Phase-field Determination of NaSICON Materials in the Quaternary System Na2 O-P2 O5 -SiO2 -ZrO2 : The Series Na3 Zr3-x Si2 Px O11.5+x/2.

Two types of solid electrolytes have reached technological relevance in the field of sodium batteries: ß/ß"-aluminas and NaSICON-type materials. Today, significant attention is paid to room-temperature stationary electricity storage technologies and all-solid-state Na batteries used in combination with these solid electrolytes are an emerging research field besides sodium-ion batteries. In comparison, NaSICON materials can be processed at lower sintering temperatures than the ß/ß"-aluminas and have a similarly attractive ionic conductivity. Since Na2 O-SiO2 -ZrO2 -P2 O5 ceramics offer wider compositional variability, the series Na3 Zr3-x Si2 Px O11.5+x/2 with seven compositions (0≤x≤3) was selected from the quasi-quaternary phase diagram in order to identify the predominant stability region of NaSICON within this series and to explore the full potential of such materials, including the original NaSICON composition of Na3 Zr2 Si2 POl2 as a reference. Several characterization techniques were used for the purpose of better understanding the relationships between processing and properties of the ceramics. X-ray diffraction analysis revealed that the phase region of NaSICON materials is larger than expected. Moreover, new ceramic NaSICON materials were discovered in the system crystallizing with a monoclinic NaSICON structure (space group C2/c). Impedance spectroscopy was utilized to investigate the ionic conductivity, giving clear evidence for a dependence on crystal symmetry. The monoclinic NaSICON structure showed the highest ionic conductivity with an optimum ionic conductivity of 1.22×10-3 at 25 °C for the composition Na3 Zr2 Si2 PO12 . As the degree of P5+ content increases, the total ionic conductivity is initially enhanced until x=1 and then decreases again. Simultaneously, the increasing amount of phosphorus leads a decrease in the sintering temperatures for all samples, which was confirmed by dilatometry measurements. The thermal and microstructural properties of the prepared samples are also evaluated and discussed.

Cognitive anosognosia is associated with frontal dysfunction and lower depression in Parkinson's disease.

BACKGROUND AND PURPOSE: Anosognosia refers to a deficit of self-awareness or impaired insight for cognitive and behavioral problems. Cognitive anosognosia was explored in de novo patients with Parkinson's disease (PD) and its relationship to cognitive function and neuropsychiatric symptoms was investigated. METHODS: The cross-sectional study enrolled 340 drug-naïve patients with PD. According to the presence of mild cognitive impairment (MCI) and subjective cognitive complaint, patients were classified as patients with cognitive anosognosia (PD-CA, n = 74), with normal cognitive recognition (PD-NR, n = 184) or with cognitive underestimation (PD-CU, n = 82). After controlling for covariates, cognitive performance and neuropsychiatric symptoms were compared between the PD groups. RESULTS: Cognitive anosognosia was found in 21.8% of patients with de novo PD. The PD-CA group showed poorer performance in all cognitive domains except for attention. Amongst PD patients with MCI, those with cognitive anosognosia showed lower composite z-scores in the Stroop color reading test than those without. The Beck Depression Inventory score in the PD-NR group was lower than that in the PD-CU group and higher than that in the PD-CA group. The Cognitive Complaints Interview score mediated the association between cognitive anosognosia and Beck Depression Inventory score. CONCLUSIONS: Cognitive anosognosia in PD was associated with greater frontal dysfunction and lower depression. Since cognitive anosognosia has a harmful impact on PD patients and their caregivers due to overestimation of their abilities in everyday life, early identification of cognitive anosognosia in PD is important in management and prognosis.

Sex-dependent association of urate on the patterns of striatal dopamine depletion in Parkinson's disease.

BACKGROUND AND PURPOSE: The aim was to investigate the relationship between the serum urate (UA) levels and patterns of striatal dopamine depletion in patients with de novo Parkinson's disease (PD). METHODS: In all, 167 de novo PD patients who underwent 18 F-fluorinated N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane positron emission tomography scans were enrolled. After quantifying dopamine transporter (DAT) availability in each striatal subregion, sex-dependent patterns of striatal dopamine depletion were analysed by measuring (i) dopamine depletion in the other striatal subregions and posterior putamen (intersubregional ratio, ISR) and (ii) the interhemispheric asymmetry of dopamine depletion in the posterior putamen (asymmetric ratio, AR). RESULTS: The interaction analysis revealed a significant interaction effect of sex and serum UA levels on the ISR but not on the AR. The ISR was negatively correlated with the serum UA levels in all patients with PD (r = -0.156, P = 0.045), and this association was more prominent in male PD patients (r = -0.422, P < 0.001). However, no significant association between the AR and serum UA levels was found in any of the patients. In addition, serum UA levels were significantly associated with DAT availability in the posterior putamen on both the more affected side (r = 0.312, P = 0.005) and the less affected side (r = 0.312, P = 0.005) only in male PD patients. CONCLUSIONS: The present study demonstrated the potentially close sex-specific relationship between the serum UA levels and the anterior-posterior gradient of DAT patterns, suggesting a sex-specific protective effect of UA on nigrostriatal dopaminergic neurons in de novo PD.

Sex-specific association of urate and levodopa-induced dyskinesia in Parkinson's disease.

BACKGROUND AND PURPOSE: As a major antioxidant, uric acid (UA) is known to be associated with the clinical progression of Parkinson's disease (PD). This study investigated whether baseline UA levels are associated with the risk for levodopa-induced dyskinesia (LID) in PD in a sex-dependent manner. METHODS: In all, 152 patients with de novo PD (78 males and 74 females) who were followed up for >2 years were enrolled. The effect of baseline serum UA levels on LID-free survival was assessed by Cox regression, separately for sex, whilst being adjusted for potential confounding factors. The optimal UA level cut-off value to determine the high-risk group for LID was set using Contal and O'Quigley's method. RESULTS: Levodopa-induced dyskinesia developed in 23 (29.5%) male patients and 30 (40.5%) female patients. Cox regression showed a significant interaction between UA level and sex. Higher UA levels were associated with a higher risk for LID in male PD patients (hazard ratio 1.380; 95% confidence interval 1.038-1.835; P = 0.027), although this relationship was not observed in female PD patients. The optimal UA level cut-off for LID in male PD was 7.2 mg/dl, and the high UA group had a 5.7-fold higher risk of developing LID than the low UA group. CONCLUSIONS: Contrary to a presumptive beneficial role of UA, the present study demonstrated that higher UA levels are associated with increased risk of LID occurrence in male patients with PD, suggesting a sex-dependent role of UA in LID.

Effects of Alzheimer's disease and Lewy body disease on subcortical atrophy.

BACKGROUND AND PURPOSE: Subcortical structures are affected by neurodegeneration in Alzheimer's disease (AD) and Lewy body disease (LBD). Although the co-occurrence of AD and LBD pathologies and their possible interaction have been reported, the effect of AD and LBD on subcortical structures remains unknown. The effects of AD and LBD on subcortical atrophy and their relationship with cognitive dysfunction were investigated. METHODS: The cross-sectional study recruited 42 patients with pure AD related cognitive impairment (ADCI), 30 patients with pure LBD related cognitive impairment (LBCI), 58 patients with mixed ADCI and LBCI, and 29 normal subjects. A general linear model was used to compare subcortical volume and shape amongst the groups, to investigate the independent and interaction effects of ADCI and LBCI on subcortical shape and volume, and to analyze the relationship between subcortical volume and cognitive dysfunction in each group. RESULTS: Alzheimer's disease related cognitive impairment and LBCI were independently associated with subcortical atrophies in the hippocampus and amygdala and in the hippocampus and putamen respectively, but their interaction effect was not significant. Compared to the control group, the pure LBCI group exhibited additional local atrophies in the amygdala, caudate and thalamus. Subcortical atrophies correlated differently with cognitive dysfunction according to the underlying causes of cognitive dysfunction. CONCLUSIONS: The patterns of subcortical atrophies and their correlation with cognitive dysfunction differ according to the underlying AD, LBD or concomitant AD and LBD.

Clinical relevance of amnestic versus non-amnestic mild cognitive impairment subtyping in Parkinson's disease.

BACKGROUND AND PURPOSE: To clarify whether subtyping of amnestic and non-amnestic mild cognitive impairment (MCI) is clinically relevant in Parkinson's disease (PD) by analyzing patterns of neuroimaging and longitudinal cognitive changes. METHODS: We performed comparative analyses of cortical thickness, hippocampal volume, white matter integrity and resting-state functional connectivity between the patients with de-novo PD with amnestic MCI (PD-aMCI) (n = 50) and non-amnestic MCI (PD-naMCI) (n = 50) subtypes. Additionally, we assessed the longitudinal rate of cognitive decline in each cognitive domain over time and the rate of dementia conversion in patients with de-novo PD-aMCI (n = 125) and PD-naMCI (n = 61). RESULTS: The demographic data showed that scores in memory domains were lower in the PD-aMCI group compared with the PD-naMCI group. There were no significant differences in cortical thickness, hippocampal volume and white matter integrity between the two groups, although the PD-aMCI group exhibited more cortical thinning and hippocampal atrophy relative to the control group. The PD-aMCI group exhibited increased functional connectivity in the left posterior parietal region with the salience network relative to the PD-naMCI group. The longitudinal cognitive assessment demonstrated that patients with PD-aMCI exhibited a more rapid cognitive decline in frontal/executive function than those with PD-naMCI (P = 0.022). In addition, the PD-aMCI group had a higher risk of dementia conversion than the PD-naMCI group. CONCLUSIONS: This study suggests that the designation of PD-MCI subtypes based on memory function would highlight the heterogeneity of functional correlates as well as the longitudinal cognitive prognosis.

Rapid eye movement sleep behaviour disorder and striatal dopamine depletion in patients with Parkinson's disease.

BACKGROUND AND PURPOSE: Rapid eye movement sleep behaviour disorder (RBD) is related to striatal dopamine depletion. This study was performed to confirm whether clinically probable RBD (cpRBD) in patients with Parkinson's disease (PD) is associated with a specific pattern of striatal dopamine depletion. METHODS: A prospective survey was conducted using the RBD Screening Questionnaire (RBDSQ) in 122 patients with PD who had undergone dopamine transporter (DAT) positron emission tomography scan. RESULTS: Patients with cpRBD (RBDSQ ≥ 7) exhibited greater motor deficits, predominantly in the less-affected side and axial symptoms, and were prescribed higher levodopa-equivalent doses at follow-up than those without cpRBD (RBDSQ ≤ 4), despite their similar disease and treatment durations. Compared to patients without cpRBD, those with cpRBD showed lower DAT activities in the putamen, particularly in the less-affected side in all putaminal subregions, and a tendency to be lower in the ventral striatum. In addition, greater motor deficits in patients with cpRBD than in those without cpRBD remained significant after controlling for DAT binding in the putamen and other confounding variables. CONCLUSIONS: These results demonstrated that the presence of RBD in patients with PD is associated with different patterns of both motor deficit distribution and striatal DAT depletion, suggesting that the presence of RBD represents a distinct PD subtype with a malignant motor parkinsonism.

Volumetric analysis of the cerebellum in patients with progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Although early cerebellar symptoms are one of the exclusive criteria in the diagnosis of progressive supranuclear palsy (PSP), cerebellar involvement in PSP is evident both clinically and pathologically. However, structural analysis focusing on the cerebellum has not been previously studied in patients with PSP. We aimed to evaluate cerebellar involvement in PSP using a magnetic resonance imaging-based segmental volumetric analysis. METHODS: We retrospectively enrolled 48 patients with PSP composed of 25 patients with PSP-Richardson's syndrome (RS) and 23 patients with pure akinesia with gait freezing, 39 patients with Parkinson's disease (PD) and 34 healthy controls. Data on both the whole and segmented cerebellar volumes were analyzed using a fully automated procedure. RESULTS: A general linear model showed that whole cerebellar volume in patients with PSP was significantly smaller compared with that of patients with PD or controls after controlling for age, sex and intracranial volume (P = 0.34). In addition, patients with PSP exhibited decreased regional volume in the crus I, lobule VIIIa and lobule VIIIb, which play roles as secondary representations of motor tasks, compared with patients with PD or controls. In subgroup analysis of PSP, volume loss in the whole and segmental cerebellum was more pronounced in patients with PSP-RS than in those with pure akinesia with gait freezing, PD or control subjects. CONCLUSION: These data demonstrate that cerebellar atrophy is evident in patients with PSP and is especially prominent in the PSP-RS group. These findings increase understanding of the clinicopathological basis of cerebellar involvement in PSP.

Comparison of 3D and 2D shear-wave elastography for differentiating benign and malignant breast masses: focus on the diagnostic performance.

AIM: To evaluate the diagnostic performance of three-dimensional (3D) image shear-wave elastography (SWE) for differentiating benign from malignant breast masses compared to two-dimensional (2D) SWE and B-mode ultrasound (US). MATERIALS AND METHODS: This study consisted of 205 breast lesions from 199 patients who underwent B-mode US and SWE before biopsy from January 2014 to March 2016. Quantitative elasticity values (maximum and mean elasticity, Emax and Emean) obtained from 2D and 3D SWE (axial, sagittal, and coronal images) were reviewed retrospectively, in addition to the histopathological findings including immunohistochemistry profiles (luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and triple-negative breast cancer) in cases of malignancy. Histopathological findings were regarded as the reference standard. The diagnostic performance of each data set was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC) analysis to compare sensitivity and specificity. RESULTS: Among 205 lesions, 105 (51.22%) were malignant and 100 (48.78%) were benign. Compared to benign masses, malignant masses had higher values of Emax and Emean on both 2D and 3D SWE, the differences of which were statistically significant (p<0.001). The AUCs of 2D, 3D axial, and sagittal SWE were significantly higher than that of 3D coronal SWE (p<0.05). In addition, the sensitivities of axial, sagittal, and coronal 3D SWE were all higher than that of 2D SWE for Emean (81.9%, 87.6%, and 89.5% versus 70.5%, respectively, p<0.05). Conversely, the specificity of 2D and 3D axial SWE was higher than that of 3D sagittal and coronal SWE (Emax, 84%, 83% versus 76%, 73%; Emean, 85%, 81% versus 68%, 50%, respectively, p<0.05). We also assessed changes in Breast Imaging-Reporting and Data System (BI-RADS) category 3 and category 4a lesions by adding each of the parameters for 2D and 3D SWE in B-mode US. The specificity, PPV, and accuracy of combined 2D or combined 3D SWE with B-mode US was statistically higher than that of B-mode US alone for differentiating benign and malignant lesions (p<0.05). CONCLUSIONS: Among SWE images, 2D SWE, and 3D SWE axial and sagittal images exhibited superior diagnostic performance compared to 3D coronal images. Addition of 3D SWE images to B-mode US improved the diagnostic performance for distinguishing benign from malignant masses.

Does serum uric acid act as a modulator of cerebrospinal fluid Alzheimer's disease biomarker related cognitive decline?

BACKGROUND AND PURPOSE: The association of serum uric acid, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and longitudinal cognitive decline was evaluated using the AD Neuroimaging Initiative database. METHODS: In 271 healthy subjects, 596 mild cognitive impairment patients and 197 AD patients, serum uric acid and CSF AD biomarkers were measured at baseline, and Mini-Mental State Examination and AD Assessment Scale - Cognitive Subscale (ADAS-cog) were assessed serially (mean duration, 2.9 years). The effect of uric acid on longitudinal cognitive decline was evaluated using linear mixed effect models for Mini-Mental State Examination and ADAS-cog scores in female and male subjects separately, with possible confounders controlled (model 1). To determine the effects of uric acid independent of CSF biomarker (Aß1-42 or tau) and to test whether the detrimental effects of CSF biomarker differ according to uric acid, CSF biomarker and its interaction with uric acid were further included in model 1 (model 2). RESULTS: Higher levels of uric acid were associated with slower cognitive decline, particularly in the mild cognitive impairment and dementia subgroups, and more prominently in female subjects. Model 2 with CSF Aß1-42 showed that higher levels of uric acid were associated with a slower cognitive decline and alleviated the detrimental effect of Aß1-42 on cognitive decline. Model 2 with CSF tau showed that higher levels of uric acid alleviated the detrimental effect of tau on cognitive decline in female subjects but not in male subjects. CONCLUSION: Higher levels of uric acid had protective effects on longitudinal cognitive decline independent of and interactively with CSF AD biomarkers.

Differentiation of benign and metastatic axillary lymph nodes in breast cancer: additive value of MRI computer-aided evaluation.

AIM: To retrospectively determine the qualitative and quantitative cut-off values of the magnetic resonance computer-aided evaluation (MR CAE) parameters to differentiate between benign and metastatic axillary lymph nodes (ALNs) and to investigate the combined diagnostic performance of MR CAE imaging. MATERIALS AND METHODS: From July 2011 to June 2014, 124 patients who underwent preoperative conventional MR, diffusion-weighted (DW), and MR CAE imaging were included. Computer-generated qualitative and quantitative features for ALNs were recorded, and two breast imaging radiologists interpreted the MR images for the presence of metastatic ALNs using conventional MR and DW, and in combination with MR CAE images by consensus. The cut-off values of MR CAE and diagnostic performance were derived from the receiver operating characteristic (ROC) curve. RESULTS: Thirty-four (26.4%) were ALN positive and 90 (73.6%) were ALN negative on the final histopathological result. On qualitative analysis, visualization on the colour map (p=0.007) and kinetic curve type (p<0.001) were significantly different between the groups. On quantitative analysis, mean values (%) of persistent, plateau, and washout ratios differed significantly (p<0.001). Of these significant parameters, a washout ratio of >49% showed the greatest diagnostic accuracy (area under the ROC curve, 0.909). With conventional MR and DW images, sensitivity, specificity, and accuracy were 82.4%, 85.6%, and 84.7%, respectively. With added information from MR CAE images, accuracy significantly improved to 93.5% (p=0.043). The sensitivity and specificity improved to 91.2% (p=0.403) and 94.4% (p=0.086), respectively. CONCLUSION: The additive use of MR CAE improved diagnostic performance and can be helpful for differentiating benign from metastatic ALNs.

Nanofluidics of Single-Crystal Diamond Nanomechanical Resonators.

Single-crystal diamond nanomechanical resonators are being developed for countless applications. A number of these applications require that the resonator be operated in a fluid, that is, a gas or a liquid. Here, we investigate the fluid dynamics of single-crystal diamond nanomechanical resonators in the form of nanocantilevers. First, we measure the pressure-dependent dissipation of diamond nanocantilevers with different linear dimensions and frequencies in three gases, He, N2, and Ar. We observe that a subtle interplay between the length scale and the frequency governs the scaling of the fluidic dissipation. Second, we obtain a comparison of the surface accommodation of different gases on the diamond surface by analyzing the dissipation in the molecular flow regime. Finally, we measure the thermal fluctuations of the nanocantilevers in water and compare the observed dissipation and frequency shifts with theoretical predictions. These findings set the stage for developing diamond nanomechanical resonators operable in fluids.

MAGNETOCALORIC RESPONSE OF NON-STOICHIOMETRIC Ni2MnGa ALLOYS AND THE INFLUENCE OF CRYSTALLOGRAPHIC TEXTURE.

Currently, there is significant interest in magnetocaloric materials for solid state refrigeration. In this work, polycrystalline Heusler alloys belonging to the Ni2+xMn1-xGa family, with x between 0.08 and 0.24, were evaluated for the purpose of finding composition(s) with an enhanced magnetocaloric effect (MCE) close to room temperature. Differential scanning calorimetry (DSC) was successfully used to screen alloy composition for simultaneous magnetic and structural phase transformations; this coupling needed for a giant MCE. The alloy with x = 0.16 showed an excellent match of transformation temperatures and exhibited the highest magnetic entropy change, ΔSM, in the as-annealed state. Furthermore, the MCE increased by up to 84 % with a 2 Tesla (T) field change when the samples were thermally cycled through the martensite to austenite transformation temperature while held under a constant mechanical load. The highest ΔSM measured for our x = 0.16 alloy for a 2 T magnetic field change was -18 J/kg-K. Texture measurements suggest that preferential orientation of martensite variants contributed to the enhanced MCE in the stress-assisted thermally cycled state.

The burden of white matter hyperintensities is a predictor of progressive mild cognitive impairment in patients with Parkinson's disease.

BACKGROUND AND PURPOSE: To evaluate whether white matter hyperintensities (WMHs) may act as an independent predictor for progression of cognitive status, the authors analyzed the longitudinal effects of WMHs on cognitive dysfunction in non-demented patients with Parkinson's disease (PD). METHODS: A total of 111 patients with PD were enrolled, including subjects with mild cognitive impairment (MCI, n = 65) and cognitively normal subjects (CN, n = 46). These individuals were classified as MCI converters (n = 22) or MCI non-converters (n = 43) and CN converters (n = 18) or CN non-converters (n = 28) based on whether they were subsequently diagnosed with PD dementia or PD-MCI during a minimum 24-month follow-up. The WMH burden and the Cholinergic Pathway Hyperintensities Scale (CHIPS) and their relationships to longitudinal changes in cognitive performance were examined. RESULTS: PD-MCI converters had larger WMH volume (14421.0 vs. 5180.4, P < 0.001) and higher CHIPS score (22.6 vs. 11.2, P = 0.001) compared with PD-MCI non-converters. Logistic regression analysis revealed in patients with PD-MCI that WMH volume (odds ratio 1.616, P = 0.009) and CHIPS score (odds ratio 1.084, P = 0.007) were independently associated with PD dementia conversion. However, WMH volume and CHIPS score did not differ between PD-CN converters and PD-CN non-converters. In patients with PD-MCI, both WMH volume and CHIPS score were closely associated with longitudinal decline in general cognition, semantic fluency and Stroop test scores. CONCLUSIONS: The present study demonstrates that WMH burden is a significant predictor of conversion from PD-MCI to PD dementia and is related to ongoing decline in frontal-lobe-based cognitive performance.

Impact of preoperative bilateral whole breast sonography in patients with invasive lobular carcinoma: results from two medical centers.

PURPOSE: The purpose of this study was to evaluate the sensitivity of bilateral whole breast sonography (BWBS) combined with mammography for the detection of additional lesions, as well as index lesions, in patients with invasive lobular carcinoma (ILC) and to evaluate the impact of BWBS on surgical treatment and cancer staging strategies. MATERIALS AND METHODS: We retrospectively reviewed mammographic and sonographic records of 97 patients with proven ILCs between November 2002 and November 2009. We evaluated the sensitivity of mammography and BWBS for the detection of additional and index lesions. We compared the impact of BWBS on surgical treatment and breast cancer staging between cases with single index lesions and with BWBS-detected additional lesions and index lesions. We compared the differences in sensitivity, surgical treatment procedures and breast cancer staging between BWBS and MRI confined to the patients underwent MRI. RESULTS: The overall sensitivity was 74.4% (93/125 lesions) for mammography and 96.0% (120/125 lesions) for BWBS (p < 0.001). The group with additional lesions detected using US alone exhibited more frequent mastectomy (p = 0.003) and higher N staging (p = 0.051) than did the group with single index lesions. Comparing the BWBS and MRI cases, there were no significant differences in lesion staging, the sensitivity of malignant foci detection (p = 0.074). CONCLUSION: BWBS has a higher sensitivity than does mammography for the detection of index and additional ILC. Detection of additional malignancies using BWBS could affect which strategy is chosen for surgical treatment.

Comparison and correlation analysis of different Swine breeds meat quality.

This study was performed to determine the influence of pig breed and gender on the ultimate pH and physicochemical properties of pork. The correlations between pH and pork quality traits directly related to carcass grade, and consumer's preference were also evaluated. The pH and meat grading scores for cold carcasses of 215 purebred pigs (Duroc, Landrace, and Yorkshire) from four different farms were obtained. Meat quality parameters of the pork loin were analyzed. Duroc and female animals were more affected compared to other breeds and male pigs. Duroc animals had the highest ultimate pH, carcass back fat thickness, marbling scores, yellowness, and fat content (p<0.05). Landrace pigs had the highest color lightness and cooking loss values (p<0.05). Among all trait parameters, marbling scores showed the highest significant differences when evaluating the impact of breed and gender on meat quality characteristics (p<0.001). Ultimate pH was positively correlated with carcass weight (0.20), back fat thickness (0.19), marbling score (0.17), and color score (0.16) while negatively correlated with cooking loss (-0.24) and shear force (-0.20). Therefore, pork samples with lower ultimate pH had lower cooking loss, higher lightness, and higher shear force values irrespective of breed.

Identification of 11 novel mutations in 49 Korean patients with mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (MPS II) or Hunter syndrome is a rare lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS). As MPS II is X-linked, patients are usually males with heterogeneous mutations ranging from point mutations to gross deletions and recombination. In 2003, we reported a mutation analysis of 25 patients with MPS II. In this study, 31 mutations in another 49 Korean patients (45 families) with MPS II are reported: 12 missense, nine deletions, four splicing, two nonsense, two insertions, one deletion/insertion, and IDS-IDS2 recombination mutations. Among these mutations, 11 were novel ones (4 missense mutations: Ser61Pro, Pro97Arg, Pro228Ala, and Pro261Ala; 5 deletions: c.344delA, c.420delG, c.768delT, c.1112delC and c.1402delC; 1 deletion/insertion: c.1222delinsTA; and 1 insertion mutation: c.359_360insATCC). The IDS-IDS2 recombination mutations were most frequently observed; all patients with this mutation had the severe MPS II phenotype. However, most of the patients (5/7) with the G374G splicing mutation had an attenuated phenotype, except for two sibling cases with the severe phenotype. Except for a few recurrent mutations such as the G374G, R443X, L522P, and recombination mutations, each patient had a unique individual mutation. Therefore, careful interpretation of genotype-phenotype correlations is warranted.

Identification of a novel HLA-DRB1 allele, DRB1*11:95.

The DRB1*11:95 showed a single nucleotide difference with the DRB1*11:01:01 allele at codon 10 (TAC/TGC).

A processed HLA-A*24:02 pseudogene found in the peripheral blood of a father and his son.

We encountered a case that exhibited a discrepancy in human leukocyte antigen-A (HLA-A) type determined by sequence-based typing (SBT) and sequence-specific primer (SSP) molecular typing. The child of this case was identified as A* 02:01 homozygote and A* 02, A* 24, respectively. The HLA-A type of his father was A* 02:01, 26:01, but low-resolution SSP also showed unexpected amplification with A* 24 primers as with the child. Serologic typing of the child and the father was A2/blank and A2/A26, respectively. Sequencing analysis of the A* 24 variant in the child and the father showed a complete deletion of all introns of the A* 24:02 allele. Though rare, this type of processed pseudogene variant can be one of the causes of discrepancies between high- and low-resolution HLA typing.

MICB polymorphisms and haplotypes with MICA and HLA alleles in Koreans.

Major histocompatibility complex (MHC) class I chain-related gene B (MICB) is located within the human MHC class I region. The location of MICB in the MHC region may imply the presence of linkage disequilibrium with polymorphic MICA and human leukocyte antigen (HLA) loci. MICB is also polymorphic; however, MICB polymorphisms have not been investigated in Koreans. Using sequence-based typing (SBT), we estimated the allelic frequencies of MICB and haplotypes with MICA, HLA-B, and HLA-DRB1 at high resolution in a population of 139 unrelated Korean individuals. Eight MICB alleles were identified. The most frequent allele was MICB*005:02/*010 (57.2%), followed by *002 (11.5%), *004 (8.3%), *005:03 (8.3%), and *008 (6.8%). The most common two-locus haplotypes were MICB*005:02/*010-MICA*010 (19.4%), MICB*005:02/*010-DRB1*15:01 (6.5%), and MICB*005:02/*010-B*15:01 (10.4%); the most common three-locus haplotypes were B*15:01-MICA*010-MICB*005:02/*010 (5.8%) and MICA*010-MICB*005:02/*010-DRB1*04:06 (10.4%); and the most common four-locus haplotype was B*15:01-MICA*010-MICB*005:02/*010-DRB1*04:06 (5.8%). This is the first study to provide information about MICB allele frequencies and haplotypes with HLA in Koreans. These study results should help understand mechanisms of disease association between the MICB locus and neighboring loci in Koreans.