Retrospective analysis of autoimmune hepatitis-primary biliary cirrhosis overlap syndrome in Korea: characteristics,treatments, and outcomes

Background/Aims

Overlap syndrome of autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) (AIH-PBC overlap syndrome) is a rare disease that has not been clearly characterized in Korean patients. This study investigated the clinical features of AIH-PBC overlap syndrome compared with those of AIH and PBC alone.

Methods

This retrospective cohort study included 158 consecutive patients who were diagnosed as AIH (n=61), PBC (n=81), or AIH-PBC overlap syndrome (n=9) based on the Paris and the International Autoimmune Hepatitis Group (IAIHG) criteria from 2001 to 2011 in Korea. We compared the clinical features of these three groups retrospectively, including their biochemical characteristics, treatments, responses, and clinical outcomes.

Results

The AIH-PBC overlap syndrome patients exhibited biochemical characteristics of both AIH and PBC, and showed a similar response to ursodeoxycholic acid (UDCA) monotherapy as for the PBC patients. However, the response of AIH-PBC overlap syndrome patients to UDCA and steroid combination therapy was worse than the response of AIH patients to steroid-based therapy (P=0.024). Liver cirrhosis developed more rapidly in AIH-PBC overlap syndrome patients than in AIH patients group (P=0.013), but there was no difference between AIH-PBC overlap syndrome patients and PBC patients. The rates of developing hepatic decompensation did not differ significantly between the groups.

Conclusions

The AIH-PBC overlap syndrome patients exhibited a worse response to UDCA and steroid combination therapy and a faster cirrhotic progression compared with AIH patients.     

Performance of the PROTIA? Allergy-Q? System in the Detection of Allergen-specific IgE: A Comparison With the ImmunoCAP? System

Purpose

The PROTIA™ Allergy-Q® enzyme immunoassay (EIA) is a recently developed screening assay for specific immunoglobulin E (sIgE) for multiple allergens. The ImmunoCAP® fluorescent EIA (FEIA) system is the most widely used method for sIgE detection. In this study, we evaluated the performance of the Allergy-Q® system compared to the ImmunoCAP® system.

Methods

We compared the 2 systems using sera from 260 Korean allergy patients suffering from asthma (26.5%), allergic rhinitis (42.3%), atopic dermatitis (67.7%), and food allergy (18.1%). We compared sIgE-measurement results for 7 inhalant allergens, 5 food allergens, and 4 microorganism allergens.

Results

Overall, 1,799 paired assay results were analyzed. Except mugwort and alternaria, most of the allergen-sIgE results showed intra-class correlation coefficients of >0.5. Inter-assay class associations were reliable for most allergens (gamma=0.858-0.987, P<0.001). Passing-Bablok regression analysis showed multiple differences in intercept and slope. The inter-method concordance was moderate to substantial for most allergens (κ=0.713-0.898, P<0.001).

Conclusions

The PROTIA™ Allergy-Q® EIA system exhibited good detection performance compared to the ImmunoCAP® FEIA system in Korean allergic patients. However, because of methodological differences between the 2 assays, careful clinical implication is required for the interpretation of Allergy-Q® EIA results.     

Comparative study of the shear bond strength of various veneering materials on grade II commercially pure titanium

PURPOSE

To compare the shear bond strength of various veneering materials to grade II commercially pure titanium (CP-Ti).

MATERIALS AND METHODS

Thirty specimens of CP-Ti disc with 9 mm diameter and 10 mm height were divided into three experimental groups. Each group was bonded to heat-polymerized acrylic resin (Lucitone 199), porcelain (Triceram), and indirect composite (Sinfony) with 7 mm diameter and 2 mm height. For the control group (n=10), Lucitone 199 were applied on type IV gold alloy castings. All samples were thermocycled for 5000 cycles in 5-55℃ water. The maximum shear bond strength (MPa) was measured with a Universal Testing Machine. After the shear bond strength test, the failure mode was assessed with an optic microscope and a scanning electron microscope. Statistical analysis was carried out with a Kruskal-Wallis Test and Mann-Whitney Test.

RESULTS

The mean shear bond strength and standard deviations for experimental groups were as follows: Ti-Lucitone 199 (12.11 ± 4.44 MPa); Ti-Triceram (11.09 ± 1.66 MPa); Ti-Sinfony (4.32 ± 0.64 MPa). All of these experimental groups showed lower shear bond strength than the control group (16.14 ± 1.89 MPa). However, there was no statistically significant difference between the Ti-Lucitone 199 group and the control group, and the Ti-Lucitone 199 group and the Ti-Triceram group. Most of the failure patterns in all experimental groups were adhesive failures.

CONCLUSION

The shear bond strength of veneering materials such as heat-polymerized acrylic resin, porcelain, and indirect composite to CP-Ti was compatible to that of heatpolymerized acrylic resin to cast gold alloy.     

Automatically Detecting Failures in Natural Language Processing Tools for Online Community Text

Background

The prevalence and value of patient-generated health text are increasing, but processing such text remains problematic. Although existing biomedical natural language processing (NLP) tools are appealing, most were developed to process clinician- or researcher-generated text, such as clinical notes or journal articles. In addition to being constructed for different types of text, other challenges of using existing NLP include constantly changing technologies, source vocabularies, and characteristics of text. These continuously evolving challenges warrant the need for applying low-cost systematic assessment. However, the primarily accepted evaluation method in NLP, manual annotation, requires tremendous effort and time.

Objective

The primary objective of this study is to explore an alternative approach—using low-cost, automated methods to detect failures (eg, incorrect boundaries, missed terms, mismapped concepts) when processing patient-generated text with existing biomedical NLP tools. We first characterize common failures that NLP tools can make in processing online community text. We then demonstrate the feasibility of our automated approach in detecting these common failures using one of the most popular biomedical NLP tools, MetaMap.

Methods

Using 9657 posts from an online cancer community, we explored our automated failure detection approach in two steps: (1) to characterize the failure types, we first manually reviewed MetaMap’s commonly occurring failures, grouped the inaccurate mappings into failure types, and then identified causes of the failures through iterative rounds of manual review using open coding, and (2) to automatically detect these failure types, we then explored combinations of existing NLP techniques and dictionary-based matching for each failure cause. Finally, we manually evaluated the automatically detected failures.

Results

From our manual review, we characterized three types of failure: (1) boundary failures, (2) missed term failures, and (3) word ambiguity failures. Within these three failure types, we discovered 12 causes of inaccurate mappings of concepts. We used automated methods to detect almost half of 383,572 MetaMap’s mappings as problematic. Word sense ambiguity failure was the most widely occurring, comprising 82.22% of failures. Boundary failure was the second most frequent, amounting to 15.90% of failures, while missed term failures were the least common, making up 1.88% of failures. The automated failure detection achieved precision, recall, accuracy, and F1 score of 83.00%, 92.57%, 88.17%, and 87.52%, respectively.

Conclusions

We illustrate the challenges of processing patient-generated online health community text and characterize failures of NLP tools on this patient-generated health text, demonstrating the feasibility of our low-cost approach to automatically detect those failures. Our approach shows the potential for scalable and effective solutions to automatically assess the constantly evolving NLP tools and source vocabularies to process patient-generated text.     

Dexmedetomidine-Induced Contraction in the Isolated Endothelium-Denuded Rat Aorta Involves PKC-δ-mediated JNK Phosphorylation

Vasoconstriction mediated by the highly selective alpha-2 adrenoceptor agonist dexmedetomidine leads to transiently increased blood pressure and severe hypertension. The dexmedetomidine-induced contraction involves the protein kinase C (PKC)-mediated pathway. However, the main PKC isoform involved in the dexmedetomidine-induced contraction remains unknown. The goal of this in vitro study was to examine the specific PKC isoform that contributes to the dexmedetomidine-induced contraction in the isolated rat aorta. The endothelium-denuded rat aorta was suspended for isometric tension recording. Dexmedetomidine dose-response curves were generated in the presence or absence of the following inhibitors: the pan-PKC inhibitor, chelerythrine; the PKC-α and -β inhibitor, Go6976; the PKC-α inhibitor, safingol; the PKC-β inhibitor, ruboxistaurin; the PKC-δ inhibitor, rottlerin; the c-Jun NH₂-terminal kinase (JNK) inhibitor, SP600125; and the myosin light chain kinase inhibitor, ML-7 hydrochloride. Western blot analysis was used to examine the effect of rottlerin on dexmedetomidine-induced PKC-δ expression and JNK phosphorylation in rat aortic vascular smooth muscle cells (VSMCs) and to investigate the effect of dexmedetomidine on PKC-δ expression in VSMCs transfected with PKC-δ small interfering RNA (siRNA) or control siRNA. Chelerythrine as well as SP600125 and ML-7 hydrochloride attenuated the dexmedetomidine-induced contraction. Go6976, safingol, and ruboxistaurin had no effect on the dexmedetomidine-induced contraction, whereas rottlerin inhibited the dexmedetomidine-induced contraction. Dexmedetomidine induced PKC-δ expression, whereas rottlerin and PKC-δ siRNA transfection inhibited dexmedetomidine-induced PKC-δ expression. Dexmedetomidine also induced JNK phosphorylation, which was inhibited by rottlerin. Taken together, these results suggest that the dexmedetomidine-induced contraction involves PKC-δ-dependent JNK phosphorylation in the isolated rat aorta.     

Lifespan extension and increased resistance to environmental stressors by N-Acetyl-L-Cysteine in Caenorhabditis elegans

OBJECTIVE:

This study was performed to determine the effect of N-acetyl-L-cysteine, a modified sulfur-containing amino acid that acts as a strong cellular antioxidant, on the response to environmental stressors and on aging in C. elegans.

METHOD:

The survival of worms under oxidative stress conditions induced by paraquat was evaluated with and without in vivo N-acetyl-L-cysteine treatment. The effect of N-acetyl-L-cysteine on the response to other environmental stressors, including heat stress and ultraviolet irradiation (UV), was also monitored. To investigate the effect on aging, we examined changes in lifespan, fertility, and expression of age-related biomarkers in C. elegans after N-acetyl-L-cysteine treatment.

RESULTS:

Dietary N-acetyl-L-cysteine supplementation significantly increased resistance to oxidative stress, heat stress, and UV irradiation in C. elegans. In addition, N-acetyl-L-cysteine supplementation significantly extended both the mean and maximum lifespan of C. elegans. The mean lifespan was extended by up to 30.5% with 5 mM N-acetyl-L-cysteine treatment, and the maximum lifespan was increased by 8 days. N-acetyl-L-cysteine supplementation also increased the total number of progeny produced and extended the gravid period of C. elegans. The green fluorescent protein reporter assay revealed that expression of the stress-responsive genes, sod-3 and hsp-16.2, increased significantly following N-acetyl-L-cysteine treatment.

CONCLUSION:

N-acetyl-L-cysteine supplementation confers a longevity phenotype in C. elegans, possibly through increased resistance to environmental stressors.     

Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β

Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1β production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL-1β, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease.Autoinflammatory syndromes are caused by dysregulation of the innate immune system, frequently affecting the inflammasome or other pathogen recognition pathways and leading to the overproduction of active IL-1β and IL-18 (Masters et al., 2009). To date, there are at least 12 known genetic causes of autoinflammatory disease, including familial Mediterranean fever (FMF), hyper-IgD syndrome, and cryopyrin-associated periodic syndrome. Therapeutic options for these diseases include nonsteroidal antiinflammatory drugs, corticosteroids, colchicine (for FMF), anti-TNF, and direct blockade of IL-1, which can be highly efficacious (Masters et al., 2009; Caso et al., 2013). IL-18 and IL-1β are produced in many cells, including monocytes and macrophages (Okamura et al., 1995; Ushio et al., 1996). IL-18 and IL-1β are produced as precursors and do not have a signal peptide to facilitate their secretion; instead, they are activated and released extracellularly as mature proteins after cleavage by caspase-1 (Li et al., 1995; Ghayur et al., 1997; Gu et al., 1997). Despite these similarities, there is no known hereditary autoinflammatory disease where the pathology is caused exclusively by IL-18.The inflammasome is an intracellular molecular platform that forms in response to pathogen- or danger-associated molecular patterns (DAMPs), leading to recruitment and activation of caspase-1 (Martinon et al., 2002; Schroder and Tschopp, 2010). A growing number of inflammasomes have been reported, each nucleated by a different innate immune receptor, such as NLRP1 (Martinon et al., 2000; Boyden and Dietrich, 2006), NLRP3 (Agostini et al., 2004), NLRC4 (Franchi et al., 2006), pyrin (Chae et al., 2011), and AIM2 (Hornung et al., 2009). Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor used by most of these innate immune receptors to interact with and recruit caspase-1 (Srinivasula et al., 2002). Activating mutations in NLRP3 result in increased IL-1β and IL-18 production, which can be prevented in mice by deleting caspase-1 or ASC. Furthermore, deleting either the IL-18R or the IL-1R can both independently protect mice from this NLRP3-mediated autoinflammatory disease (Brydges et al., 2013). For the FMF protein, pyrin, activating mutations induce ASC-dependent but NLRP3-independent IL-1β activation and cause severe autoinflammation in mice (Chae et al., 2011). Interestingly, pyrin interacts with ASC, microtubules, and actin filaments (Mansfield et al., 2001; Richards et al., 2001; Waite et al., 2009), and it has recently been shown that modification of RhoGTPases by bacterial toxins can trigger the pyrin inflammasome, perhaps via modulation of actin dynamics (Xu et al., 2014). This raises the fascinating prospect of a link between perturbations in the actin cytoskeleton and autoinflammatory disease.Wdr1 is required for disassembly of actin filaments in conjunction with the actin-depolymerizing factor/cofilin family of proteins. Mice homozygous for a hypomorphic allele of Wdr1 (Wdr1^rd/rd) exhibit spontaneous autoinflammatory disease and thrombocytopenia (Kile et al., 2007). Both defects have been suggested to result from a disruption in actin dynamics. Thrombocytopenia results from defects in megakaryocytes, a cell type that is entirely dependent on a functional cytoskeleton to shed platelets (Patel et al., 2005). Wdr1 mutant mice also exhibit neutrophilia; however, the critical inflammatory mediators and cell types important for the development of inflammation in this genetic condition are unclear (Kile et al., 2007). Intriguingly, Wdr1 was found to be secreted after caspase-1 activation (Keller et al., 2008).We examined the role of key inflammatory mediators that drive autoinflammation in Wdr1^rd/rd mice and demonstrated that this disease is IL-18 dependent, but IL-1 independent. As expected, this IL-18 is produced by the inflammasome; however, it is not produced from neutrophils or macrophages, but instead only from monocytes. Finally, we found that the autoinflammatory disease was mediated by pyrin, providing evidence that this innate immune receptor recognizes alterations in the actin polymerization pathway.