Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions.

The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-ß and α-synuclein pathology were rated on a scale of 0 (absent)-3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm3 post-mortem MRI scans of excised MTL specimens from the contralateral hemisphere using a semi-automated approach. Spearman's rank correlations were performed between neurodegenerative pathologies and thickness, correcting for age, sex and hemisphere, including all four proteinopathies in the model. We found significant associations of (1) TDP-43 with thickness in all subregions (r = - 0.27 to r = - 0.46), and (2) tau with BA35 (r = - 0.31) and SRLM thickness (r = - 0.33). In amyloid-ß and TDP-43 negative cases, we found strong significant associations of tau with ERC (r = - 0.40), BA35 (r = - 0.55), subiculum (r = - 0.42) and CA1 thickness (r = - 0.47). This unique dataset shows widespread MTL atrophy in relation to TDP-43 pathology and atrophy in regions affected early in Braak stageing and tau pathology. Moreover, the strong association of tau with thickness in early Braak regions in the absence of amyloid-ß suggests a role of Primary Age-Related Tauopathy in neurodegeneration.

Pathological drivers of neurodegeneration in suspected non-Alzheimer's disease pathophysiology.

BACKGROUND: Little is known about the heterogeneous etiology of suspected non-Alzheimer's pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of ß-amyloid. Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal lobe (MTL) measures in ß-amyloid-negative subjects. METHODS: Subjects with antemortem MRI and autopsy data were selected from ADNI (n=63) and the University of Pennsylvania (n=156). Pathological diagnoses and semi-quantitative scores of MTL tau, neuritic plaques, α-synuclein, and TDP-43 pathology and MTL structural MRI measures from antemortem T1-weighted MRI scans were obtained. ß-amyloid status (A+/A-) was determined by CERAD score and neurodegeneration status (N+/N-) by hippocampal volume. RESULTS: SNAP reflects a heterogeneous group of pathological diagnoses. In ADNI, SNAP (A-N+) had significantly more neuropathological diagnoses than A+N+. In the A- group, tau pathology was associated with hippocampal, entorhinal cortex, and Brodmann area 35 volume/thickness and TDP-43 pathology with hippocampal volume. CONCLUSION: SNAP had a heterogeneous profile with more mixed pathologies than A+N+. Moreover, a role for TDP-43 and tau pathology in driving MTL neurodegeneration in the absence of ß-amyloid was supported.

Hippocampal subfield pathologic burden in Lewy body diseases vs. Alzheimer's disease.

AIMS: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aß) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing. METHODS: Hippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aß. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing. RESULTS: LBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P < 0.02). In LBD, SYN correlated with tau across subfields (R = 0.49, P < 0.001). Tau burden was higher in AD than LBD + AD (P < 0.001), CA1/subiculum and entorhinal cortex (ERC) being most affected regions (P = 0.04 to <0.01). However, tau pathology in LBD - AD was greatest in CA2/3, which was equivalent to LBD + AD. Aß severity and distribution was similar between LBD + AD and AD. Total hippocampal tau and CA2/3 tau was inversely correlated with memory performance in LBD (R = -0.52, -0.69, P = 0.04, 0.009). CONCLUSIONS: Our findings suggest that tau burden in hippocampal subfields may map closely with the distribution of SYN pathology in subfield CA2/3 in LBD diverging from traditional AD and contribute to episodic memory dysfunction in LBD.

Comparative risk of osteoporotic fracture among patients with rheumatoid arthritis receiving TNF inhibitors versus other biologics: a cohort study.

In this population-based cohort study on comparative osteoporotic fracture risks between different biologic disease-modifying drugs among patients with rheumatoid arthritis (RA), we did not find a significant difference in the risk of osteoporotic fractures between RA patients receiving TNF inhibitors versus abatacept or tocilizumab. INTRODUCTION: We aimed to investigate the comparative risk of osteoporotic fractures between rheumatoid arthritis (RA) patients who initiated TNF inhibitors (TNFis) versus abatacept or tocilizumab. METHODS: Using the Korea National Health Insurance Service datasets from 2002 to 2016, RA patients who initiated TNFis, abatacept, or tocilizumab were identified. The primary outcome was a composite end point of non-vertebral fractures and hospitalized vertebral fractures; secondary outcomes were two components of the primary outcome and fractures occurring at the humerus/forearm. Propensity score (PS) matching with a variable ratio up to 10 TNFi initiators per 1 comparator drug initiator was used to adjust for > 50 baseline confounders. We estimated hazard ratios (HRs) and 95% confidence interval (CI) of fractures comparing TNFi initiators to abatacept and to tocilizumab by Cox proportional hazard models stratified by a matching ratio. RESULTS: After PS-matching, 2307 TNFi initiators PS-matched on 588 abatacept initiators, and 2462 TNFi initiators on 640 tocilizumab initiators were included. A total of 77 fractures occurred during a mean follow-up of 454 days among TNFi and abatacept initiators and 83 fractures during 461 days among TNFi and tocilizumab initiators. The PS-matched HR (95% CI) was 0.91 (0.48-1.71) comparing TNFi versus abatacept initiators, and 1.00 (0.55-1.83) comparing TNFi versus tocilizumab initiators. Analysis on vertebral and non-vertebral fractures showed similar results. CONCLUSIONS: In this nationally representative cohort, we did not find a significant difference in the risk of fractures between TNFi initiators versus abatacept or tocilizumab among RA patients.

Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating and fatal motor neuron disease. Diagnosis typically occurs in the fifth decade of life and the disease progresses rapidly leading to death within ~ 2-5 years of symptomatic onset. There is no cure, and the few available treatments offer only a modest extension in patient survival. A protein central to ALS is the nuclear RNA/DNA-binding protein, TDP-43. In > 95% of ALS patients, TDP-43 is cleared from the nucleus and forms phosphorylated protein aggregates in the cytoplasm of affected neurons and glia. We recently defined that poly(ADP-ribose) (PAR) activity regulates TDP-43-associated toxicity. PAR is a posttranslational modification that is attached to target proteins by PAR polymerases (PARPs). PARP-1 and PARP-2 are the major enzymes that are active in the nucleus. Here, we uncovered that the motor neurons of the ALS spinal cord were associated with elevated nuclear PAR, suggesting elevated PARP activity. Veliparib, a small-molecule inhibitor of nuclear PARP-1/2, mitigated the formation of cytoplasmic TDP-43 aggregates in mammalian cells. In primary spinal-cord cultures from rat, Veliparib also inhibited TDP-43-associated neuronal death. These studies uncover that PAR activity is misregulated in the ALS spinal cord, and a small-molecular inhibitor of PARP-1/2 activity may have therapeutic potential in the treatment of ALS and related disorders associated with abnormal TDP-43 homeostasis.

Urinary vitamin D-binding protein, a novel biomarker for lupus nephritis, predicts the development of proteinuric flare.

Lupus nephritis (LN) is a major complication of systemic lupus erythematosus (SLE). Conventional biomarkers for assessing renal disease activity are imperfect in predicting clinical outcomes associated with LN. The aim of this study is to identify urinary protein biomarkers that reliably reflect the disease activity or predict clinical outcomes. A quantitative proteomic analysis was performed to identify protein biomarker candidates that can differentiate between SLE patients with and without LN. Selected biomarker candidates were further verified by enzyme-linked immunosorbent assay using urine samples from a larger cohort of SLE patients ( n = 121) to investigate their predictive values for LN activity measure. Furthermore, the association between urinary levels of a selected panel of potential biomarkers and prognosis of LN was assessed with a four-year follow-up study of renal outcomes. Urinary vitamin D-binding protein (VDBP), transthyretin (TTR), retinol binding protein 4 (RBP4), and prostaglandin D synthase (PTGDS) were significantly elevated in SLE patients with LN, especially in patients with active LN ( n = 21). Among them, VDBP well correlated with severity of proteinuria (rho = 0.661, p < 0.001) and renal SLE Disease Activity Index (renal SLEDAI) (rho = 0.520, p < 0.001). In the four-year follow-up, VDBP was a significant risk factor (hazard ratio 9.627, 95% confidence interval 1.698 to 54.571, p = 0.011) for the development of proteinuric flare in SLE patients without proteinuria ( n = 100) after adjustments for multiple confounders. Urinary VDBP correlated with proteinuria and renal SLEDAI, and predicted the development of proteinuria.

Progression of alpha-synuclein pathology in multiple system atrophy of the cerebellar type.

AIMS: The aim of this study was to identify early foci of α-synuclein (α-syn pathology) accumulation, subsequent progression and neurodegeneration in multiple system atrophy of the cerebellar type (MSA-C). METHODS: We analysed 70-µm-thick sections of 10 cases with MSA-C and 24 normal controls. RESULTS: MSA-C cases with the lowest burden of pathology showed α-syn glial cytoplasmic inclusions (GCIs) in the cerebellum as well as in medullary and pontine cerebellar projections. Cerebellar pathology was highly selective and severely involved subcortical white matter, whereas deep white matter and granular layer were only mildly affected and the molecular layer was spared. Loss of Purkinje cells increased with disease duration and was associated with neuronal and axonal abnormalities. Neocortex, basal ganglia and spinal cord became consecutively involved with the increasing burden of α-syn pathology, followed by hippocampus, amygdala, and, finally, the visual cortex. GCIs were associated with myelinated axons, and the severity of GCIs correlated with demyelination. CONCLUSIONS: Our findings indicate that cerebellar subcortical white matter and cerebellar brainstem projections are likely the earliest foci of α-syn pathology in MSA-C, followed by involvement of more widespread regions of the central nervous system and neurodegeneration with disease progression.

The role of body image psychological flexibility on the treatment of eating disorders in a residential facility.

OBJECTIVE: The purpose of this study was to test whether pre-treatment levels of psychological flexibility would longitudinally predict quality of life and eating disorder risk in patients at a residential treatment facility for eating disorders. METHOD: Data on body image psychological flexibility, quality of life, and eating disorder risk were collected from 63 adolescent and 50 adult, female, residential patients (N=113) diagnosed with an eating disorder. These same measures were again collected at post-treatment. Sequential multiple regression analyses were performed to test whether pre-treatment levels of psychological flexibility longitudinally predicted quality of life and eating disorder risk after controlling for age and baseline effects. RESULTS: Pre-treatment psychological flexibility significantly predicted post-treatment quality of life with approximately 19% of the variation being attributable to age and pre-treatment psychological flexibility. Pre-treatment psychological flexibility also significantly predicted post-treatment eating disorder risk with nearly 30% of the variation attributed to age and pre-treatment psychological flexibility. DISCUSSION: This study suggests that levels of psychological flexibility upon entering treatment for an eating disorder longitudinally predict eating disorder outcome and quality of life.

A genetic variation in microRNA target site of KRT81 gene is associated with survival in early-stage non-small-cell lung cancer.

BACKGROUND: MicroRNAs (miRNAs) have a key role in carcinogenesis through negative regulation of their target genes. Therefore, genetic variations in miRNAs or their target sites may affect miRNA-mRNA interactions, thereby result in altered expression of target genes. This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) located in the miRNA target sites (poly-miRTSs) and survival of patients with early-stage non-small-cell lung cancer (NSCLC). METHODS: Using public SNP database and miRNA target sites prediction program, 354 poly-miRTSs were selected for genotyping. Among these, 154 SNPs applicable to Sequenom's MassARRAY platform were investigated in 357 patients. A replication study was carried out on an independent patient population (n = 479). Renilla luciferase assay and reverse transcription-polymerase chain reaction were conducted to examine functional relevance of potentially functional poly-miRTSs. RESULTS: Of the 154 SNPs analyzed in a discovery set, 14 SNPs were significantly associated with survival outcomes. Among these, KRT81 rs3660G>C was found to be associated with survival outcomes in the validation cohort. In the combined analysis, patients with the rs3660 GC + CC genotype had a significantly better overall survival compared with those with GG genotype [adjusted hazard ratio (aHR) for OS, 0.65; 95% confidence interval (CI) 0.50-0.85; P = 0.001]. An increased expression of the reporter gene for the C allele of rs3660 compared with the G allele was observed by luciferase assay. Consistently, the C allele was associated with higher relative expression level of KRT81 in tumor tissues. CONCLUSION: The rs3660G>C affects KRT81 expression and thus influences survival in early-stage NSCLC. The analysis of the rs3660G>C polymorphism may be useful to identify patients at high risk of a poor disease outcome.

Baseline MRA predicts the treatment response to vasodilator udenafil in patients with secondary Raynaud's phenomenon.

OBJECTIVES: High-resolution MR angiography (HR-MRA) demonstrates blood flow in the digital arteries, which correlates with the severity of Raynaud's phenomenon (RP). This study investigates whether baseline HR-MRA of the hand can predict the treatment response to udenafil, a new PDE5-inhibitor, in patients with secondary RP. METHODS: Baseline MRA and Doppler ultrasound were obtained in 12 patients with secondary RP. The patients were treated with udenafil 100 mg/day for 4 weeks and changes in blood flow were measured. Blood flow on MRA was scored on a 4-point scale: 0, no visible flow; 1, visible flow to the proximal phalanx; 2, to the middle phalanx; and 3, to the distal phalanx. Peak systolic velocity (PSV) was measured to determine blood flow. Paired t-test and ANOVA were used to determine the treatment response of the different MRA scores. RESULTS: On baseline MRA, 53.3% of digital arteries had an MRA score of 0, 25.8% MRA score of 1, 9.2% MRA score of 2, and 11.6% MRA score of 3. Overall, 4-week udenafil treatment improved digital flow (p<0.05) in all MRA scores. Digital arteries with MRA score 2 showed the best response with improvement in PSV by 14.5 mm/sec (p<0.01), whereas improvement in arteries of MRA scores 1 and 3 were not better than an MRA score of 0 (all, p>0.05). CONCLUSIONS: Digital arteries with moderate blood flow observed on MRA respond best to treatment with udenalfil. Therefore, baseline MRA may help predict treatment response in patients with secondary RP.

Decreased tumour necrosis factor-α production by monocytes of granulomatosis with polyangiitis.

OBJECTIVES: We hypothesized that monocytes in patients with granulomatosis with polyangiitis (GPA) are polarized towards alternative activation with decreased tumour necrosis factor (TNF)-α production and that tissue-infiltrating monocytes/macrophages in granulomatous GPA lesions express CD163, a marker of alternative macrophage activation. METHOD: CD16+ monocytes in peripheral blood mononuclear cells (PBMCs) were quantified by flow cytometry. Monocytes were stimulated with increasing concentrations of lipopolysaccharide (LPS), and TNF-α production was measured at 4 and 24 h. CD163 expression in lung biopsies of patients with GPA was detected by immunohistochemistry. RESULTS: Circulating CD16+ monocytes were more frequent in GPA patients compared to controls (4.7 ± 2.8% vs. 1.9 ± 1.2%, p < 0.001). Upon activation with LPS, TNF-α production did not differ between CD16+ and CD16- monocytes. Stimulated monocytes from GPA patients produced significantly less TNF-α compared with monocytes from healthy controls (2903 ± 1320 pg/mL vs. 8335 ± 4569 pg/mL, p < 0.001). Macrophages expressing CD163 were enriched in granulomatous lung lesions of GPA patients. CONCLUSIONS: Decreased TNF-α production by circulating monocytes and CD163 overexpression by tissue monocytes/macrophages in granulomatous pulmonary lesions may suggest that monocytes/macrophages are alternatively activated in GPA.

Bone marrow analysis of immune cells and apoptosis in patients with systemic lupus erythematosus.

OBJECTIVES: To examine the immune cell profile in the bone marrow of systemic lupus erythematosus (SLE) patients and to assess its clinical relevance. METHODS: Sixteen bone marrow samples from 14 SLE patients were compared with seven healthy control samples. The numbers of immune cells and apoptotic cells in the bone marrow were examined by immunohistochemistry. The association between immune cell subsets and clinical features was investigated. RESULTS: CD4+ T cells, macrophages and plasma cells were more common in the bone marrow of SLE patients than in healthy controls (p=0.001, p=0.004 and p<0.001, respectively). Greater numbers of CD4+ T cells and macrophages were associated with high-grade bone marrow damage. The percentage of apoptotic cells in bone marrow of SLE patients was significantly higher than that in controls (p<0.001) and was positively correlated with the number of plasmacytoid dendritic cells (p=0.013). Increased number of plasma cells along with high interleukin-6 expression was correlated with anti-double stranded DNA antibody levels and the SLE disease activity index (p=0.031 and 0.013, respectively). CONCLUSION: Bone marrow from SLE patients showed a distinct immune cell profile and increased apoptosis. This, coupled with a correlation with disease activity, suggests that the bone marrow may play a critical role in the pathogenesis of SLE.

Costs of illness and quality of life in patients with systemic lupus erythematosus in South Korea.

OBJECTIVE: To assess the costs of illness, health-related quality of life (HRQOL) and their associated factors in patients with systemic lupus erythematosus (SLE) in South Korea. METHOD: Two hundred and one patients with SLE were enrolled at the Rheumatology clinic of Seoul National University Hospital. Direct, indirect and total costs and HRQOL were measured using hospital electronic data and face-to-face interview. Socio-demographic and clinical factors associated with cost of illness and HRQOL were analyzed using multiple regression and multivariate logistic regression. RESULTS: The average total cost of illness was estimated to be KRW 9.82 million (US $ 8993) per year, of which 41.6% was accounted for by direct costs and 58.4% by indirect costs. In multivariate regression, patients with renal involvement and those with depression incurred an average increment in annual total costs of 37.6% (p = 0.050) and 49.1% (p = 0.024), respectively, and an average increment in annual direct costs of 26.4% (p = 0.050) and 43.3% (p = 0.002), respectively, compared with patients without renal involvement and depression, respectively. In addition, disease damage was positively associated with an average increment in annual total and direct costs (55.3%, p = 0.006; 33.3%, p = 0.013, respectively), and the occurrence of indirect costs (OR 2.21, 1.09-4.88). There was no significant difference in HRQOL between patients with and without renal involvement (0.655 vs. 0.693, p = 0.203) CONCLUSION: Renal involvement, depression, and disease damage were major factors associated with higher total and medical costs for patients with SLE in South Korea. Effective treatment of renal disorders and depression may reduce the high economic burden of SLE.

Adenosine A2A receptor polymorphisms in Korean patients with systemic sclerosis.

Adenosine A2A receptor (ADORA2A) regulates inflammation, promotes tissue repair and collagen production by human dermal fibroblasts. We investigated the genetic polymorphisms of ADORA2A in susceptibility to systemic sclerosis (SSc). We genotyped 142 Korean SSc patients and 150 controls for polymorphisms of -1751A/C (rs5996696) and 1976C/T (rs5751876), to cover the promoter and all exon sequences of ADORA2A in Koreans, using TaqMan fluorogenic 5' nuclease assay and single base primer extension assay. Neither -1751A/C nor 1976C/T polymorphism showed difference in the distribution of alleles or genotypes between patients and controls with allele frequency of 89.9% v 91.0% for -1751A (p=0.64) and 56.5% v 54.0% for 1976C (p=0.55). Our findings suggest that the role of ADORA2A in SSc may not be genetically related.

Surgical resection of chest wall tuberculosis.

BACKGROUND: Chest wall tuberculosis is a rare disease. After reviewing cases previously treated by surgical resection, the methods of resection, results, perioperative complications, and recurrence of the disease were analyzed. METHODS: The clinical and radiological data of 21 patients with chest wall tuberculosis treated between March 1998 and May 2007 were reviewed retrospectively. RESULTS: Symptoms included growing chest wall mass, with the time intervals of surgical resection from symptoms ranging from one to eight months (mean 2.3 months). Fourteen patients had a past history of tuberculosis. Preoperative needle aspiration was performed in 10 patients. The lesion was confined to the chest wall without a pleural lesion in 4 patients; 14 patients had a chest wall lesion with a pleural space. Resection of the abscess without rib resection was performed in nine patients. Complete resection of the abscess together with soft tissue and the involved rib was performed in 12 patients. Recurrence occurred in two patients (9.5 %): one underwent complete resection with rib resection while the other had resection without rib resection. CONCLUSION: Chest wall tuberculosis requires surgical resection in most cases and complete surgical resection may be needed to keep the recurrence rate low.