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Background: Inflammatory events may contribute to the pathogenesis of dementia and interleukin-1 (IL-1) may exert both neurotoxic and neuroprotective effects. We investigated whether IL-1alpha -889 C/T and IL-1beta -511 C/T promoter polymorphisms are associated with the risk of Alzheimer's disease (AD) and vascular dementia (VaD). Methods: AD patients (n = 219) and VaD patients (n = 82), who fulfilled the criteria of the NINCDS-ADRDA and NINDS-AIREN, and ethnic-matched and nondemented controls (n = 209) were analyzed by means of genotype association method. Results: No significant difference in the genotype distribution of the analyzed single nucleotide polymorphisms was found between AD or VaD cases and controls. However, the frequency of the IL-1alpha -889 CT genotype was notably lower in VaD patients aged over 70 years than the age-matched controls (9.1 vs. 22.9%, p = 0.036) andtheIL-1alpha -889 CT genotype demonstrated a trend toward decrease in risk of developing VaD (odds ratio: 0.34; 95% confidence interval: 0.12-0.83, p = 0.026). Multivariate analysis revealed that the IL-1beta -511T-carrying genotype slightly strengthens the negative association of the IL-1alpha -889 CT genotype with VaD (odds ratio: 0.26; 95% confidence interval: 0.08-0.79, p = 0.024). Conclusion: Our data suggest a protective role of the IL-1alpha -889 CT genotype in VaD susceptibility among Taiwanese aged over 70 years. Copyright (c) 2007 S. Karger AG, Basel. [ABSTRACT FROM AUTHOR]

Background: The relationships among small fiber neuropathy, age, sex and pain intensity in the context of Fabry's disease remain unclear. We aim to study the correlations of small fiber neuropathy, age, sex and pain intensity in Fabry patients., Methods: We evaluated C-fiber function by recording the withdrawal latencies to painful heat stimulus (WLPHS) when each subject's right hand was immersed in a 50 °C hot water bath and correlated this parameter with the patient's perceived pain intensity and quality of life assessed by the short-form McGill Pain Questionnaire (SF-MPQ) in a large Taiwanese Fabry family and normal controls., Results: Male Fabry patients showed a significantly increased WLPHS compared to that of normal controls. Furthermore, male Fabry patients showed a positive correlation of increased WLPHS with patient age. The SF-MPQ of male Fabry patients showed a bell distribution with age, and maximal pain scores were detected between the ages of the early 20s and late 40s. In contrast, the female Fabry patients had variable associations of WLPHS and SF-MPQ with age., Conclusions: We proposed a probable mechanism by which globotriaosylceramide (Gb3) or globotriaosylsphingosine (lyso-Gb3) is gradually deposited into the small nerve bundles with increasing age, which induces continuous damage and produces injury discharges to sustain neuropathic pain in young male Fabry patients. However, once the small fibers are reduced to a certain degree, they no longer produce enough noxious discharges to sustain neuropathic pains in older male Fabry patients, which leads these patients to have lower SF-MPQ scores. In contrast, female Fabry patients had less and variable small fiber damage, pain intensity and clinical signs/symptoms., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2021 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Objective: A meta-analysis of locus-based genome-wide association studies recently identified a relationship between AXIN1 and Parkinson's disease (PD). Few studies of Asian populations, however, have reported such a genetic association. The influences of rs13337493, rs758033, and rs2361988, three PD-associated genetic variants of AXIN1, were investigated in the present study because AXIN1 is related to Wnt/β-catenin signaling., Methods: A total of 2,418 individuals were enrolled in our Taiwanese cohort for analysis of the genotypic and allelic frequency. Polymerase chain reaction-restriction fragment length polymorphism analysis was employed for rs13337493 genotyping, and the Agena MassARRAY platform (Agena Bioscience, San Diego, CA, USA) was used for rs758033 and rs2361988 genotyping in 672 patients with PD and 392 controls. Taiwan Biobank data of another 1,354 healthy controls were subjected to whole-genome sequencing performed using Illumina platforms at approximately 30× average depth., Results: Our results revealed that rs758033 {odds ratios [OR] (95% confidence interval [CI]) = 0.267 [0.064, 0.795], p = 0.014} was associated with the risk of PD, and there was a trend toward a protective effect of rs2361988 (OR [95% CI] = 0.296 [0.071, 0.884], p = 0.026) under the recessive model. The TT genotype of rs758033 (OR [95% CI] = 0.271 [0.065, 0.805], p = 0.015) and the CC genotype of rs2361988 (OR [95% CI] = 0.305 [0.073, 0.913], p = 0.031) were less common in the PD group than in the non-PD group., Conclusion: Our findings indicate that the rs758033 and rs2361988 polymorphisms of AXIN1 may affect the risk of PD in the Taiwanese population.

Introduction: Variants in the low-density lipoprotein receptor-related protein 10 (LRP10), linked to inherited forms of α-synucleinopathies, have been reported. Nine variants of LRP10 were identified in the first such report, and subsequent studies have identified possible pathogenic variants in patients with sporadic Parkinson's disease (PD). Few studies have investigated the role of LRP10 in PD. We sought to validate the role of this gene in Taiwanese patients with PD., Methods: In total, 1277 individuals were included in this study (669 had PD and 608 were controls). The entire LRP10 coding exons and exon-intron boundaries were sequenced in 103 probands with early-onset PD or familial PD. We then genotyped the newly identified variants from the 103 patients and previously reported potential pathogenic variants in our cohort. The frequencies of variants were analyzed., Results: Five new and possibly pathogenic variants were identified initially. In total, 14 potentially pathogenic variants (including nine previously reported and five newly identified variants) were analyzed thereafter. We did not find any significant associations between any variant and the risk of PD. However, c.1424+5delG was identified in a patient with sporadic PD who was diagnosed as having PD and dementia and who had prominent psychiatric symptoms., Conclusion: Although we identified a patient with sporadic PD and dementia carrying a c.1424+5delG variant, our data did not provide sufficient evidence to support the role of LRP10 in PD in Taiwanese adults., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Studies have suggested that cytokines are crucial mediators in the pathogenesis of Parkinson's disease (PD). The multifunctional cytokine interleukin (IL)-6 and its single nucleotide polymorphisms (SNPs) were found to have an impact on the development of PD. However, different studies in associations of IL-6 genetic variants with PD showed inconsistent results and it has never been explored in a Taiwanese population. Both IL-1α and IL-8 contribute to the same inflammation pathway. IL-1α genetic polymorphism has an effect on late-onset PD in Taiwan, whereas the associations of IL-8 genetic variants with PD in Taiwan remain to be investigated., Methods: This study examined the frequencies of polymorphisms within the critical promoter areas of the proinflammatory cytokine genes: IL-6 G-174C (rs1800795) and IL-8 A-251T (rs4073) in Taiwanese PD patients compared with age-and gender-matched healthy subjects. Comparisons were also made in genotype and allele frequencies of IL-6 G-174C (rs1800795) and IL-8 A-251T (rs4073) among different populations in previous studies., Results: In total, 1120 subjects, including 509 PD patients (female/male: 259/250) and 511 control subjects (female/male: 252/259), were recruited. We found no statistically significant differences in IL-6 G-174C (rs1800795) or IL-8 A-251T (rs4073) genotypic and allelic distribution between PD and controls, even after being stratified by age at onset and gender., Conclusions: The results did not demonstrate any association of IL-6 G-174C (rs1800795) or IL-8 A-251T (rs4073) with PD in a Taiwanese population. Despite the negative results, this is the first study in associations of IL-6 G-174C (rs1800795) and IL-8 A-251T (rs4073) with PD in Taiwan. The relevance of genetic variants of IL-6 G-174C (rs1800795) or IL-8 A-251T (rs4073) on PD susceptibility warrants further investigation.

Parkinson's disease (PD) is a neurodegenerative disease with the pathological hallmark of Lewy bodies and Lewy neurites composed of α-synuclein. The SNP rs591323 is one of the risk loci located near the FGF20 gene that has been implicated in PD. The variation of FGF20 in the 3' untranslated region was shown to increase α-synuclein expression. We examined the association of rs591323 with the risk of PD in a Taiwanese population and conducted a meta-analysis, including our study and two other studies from China, to further confirm the role of this SNP in Taiwanese/Chinese populations. A total of 586 patients with PD and 586 health controls (HCs) were included in our study. We found that the minor allele (A) and the AA + GA genotype under the dominant model are significantly less frequent in PD than in controls. The meta-analysis consisted of 1950 patients with PD and 2073 healthy controls from three studies. There was significant association between rs591323 and the risk of PD in the additive (Z = -3.96; p < 0.0001) and the dominant models (Z = -4.01; p < 0.0001). Our study results and the meta-analysis support the possible protective role of the rs591323 A allele in PD in Taiwanese/Chinese populations.

Several genome-wide association studies and meta-analyses on Parkinson's disease (PD)-related genes have identified several risk foci in Ras-related genes, particularly among Caucasian individuals. However, the corresponding results have been controversial among Asian individuals. We investigated whether 2 single-nucleotide polymorphisms of Ras-related genes, RIT2 (rs12456492) and RAB7L1 (rs823118), are associated with PD risk in Taiwanese individuals. In addition, we conducted a meta-analysis of all studies related to rs12456492 in Asian populations to resolve inconsistency in this locus. In total, 1103 Taiwanese individuals (588 patients with PD and 515 controls) and 1111 Taiwanese individuals (594 patients with PD and 517 controls) were genotyped for rs12456492 and rs823118. However, we could not confirm the association of rs12456492 and rs823118 with PD. Our current meta-analysis involving the rs12456492(A/G) variant demonstrated that the GG + GA genotypes, GG genotypes, and G allele may be risk factors for PD. RIT2 may increase PD risk in Asian individuals. The discrepancies between Caucasian and Asian populations may be due to differences in geographic region-specific genetic backgrounds and gene-environmental interactions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Previous genome-wide association studies in Caucasians suggest genetic loci of human leukocyte antigen (HLA)-DR region may be associated with Parkinson's disease (PD). However, these gene-disease associations were limitedly reported in Asian populations. Herein, we investigated the effects of 5 top PD-associated genetic variants within HLA-DR region in Caucasians, including rs4248166, rs9268515, rs2395163, rs75855844, and rs660895, by genotyping 486 Taiwanese patients with PD and 473 age-matched control subjects. Although the association between rs2395163 C allele and patients with PD demonstrated marginal significance (odds ratio [OR] = 0.74, 95% CI: 0.55-0.99, p = 0.045). The frequency of rs2395163 C allele (8.65%) in male patients with PD was significantly lower than in male control subjects (14.02%; OR = 0.58, 95% CI: 0.39-0.88, p = 0.009). The genetic associations between patients with PD and other tested genetic variants were negative. Although strong linkage disequilibrium (rs4248166-rs9626515-s2395163 and rs9626515-rs660895) were observed, the haplotype analysis did not find any significant risk-associated allelic combinations. These results suggest a distinct genetic background within HLA-DR region between Taiwanese and Caucasian patients with PD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cerebral cavernous malformation (CCM) is a vascular malformation characterized by clustered enlarged capillary-like channels in the central nervous system. The genes harboring variants in patients with CCM include CCM1/Krev interaction trapped-1, CCM2/MGC4607, and CCM3/programmed cell death protein 10. We aimed to identify pathogenic variants in an ethnic Chinese population in Taiwan. We recruited 95 patients with multiple CCMs or a single lesion with a relevant family history. Sanger sequencing was performed for 41 patients. Variants were identified using sequence alignment tools, and the clinical significance of these variants was determined using American College of Medical Genetics and Genomics standards and guidelines. Several pathogenic variants were found in six patients, including three unrelated patients and three affected members of one family. Two novel pathogenic variants leading to early truncation comprised a deletion variant in exon 18 of CCM1 (c.1846delA; p.Glu617LysfsTer44) and an insertion variant in exon 4 of CCM2 (c.401&#95;402insGCCC; p.Ile136AlafsTer4). One novel pathogenic splice site variant was c.485 + 1G > C at the beginning of intron 8 of CCM1. In this study, we identified novel variants related to CCM in an ethnically Chinese population in Taiwan.

Background: Programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are frequently expressed in T-cell lymphomas. This provides a rationale for exploration of immune checkpoint inhibitors in the management of T-cell lymphomas., Patients and Methods: In this phase II single-arm multicenter trial, patients with relapsed or refractory systemic T-cell lymphoma were treated with 200 mg pembrolizumab intravenously every 21 days. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate, overall survival, response duration, and safety. We assessed PD-L1, p-AKT expression, and peripheral blood immune cells as potential predictive biomarkers., Results: Of 18 enrolled patients, 13 were evaluable for the primary endpoint. The trial was halted early after a preplanned interim futility analysis. The overall response rate was 33% (95% confidence interval [CI], 9%-55%); 4 patients achieved a complete response (27%; 95% CI, 5%-49%). The median PFS was 3.2 months (95% CI, 1.2-3.7 months), and the median overall survival was 10.6 months (95% CI, 3.2-100 months). The median duration of response was 2.9 months (95% CI, 0-10.1 months). Two of the 4 complete responders remain in remission > 15 months. Rash was the most common adverse event (17%; n = 3). The most common ≥ grade 3 treatment-emergent adverse events were rash and pneumonitis (11%; n = 2 each). Neither PD-L1 nor p-AKT expression were associated with outcomes. However, a higher relative frequency of CD4 + T lymphocytes pre-treatment was associated with improved PFS (hazard ratio, 0.15; 95% CI, 0.03-0.74)., Conclusion: Pembrolizumab demonstrated modest single-agent activity in relapsed or refractory T-cell lymphoma., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: The novel D678H amyloid precursor protein (APP) gene mutation has been called the "Taiwan mutation". The study aims to identify amyloid deposition patterns and clinical features associated with this mutation., Methods: we analyzed the clinical manifestations, brain neuroimages and 18 F-AV-45 positron emission tomography (PET) findings in symptomatic patients and asymptomatic subjects with the autosomal-dominant Alzheimer's disease (AD). We compared the amyloid deposition pattern among 10 patients with genetically-positive familial cognitive decline (CD), 18 patients with sporadic CD, and 19 healthy controls., Results: The clinical features were the early onset of memory impairment in all 10 patients and cerebral amyloid angiopathy in 3 patients. The characteristic results of brain 18 F-AV-45 PET included the highest standard uptake value ratio (SUVR) in the occipital and cerebellar cortical areas in the genetically-positive CD patients. In subgroup analysis, the familial AD patients had a decreased amyloid SUVR trend in most areas except for cerebellar cortex compared to those with familial mild cognitive impairment., Conclusion: Our data indicate that the familial D678H gene mutation have resulted in a more potent amyloid burden than in the patients with sporadic AD patients. The high amyloid uptake in the occipital area is characteristic of the specific Taiwan APP gene., (Copyright © 2018. Published by Elsevier B.V.)

Previous genome-wide association studies in Caucasian populations suggest that genetic loci in amino acid catabolism may be associated with Parkinson's disease (PD). However, these genetic disease associations were limitedly reported in Asian populations. Herein, we investigated the effect of top three PD-associated genetic variants related to amino acid catabolism in Caucasians listed on the top risk loci identified by meta-analysis of genome-wide association studies in PDGene database, including aminocarboxymuconate-semialdehyde decarboxylase- ( ACMSD- ) transmembrane protein 163 ( TMEM163 ) rs6430538, methylcrotonyl-CoA carboxylase 1 ( MCCC1 ) rs12637471, and branched-chain ketoacid dehydrogenase kinase- ( BCKDK- ) syntaxin 1B ( STX1B ) rs14235, by genotyping 599 Taiwanese patients with PD and 598 age-matched control subjects. PD patients demonstrate similar allelic and genotypic frequencies in all tested genetic variants. These ethnic discrepancies of genetic variants suggest a distinct genetic background of amino acid catabolism between Taiwanese and Caucasian PD patients.

Purpose: The aim of this trial was to compare the efficacy and safety of two formulations of levetiracetam in people with partial epilepsy over a 12-week treatment period., Methods: We performed a randomized, paralleled, and multicenter trial that consisted of a 4-week single-blind placebo run-in, followed by a 12-week double-blind, double-dummy treatment phase to compare the efficacy and safety of levetiracetam extended-release (LEV-ER) and immediate-release (LEV-IR) tablets as an adjunctive treatment in adult patients with uncontrolled epilepsy., Results: The median partial-onset seizure (POS) frequency per week (min-max) was 0.3 (0.0, 17.4; 95% confidence interval [95% CI] 1.3, 4.8) in the LEV-ER group and 0.3 (0.0, 31.4; 95% CI - 0.1, 4.3) in the LEV-IR group. No serious adverse events occurred during the trial period. Both groups had the same responder rate (58.6%), while a higher rate of seizure freedom over the treatment period was noted in the LEV-ER group compared with the LEV-IR group (27.6% vs. 13.8%, respectively). The European Quality of Life-5 Dimensions scores significantly increased in the LEV-ER-treated group, in contrast to the scores in the LEV-IR group, which decreased (7.2 vs. - 1.5, p = 0.03)., Conclusion: These results suggest that LEV-ER is equivalent to LEV-IR in reducing the frequency of POS and has a similar tolerability as LEV-IR as an add-on therapy. In addition, LEV-ER treatment improved the health-related quality of life of people with uncontrolled partial epilepsy., (Copyright © 2018. Published by Elsevier Ltd.)

Transmembrane or membrane-associated protein dysfunction is increasingly recognized as an important mechanism of pathogenesis in Parkinson's disease (PD). Previous genome-wide association studies and their meta-analysis in PD genes have identified several risk foci in transmembrane protein-encoding genes. Herein, we investigated the effect of 4 such PD-associated genetic variants reported in Caucasians, including discs-large membrane-associated guanylate kinase scaffolding protein 2 (DLG2 rs3793947), transmembrane protein 229B (TMEM229B rs1555399), glycoprotein nonmetastatic melanoma protein B (GPNMB rs199347), and integrin subunit alpha 8 (ITGA8 rs7077361). A total of 1185 Taiwanese subjects comprising 592 PD patients and 593 unrelated age-matched controls were genotyped. DLG2 rs3793947 AA genotype showed a significantly lower prevalence in female PD patients compared to the female controls (p = 0.019). The recessive model analysis also demonstrated a reduced PD risk for females in AA genotype (odds ratio = 0.573, 95% confidence interval: 0.379-0.868, p = 0.008). The frequencies of TMEM229B rs1555399 and GPNMB rs199347 genotypes and alleles were similar in PD patients and controls. ITG8 rs7077361 was not polymorphic in all subjects of this study. These data suggested that DLG2, but not TMEM229B, GPNMB, and ITGA8, influenced the risk of PD in Taiwan., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, evaluation, treatment, including supportive-care, and follow-up for patients with myeloma. These NCCN Guidelines Insights highlight the important updates/changes specific to the myeloma therapy options in the 2018 version of the NCCN Guidelines., (Copyright © 2018 by the National Comprehensive Cancer Network.)

In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults ≥70 years with hematologic malignancies across the United States. Adults ≥70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients ≥70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS: 26% [95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to 42%] in 2008-2013, P < .001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95% CI, 29% to 36%] in 2008-2013, P = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time ( P = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index ≥3 (hazard ratio [HR], 1.27; P = .006), umbilical cord blood graft (HR, 1.97; P = .0002), and myeloablative conditioning (HR, 1.61; P = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients ≥70 years. Select adults ≥70 years with hematologic malignancies should be considered for transplant.

One of the criteria used by the International Union for Conservation of Nature (IUCN) to assess threat status is the rate of decline in abundance over 3 generations or 10 years, whichever is longer. The traditional method for calculating generation length (T) uses age-specific survival and fecundity, but these data are rarely available. Consequently, proxies that require less information are often used, which introduces potential biases. The IUCN recommends 2 proxies based on adult mortality rate, T̂d = α + 1/d, and reproductive life span, T̂z = α + z * RL, where α is age at first reproduction, d is adult mortality rate, RL is reproductive life span, and z is a coefficient derived from data for comparable species. We used published life tables for 78 animal and plant populations to evaluate precision and bias of these proxies by comparing T̂d and T̂z with true generation length. Mean error rates in estimating T were 31% for T̂d and 20% for T̂z, but error rates for T̂d were 16% when we subtracted 1 year ( T̂d( adj )=T̂d-1 ), as suggested by theory; T̂d( adj ) also provided largely unbiased estimates regardless of the true generation length. Performance of T̂z depends on compilation of detailed data for comparable species, but our results suggest taxonomy is not a reliable indicator of comparability. All 3 proxies depend heavily on a reliable estimate of age at first reproduction, as we illustrated with 2 test species. The relatively large mean errors for all proxies emphasized the importance of collecting the detailed life-history information necessary to calculate true generation length. Unfortunately, publication of such data is less common than it was decades ago. We identified generic patterns of age-specific change in vital rates that can be used to predict expected patterns of bias from applying T̂d( adj )., (Published 2017. This article is a U.S. Government work and is in the public domain in the USA.)

Multiple myeloma (MM) is caused by the neoplastic proliferation of plasma cells. These neoplastic plasma cells proliferate and produce monoclonal immunoglobulin in the bone marrow causing skeletal damage, a hallmark of multiple myeloma. Other MM-related complications include hypercalcemia, renal insufficiency, anemia, and infections. The NCCN Multiple Myeloma Panel members have developed guidelines for the management of patients with various plasma cell dyscrasias, including solitary plasmacytoma, smoldering myeloma, multiple myeloma, systemic light chain amyloidosis, and Waldenström's macroglobulinemia. The recommendations specific to the diagnosis and treatment of patients with newly diagnosed MM are discussed in this article., (Copyright © 2017 by the National Comprehensive Cancer Network.)

Background: Neurofibrillary tangles formed from tau misfolding have long been considered one of the pathological hallmarks of Alzheimer's disease (AD). The misfolding of tau in AD correlates with the clinical progression of AD and inhibition or reversal of tau misfolding may protect the affected neurons., Methods: We generated 293 and SH-SY5Y cells expressing DsRed-tagged pro-aggregation mutant of repeat domain of tau (ΔK280 tau RD ) to test indole/indolylquinoline derivatives for reducing tau misfolding and neuroprotection., Results: Four of the 10 derivatives tested displayed good misfolding-inhibitory effects on Tet-On 293 cells. Among them, NC009-1 and NC009-7 enhanced heat-shock 27 kDa protein 1 (HSPB1) expression to increase ∆K280 tau RD -DsRed solubility and promoted neurite outgrowth in Tet-On SH-SY5Y cells. Knockdown of HSPB1 resulted in decreased ∆K280 tau RD -DsRed solubility and reduced neurite outgrowth, which were rescued by addition of NC009-1/NC009-7. Treatment with indole/indolylquinoline derivatives also improved neuronal cell viability and neurite outgrowth in mouse hippocampal primary culture under tau cytotoxicity., Conclusion: Our results demonstrate how indole/indolylquinoline derivatives are likely to work in tau misfolding reduction, providing insight into the possible working mechanism of indole and indolylquinoline derivatives in AD treatment., (© 2016 John Wiley & Sons Ltd.)

Background/purpose: Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Although idiopathic PD accounts for most of the cases, several genetic mutations have been found to cause PD. Mutations in the eukaryotic translation initiation factor 4-γ, 1 (EIF4G1) gene have been identified since 2011, which were reported to be associated with PD among Caucasians in subsequent research. However, this observation was not consistent. The contribution to other ethnic groups remains limited, with < 1% of sporadic cases. We conducted a case-control study to analyze if EIF4G1 is a risk factor for PD patients in Taiwan., Methods: There were 595 PD patients and 600 controls without neurological diseases enrolled in this study. Four reported mutations-A502V (c.1505C>T), G686C (c.2056 G>T), R1197W (c.3589C>T), and R1205H (c.3614G>A)-were analyzed., Results: There were no mutations found in either PD patients or controls., Conclusion: This study indicates that the EIF4G1 mutation is rare in Taiwan, which is consistent with other reports from Asia. Ethnicity could have a great influence on EIF4G1 in PD. Further large scale studies are warranted to evaluate the association of PD and EIF4G1 gene., (Copyright © 2015. Published by Elsevier B.V.)

Mounting evidence shows that hyperhomocysteinemia is a risk factor for cognitive decline. This study enrolled subjects with normal serum levels of B12 and folate and performed thorough neuropsychological assessments to illuminate the independent role of homocysteine on cognitive functions.Participants between ages 50 and 85 were enrolled with Modified Hachinski ischemic score of <4, adequate visual and auditory acuity to allow neuropsychological testing, and good general health. Subjects with cognitive impairment resulting from secondary causes were excluded. Each of the participants completed evaluations of general intellectual function, including the Mini-Mental State Examination, Cognitive Abilities Screening Instrument, Clinical Dementia Rating, and a battery of neuropsychological assessments.This study enrolled 225 subjects (90 subjects younger than 65 years and 135 subjects aged 65 years or older). The sex proportion was similar between the 2 age groups. Years of education were significantly fewer in the elderly (7.49 ± 5.40 years) than in the young (9.76 ± 4.39 years, P = 0.001). There was no significant difference in body mass index or levels of vitamin B12 and folate between the 2 age groups. Homocysteine levels were significantly higher in the elderly group compared to the younger group (10.8 ± 2.7 vs. 9.5 ± 2.5 μmol/L, respectively, P = 0.0006). After adjusting for age, sex, and education, only the Digit Symbol Substitution (DSS) score was significantly lower in subjects with hyperhomocysteinemia (homocysteine >12 μmol/L) than those with homocysteine ≤12 μmol/L in the elderly group (DSS score: 7.1 ± 2.7 and 9.0 ± 3.0, respectively, beta = -1.6, 95% confidence interval [CI] = -2.8∼-0.5, P = 0.001) and borderline significance was noted in the combined age group (beta = -1.1, 95% CI = -2.1∼-0.1, P = 0.04). We did not find an association between hyperhomocysteinemia and other neuropsychological assessments.This is the first study to demonstrate a significant association between hyperhomocysteinemia (>12 μmol/L) and low DSS score, suggesting that DSS score may be an independent marker of cognitive impairment in response to hyperhomocysteinemia, especially in the elderly. Further replication studies with larger cohorts are needed to confirm our results., Competing Interests: The authors report no conflicts of interest.

These NCCN Guidelines Insights highlight the important updates/changes specific to the 2016 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include updated recommendations to the overall management of multiple myeloma from diagnosis and staging to new treatment options., (Copyright © 2016 by the National Comprehensive Cancer Network.)

Recently, a large-scale meta-analysis of genome-wide association study (GWAS) data identified several new risk loci that can modulate the risk of Parkinson's disease (PD). These associations have yet to be examined in PD patients in Chinese or Asian population. Because ethnic-specific effect is an important concern for GWAS analysis, we genotyped single-nucleotide polymorphisms in the new genetic loci, GCH1 (rs11158026), SIPA1L2 (rs10797576), VPS13C (rs2414739), and MIR4697 (rs329648), to investigate their associations with risk of PD in Taiwan. Another single-nucleotide polymorphism GCH1 rs7155501, previously identified by GWAS listed at the top 20 genes in PDGene database was also included. A total of 1151 study subjects comprising 598 patients with PD and 553 unrelated healthy controls were recruited. The frequency of minor allele (C allele) of GCH1 rs11158026 was found to be significantly higher in PD cases than in controls (p = 0.003). The CC genotype of rs11158026 increased PD risk compared to TT genotype (odds ratio [OR] = 1.29, 95% confidence interval [CI] = 1.09, 1.53, p = 0.004). Under additive model, the GCH1 rs11158026 increased the risk of developing PD (OR = 1.30, 95% CI = 1.10, 1.54, p = 0.002). In recessive model, the genotype TT of MIR4697 rs329648 marginally decreased the PD risk (OR = 0.62, 95% CI = 0.43, 0.90, p = 0.01). The PD patients demonstrated similar genotypic and allelic frequencies in GCH1 rs7155501, SIPA1L2 rs10797576, and VPS13C rs2414739 with the controls. These findings suggest that the GCH1 and MIR4697 but not SIPA1L2 and VPS13C are genetic loci influencing risk of PD in Taiwan., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Donor lymphocyte infusion (DLI) has been used with variable success in a variety of hematologic malignancies., Patients and Methods: We conducted a retrospective analysis of all patients who were treated with DLI for persistent or relapsed disease at the Temple University Bone Marrow Transplant Unit from July 1, 1993 to December 31, 2013 to evaluate the effect of the type of DLI (fresh vs. cryopreserved) on event-free survival (EFS) and overall survival (OS). Median follow-up was 64.8 months (range, 0.3-142.6 months)., Results: We found that EFS and OS were similar between patients receiving cryopreserved cells and those receiving fresh DLI (median OS for cryopreserved cells, 0.39 years; median OS for fresh cells, 0.32 years; P = .793; median EFS for cryopreserved cells, 0.410 years; median EFS for fresh cells, 0.420 years; P = .4264). In the setting of relapsed disease, treatment with any chemotherapy regimen before receiving DLI did not significantly impact OS (n = 63; P = .2203) or EFS (n = 40; P = .542). A subgroup analysis limited to patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) (32 patients) showed that differences in OS and EFS between cryopreserved and fresh DLI approached significance (median OS for cryopreserved cells, 0.34 years; median OS for fresh cells, 0.17 years; P = .16; median EFS for cryopreserved cells, 0.37 years; median EFS for fresh cells, 0.094 years; P = 0.11)., Conclusion: We conclude that the use of fresh cells versus cryopreserved cells does not have an impact on outcomes, and selected patients can achieve long-term survival with DLI for treatment of relapse after transplantation, although the overall outcomes remain dismal., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the most prevalent form of dementia associated with progressive cognitive decline and memory loss. Extracellular β-amyloid (Aβ) is a major constituent of senile plaques, one of the pathological hallmarks of AD. Aβ deposition causes neuronal death via a number of possible mechanisms such as increasing oxidative stress. Therefore therapeutic approaches to identify novel Aβ aggregate reducers could be effective for AD treatment. Using a Trx-His-Aβ biochemical assay, we screened 11 synthetic indolylquinoline compounds, and found NC009-1, -2, -6 and -7 displaying potential to reduce Aβ aggregation. Treating Tet-On Aβ-GFP 293 cells with these compounds reduced Aβ aggregation and reactive oxygen species. These compounds also promoted neurite outgrowth in Tet-On Aβ-GFP SH-SY5Y cells. Furthermore, treatment with above compounds improved neuronal cell viability, neurite outgrowth, and synaptophysin expression level in mouse hippocampal primary culture under oligomeric Aβ-induced cytotoxicity. Moreover, the tested NC009-1 significantly ameliorated Aβ-induced inhibition of hippocampal long-term potentiation in mouse hippocampal slices. Our results demonstrate how synthetic indolylquinoline compounds are likely to work as chemical chaperones in Aβ-aggregation reduction and neuroprotection, providing insight into the possible applications of indolylquinoline compounds in AD treatment., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Allogeneic hematopoietic stem cell transplant patients are at risk of invasive fungal infections and prophylaxis with azole agents is common practice. The concomitant use of these agents with sirolimus and tacrolimus for the prevention of graft-versus-host disease may result in excessive immunosuppression or toxicity., Methods: This retrospective study identified hospitalized patients who underwent allogeneic hematopoietic stem cell transplantation between August 2009 and April 2011 at Rush University Medical Center. From this group, patients who underwent concomitant tacrolimus, sirolimus, and azole therapy were included for evaluation. The immunosuppression dosing in conjunction with azole use at discharge was analyzed to develop a dosing algorithm dependent on whether fluconazole, posaconazole, or voriconazole was used., Results: A total of 36 patients were screened for inclusion, of which 8 were excluded due to acute renal failure and/or hemolysis. The remaining patients were stratified by the azole they were concomitantly taking with tacrolimus and sirolimus. The fluconazole arm required the lowest magnitude of dose reductions, while voriconazole required the greatest., Conclusion: Dose reductions of 50-75% for both sirolimus and tacrolimus, in combination with standard dosing of azole antifungal agents, were necessary to achieve therapeutic drug concentrations for immunosuppressants and potentially avoid toxicities., (© The Author(s) 2014.)

Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. Recent statistics from the American Cancer Society indicate that the incidence of MM is increasing. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) included in this issue address management of patients with solitary plasmacytoma and newly diagnosed MM., (Copyright © 2015 by the National Comprehensive Cancer Network.)

The purpose of this study was to analyze the impact of graft-versus-host disease (GVHD) on the relapse rate of different lymphoma subtypes after allogeneic hematopoietic cell transplantation (allo-HCT). Adult patients with a diagnosis of Hodgkin lymphoma, diffuse large B cell lymphoma, follicular lymphoma (FL), peripheral T cell lymphoma, or mantle cell lymphoma (MCL) undergoing HLA-identical sibling or unrelated donor hematopoietic cell transplantation between 1997 and 2009 were included. Two thousand six hundred eleven cases were included. A reduced-intensity conditioning (RIC) regimen was used in 62.8% of the transplantations. In a multivariate analysis of myeloablative cases (n = 970), neither acute (aGVHD) nor chronic GVHD (cGVHD) were significantly associated with a lower incidence of relapse/progression in any lymphoma subtype. In contrast, the analysis of RIC cases (n = 1641) showed that cGVHD was associated with a lower incidence of relapse/progression in FL (risk ratio [RR], .51; P = .049) and in MCL (RR, .41; P = .019). Patients with FL or MCL developing both aGVHD and cGVHD had the lowest risk of relapse (RR, .14; P = .007; and RR, .15; P = .0019, respectively). Of interest, the effect of GVHD on decreasing relapse was similar in patients with sensitive disease and chemoresistant disease. Unfortunately, both aGVHD and cGVHD had a deleterious effect on treatment-related mortality and overall survival (OS) in FL cases but did not affect treatment-related mortality, OS or PFS in MCL. This study reinforces the use of RIC allo-HCT as a platform for immunotherapy in FL and MCL patients., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Neuroinflammation is emerging as an important pathway involved in Parkinson's disease (PD) pathogenesis. Herein, we investigated the effect of 4 top PD-associated genetic variants in Caucasians listed on the top risk loci identified by meta-analysis of genome wide-association studies in PDGene database (http://www.pdgene.org/top&#95;results), including serine threonine kinase 39 (STK39) rs1955337, bone marrow stromal cell antigen 1 (BST1) rs11724635, major histocompatibility complex, class II, DQ beta 1 (HLA-DQB1) rs9275326, and signal peptide peptidase-like 2B (SPPL2B) rs62120679, by genotyping 596 Han-Chinese patients with PD and 597 age-matched control subjects. Compared with subjects with STK39 rs1955337 GG genotype, those with TT genotype had a 1.64-fold increased risk of PD (95% confidence interval: 1.13-2.39, P = 0.010). The recessive model also demonstrated an increased PD risk in TT genotype (odds ratio: 1.59, 95% confidence interval: 1.12-2.27) compared with the other genotypes (GT + GG). PD patients demonstrate a similar genotypic and allelic frequency in BST1 rs11724635, HLA-DQB1 rs9275326, and SPPL2B rs62120679 compared with controls. These findings suggested that the STK39 rs1955337 TT genotype is a risk factor for Han-Chinese patients with PD in Taiwan. The ethnic discrepancies of the other 3 genetic variants may indicate a distinct genetic background of neuroinflammation between PD patients in Han-Chinese and Caucasians.

Background: Patients undergoing hematopoietic stem cell transplant (HSCT) can experience gastrointestinal (GI) side effects as a complication of the treatment. Limited research exists describing how the duration and severity of GI side effects influence the consumption of adequate calorie intake in this population. The purpose of this study was to assess differences in GI side effects between patients who consumed adequate calories compared with those who did not., Methods: The MD Anderson Symptom Inventory-Gastrointestinal (MDASI-GI) tool was used to record daily GI side effects of 72 HSCT patients. Daily calorie intake was determined via calorie counts. Data were collected from day of transplant until engraftment., Results: Median percentage of caloric needs consumed for all patients was 49.2% (interquartile range, 35.1-66.6). Calorie intake decreased from baseline to transplant day 8 as severity of GI symptoms increased. An inverse relationship between percentage of caloric needs met and MDASI-GI component score, MDASI-GI symptom score, and lack of appetite score was observed. The only significant difference in MDASI-GI symptom scores between those who consumed adequate calories and those who consumed inadequate calories was for diarrhea; subjects who consumed >60% of caloric needs had significantly lower median diarrhea scores., Conclusion: Most patients consumed <60% of their caloric needs from time of transplant to time of engraftment. More research is needed to provide insight into strategies to increase intake and to describe the implications of prolonged inadequate intake in HSCT patients., (© 2014 American Society for Parenteral and Enteral Nutrition.)

Objective: Patient anger can be challenging for providers, and may hinder the patient-provider relationship. Research on the relationships among patient anger, relationships with health care providers and medical outcomes, however, has been limited to anecdotal accounts and cross-sectional studies. This study examined relationships among patient anger, perceptions of provider positive support and negative interactions, by prospectively studying a sample of stem cell transplant (SCT) patients., Method: A prospective design was used to study patient anger, perceived positive support from providers and perceived negative interactions with providers among 88 SCT patients. Data were obtained upon patient's hospitalization before SCT and at 1, 2, and 3 month follow up periods. Repeated-measures mixed models assessed relationships among study variables., Results: Patient anger was associated with a gradual decline in perceived positive support and higher levels of concurrent perceived negative interactions with providers. Further, a significant lagged relationship was found such that patient anger was associated with increased perceived negative interactions with providers 1 month later. Exploratory analyses revealed that perceived negative interactions were also associated with higher levels of physical distress. Perceived positive support buffered the relationship between patient anger and physical distress, such that anger was not associated significantly with physical distress when perceived provider support was high., Conclusions: Patient anger may contribute to a deterioration of the patient-provider relationship, and contribute to negative medical outcomes including physical distress. The association between patient anger and physical distress may be reduced by supportive providers., (PsycINFO Database Record (c) 2015 APA, all rights reserved.)

Autologous hematopoietic cell transplantation (AHCT) for plasma cell myeloma is performed less often in people >70 years old than in people ≤70 years old. We analyzed 11,430 AHCT recipients for plasma cell myeloma prospectively reported to the Center for International Blood and Marrow Transplant Research between 2008 and 2011, representing the majority of US AHCT activity during this period. Survival (OS) was compared in 3 cohorts: ages 18 to 59 years (n = 5818), 60 to 69 years (n = 4666), and >70 years (n = 946). Median OS was not reached for any cohort. In multivariate analysis, increasing age was associated with mortality (P = .0006). Myeloma-specific mortality was similar among cohorts at 12%, indicating an age-related effect on nonmyeloma mortality. Analyses were performed in a representative subgroup comparing relapse rate, progression-free survival (PFS), and nonrelapse mortality (NRM). One-year NRM was 0% for age >70 years and 2% for other ages (P = not significant). The three-year relapse rate was 56% in age 18 to 59 years, 61% in age 60 to 69 years, and 63% age >70 (P = not significant). Three-year PFS was similar at 42% in age 18 to 59 years, 38% in age 60 to 69 years, and 33% in age >70 years (P = not significant). Postrelapse survival was significantly worse for the older cohort (P = .03). Older subjects selected for AHCT derived similar antimyeloma benefit without worse NRM, relapse rate, or PFS., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Contactin-associated protein 2 (Caspr2) antibody is a neuronal surface antibody (NSAb) capable of causing disorders involving central and peripheral nervous systems (PNS). Thymoma can be found in patients with Caspr2 antibodies and is most frequently associated with PNS symptoms. Myasthenia gravis can be found in these patients, but Hashimoto thyroiditis (HT) has not been reported., Methods: A 76-year-old woman presented with sub-acute-onset changes in mental status. Further investigations revealed thymoma and HT. The presence of NSAb was tested by immunofluorescence on human embryonic kidney-293 cells. Treatment included corticosteroids, azathioprine, thyroxine, plasmapheresis, and thymectomy., Results: Caspr2 antibody was positive in serum but absent in CSF. Brain magnetic resonance imaging (MRI) showed diffuse cortical atrophy, but did not change significantly after treatments. Brain positron emission tomography (PET) revealed diffuse hypometabolism over the cerebral cortex. The patient's mental status only partially improved., Conclusions: In Caspr2 antibody-associated syndromes, thymoma can occur in patients presenting only with LE, and HT can be an accompanying disease. Brain MRI and PET may not show specific lesions in limbic area. Patients with Caspr2 antibodies and thymoma may not have good prognosis., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Haplotype structure of the microtubule-associated protein tau (MAPT) gene is associated with various tauopathies in the Caucasian population. With the knowledge that the association between MAPT structure and disease may be distinct in different ethnics, we intend to investigate the haplotype structure of MAPT in Taiwanese and test it for association with Alzheimer's disease (AD)., Methods: One hundred and eight AD patients and 108 sex- and-age matched healthy controls were recruited from the dementia outpatient clinic of Chang Gung Medical center. We genotyped the del-In9 marker that defines the extended H1 and H2 clades. We selected 21 single-nucleotide polymorphisms (SNPs) in the extended MAPT region from Japanese SNPs database and dbSNP database. Using the software TagIt, we analyzed the linkage disequilibrium structure of MAPT and compared the allele and genotype distribution between patient group and control group., Results: All the Taiwanese participants were H1 haplotypes. Linkage disequilibrium analysis showed the haplotype blocks in Taiwanese population had a smaller size in comparison to that of the Caucasian population. Single locus association showed significant p value in one of the tagging variants (rs242557) in our Taiwanese AD case-control cohorts., Conclusion: MAPT gene has four haplotype blocks in the Taiwanese population, each of around 40 kbp. In both European study and our study, the SNP rs242557 showed association with AD. Given the position of this SNP, the most possible explanation is that genetic variability in tau expression contributes to the risk of developing AD.

Rationale and Objectives: The primary objective of the current investigation was to characterize white matter integrity in different subtypes of mild cognitive impairment (MCI) using tract-based spatial statistics of diffusion tensor imaging., Materials and Methods: The study participants were divided into 4 groups of 30 subjects each as follows: cognitively healthy controls, amnestic MCI, dysexecutive MCI, and Alzheimer's disease (AD). All subjects underwent a comprehensive neuropsychological assessment, apolipoprotein E genotyping, and 3-tesla MRI. The diffusion tensor was reconstructed and then analyzed using tract-based spatial statistics. The changes in brain white matter tracts were also examined according to the apolipoprotein E ε 4 status., Results: Compared with controls, amnestic MCI patients showed significant differences in the cerebral white matter, where changes were consistently detectable in the frontal and parietal lobes. We found a moderate impact of the apolipoprotein E ε 4 status on the extent of white matter disruption in the amnestic MCI group. Patients with AD exhibited similar but more extensive alterations, while no significant changes were observed in dysexecutive MCI patients., Conclusion: The results from this study indicate that amnestic MCI is the most likely precursor to AD as both conditions share significant white matter damage. By contrast, dysexecutive MCI seems to be characterized by a distinct pathogenesis.

Background: The purpose of this study was to examine sex dimorphism in water diffusion in the brain throughout the normal aging process by magnetic resonance imaging., Methods: Diffusion-weighted images covering the majority of the brain were acquired from 77 healthy participants. Both the mean water diffusivity and diffusion kurtosis were calculated from the cortical regions and parcellated according to the template in anatomical automatic labeling. The mean water diffusivity and diffusion kurtosis from both sexes were examined and subsequently correlated with age. Statistical significance was set at a threshold of p < 0.01 after correction for multiple comparisons. In regions that reached statistical significance, a linear regression model was performed. Analysis of variance was conducted to determine the interaction between aging and sex., Results: Sex differences were observed for three aspects. First, compared to females, males presented increased mean water diffusivity and a decreased diffusion kurtosis in the frontal and temporal lobes. Second, a widespread age-related increase in mean water diffusivity was observed, which was more significant in the frontal, occipital, and temporal areas and in the cingulum in females. Third, the diffusion kurtosis decreased with aging but only in restricted areas for both sexes. For the interaction of aging and sex, the most significant change was observed with regards to mean diffusivity, mostly in the right amygdala., Conclusions: A sex-related dimorphism in water diffusion throughout the aging process was observed in the cortex using magnetic resonance imaging.

Background: A firm understanding of the biology of hematopoietic stem and progenitor cell (HSC/HPC) trafficking is critical to improve transplant efficiency and immune reconstitution during hematopoietic stem cell transplantation (HSCT). Our earlier findings suggested that suppression of CD26 (dipeptidyl peptidase IV) proteolytic activity in the donor cell population can be utilized as a method for increasing transplant efficiency. However, factors in the recipient should not be overlooked, given the potential for the bone marrow (BM) microenvironment to regulate HSCT., Study Design and Methods: We first evaluated CD26 expression and then investigated the effects of the CD26 inhibitor diprotin A and the absence of CD26 (CD26-/-) in recipient mice on HSC/HPC homing and engraftment using an in vivo congenic mouse model of HSCT., Results: A significant increase in donor cell engraftment into the peripheral blood (PB), and to a lesser extent homing into the BM, was observed in CD26-/- mice or CD26 inhibitor-treated mice. Increased PB engraftment of CD26-/- mice was significant at 3 and 6 months, but not 1 month, after transplant. It was noted that the increased homing was statistically greater with donor cell manipulation (CD26-/- donor cells) than with recipient manipulation (CD26-/- recipient mice). Conversely, donor and recipient manipulation both worked well to increase PB engraftment at 6 months., Conclusion: These results provide preclinical evidence of CD26, in the HSCT recipient, as a major regulator of HSC/HPC engraftment with minor effects on HSC/HPC homing and suggest the potential use of CD26 inhibitors in HSCT patients to improve transplant efficiency., (© 2012 American Association of Blood Banks.)