performing a monetary reward task. Neural activity in high- and low-monetary-reward conditions was compared between CCFS and HCA groups. Severity of fatigue and the reward obtained from learning in daily life were evaluated by questionnaires. Activity of the putamen was lower in the CCFS group than in the HCA group in the low-reward condition, but not in the high-reward condition. Activity of the putamen in the low-reward condition in CCFS patients was negatively and positively correlated with severity of fatigue and the reward from learning in daily life, respectively. We previously revealed that motivation to learn was correlated with striatal activity, particularly the neural activity in the putamen. This suggests that in CCFS patients low putamen activity, associated with altered dopaminergic function, decreases reward sensitivity and lowers motivation to learn.

Stereochemistry of N-Benzoyl-5-substituted-1-benzazepines Revisited: Synthesis of the Conformationally Biased Derivatives and Revision of the Reported Structure.

The syn (aR*,5R*) and anti (aS*,5R*) diastereomers of N-benzoyl-C5-substituted-1-benzazepines originating in the chiralities at C5 and the Ar-N(C═O) axis were first stereoselectively synthesized by biasing the conformation with a substituent at C6 and C9, respectively. Detailed examination of the stereochemistry (i.e., conformation and configuration) of these N-benzoyl-1-benzazepines by X-ray crystallographic analysis, VT NMR, and DFT calculations revealed new physicochemical aspects of these heterocycles including revision of the stereochemistry previously reported.