Profiles of Globotriaosylsphingosine Analogs and Globotriaosylceramide Isoforms Accumulated in Body Fluids from Various Phenotypic Fabry Patients.

Objectives Fabry disease is characterized by the systemic accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3), which are widely used as biomarkers of the disease. However, few reports have described the relationship of Lyso-Gb3 analogs and Gb3 isoforms with the disease. The present study determined the profiles of Lyso-Gb3 analogs and Gb3 isoforms accumulated in body fluids from various phenotypic Fabry patients to elucidate the basis of the disease. Methods Plasma Lyso-Gb3 and related analogs were measured in 15 classic Fabry men, 6 later-onset Fabry men, 11 Fabry women, and 36 controls, while urinary Gb3 isoforms were measured in 5 classic Fabry men, 5 later-onset Fabry men, 17 Fabry women, and 11 controls, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Furthermore, these values were monitored for a classic Fabry man, in whom neutralizing anti-drug antibodies had developed following enzyme replacement therapy (ERT). Results The levels of plasma Lyso-Gb3 analogs/urinary Gb3 isoforms were higher in Fabry patients than in controls, especially in classic Fabry men. However, minor differences in the ratio of each Lyso-Gb3 analog and Gb3 isoform with respect to the total Lyso-Gb3 analogs and Gb3 isoforms, respectively, were observed among individual classic Fabry men. Their time courses were well associated with the development and attenuation of anti-drug antibodies in a patient with classic Fabry disease during ERT. Conclusion Quantification of Lyso-Gb3 analogs and Gb3 isoforms provides us with more detailed information about the substrates that accumulated in the body fluids of Fabry patients than does quantification of Lyso-Gb3 and Gb3 alone, so this approach may be useful for elucidating the basis of Fabry disease.

Monitoring of anti-drug antibodies and disease-specific biomarkers in three patients from a Japanese Fabry family treated with enzyme replacement therapy.

We monitored anti-drug antibodies and disease-specific biomarkers in three patients with a nonsense mutation from a Japanese Fabry family treated with enzyme replacement therapy (ERT). In two male patients from the family, neutralizing anti-drug antibodies were induced at an early stage of ERT, the antibody titer peak being found at an earlier stage of ERT in the patient treated with 1.0 mg/kg agalsidase beta than in that treated with 0.2 mg/kg agalsidase alfa. Then, the antibody titers decreased with continuation of ERT. The formation of neutralizing anti-drug antibodies adversely affected the plasma globotriaosylsphingosine (Lyso-Gb3) level and urinary globotriaosylceramide (Gb3) excretion in both patients, the impact being greater in the patient treated with 0.2 mg/kg agalsidase alfa than in that treated with 1.0 mg/kg agalsidase beta. The difference might be explained by the different doses of the infused enzymes based on supersaturation of the antibodies. In a heterozygous Fabry female from the family, no sign of antibody formation was found, and both the plasma Lyso-Gb3 level and urinary Gb3 excretion, which were moderately increased at the baseline, decreased gradually. No deterioration of the manifestations or laboratory findings was observed during ERT in either of the patients. Thus, monitoring of anti-drug antibodies and biomarkers in these Fabry patients provided us with important information on their pathological condition during ERT.

Relative abundance of Megamonas hypermegale and Butyrivibrio species decreased in the intestine and its possible association with the T cell aberration by metabolite alteration in patients with Behcet's disease (210 characters).

OBJECTIVES: We have previously demonstrated that the phylum Actinobacteria, the family Lactobacillaceae, and the genus Bifidobacterium increased in relative abundance of gut microbiota in patients with Behcet's disease (BD). The phylum Firmicutes and the class Clostridia were predominant in the feces of normal individuals. The class Clostridia includes short-chain fatty acid-producing bacteria, important for the balance between regulatory T cells and helper T type 17 (Th17) cells. It is possible that the bacterial compositional alteration causes low intestinal short-chain fatty acid concentrations, leading to skewed immune functions in patients with BD. METHODS: To test the hypothesis, we examined species composition and gene functions from the 16S rRNA data by utilizing PICRUSt software. RESULTS: We have shown that relative abundance of Eggerthella lenta, Acidaminococcus species, Lactobacillus mucosae, Bifidobacterium bifidum, Lactobacillus iners, Streptococcus species, and Lactobacillus salivarius increased significantly in patients with BD. Relative abundance of Megamonas hypermegale, Butyrivibrio species, Streptococcus infantis, and Filifactor species increased significantly in normal individuals compared with BD patients. In the functional annotation analysis by PICRUSt, we found prevalent gene functions of the pentose phosphate pathway and the inosine monophosphate biosynthesis in patients with BD. The data suggested that BD gut microbes altered nucleic acid and fatty acid synthesis. CONCLUSIONS: These compositional and functional alterations of gut microbes may accompany unfavorable molecular exchanges between intestinal immunocompetent cells and gut microbes, and these interactions may have an association with the immune aberration in patients with BD.

Propionate-producing bacteria in the intestine may associate with skewed responses of IL10-producing regulatory T cells in patients with relapsing polychondritis.

Relapsing polychondritis (RP) is an inflammatory disease of unknown causes, characterized by recurrent inflammation in cartilaginous tissues of the whole body. Recently, researchers have reported that, in mouse experiments, altered gut microbe-dependent T cell differentiation occurred in gut associated lymphoid tissues. Here, we investigated whether gut microbe alteration existed, and if so, the alteration affected peripheral T cell differentiation in patients with RP. In an analysis of gut microbiota, we found increased annotated species numbers in RP patients compared with normal individuals. In the RP gut microbiota, we observed several predominant species, namely Veillonella parvula, Bacteroides eggerthii, Bacteroides fragilis, Ruminococcus bromii, and Eubacterium dolichum, all species of which were reported to associate with propionate production in human intestine. Propionate is a short-chain fatty acid and is suggested to associate with interleukin (IL)10-producing regulatory T (Treg) cell differentiation in gut associated lymphoid tissues. IL10 gene expressions were moderately higher in freshly isolated peripheral blood mononuclear cells (PBMC) of RP patients than those of normal individuals. Six hours after the initiation of the cell culture, regardless of the presence and absence of mitogen stimulation, IL10 gene expressions were significantly lower in RP patients than those in normal individuals. It is well known that PBMC of patients with autoimmune and inflammatory diseases show hyporesponsiveness to mitogen stimulation. We suggest that, in RP patients, continuous stimulation of intestinal T cells by excessive propionate leads to the spontaneous IL10 production and a subsequent refractory period of T cells in patients with RP. The hyporesponsiveness of Treg cells upon activation may associate with inflammatory cytokine production of PBMC and subsequently relate to chondritis in RP patients.

Bifidobacteria Abundance-Featured Gut Microbiota Compositional Change in Patients with Behcet's Disease.

Gut microbiota compositional alteration may have an association with immune dysfunction in patients with Behcet's disease (BD). We conducted a fecal metagenomic analysis of BD patients. We analyzed fecal microbiota obtained from 12 patients with BD and 12 normal individuals by sequencing of 16S ribosomal RNA gene. We compared the relative abundance of bacterial taxa. Direct comparison of the relative abundance of bacterial taxa demonstrated that the genera Bifidobacterium and Eggerthella increased significantly and the genera Megamonas and Prevotella decreased significantly in BD patients compared with normal individuals. A linear discriminant analysis of bacterial taxa showed that the phylum Actinobacteria, including Bifidobacterium, and the family Lactobacillaceae exhibited larger positive effect sizes than other bacteria in patients with BD. The phylum Firmicutes and the class Clostridia had large effect sizes in normal individuals. There was no significant difference in annotated species numbers (as numbers of operational taxonomic unit; OTU) and bacterial diversity of each sample (alpha diversity) between BD patients and normal individuals. We next assigned each sample to a position using three axes by principal coordinates analysis of the OTU table. The two groups had a significant distance as beta diversity in the 3-axis space. Fecal sIgA concentrations increased significantly in BD patients but did not correlate with any bacterial taxonomic abundance. These data suggest that the compositional changes of gut microbes may be one type of dysbiosis (unfavorable microbiota alteration) in patients with BD. The dysbiosis may have an association with the pathophysiology of BD.

Assessment of the accuracy and reliability of new 3-dimensional scanning devices.

INTRODUCTION: The primary objective of this study was to assess the accuracy and the reliability of the SureSmile OraScanner (Orametrix, Richardson, Tex) by comparing it with other desktop 3-dimensional scanners: VIVID910 (Konica Minolta, Tokyo, Japan) and R700 (3Shape, Copenhagen, Denmark). A laser-based scanner, the SLP250 Laser Probe (Laser Design, Detroit, Mich), served as the gold standard. METHODS: Five sets of dental casts were used. First, the accuracy of each scanner was studied by comparing the 3-dimensional models created by OraScanner, VIVID910, and R700 with the gold standard 3-dimensional models of the SLP250. To assess the reliability of the 3-dimensional models, the shell/shell deviation of each model was calculated based on the same surface-based registrations for all 5 sets of dental casts. RESULTS: OraScanner, VIVID910, and R700 were sufficiently accurate when compared with the gold standard. In the assessment of reliability, there were no significant differences between all comparisons. CONCLUSIONS: The results showed that the OraScanner system has a sophisticated algorithm for 3-dimensional surface registration and can be used to generate accurate and reliable 3-dimensional digital models for use by clinicians.

A successfully treated case of hyperosmolar hyperglycemic state complicated with rhabdomyolysis, acute kidney injury, and ischemic colitis.

A 48-year-old Japanese male was admitted to our hospital due to hyperosmolar hyperglycemic state (HHS), combined with rhabdomyolysis and acute kidney injury. His blood sugar levels were gradually decreased by fluid resuscitation and insulin infusion; however, his renal function worsened, and he developed bloody stools. He required continuous hemodiafiltration to improve his hemodynamics. As colonoscopy revealed longitudinal ulcers, ischemic colitis was diagnosed. We treated him conservatively at first, but when we found the ulceration of the sigmoid colon had penetrated the mesenterium, colectomy was indicated. After surgery, his general condition improved. Careful monitoring of complications related to HHS is important.

Intense F-18 FDG accumulation in idiopathic tumoral calcinosis.

An elderly Japanese woman presented to our hospital with a 5-month history of a growing mass on her right cheek. She did not complain of local pain, headache, hearing difficulty, or tinnitus. CT and MRI showed a dense calcified mass and F-18 fluorodeoxyglucose (FDG) PET demonstrated intense accumulation in the mass. Resection of the mass was performed and it was histologically diagnosed as idiopathic tumoral calcinosis.

Is it possible to define salvageable ischemic penumbra using semiquantitative rCBF levels derived from MR perfusion-weighted imaging?

INTRODUCTION: The purpose of this study was to test if magnetic resonance (MR) perfusion-weighted imaging (PWI) can reliably characterize the ischemic penumbra. MATERIALS AND METHODS: Sixteen patients with nonlacunar ischemic stroke who were scanned within 24 h after onset of symptoms were selected for the study. In previous studies, the level of regional cerebral blood flow (rCBF) in the normal white matter of the contralateral hemisphere was defined as 22 ml/100 g/min. We used this level as a standard of reference. We hypothesized that rCBF below this level would be amenable to infarct. The lesion-to-white matter ratios of rCBF were measured in the regions of ischemic core ("Core"), infarcted penumbra ("Growth"), salvaged penumbra ("Reversed"), and contralateral normal cortex ("Normal"). RESULTS: The rCBF of "Growth" and "Reversed" areas showed substantial overlap, which hampered the delineation of areas that would become infarcted. CONCLUSION: The semiquantitative rCBF derived from MR PWI may not accurately characterize the ischemic penumbra.

Effect of vascular stenosis on perfusion-weighted imaging; differences between calculation algorithms.

PURPOSE: To determine the most suitable postprocessing technique for magnetic resonance (MR) perfusion imaging in patients with vascular stenosis, by comparing the cerebral blood flow (CBF) maps of single photon emission tomography (SPECT) and perfusion MR imaging (MRI). MATERIALS AND METHODS: In 15 consecutive patients (14 men and one woman, mean age 73.9 +/- 6.0 years) with stenosis of common carotid artery (CCA) or internal carotid artery (ICA) of more than 75%, both brain perfusion MRI and brain perfusion SPECT were performed. From perfusion MR images, CBF maps were calculated with the first moment, singular value decomposition (SVD), and block circulant SVD (b-SVD) methods, and CBF maps from each algorithm were compared with those from SPECT. RESULTS: The b-SVD method had the best correlation with SPECT (R = 0.814), followed by the first moment method (R = 0.776) and the SVD method (R = 0.723). The b-SVD method has the least mean difference with SPECT (0.118), the first moment method also had less difference (0.121), and the SVD had greatest mean difference (0.164). CONCLUSION: Our results suggest that in patients with vascular impairment the b-SVD method will be the technique of choice rather than SVD or first moment method.

The pyramidal tract has a predictable course through the centrum semiovale: a diffusion-tensor based tractography study.

PURPOSE: To identify reproducible anatomical landmarks that would allow predicting the course of the pyramidal tract (PT) through centrum semiovale. MATERIALS AND METHODS: A total of 20 normal volunteers (12 males, eight females) with a mean age of 34 years (range, 20-59 years) were scanned using a 1.5-Tesla clinical MR unit to assess the trajectory of the PT. Neuroanatomical characteristics of the PT passing through the centrum semiovale were assessed by two independent observers. Tractography data of 10 consecutive patients with brain tumor were used to test the precision of anatomy-based prediction of the tract location. RESULTS: On sagittal view, 95% of the PT depicted on tractography displayed a completely straight or primarily straight course through the supratentorial brain. In 98% of tracts, the bending point of the PT was identified < or = 3 mm from the level of the anterior commissure-posterior commissure (AC-PC) plane. In 80% of PT, the intersection with the AC-PC plane occurred midway between the AC and the PC as seen on the sagittal view. Evaluation of the PT in 10 patients with brain tumor revealed that the anatomy-based prediction of PT on the contralesional hemisphere was not substantially deviated from the actual tractography depicted PT. PT on the lesional hemispheres, however, had deviations of various degrees. CONCLUSION: The course of the PT through supratentorial brain can be predicted based on easily identifiable landmarks. This anatomy-based prediction can be clinically applied for cases without substantial mass effect from a space occupying lesion.

Decreased cerebral blood flow and prognosis of Alzheimer's disease: a multicenter HMPAO-SPECT study.

PURPOSE: To determine the usefulness of brain perfusion SPECT for evaluating the severity and progression of Alzheimer's disease (AD). METHODS: Eighty-four AD patients were included. At entry, 99mTc-HMPAO-SPECT, the Mini Mental State Examination (MMSE), Mental Function Impairment Scale (MENFIS), and the Raven Colored Progression Matrix (RCPM) were performed for all 84 patients. During the follow-up periods, two individual MMSE evaluations in 34 patients, two MENFIS evaluations in 30 patients, and two RCPM evaluations in 20 patients were performed. Based on the regions of decreased cerebral blood flow demonstrated on 3D-SSP images of SPECT, the cases were classified as type A (no decrease), type B (decreased blood flow in the parietal or temporal lobe), type C (decreased blood flow in the frontal lobe and parietal or temporal lobe), type Pc (decreased blood flow in posterior cingulate gyrus only), and "other types". The types of decreased blood flow, scores on neuropsychological evaluations, and symptom progression were analyzed. RESULTS: The MENFIS, MMSE, and RCPM scores were poorest in type C patients at entry. The degree of decrease of these scores during the follow-up periods was also greatest in type C. The greatest difference between patients with and without rapid progression in SPECT data of the mild AD patients (MMSE score > or = 24) was in the frontal lobe. CONCLUSION: Decreased blood flow in the frontal lobe of AD patients is correlated not only with reduced cognitive function at the time of the evaluation but with rapid progression in the subsequent clinical course.

Somatotopic organization of thalamocortical projection fibers as assessed with MR tractography.

PURPOSE: To prospectively evaluate the course of sensory fibers through the supratentorial brain with diffusion-tensor-based tractography. MATERIALS AND METHODS: This study was approved by the institutional review board. Informed consent was obtained. Seven healthy volunteers (five men, two women; age range, 20-55 years) underwent 1.5-T magnetic resonance imaging. Diffusion-tensor images with isotropic voxels (2 x 2 x 2 mm) were obtained by using a single-shot echo-planar imaging technique, with a motion-probing gradient in 15 orientations, a b value of 1000 sec/mm(2), and nine signals acquired. The total imaging time was approximately 30 minutes. Fiber tracking of the sensorimotor pathways was performed with the fiber assignment by continuous tracking method. RESULTS: All the pyramidal tracts rotated anteriorly as they traveled through the centrum semiovale. On the other hand, the sensory tracts rotated posteriorly as they coursed through the centrum semiovale toward the cortex. When the sensorimotor tracts were viewed as a unit, the tracts of the lower extremity formed the axis of rotation around which the other parts of the pyramidal and sensory homunculus rotated. CONCLUSION: Sensorimotor fibers of the lower extremity form an axis of rotation, around which the pyramidal fibers rotate anteriorly and the sensory fibers rotate posteriorly.

Diagnosis of breast tumors by contrast-enhanced MR imaging: comparison between the diagnostic performance of dynamic enhancement patterns and morphologic features.

PURPOSE: To compare the diagnostic performance of breast lesions by the enhancement patterns and morphologic criteria on magnetic resonance imaging (MRI). MATERIALS AND METHODS: Both T1-weighted 3D gradient-echo sequences with high temporal resolution and high-spatial-resolution MRI were performed on 190 patients with a total of 204 enhancing lesions (144 malignant and 60 benign). The enhancement patterns and morphologic features of each mass and nonmass lesion were analyzed, and the diagnostic performance was compared. RESULTS: The sensitivity and specificity of the morphologic criteria were statistically significantly higher than those of the enhancement patterns (sensitivity: P = 0.0012, specificity: P = 0.0003), and the A(z) values for the three observers were 0.900, 0.919, and 0.900. The diagnostic accuracy of the morphologic criteria for both types of lesions was superior, and the differences were statistically significant (mass: P = 0.0001, nonmass: P = 0.0389). CONCLUSION: The analysis of the morphologic features of enhancing breast lesions alone showed higher diagnostic performance; therefore, signal intensity (SI) time-course data may not be needed to diagnose malignant breast lesions.

Regional cerebral blood flow in Alzheimer's disease: comparison between short and long-term donepezil therapy.

OBJECTIVE: Treatment with donepezil improves cognitive function of patients with Alzheimer's disease (AD) when compared to a placebo-controlled group. The purpose of this study was to investigate changes in regional cerebral blood flow (rCBF) of AD patients in short-term and long-term treatment with donepezil. METHODS: rCBF was measured by N-isopropyl-p-123I-iodoamphetamine (IMP) autoradiography method. CBF measurements were performed in 17 AD patients before treatment and after 3 months (short-term therapy) and 1 year (long-term therapy). Regions of interest were set at cerebral cortex and cerebellar hemisphere. We used absolute CBF and relative CBF expressed as ratio to cerebellar CBF. RESULTS: Significant increases in relative rCBF were noted in the frontal, parietal and temporal lobes at the end of short-term therapy. rCBF was decreased after the long-term therapy, whereas rCBF was still increased to a slight extent, as compared with the pre-treatment levels. Absolute rCBF showed minimal change and a tendency to decline. CONCLUSION: Relative rCBF significantly increased in the short-term donepezil therapy, while following the long-term therapy, rCBF decreased to the pre-treatment level.

Age-related changes in the hemodynamics of the femoral head as evaluated by early phase of bone scintigraphy.

OBJECTIVE: The femoral head is reported to be in a markedly hypoemic state as compared with other tissues even under normal conditions, and it is therefore necessary to understand its hemodynamics to investigate the pathogenesis of hip disorders. It is known that aspects of intraosseous hemodynamics including blood flow and blood pool can be evaluated soon after radioisotope administration. In this study, hemodynamic changes in the femoral head according to gender and age were examined by investigating accumulation of radioisotope in the tissue during the early phase of bone scintigraphy. METHODS: The subjects of this study consisted of 58 joints of 31 men and 75 joints of 41 women, whose ages ranged from 15 to 87 years (average age: 67.9 years). Images of bone scintigraphy were obtained for 15 to 20 minutes at 5 minutes and at 3 hours after radioisotope administration. The ratio of accumulation in the femoral head to that in the diaphysis (head-to-diaphysis ratio, HD ratio) was calculated. RESULTS: HD ratios obtained 15-20 minutes later ranged from 0.01 to 7.35 (1.88 +/- 0.91, mean +/- SD). HD ratios decreased with age, and a significant inverse correlation was observed between age and HD ratio, demonstrating a correlation coefficient of -0.27 (p = 0.001). The HD ratio among men was 0.01-3.57 (1.66 +/- 0.71), while that among women was 0.53-7.35 (2.05 +/- 1.01), and a significant difference was observed in HD ratio between men and women (p = 0.02). There was a significant difference in HD ratios between men and women in their teens to forties (p = 0.03), while no significant differences was observed in the other age groups.. HD ratios obtained 3 hours later ranged from 0.44 to 6.32 (1.95 +/- 0.79, mean +/- SD), and no significant correlation was observed between age and HD ratio, demonstrating a correlation coefficient of -0.14. CONCLUSION: The present study demonstrated that blood flow and blood pool of the femoral head decrease with aging particularly in women. This hemodynamic deterioration of the femoral head caused by aging may have an effect on the onset and progression of hip disorders by influencing bone metabolism.