Search

Fanconi syndrome and chronic kidney disease associated with paroxysmal nocturnal hemoglobinuria is rarely reported. We describe a 51-year-old woman with glomerular filtration rate decrease and hypokalemia, glucosuria, and proteinuria during a 4-year period. Paroxysmal nocturnal hemoglobinuria was diagnosed 17 years earlier, and she has received multiple blood transfusions because of hemolytic episodes during the last 5 years. Deteriorating kidney function and persistent Fanconi syndrome were accompanied by a progressive increase in serum ferritin levels. Laboratory studies showed proximal renal tubular acidosis, hypophosphotemic hyperphosphaturia, normoglycemic glucosuria, and aminoaciduria. Serologic testing, tumor markers, Bence-Jones protein, and heavy-metal screening results were negative. Abdominal magnetic resonance imaging showed characteristic features of iron deposition in the bilateral renal cortices. Kidney biopsy showed chronic interstitial nephritis with prominent hemosiderin deposition in the proximal tubules. With potassium citrate, calcitriol, and deferoxamine therapy, Fanconi syndrome persisted, but kidney function was stable. Renal hemosiderosis secondary to both chronic repetitive hemolytic episodes and transfusion-related iron overload in patients with paroxysmal nocturnal hemoglobinuria can lead to Fanconi syndrome and chronic kidney disease. [ABSTRACT FROM AUTHOR]

Background: Antibody-mediated rejection (AMR) often leads to chronic kidney allograft damage and is a critical cause of allograft failure. The Banff classification, used to diagnose AMR, has become complex and challenging for clinicians. A Banff-based histologic chronicity index (CI) was recently proposed as a simplified prognostic indicator. Its reliability and reproducibility have not been externally validated., Methods: This study investigated 71 kidney allograft biopsies diagnosed with AMR. Interobserver reproducibility of the recently proposed CI and its components (cg, cv, ct, and ci) were assessed. The association between CI and allograft failure was analyzed, and CI cut-off values were evaluated by Cox proportional hazards regression and Kaplan-Meier estimator with log-rank test., Results: The study confirmed the association of CI with allograft failure, but also revealed that the assessment of CI varied between pathologists, impacting its reproducibility as a prognostic tool. Only 49 (69.0%) of the biopsies showed complete agreement on the proposed cut-off value of CI < 4 or CI ≥ 4. Furthermore, this cut-off did not reliably stratify allograft failure. Notably, the cg score, which carries significant weight in the CI calculation, had the lowest agreement between observers (kappa = .281)., Conclusions: While a simplified prognostic indicator for AMR is needed, this study highlights the limitations of CI, particularly its poor interobserver reproducibility. Our findings suggest that clinicians should interpret CI cautiously and consider establishing their own cut-off values. This study underscores the need to address interobserver reproducibility before CI can be widely adopted for AMR management., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Lupus nephritis (LN), a common manifestation of systemic lupus erythematosus, is associated with a higher risk of kidney failure and death. The renal pathology of LN helps elucidate the severity of inflammation and the extent of irreversible damage. We aimed to identify histologic variables that correlate with risks of kidney failure and mortality., Methods: Between 2006 and 2019, a total of 526 patients with LN were enrolled. Renal pathology was classified according to the International Society of Nephrology/Renal Pathology Society classification. Components of activity and chronicity indices were analyzed to determine which variables correlated with an increased risk of kidney failure and death, with the adjustment of potential confounders., Results: During the follow-up period (median 7.5, IQR 3.5-10.7 years), 58 patients progressed to kidney failure and 64 died. In the multivariate Cox regression analysis, tubular atrophy (hazard ratio [HR] 2.28, 95% CI 1.66-3.14) and tubulointerstitial inflammation (HR 3.13, 95% CI 1.34-7.33) predicted kidney failure. The renal outcome was even worse if tubular atrophy and tubulointerstitial inflammation coexisted (10-year kidney survival rate: 63.22%). The presence of cellular crescents was associated with an increased risk of death in male patients with LN (HR 1.91, 95% CI 1.02-3.57), whereas the presence of fibrous crescents predicted death in female patients with LN (HR 5.70, 95% CI 1.61-20.25)., Conclusion: Histologic variables of renal biopsy in LN could be regarded as prognostic indicators for kidney failure and mortality., (Copyright © 2023 by the Journal of Rheumatology.)

Interstitial fibrosis assessment by renal pathologists lacks good agreement, and we aimed to investigate its hidden properties and infer possible clinical impact. Fifty kidney biopsies were assessed by 9 renal pathologists and evaluated by intraclass correlation coefficients (ICCs) and kappa statistics. Probabilities of pathologists' assessments that would deviate far from true values were derived from quadratic regression and multilayer perceptron nonlinear regression. Likely causes of variation in interstitial fibrosis assessment were investigated. Possible misclassification rates were inferred on reported large cohorts. We found inter-rater reliabilities ranged from poor to good (ICCs 0.48 to 0.90), and pathologists' assessments had the worst agreements when the extent of interstitial fibrosis was moderate. 33.5% of pathologists' assessments were expected to deviate far from the true values. Variation in interstitial fibrosis assessment was found to be correlated with variation in interstitial inflammation assessment (r 2  = 32.1%). Taking IgA nephropathy as an example, the Oxford T scores for interstitial fibrosis were expected to be misclassified in 21.9% of patients. This study demonstrated the complexity of the inter-rater reliability of interstitial fibrosis assessment, and our proposed approaches discovered previously unknown properties in pathologists' practice and inferred a possible clinical impact on patients., (© 2023. Springer Nature Limited.)

Extraskeletal myxoid chondrosarcoma (EMC) is an ultrarare sarcoma typically exhibiting myxoid/reticular histology and NR4A3 translocation. However, morphologic variants and the relevance of non-EWSR1::NR4A3 fusions remain underexplored. Three challenging pan-Trk-expressing cases, featuring cellular to solid histology, were subjected to RNA exome sequencing (RES), unveiling different NR4A3-associated fusions. Alongside RES-analyzed cases, fluorescence in situ hybridization was performed to confirm 58 EMCs, with 48 available for pan-Trk immunostaining and KIT sequencing. Except for 1 (2%) NR4A3-rearranged EMC without identifiable partners, 46 (79%), 9 (16%), and 2 (3%) cases harbored EWSR1::NR4A3, TAF15::NR4A3, and TCF12::NR4A3 fusions, respectively. Five EWSR1::NR4A3-positive EMCs occurred in the subcutis (3) and bone (2). Besides 43 classical cases, there were 8 cellular, 4 rhabdoid/anaplastic, 2 solid, and 1 mixed tumor-like variants. Tumor cells were oval/spindle to pleomorphic and formed loose myxoid/reticular to compact sheet-like or fascicular patterns, imparting broad diagnostic considerations. RES showed upregulation of NTRK2/3, KIT, and INSM1. Moderate-to-strong immunoreactivities of pan-Trk, CD117, and INSM1 were present in 35.4%, 52.6%, and 54.6% of EMCs, respectively. KIT p. E554K mutation was detected in 2/48 cases. TAF15::NR4A3 was significantly associated with size >10 cm (78%, P = .025). Size >10 cm, moderate-to-severe nuclear pleomorphism, metastasis at presentation, TAF15::NR4A3 fusion, and the administration of chemotherapy portended shorter univariate disease-specific survival, whereas only size >10 cm (P = .004) and metastasis at presentation (P = .032) remained prognostically independent. Conclusively, EMC may manifest superficial or osseous lesions harboring EWSR1::NR4A3, underrecognized solid or anaplastic histology, and pan-Trk expression, posing tremendous challenges. Most TAF15::NR4A3-positive cases were >10 cm in size, ie, a crucial independent prognosticator, whereas pathogenic KIT mutation rarely occurred., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

This study investigated the effects of a minor Zr addition (0.15 wt%) and heterogenization treatment (one-stage/two-stage) on the hot-working temperature and mechanical properties in Al-4.9Cu-1.2Mg-0.9Mn alloy. The results indicated that the eutectic phases (α-Al + θ-Al 2 Cu + S-Al 2 CuMg) dissolved after heterogenization, retaining θ-Al 2 Cu and τ 1 -Al 29 Cu 4 Mn 6 phases, while the onset melting temperature increased to approximately 17 °C. A change in the onset melting temperature and evolution of the microstructure is used to assess an improvement in hot-working behavior. With the minor Zr addition, the alloy exhibited enhanced mechanical properties due to grain growth inhibition. Zr-added alloys show 490 ± 3 MPa ultimate tensile strength and 77.5 ± 0.7 HRB hardness after T4 tempering, compared to 460 ± 2.2 MPa and 73.7 ± 0.4 HRB for un-added alloys. Additionally, combining minor Zr addition and two-stage heterogenization resulted in finer Al 3 Zr dispersoids. Two-stage heterogenized alloys had an average Al 3 Zr size of 15 ± 5 nm, while one-stage heterogenized alloys had an average size of 25 ± 8 nm. A partial decrease in the mechanical properties of the Zr-free alloy was observed after two-stage heterogenization. The one-stage heterogenized alloy had 75.4 ± 0.4 HRB hardness after being T4-tempered, whereas the two-stage heterogenized alloy had 73.7 ± 0.4 HRB hardness after being T4-tempered.

Background: The incidence of post-transplant lymphoproliferative disorder (PTLD) in adult kidney transplant (KTx) recipients is less common in Taiwan. In our institute, we observed that brain lymphoma was the most notorious type., Methods: The study describes the clinical, histologic, and radiological features of primary central nervous lymphoma (PCNSL) and the outcomes and associations with Epstein-Barr virus (EBV) infection in our center., Results: Among 1470 KTx recipients, 5 patients had tissue-proven brain lymphoma (0.34%). The brain pathology disclosed diffuse large B-cell lymphoma in all patients. EBV was detected through in situ hybridization for Epstein-Barr encoding region (EBER) to disclose the EBV inclusion in the nuclei of lymphoma cells. The first treatment step was the reduction of immunosuppressants; 4 patients received whole-brain radiotherapy after complete resection of PCNSL, and 1 received concurrent chemoradiotherapy. Only one patient had poor performance status at the time of diagnosis and had a poor response to treatment with steroids. Four patients survived (mean 36.5 months, range 8.6 to 57.6 months), but one died after rapid neurologic deterioration., Conclusion: Epstein-Barr virus inclusion was found in PCNSL in our patients; however, the role of EBV in PCNSL remains to be clarified. Post-transplant lymphoproliferative disorder is a rare malignancy after KTx with a predilection of brain involvement in Taiwan. We report a successful care experience in a patient with primary CNS lymphoma with better survival., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Interstitial inflammation scoring is incorporated into the Banff Classification of Renal Allograft Pathology and is essential for the diagnosis of T-cell mediated rejection. However, its reproducibility, including inter-rater and intra-rater reliabilities, has not been carefully investigated. In this study, eight renal pathologists from different hospitals independently scored 45 kidney allograft biopsies with varying extents of interstitial inflammation. Inter-rater reliabilities and intra-rater reliabilities were investigated by kappa statistics and conditional agreement probabilities. Individual pathologists' scoring patterns were examined by chi-squared tests and proportions tests. The mean pairwise kappa values for inter-rater reliability were 0.27, 0.30, and 0.26 for the Banff i score, ti score, and i-IFTA, respectively. No rater pair performed consistently better or worse than others on all three scorings. After dichotomizing the scores into two groups (none/mild and moderate/severe inflammation), the averaged conditional agreements ranged from 47.1% to 50.0%. The distributions of the scores differed, but some pathologists persistently scored higher or lower than others. Given the important role of interstitial inflammation scoring in the diagnosis of T-cell mediated rejection, transplant practitioners should be aware of the possible clinical implications of the far-from-optimal reproducibility., (© 2023. The Author(s).)

Goals: To assess the efficacy and safety of Chinese Medicine Prescription "W-LHIT" in subjects with simple obesity, and to explore its potential mechanism of action., Methods: Thirty-seven patients aged 18 to 60 from Wei-En hospital (Weifang City, Shandong, China), participated in a double blinded, placebo-controlled study. Subjects were randomly divided into 2 groups, 18 in treatment and 19 in placebo group. The treatment group took the "W-LHIT" capsules for two months, while the control group received placebo capsules. Both groups accepted healthy lifestyle education materials. After a 2-month treatment, the placebo group transferred to open-label treatment after unblinding., Results: 72.22% participants in the treatment group lost more than 5% of their body weight, compared with 36.84% in the placebo group ( p < 0.001). Body weight loss and body mass index reduction of the treatment group were also significantly higher than those of the placebo group ( p < 0.05). These changes were accompanied by increased abundance of Akkermansia muciniphila and Enterococcus faecium , and decreased abundance of Proteobacteria in gut microbiota. Furthermore, the treatment group also showed improvement in obesity-related comorbidities such as hypertension and elevation of liver enzymes. No serious adverse reactions were found during the study period. Weight did not rebound at a follow-up visit 2 months after treatment., Conclusion: W-LHIT significantly improved body weight and comorbid conditions without obvious adverse reaction or rebound weight gain. These effects were associated with increased abundance of probiotics in gut microbiota. W-LHIT may have a potential for treating obesity in conjunction with healthy lifestyle modifications., Competing Interests: This study shared the US Patent No: US20160296573A1 Weight loss formulations, methods, and compositions based on Traditional Chinese Medicine by X-ML, DC, etc. Author DC was employed by Healthy Freedom LLC. Authors NY and K.S are members of General Nutraceutical Technology LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cao, Wei, Wen, Song, Srivastava, Yang, Shi, Miao, Chung and Li.)

Tumor-infiltrating lymphocytes (TILs) have emerged as a prognostic marker in endometrial cancer (EC). However, the role of TILs in EC with distinct histology grades and molecular types (such as mismatch repair [MMR] deficiency) has not yet been made clear. We retrospectively included 237 patients with primary EC who underwent a standard staging operation of laparoscopic or laparotomy total hysterectomy and bilateral salpingo-oophorectomy for analyses. An independent pathologist who was blind to the study patients' information reviewed the pathologic slides to assess TILs according to the method introduced by the International Immuno-Oncology Biomarkers Working Group in 2017. The outcomes of interest included both progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method was used to determine the curves of PFS and OS according to TILs, and also in the relevant subgroups (low-grade vs. high-grade, MMR-proficient vs. MMR-deficient). After a median follow-up duration of 1.82 years, 18 patients had experienced either disease progression or death. Overall, TILs (+) were not associated with PFS or OS. We did observe, however, that TILs (+) were associated with a better PFS ( p = 0.045) in patients with high-grade EC, but not in those with low-grade tumors ( p = 0.733). The effect of TILs on PFS was not observed in patients with MMR-proficient ( p = 0.347) or MMR-deficient ( p = 0.168) EC. TILs were associated with a better PFS in patients with high-grade EC. Our results suggest that TILs may be a potential prognostic marker in these patients.

The elderly population is expanding rapidly, and that has become a major healthcare burden in terms of chronic kidney disease. The distribution patterns of kidney diseases in these elderly patients remain largely unclear. Here, we compared biopsy-based renal disease patterns between elderly and nonelderly patients. We performed a single-center, retrospective study (1992-2008) on biopsy-proven renal diseases to compare results between geriatric patients (age ≥ 65 years; n = 254) and nongeriatric patients (18 ≤ age < 65 years; n = 2592). Renal pathology was interpreted by pathologists based on light microscopy, immunofluorescence, and electron microscopy. The ages of the geriatric and nongeriatric groups were 71.8 ± 4.5 (65.1-87.3) and 39.7 ± 17.6 (18-64.9) years, respectively, and 74% and 41% of them, respectively, were men. In the geriatric group, the most frequent diagnosis was membranous nephropathy (46.1%), followed by minimal change disease/focal segmental glomerulosclerosis (16.9%), diabetic nephropathy (8.3%), hypertensive nephrosclerosis (7.5%), and IgA nephropathy (5.9%). The geriatric group had more membranous nephropathy and less lupus nephritis and IgA nephropathy than the nongeriatric group. Furthermore, the 5-year survival rate of the geriatric group was significantly low. Our results demonstrated the different distributions of renal biopsy patterns in geriatric patients diagnosed with acute or chronic progressive kidney injury and proteinuria through renal biopsy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The extent of interstitial fibrosis in the kidney not only correlates with renal function at the time of biopsy but also predicts future renal outcome. However, its assessment by pathologists lacks good agreement. The aim of this study is to construct a machine learning-based model that enables automatic and reliable assessment of interstitial fibrosis in human kidney biopsies., Methods: Validated cortex, glomerulus and tubule segmentation algorithms were incorporated into a single model to assess the extent of interstitial fibrosis. The model performances were compared with expert renal pathologists and correlated with patients' renal functional data., Results: Compared with human raters, the model had the best agreement [intraclass correlation coefficient (ICC) 0.90] to the reference in 50 test cases. The model also had a low mean bias and the narrowest 95% limits of agreement. The model was robust against colour variation on images obtained at different times, through different scanners, or from outside institutions with excellent ICCs of 0.92-0.97. The model showed significantly better test-retest reliability (ICC 0.98) than humans (ICC 0.76-0.94) and the amount of interstitial fibrosis inferred by the model strongly correlated with 405 patients' serum creatinine (r = 0.65-0.67) and estimated glomerular filtration rate (r = -0.74 to -0.76)., Conclusions: This study demonstrated that a trained machine learning-based model can faithfully simulate the whole process of interstitial fibrosis assessment, which traditionally can only be carried out by renal pathologists. Our data suggested that such a model may provide more reliable results, thus enabling precision medicine., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Decoy receptor 3 (DcR3) belongs to the tumor necrosis factor (TNF) receptor superfamily and neutralizes TNF ligands, including FasL and TRAIL, to prevent T activation during T-cell priming. However, the cellular mechanisms underlying acute cell-mediated rejection (ACMR) remain unknown., Methods: We generated DcR3 transgenic (Tg) mice and mice with high DcR3 expression (HDE) to study both in vivo and in vitro . FasR RNA knockdown in immortalized CD4 + CD8 + T-cells was used to survey the role of DcR3 on FasR/Fas-associated protein with death domain (FADD)/caspase 8 pathway and its cross-link to TNF receptor-associated factor 1 (TNFR1)-associated death domain protein (TRADD) in suppressing TNFR1. TNF/TRADD knockout mice were used to show the importance of TNF adaptor protein., Results: DcR3.Fc suppressed C57BL/6 female T-cell activation and transformation into CD4 + CD69 + , CD4 + CD44 + , and CD4 + CD25 + Foxp3 + when compared with isotype IgG1 and its co-treatment with FasL/TRAIL after exposing to bone marrow-derived dendritic cells (BMDCs) that carried alloantigen with male H-Y and minor antigenic determinant. Interleukin-17 and interferon-γ productions by BMDC-activated T-cells were lowered after co-treating with DcR3.Fc. DcR3.Fc induced effector T-cells (Teffs) and was susceptible to FasR-mediated apoptosis through the FADD/TRADD/caspase 8 pathway. After exposing to DcR3.Fc, TRADD was silenced, likely turning down the inflammatory response. The systemic effects of DcR3 Tg mice and HDE phenotype induced by the promoter of cytomegalovirus not only attenuated ACMR severity but also ameliorated the high serum creatinine and blood urea nitrogen levels even with high T-cell exposure frequencies. Besides this, DcR3 has minor biological effects on both MHC-matched and MHC-mismatched models., Conclusions: High DcR3 doses protect renal tubular epithelial cells from acute T-cell attack during the T-cell priming stage via interfering with TNF ligand-mediated reverse signaling and possibly promoting Teff apoptosis through FasR upregulation. Our findings supported that the decoy receptor is involved in T-cell modulation in kidney transplant rejection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Weng, Wen, Hsieh, Chen and Tarng.)

Background: Apathy is common in Parkinson's disease (PD) but its underlying white matter (WM) architecture is not well understood. Moreover, how apathy affects cognitive functions in PD remains unclear. We investigated apathy-related WM network alterations and the impact of apathy on cognition in the context of PD., Methods: Apathetic PD patients (aPD), non-apathetic PD patients (naPD), and matched healthy controls (HCs) underwent brain scans and clinical assessment. Graph-theoretical and network-based analyses were used for group comparisons of WM features derived from diffusion spectrum imaging (DSI). Path analysis was used to determine the direct and indirect effects of apathy and other correlates on different cognitive functions., Results: The aPD group was impaired on neural integration measured by global efficiency (p = 0.009) and characteristic path length (p = 0.04), executive function (p < 0.001), episodic memory (p < 0.001) and visuospatial ability (p = 0.02), and had reduced connectivity between the bilateral parietal lobes and between the putamen and temporal regions (p < 0.05). In PD, executive function was directly impacted by apathy and motor severity and indirectly influenced by depression; episodic memory was directly and indirectly impacted by apathy and depression, respectively; conversely, visuospatial ability was not related to any of these factors. Neural integration, though being marginally correlated with apathy, was not associated with cognition., Conclusions: Our results suggest compromised neural integration and reduced structural connectivity in aPD. Apathy, depression, and motor severity showed distinct impacts on different cognitive functions with apathy being the most influential determinant of cognition in PD.

Background: Lupus nephritis (LN) often lead to end-stage renal disease in systemic lupus erythematosus patients. This study aimed to investigate the clinical application of renal gallium-67 scans for determining renal histological parameters in LN patients., Methods: Between 2006 and 2018, 237 biopsy-proven and 35 repeat biopsies LN patients who underwent renal gallium scans before or after biopsy were included for analysis. The classification and scoring of LN were assessed according to the International Society of Nephrology/Renal Pathology Society. A delayed 48-h gallium scan was performed and interpreted by semiquantitative methods using left kidney/spine (K/S) ratio. The renal histological results were compared with gallium uptake., Results: Out of 237 participants, 180 (76%) had proliferative LN. Baseline gallium left K/S ratio was significantly higher in class IV LN as compared to class III (median (interquartile range, IQR): 1.16 (1.0-1.3), 0.95 (0.9-1.1), respectively, p < 0.001). Furthermore, changes in gallium uptake between two biopsies were positively correlated with changes activity index (r = 0.357, p = 0.035), endocapillary hypercellularity (r = 0.385, p = 0.032), and neutrophils infiltration (r = 0.390, p = 0.030) in renal pathology., Conclusions: Renal gallium uptake is associated with active inflammation in LN. Changes in renal gallium uptake positively correlated with changes in activity index in renal pathology.

Introduction: Multiple wasp stings is an emergency result from systemic reactions to the toxin with a wide range of manifestations, and we presented 2 patients with distinct clinical and transcriptomic findings., Patient Concerns: Two patients without systemic disease presented with nearly 90 painful papules after attacked by a swarm of wasps (Vespa basalis)., Diagnosis: Patient 1 was a 44-year-old healthy male whose clinical manifestations mainly comprised hemolysis, hepatic injury, rhabdomyolysis, and acute kidney injury. Patient 2 was a 49-year-old healthy female who presented with severe acute respiratory distress syndrome (ARDS) in addition to certain clinical manifestations that were also found in patient 1. We used ribo- nucleic acid sequencing (RNA-Seq) to characterize the inflammatory responses of 2 patients with distinct clinical manifestations after multiple wasp stings., Interventions: Both 2 patients received 5 sessions of plasmapheresis, and patient-1 further received mechanical ventilation for 8 days as well as 8 sessions of hemodialysis until day 17., Outcomes: Both patients recovered uneventfully after the aforementioned management. We used RNA-Seq to demonstrate a largely regulated neutrophil-predominated immune response in patient 1. In patient 2, we found a profound neutrophilc response on week 1 and a robust neutrophilic as well as pro-inflammatory responses on week 2. Furthermore, we found increased expression of signals that were associated with renal system process on week 2., Conclusion: In conclusion, we report 2 patients who manifested with shared and distinct presentations after an attack by the same swarm of wasps. Both patients had hemolysis, rhabdomyolysis, hepatic injury and acute kidney injury, and 1 patient had ARDS. The whole transcriptomic analyses were consistent with the distinct clinical manifestation, and these results suggest the potential of RNA-Sequencing to disentangle complex inflammatory responses in patients with multiple wasp stings. Plasmapheresis and corticosteroid were administered to both patients and case 2 also underwent 8 sessions of hemodialysis., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Subjective cognitive complaints (SCC) and affective symptoms are highly prevalent in Parkinson's Disease (PD). In early PD, SCC prevalence and its affective correlates, using recommended Movement Disorders Society (MDS) Level II Criteria to define the underlying cognitive impairment, has not been previously explored., Methods: We recruited 121 participants with early PD from two tertiary hospitals in Singapore. The presence of SCC was defined using a Non-Motor Symptoms Scale Domain-5 Score ≥1. Comprehensive neuropsychological testing was conducted with Mild Cognitive Impairment (PD-MCI) defined using recommended MDS Level II Criteria. Affective symptoms were assessed using the Hospital Anxiety Depression Scale (HADS), Geriatric Depression Scale (GDS) and Apathy Scale (AS). Analysis using multivariable linear regression model was performed., Results: In our early PD cohort, SCC prevalence independent of underlying cognitive status was 38.8%. Prevalence of SCC in cognitively impaired and cognitively normal participants was 10.7% and 28.1% respectively (р = 0.241). In cognitively normal PD participants, multivariable linear regression analysis revealed that SCC was significantly associated with anxiety (β = 0.28, 95% CI = 0.09-0.79, p = 0.014), depression (β = 0.31, 95% CI = 0.10-0.59, p = 0.006) and apathy (β = 0.32, 95% CI = 1.15-5.98, p = 0.004). Such an association was not found in cognitively impaired PD participants., Conclusion: SCC is highly prevalent even in early PD. Its implications in early PD differ depending on underlying cognitive status. SCC in cognitively impaired participants underestimates the true prevalence of PD-MCI. In contrast, SCC in cognitively normal participants is suggestive of an underlying affective disorder., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The effect of natural aging on the stress corrosion cracking (SCC) of A201-T7 alloy was investigated by the slow strain rate testing (SSRT), transmission electron microscopy (TEM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), conductivity, and polarization testing. The results indicated that natural aging could significantly improve the resistance of the alloys to SCC. The ductility loss rate of the unaged alloy was 28%, while the rates for the 24 h and 96 h aged alloys were both 5%. The conductivity of the as-quenched alloy was 30.54 (%IACS), and the conductivity of the 24 h and 96 h aged alloys were decreased to 28.85 and 28.65. After T7 tempering, the conductivity of the unaged, 24 h, and 96 h aged alloys were increased to 32.54 (%IACS), 32.52 and 32.45. Besides, the enthalpy change of the 24 h and 96 h aged alloys increased by 36% and 37% compared to the unaged alloy. The clustering of the solute atoms would evidently be enhanced with the increasing time of natural aging. Natural aging after quenching is essential to improve the alloy's resistance to SCC. It might be due to the prevention of the formation of the precipitation free zone (PFZ) after T7 tempering.

Background: Colonoscopy is considered a safe and effective tool for detecting colorectal cancer. Nevertheless, the proportion of patients are hesitating to receive colonoscopy. Smartphone education may decrease the barrier of colonoscopy. The aim of this study is to examine the effectiveness of smartphone education in colonoscopy., Methods: We conducted a prospective, double-blinded, randomized, controlled study to examine the effectiveness of smartphone education on embarrassment, bowel preparation, and satisfaction in colonoscopy. The patients' embarrassment was measured by the colonoscopy embarrassment scale. The quality of the bowel preparation was evaluated by gastroenterologists according to the Aronchik Scale. The satisfaction of colonoscopy care was assessed by a satisfaction scale developed by the authors., Results: A total of 150 patients were analyzed in the smartphone education and control groups (n = 75 in each group). The smartphone education group reported fewer embarrassment (B = -2.78, P = .02) than those of the control group, the patients who were older (B = .15, P = .001) and who were male (B = 2.91, P = .003) showed higher embarrassment. Additionally, smartphone education group were likely to have better colon preparation (odds ratio = 2.46, 95% confidence interval: 1.20-5.02) than that of the control group. Smartphone education also improved the satisfaction with care (β = 4.60, P < .001), and above normal body mass index decreased the satisfaction with care (β = -0.19, P < .05)., Conclusion: Smartphone education improves embarrassment, bowel preparation, and satisfaction with care in patients receiving colonoscopy.

Background: Transplantation with a diabetic donor kidney may have some benefits compared to remaining on the waitlist for selected patients. However, we found that some kidney transplant recipients have ongoing donor-transmitted diabetic kidney disease (DT-DKD) despite fair blood sugar control. This study aimed to survey the incidence and clinical pattern of DT-DKD in kidney transplant recipients., Methods: We retrospectively reviewed the medical records of kidney transplantations in our hospital. We found 357 kidney transplantations from February 2006 to April 2018. Among these, 23 (6.4%) diabetic donor kidney transplantations were done in the study period., Results: Among the 23 recipients, 6 (26.1%) displayed biopsy-proven DKD. Recipients with biopsy-proven DKD had longer dialysis vintage, higher proteinuria amount, lower last estimated glomerular filtration rate (eGFR), and a more rapid decline in the eGFR. The median fasting blood sugar level in the biopsy-proven DKD group was unexpectedly lower than the non-DKD group. Most of the pre-implantation frozen sections in biopsy-proven DKD group showed diabetic lesions worse than diabetic nephropathy (DN) class IIa. In the biopsy-proven DKD group, 5 recipients had no history of diabetes before or after transplantation. Among the 23 recipients, 5 (21.7%) were diagnosed with DT-DKD. Serial post-transplant biopsies showed the histological progression of allograft DN., Conclusions: To the best of our knowledge, this is the first study to report the phenomenon of ongoing DT-DKD in kidney transplant recipients with fair blood sugar control. The zero-time pre-transplant kidney biopsy may be an important examination before the allocation of diabetic donor kidneys. Further study is needed to elucidate the possible mechanism of ongoing DT-DKD in non-diabetic recipients with fair blood sugar control as well as the impaction of pre-implantation diabetic lesion on the graft outcome.

Background and Objectives: Immunoglobulin A Nephropathy (IgAN) is the most common type of glomerulonephritis with variable renal outcome. The association between IgAN and patient survival is limited. The effect of crescents on patient survival was never studied., Materials: We conducted a retrospective cohort study between January 2003 and December 2013. All patients with the biopsy-proved IgAN was enrolled for the analysis of patient survival and renal survival. Cox regression model was used analyze the associated factors for patient survival., Results: All 388 participants with IgAN were enrolled, in which 45 patients with crescents. The mean percentage of glomeruli involvement was 23±18.9%. After long-term follow-up, crescents group had both worse renal (p = 0.034) and patient survivals (p = 0.016). In univariate Cox regression model, the age (HR = 1.08, 95% CI = 1.05-1.12, p<0.001), crescents (HR = 3.93, 95% CI = 1.18-13.07, p = 0.025), serum albumin (HR = 0.023, 95%CI = 0.11-0.50, p<0.001), blood total protein (HR = 0.46, 95%CI = 0.28-0.75, p = 0.002), HDL (HR = 0.95, 95%CI = 0.91-0.99, p = 0.009), daily urine protein (HR = 1.14, 95%CI = 1.01-1.29, p = 0.038), urine PCR (HR = 1.07, 95%CI = 1.02-1.12, p = 0.003), serum IgM (HR = 0.98, 95%CI = 0.96-1.00, p = 0.036), BUN (HR = 1.02, 95%CI = 1.01-1.02, p = 0.005), and eGFR (HR = 0.097, 95%CI = 0.94-0.99, p = 0.0011) were associated with patient survival. After multivariate Cox regression analysis, age (HR = 1.08, 95%CI = 1.01-1.13, p = 0.013), crescents (HR = 5.57, 95%CI = 1.14-29.05, p = 0.034), and HDL (HR = 0.94, 95%CI = 0.90-0.99, p = 0.026) were associated with patient survival. Crescents IgAN is with the highest risk (up to 5.75 of HR) for patient mortality., Conclusions: The major strengths of the present study is that crescents IgAN had worse patient survival compared to non-crescents IgAN. Clinicians should be more careful to care patients with crescents IgAN., Competing Interests: The authors have declared that no competing interests exist.

Background and Purpose: This study quantified the total brain and periventricular white matter hyperintensity (WMH) burdens in patients with early Parkinson's disease (PD) and explored their associations with cardiovascular risk factors and cognitive performance., Methods: A total of 175 non-demented patients with early PD who had undergone baseline brain magnetic resonance imaging were included. Comprehensive neurocognitive testing was conducted to identify PD with mild cognitive impairment (PD-MCI) and to evaluate performances in individual cognitive domains. Cardiovascular risk was expressed as a modified Framingham 10-year cardiovascular risk score (mFRS)., Results: A total of 53.7% of this early PD cohort fulfilled the diagnostic criteria for PD-MCI. An increase in mFRS was significantly associated with increases in the total brain WMH (P = 0.015) and periventricular WMH (P = 0.040) burden, independent of age and gender. The periventricular WMH burden was significantly associated with PD-MCI (P = 0.046) in early PD, independent of cardiovascular risk factors. Patients in the 5th quintile of periventricular WMH burden were 8.6 times more likely to have PD-MCI compared with patients in the 1st quintile of periventricular WMH burden (P = 0.004). However, total brain WMH burden was not associated with PD-MCI (P = 0.158). In individual cognitive domains, heavier periventricular WMH burden was associated with worse executive function and visuospatial function independent of cardiovascular risk factors., Conclusion: Periventricular WMHs are a useful imaging biomarker for cognitive impairment in early PD. Cardiovascular risk factors, although associated with periventricular WMHs, were unable to fully explain the association between periventricular WMHs and cognitive impairment in early PD., (© 2020 European Academy of Neurology.)

Calcifying fibrous tumour (CFT) has some of the histopathological features, such as abundant plasma cells and stromal fibrosis, that are exhibited by IgG4-related diseases (IgG4-RD). The possible role of IgG4-positive plasma cells in calcifying fibrous tumour was investigated. The aim of this study was to determine any potential relationship between IgG4-RD and CFT. Thirteen cases with a total of 16 CFTs were reviewed. Lesion samples were immunostained with anti-IgG4 and anti-IgG antibodies. The number of IgG4-positive and IgG-positive plasma cells (IgG + PC) and their ratios were estimated. Plasma cells were found in all tumours. IgG4-positive plasma cells ranged from 0 to 71 per high-power field (HPF; mean 17.8/HPF), and IgG + PC ranged from 2 to 93/HPF (mean 42.6/HPF). The IgG4/IgG ratio ranged from 0% to 80% (mean 29%). There were seven tumours with the ratio of IgG4/IgG + PC that exceeded 40%. Various degrees of stromal fibrosis were present in eight tumours. All tumours have variable calcification. The histopathological features of CFT were found to be similar to those of IgG4-RD. Some CFT also showed a high number of IgG4-positive plasma cells, and the ratio of IgG4/IgG + PC exceeded 40%, most notably in patients with concomitant inflammatory or autoimmune disease. The long-term follow-up showed no evidence of IgG4-RD in any of these patients. Our findings suggest that while CFT overlaps morphologically with IgG4-RD, it probably should not be classified as an IgG4-RD., (©2020 Company of the International Journal of Experimental Pathology (CIJEP).)

Background: Chronic active antibody-mediated rejection is a major etiology of graft loss in renal transplant recipients. However, there is no consensus on the optimal treatment strategies., Methods: Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of chronic active antibody-mediated rejection. The patients were divided into two groups according to treatment strategy: Group 1 received aggressive treatment (double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy); and group 2 received supportive treatment., Results: From February 2009 to December 2017, a total of 82 patients with biopsy-proven chronic antibody mediated rejection were identified. Kaplan-Meier analysis of death-censored graft survival showed a worse survival in group 2 (P = 0.015 by log-rank test). Adverse event-free survival was lower in group 1, whereas patient survival was not significantly different. Proteinuria and supportive treatment were independent risk factors for graft loss in multivariate analysis., Conclusions: Aggressive treatment was associated with better graft outcome. However, higher incidence of adverse events merit personalized treatment, especially for those with higher risk of infection. Appropriate prophylactic antibiotics are recommended for patients undergoing aggressive treatment.

Background: Mild parkinsonian signs (MPS) are common in the older adult and associated with a wide range of adverse health outcomes. There is limited data on the prevalence of MPS and its significance., Objective: To determine the prevalence of MPS in the community ambulant population and to evaluate the relationship of MPS with prodromal features of Parkinson's disease (PD) and cognition., Methods: This cross-sectional community-based study involved participants aged ≥50 years. Parkinsonian signs were assessed using the modified Unified Parkinson's Disease Rating Scale (mUPDRS) and cognition using the Montreal Cognitive Assessment (MoCA). Premotor symptoms of PD were screened using a self-reported questionnaire. Linear regression was used to assess the association of MPS with premotor symptoms of PD and cognitive impairment., Results: Of 392 eligible participants, MPS was present in 105 (26.8%). Mean age of participants with MPS was 68.8±6.9 years and without MPS was 66.1±5.9 years (p < 0.001). Multivariate analysis revealed that MoCA scores were significantly lower in the MPS group (β= -0.152, 95% CI = -0.009, -0.138, p < 0.05). A significant correlation between the presence of REM sleep behavior disorder (RBD) and total MPS scores (β= 0.107, 95% CI = 0.053, 1.490, p < 0.05) was also found. Neither vascular risk factors nor other premotor symptoms were significantly associated with MPS., Conclusion: MPS is common and closely related to cognitive impairment and increasing age. Presence of RBD is predictive of higher MPS scores. This study highlights the necessity of other investigations or sensitive risk markers to identify subjects at future risk of PD.

Background and Objectives: The underlying neuropathology of excessive daytime sleepiness (EDS) remains elusive in Parkinson's disease (PD). We aim to investigate neural network changes that underlie EDS in PD., Methods: Early PD patients comprising eighty-one patients without EDS (EDS-) and seventeen patients with EDS (EDS+) received a resting state functional MRI scan and the Epworth Sleepiness Scale (ESS). Connectivities within the default mode network (DMN), motor and basal ganglia networks were compared between the EDS+ and EDS- groups. Correlations between network connectivity and the severity of EDS were investigated through linear regression., Results: EDS+ patients displayed a trend of increased network connectivity of the posterior DMN (pDMN). A significant positive correlation was found between connectivity of the ventromedial prefrontal cortex in the pDMN and ESS., Conclusion: EDS+ patients are likely to display increased activation in the DMN, suggesting neural compensation in early PD or impaired attentiveness due to mechanisms such as mind-wandering., (Copyright © 2019 Ooi, Wen, Ng, Chia, Chew, Lee, Xu, Hartono, Tan, Chan and Tan.)

Background and objective : The Haas classification of IgA nephropathy should be validated for Asian populations. More detailed and newer predictions regarding renal outcome of IgA nephropathy remains mandatory. Materials : We conducted a retrospective cohort study between January 2003 and December 2013. Clinical, Pathological, and laboratory data were all collected via available medical records. A Mann-Whitney U test was used for continuous variables and the Chi-square test was implemented for categorical variables. A Kaplan-Meier curve was put in place in order to determine patient survival and renal survival. The Youden index and Cox proportional hazard regression were used to investigate the possible factors for renal survival and predictive power. Results : All 272 renal biopsy-confirmed IgAN patients were enrolled for further studies. The univariate analysis showed that risk factors for poor renal outcome included stage 4-5 of Haas classification (HR = 3.67, p < 0.001), a poor baseline renal function (HR = 1.02 and p < 0.001 for higher BUN; HR = 1.14 and p < 0.001 for higher serum creatinine; HR = 0.95, p < 0.001 for higher eGFR), IgG ≤ 907 (HR = 2.29, p = 0.003), C3 ≤ 79.7 (HR = 2.76, p = 0.002), a higher C4 (HR = 1.02, p = 0.026), neutrophil-to-lymphocyte ratio > 2.75 (HR = 2.92, p < 0.001), and a platelet-to-lymphocyte ratio ≥ 16.06 (HR = 2.02, p = 0.012). A routine-checked markers, such as neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio, in order to predict the renal outcome, is recommended. Conclusions : This is the first study to demonstrate that Haas classification is also useful for establishing predictive values in Asian groups. A lower serum IgG (≤907 mg/dL) and serum C3 (≤79.7 mg/dL) were both risk factors for poor renal outcome. Additionally, this is the first study to reveal that serum C4 levels, an NLR > 2.75 and a PLR > 16.06, S could suggest poor renal outcome.

Individuals with mild cognitive impairment (MCI) exhibit varying serial position effect (SPE) performances. The relationship between SPE performance in word list recall and clinical, genetic, and neuroimaging features of MCI requires elucidation. 119 MCI and 68 cognitively normal (CN) participants underwent cognitive assessment, apolipoprotein E (ApoE) genotyping, and volumetric MRI brain scans processed via voxel-based morphometry. A 10-word recall task was used to assess SPE performance in relation to recency and primacy recall. MCI participants were classified as having Good SPE performance (high primacy and recency, Good SPE) or Poor SPE performance (low primacy only, LP-SPE; low recency only, LR-SPE; or both low, Low SPE). Poor SPE participants had reduced grey matter (GM) volumes and increased white matter hyperintensities (WMH) volumes. Participants with LP-SPE demonstrated reduced hippocampal GM volumes and were more likely to be ApoE ε4 carriers. LR-SPE was associated with higher WMH volumes. Presence of both greater WMH volumes and ApoE ε4 resulted in Low SPE. LP-SPE MCI participants had features typical of Alzheimer's disease. LR-SPE MCI was associated with increased WMH volumes, likely representing vascular pathology. SPE profiles are associated with distinct clinical patterns of MCI pathophysiology and could have potential as a clinical marker.

[ 18 F]9-fluoropropyl-(+)-dihydrotetrabenazine ( 18 F-(+)DTBZ) is a recently developed PET tracer to investigate the vesicular monoamine transporter type 2 (VMAT2) activity in measuring dopaminergic degeneration in vivo and monitoring the severity of Parkinson's disease (PD). However, manual drawing of the striatal regions is time consuming and prone to human bias. In the current study, we developed an automated method to quantify the signals of the striatum on 18 F-(+)DTBZ images. 39 patients with PD and 26 controls were enrolled. Traditional brain magnetic resonance imaging (MRI) and 18 F-(+)DTBZ PET were acquired. Both indirect normalization of native PET images to the standard space through individual brain MRI and directly coregistration of native images to the transporter-specific PET template in standard space were performed. Specific uptake ratios (SURs) in 10 predefined regions were used as indicators of VMAT2 activities to correlate with motor severity. Our results showed patients with PD had significant lower SURs in the bilateral putamina, caudates and globus pallidi than controls. SURs in the caudate and putamen were significantly correlated with motor severity. The contralateral putaminal region performed best in discriminating between PD patients and controls. Finally, the results from the application of the 18 F-(+)DTBZ PET template were comparable to those derived from the traditional MRI based method. Thus, 18 F-(+)DTBZ PET imaging holds the potential to effectively differentiate PD patients from controls. The 18 F-(+)DTBZ PET template-based method for automated quantification of presynaptic VMAT2 transporter density is easier to implement and may facilitate efficient, robust and user-independent image analysis.

Background: The aim of this study was to investigate the expression of transforming growth factor β (TGF-β) in the different stages of Barrett's esophagus (BE)., Methods: Paired endoscopic esophageal biopsy samples were obtained from patients with BE prospectively. Subjects were classified into three groups: BE, BE with dysplasia, and adenocarcinoma (AC) arising from BE. Biopsy specimens over normal esophageal epithelium and gastric cardiac epithelium of limited cases were done. Four cell lines, HETA1 (human esophageal epithelium), CA-A and CP-C (non-dysplastic metaplasia), and OE33 (AC) were analyzed for quantitative mRNA and Western blotting of TGF-β., Results: All 30 subjects with BE were enrolled. Expression of TGF-β mRNA in BE were significantly (P < 0.01) lower than that in the normal esophagus and cardiac epithelium. The BE tissue showed a lower positive ratio of TGF-β immunohistochemical (IHC) stain than the cardiac epithelium. The expression of TGF-β mRNA in the cell lines CA-A, CP-3, OE-33, was significantly (P < 0.05) lower than that in the cell line HETA-1. The Western blotting result showed lower TGF-β protein expression of the cell lines CA-A, CP-3, and OE-33., Conclusions: The expression of TGF-β was lower in the tissue of BE.

To clarify the nature of power Doppler (PD) signals in rheumatoid synovium and to establish the connection between PD signals and active inflammation using synovial histopathology. Ten adult patients (median age 57.0 years, 9 women and one man) with rheumatoid arthritis (RA) were enrolled and received ultrasound (US) examinations. US-guided synovial biopsies using core needle were performed in 7 knees, 2 wrists and one elbow. Each patient had one joint biopsied. In total, 11 synovial specimens were obtained for hematoxylin and eosin staining and histopathologic examinations. The US examinations revealed prominent synovial hypertrophy in all biopsied joints. Six synovial specimens were PD-positive (from 3 knees, 2 wrists and 1 elbow) while 5 synovial specimens were PD-negative (from 5 knees). In comparison with the PD-negative synovial specimens, the PD-positive synovial specimens had significantly more lymphocyte infiltration, vessel proliferation and lining hyperplasia on histologic examination. There was no significant difference in fibrin exudate and stromal fibrosis between the PD-positive and the PD-negative synovial specimens. PD signals in rheumatoid synovium indicate active inflammation and vascularization supported by synovial histopathology. Our study establishes the connection between synovial PD signals and active synovitis in RA., (Copyright © 2018. Published by Elsevier Taiwan LLC.)

Background: Parkinson's disease (PD) can be classified into tremor dominant (TD) and postural instability and gait difficulty (PIGD) subtypes with TD considered as the benign subtype. The neural alterations of the 2 subtypes in the early stages before administration of medications remain elusive., Objective: This study assessed the subtype-related white matter (WM) microstructural features in newly diagnosed and drug-naive PD patients from the Parkinson's Progression Markers Initiative (PPMI)., Methods: Sixty-five early PDs with stable subtypes (52 TD and 13 PIGD patients) and 61 controls underwent diffusion tensor imaging (DTI) scanning and clinical assessment. Tract-based special statistics (TBSS), graph-theoretical and network-based analyses were used to compare WM regional and network features between groups., Results: No differences in disease stages and duration were found between the 2 patient groups. TD patients showed increased fractional anisotropy (FA), but decreased radial and axial diffusivities (RD and AD) in several projection, association, and commissural tracts, compared with PIGD patients and controls. Motor severity had mild-to-moderate correlations with FA and RD of the corpus callosum (genu) in TD, but strong correlations with FA and RD of multiple association tracts in PIGD. Conversely, no significant network changes were noted., Conclusions: TD patients showed regionally increased FA but decreased diffusivities, implying neural reorganization to compensate PD pathology in early stages. PIGD patients, despite having similar disease stages and duration, exhibited more WM degradation. These results demonstrate differential WM regional features between the 2 subtypes in early PD and support the notion of TD being a benign subtype.

Background: Although the clinical signs of prodromal Parkinson's disease (PD) have been identified, little is known about the neural features of the prodromal phase of PD (proPD). The aim of this study was to examine the structural network alterations from healthy aging to proPD and to early PD., Methods: 181 non-demented and non-depressed participants comprising 55 healthy controls (HCs), 20 proPDs, and 106 de novo PD patients (dPDs) were included in the study and underwent clinical assessment and diffusion tensor imaging scanning. Graph-theoretical analysis and network-based statistics, with age and gender as nuisance covariates, were used., Results: Compared with HCs and dPDs, proPD patients showed significantly elevated small-worldness and clustering coefficient (Ps < 0.01) and greater local connectivity between regions relating to motor, olfactory and sleep functions (Ps < 0.05). Although dPDs and HCs did not differ on all graph-theoretic metrics, dPD patients showed decreased connectivity within the prefrontal regions and between the left temporal and occipital lobes (P < 0.05). The connectivity strength between these regions significantly distinguished between diagnostic groups. Connectivity between bilateral SMAs was correlated with UPSIT in HCs and with UPDRS-III in dPDs. Connectivity between the right SMA and putamen was correlated RBDSQ in proPDs., Conclusions: Increased network efficiency and connectivity of proPDs and decreased local connectivity of dPDs might suggest the emergence and dissipation of neural compensation in the prodromal phase and in early PD, respectively. Nonetheless, longitudinal studies are needed to follow up the long-term structural network changes of proPD patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Olfactory dysfunction is a robust and early sign for Parkinson's disease (PD). Previous studies have revealed its association with dementia and related neural changes in PD. Yet, how olfactory dysfunction affects white matter (WM) microstructure in newly diagnosed and untreated PD remains unclear. Here we comprehensively examined WM features using unbiased whole-brain analyses. 88 newly diagnosed PD patients without dementia (70 with hyposmia and 18 without hyposmia) and 33 healthy controls underwent clinical assessment and diffusion tensor imaging (DTI) scanning. Tract-based special statistics (TBSS), graph-theoretic methods and network-based statistics (NBS) were used to compare regional and network-related WM features between groups. TBSS analysis did not show any differences in fractional anisotropy and mean diffusivity between groups. Compared with controls, PD patients without hyposmia showed a significant decrease in global efficiency, whilst PD patients with hyposmia exhibited significantly reduced global and local efficiency and additionally a disrupted connection between the right medial orbitofrontal cortex and left rectus and had poorer frontal-related cognitive functioning. These results demonstrate that hyposmia-related WM changes in early PD only occur at the network level. The confined disconnectivity between the bilateral olfactory circuitry may serve as a biomarker for olfactory dysfunction in early PD.

Background: Mild cognitive impairment in Parkinson's disease (PD-MCI) is a common clinical condition. Understanding its pathology and clinical features is important for early intervention before the onset of dementia. In the past, variable definitions and differences in neuropsychological batteries generated divergent results of the affected cognitive patterns., Main Body: The introduction of PD-MCI criteria by the Movement Disorders Society (MDS) Task Force provides a more uniform system for defining and measuring PD-MCI and may improve the validity of future research. PD-MCI is likely to be heterogeneous since it can coexist with Alzheimer's disease and/ or Lewy body pathologies in PD. Pathogeneses of neuropsychiatric disturbances, such as depression, anxiety and apathy, are associated with PD with or without MCI. In addition, cognitive reserve formed by patients' unique life experiences may influence the outward cognitive performance despite the presence of the aforementioned pathogeneses and hence alter the diagnosis of MCI., Conclusion: The overlap of cognitive impairment across different neurodegenerative diseases suggests that PD-MCI is likely to result from a mixture of complex pathophysiologies, rather than being a distinct pathologic entity. Differentiating MCI from other organic symptoms in PD would facilitate novel therapeutic strategies.

For patients with Parkinson's disease (PD), excessive daytime sleepiness (PD-EDS) is a debilitating non-motor symptom and may be affected by mood symptoms, especially depression and anxiety. Few neuroimaging works have attempted to identify the neural features of PD-EDS, but various findings were reported. The purpose of this study was to systematically review the literature on mood and neuroimaging correlates of PD-EDS. A MEDLINE, PubMed, EMBASE, and PsycInfo search for peer-reviewed original research articles on depression, anxiety, and neuroimaging in PD-EDS identified 26 studies on depression, nine on anxiety, and eight on neuroimaging. Half of the studies reported greater depression in PD-EDS-positive patients compared with PD-EDS-negative patients. There was a significantly positive correlation between depression and PD-EDS. Limited studies on anxiety in PD-EDS suggested a weak correlation between anxiety and EDS. For depression and anxiety, the effect sizes were medium when EDS was subjectively measured, but became small when EDS was objective measured. Current neuroimaging studies generally suggested diminished neural structural and functional features (eg, brain volume, white matter integrity as indicated by fractional anisotropy, and cerebral metabolism) in patients with PD-EDS. Future studies should apply objective and subjective measures of mood symptoms and EDS and improve the neuroimaging methodology via using multimodal techniques and whole-brain analysis to provide new clues on the mood and neural correlates of PD-EDS., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate the impact of diabetes mellitus (DM) on cognitive performance and longitudinal volumetric brain changes in a cohort of cognitively normal mild PD patients., Methods: Prospective study of idiopathic PD subjects who underwent baseline and follow-up MRI imaging and neuropsychological assessments at 6month intervals for 3years. Subjects were classified based on the presence (PD-DM) or absence of DM (PD-No DM) at baseline. Volumetric analysis was performed using FreeSurfer 5.3 image analysis suite. Brain volume and cognition were compared and analyzed cross-sectionally and longitudinally. Analyses were corrected for intracranial volume., Results: There were 65 PD-no DM and 12 PD-DM subjects at baseline with comparable global cognition at baseline. PD-DM subjects had lower cortical grey matter (GM), amygdala, frontal white matter and temporal white matter volumes and higher total white matter hyperintensity and periventricular hyperintensities. After mean follow-up of 29.08months, there were 51 PD-no DM and 11 PD-DM subjects. PD-DM subjects demonstrated greater decline in MMSE and MOCA scores compared to PD-No DM. PD-DM subjects had a higher rate of atrophy in the cortical WM, particularly in the parietal and occipital white matter., Conclusion: Mild PD patients with DM have lower GM and WM volumes at baseline and higher WMH volumes, despite comparable cognitive scores. Longitudinally, DM in PD results in greater rate of cognitive decline, associated with higher WM atrophy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: Mild cognitive impairment (MCI) is associated with pronounced grey matter atrophy in various brain regions. However, the association between atrophy patterns and progression from no cognitive impairment (NCI) to Parkinson's disease (PD)-MCI is not clearly known. We investigated the pattern and progression of atrophy in subcortical structures and its impact on cognition in patients with mild PD., Methods: Sixty-five patients with mild PD with baseline and longitudinal clinical and neuropsychological assessments, and structural magnetic resonance imaging scans were studied. Movement Disorder Society Task Force criteria were used to classify patients with PD into PD-NCI (n = 54) and PD-MCI (n = 11). Based on progression over time, those who remained without cognitive impairment were classified as PD-stable (n = 42) and those who converted to MCI over 18 months were classified as PD-converters (n = 12). FreeSurfer was used to measure cortical thickness and subcortical volumes at baseline and follow-up., Results: Parkinson's disease-MCI showed baseline thalamus atrophy and progressive atrophy in the thalamus, caudate, presubiculum, cornu ammonis 1 and 2-3, and significant memory and executive dysfunction compared with PD-NCI. PD-converters had greater accumbens atrophy at baseline and progressive atrophy in the thalamus, caudate and accumbens with dysfunctions in memory and executive domains., Conclusions: Progression of cognitive impairment in non-demented PD is associated with a specific pattern of subcortical atrophy. Findings from this study will allow future studies to investigate in the role of subcortical structures as a biomarker for PD dementia., (© 2016 EAN.)

Background: Proton pump inhibitors (PPIs) are widely applied for acid related disorders, and possess pleiotropic biological functions. The effect of PPIs on the gastric mucosa, neutrophil and Helicobacter pylori (H. pylori) infiltration and glandular atrophy has not been well investigated, particularly the duration of the effects of PPIs., Objectives: To investigate the effects of PPIs on neutrophil infiltration, H. pylori infiltration and the gastric mucosa., Material and Methods: A total of 76 adult patients with gastrointestinal symptoms who had undergone upper gastrointestinal endoscopy were enrolled in the study. Each patient's history was recorded, including smoking, alcohol consumption and the duration of PPI use prior to gastric biopsy. Endoscopic biopsies of gastric antral mucosa were performed and evaluated by histology. Neutrophil and H. pylori infiltration were graded by H & E staining in accordance with the updated Sydney system., Results: Among the 76 patients, 44 patients had H. pylori infection and 19 patients had taken PPIs for varying durations prior to gastric biopsy. Neutrophil infiltration was significantly inhibited by PPIs (p = 0.005). The duration of PPI use was correlated with inhibition of neutrophil and H. pylori infiltration. A logistical regression analysis demonstrated that PPIs significantly inhibited neutrophil infiltration in the gastric mucosa and were associated with atrophy of the mucosa., Conclusions: PPIs attenuated neutrophil infiltration of gastric mucosa, and may be related to atrophy of the mucosa.

Background: Anxiety is prevalent in patients with Parkinson's disease (PD) and may affect patients' quality of life. Yet, little is known about the neural basis of anxiety in PD, and none have used a longitudinal design., Methods: 73 patients with mild PD were recruited and followed up for 18months. A whole-brain analysis was first used to identify brain regions associated with anxiety symptoms, followed by a regional analysis focusing on a priori hypothesised regions at baseline. A multivariate generalized estimating equations analysis was then conducted to determine the longitudinal association between grey matter (GM) volumetric changes of these significant regions and changes of anxiety symptoms., Results: At baseline, anxiety symptom severity was associated with decreased GM volumes in the bilateral precuneus and anterior cingulate cortex (ACC). Over 18months, increased severity of anxiety symptoms was associated with decreased GM volume in the left precuneus and ACC, independent of age, gender, education, depressive symptom severity or use of psychiatric medication., Conclusions: These results mainly implicate the precuneus and ACC in the pathogenesis of anxiety in PD. We speculate that these structural changes could reflect the disrupted default mode network due to PD pathology, contributing to spontaneous anxiety-related self-focused thoughts., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aims: BCOR-CCNB3 sarcoma is a genetically defined undifferentiated malignancy with Ewing sarcoma (ES)-like round cells, and preferentially affects the bones of male adolescents. Sarcomas harbouring BCOR-CCNB3 rarely arise from soft tissues; therefore, we aimed to report four cases to expand the clinicopathological spectrum., Methods and Results: By reverse transcription polymerase chain reaction and confirmatory sequencing, we detected a BCOR-CCNB3 transcript in primary undifferentiated sarcomas of the deep musculature of four male patients, comprising two teenagers (aged 14 and 17 years) and two adults (aged 34 and 44 years). The tumours originated in the back (n = 2), pelvis (n = 1), and thigh (n = 1), and were 70-140 mm in size (mean, 107 mm). All tumours showed sheets of primitive round or ovoid cells with vesicular nuclei, active mitosis (28-41/10 high-power fields), variably prominent nucleoli, and geographical necrosis. This major component transformed into fascicles of elongated spindle cells with staghorn vessels and a myxoid reticular stroma, accounting for 10-50% of areas. All cases were positive for CD99, three were positive for TLE1, and one was positive for EMA, indicating poorly differentiated synovial sarcomas (PDSSs). Nuclear cyclin B3 reactivity was present in all cases, but not in molecularly confirmed atypical ESs and PDSSs. At the last follow-up (median, 13.5 months), one patient had died of lung metastasis, two were alive with tumours, and one was tumour-free., Conclusions: BCOR-CCNB3-positive sarcomas may primarily occur in soft tissues of adults and show PDSS-mimicking round-cell and spindle-cell histology with aggressive behaviour. Cyclin B3 is useful for selecting candidates for BCOR-CCNB3 molecular testing., (© 2016 John Wiley & Sons Ltd.)

Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Findings on specific white matter (WM) alterations in PD have been inconsistent. We hypothesized that WM changes occur in early PD patients and unbiased whole-brain analysis may provide additional evidence of pathological WM changes in PD. In this study, we examined various indexes of WM microstructure in newly diagnosed PD patients at the whole-brain level. 64 PDs with Hoehn &Yahr stage 1 (HY1PDs), 87 PDs with Hoehn &Yahr stage 2 (HYPD2s), and 60 controls (HCs) were recruited. Tract-based spatial statistics (TBSS) and diffusion connectometry were used to identify changes of WM pathways associated with PD. There were no significant differences in axial diffusivity, but HY1PDs exhibited greater fractional anisotropy (FA) and decreased mean and radial diffusivities (MD and RD) in callosal, projection, and association fibres than HCs and HY2PDs. Motor severity was inversely correlated with FA, but positively correlated with MD and RD in PD patients. Connectometry analysis also revealed increased WM density in the aforementioned tracts in PD patients, compared with HCs. Our study reveals WM enhancement, suggesting neural compensations in early PD. Longitudinal follow-up studies are warranted to identify the trajectory of WM changes alongside the progression of PD.

Objective: Cerebral small-vessel disease (SVD) is a risk factor for dementia in Parkinson's disease (PD), however the pathophysiological role of SVD in PD-dementia is unclear. We investigated the impact of baseline and progression of SVD on cortical thickness and the correlation to cognition., Methods: Seventy-three mild PD patients with baseline and follow-up structural MRI scans, serial clinical and neuropsychological assessments were studied. SVD included the load of white matter hyperintensities (WMH), lacunes and perivascular spaces (PVS). WMH progression was assessed using the modified Rotterdam Progression scale, while for lacunes and PVS, development of new lesions was considered as lesion progression. Patients were classified as having SVD-progression and SVD-no-progression based on the longitudinal changes in their SVD measures. Freesurfer was used to measure baseline and follow-up regional cortical thickness and subcortical volumes and correlated to cognitive performance., Results: Fourteen patients were classified as SVD-progression and 59 as SVD-no-progression. Over 18 months, PD SVD-progression demonstrated significant cortical thinning in the left frontal and bilateral parietal regions with associated decline in memory, executive function, and motor functions. PD SVD-progression also had reduced volumes in the nucleus accumbens and amygdala at baseline and greater atrophy in the caudate nucleus over 18 months., Discussion: The extent and progression of SVD is associated with focal cerebral atrophy and domain-specific cognitive dysfunction. Measures to retard SVD may be potentially useful in preventing dementia in PD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)