Serum-free immunoglobulin E: A useful biomarker of atopy and type 2 asthma in adults with asthma.

BACKGROUND: It has been known that a high serum total immunoglobulin E (IgE) level is a predisposing factor of allergic asthma; however, there are considerable limitations to apply it in clinical practice. OBJECTIVE: To determine the clinical significance of the serum-free IgE level in patients with adult asthma. METHODS: We measured free IgE levels using our homemade enzyme-linked immunosorbent assay by applying a novel IgE TRAP protein (GI innovation, Seoul, Republic of Korea) in sera of adults with asthma (n = 116) compared with healthy controls (n = 32); enzyme-linked immunosorbent assay inhibition test was performed to validate its binding specificity. Associations between asthma-related clinical and laboratory parameters were analyzed. The diagnostic value and cutoff point for detecting atopy and type 2 asthma were determined using receiver operating characteristic curve analysis. RESULTS: The serum-free IgE levels were significantly higher in adults with asthma than in healthy controls and were significantly associated with atopic status and type 2 asthma (all P < .001). In the receiver operating characteristic analysis, serum-free IgE had a significantly greater area under the curve (AUC) than serum total IgE for assessing asthma, especially type 2 asthma (AUC, 0.810 vs 0.743; P = .006 and AUC, 0.729 vs 0.572; P < .001). The optimal cutoff points for predicting atopy and type 2 asthma were 82.8 and 120.8 ng/mL, respectively. CONCLUSION: It is suggested that a higher serum-free IgE level may be a useful biomarker of atopy and type 2 asthma in adults with asthma.

Long-term Intraocular Pressure Elevation after Primary Angle Closure Treated with Early Phacoemulsification.

PURPOSE: To assess long-term changes in intraocular pressure (IOP) and the development of glaucoma after early phacoemulsification in acute primary angle closure. METHODS: Retrospective chart review of acute primary angle closure patients treated with phacoemulsification in attack eyes versus fellow eyes. Within a month after the angle closure attack, all subjects underwent cataract surgery and were divided into two groups: group A received cataract surgery on their attack eyes. Group B also received cataract surgery on their fellow eye after phacoemulsification of the attack eyes. Study outcomes were the prevalence of IOP rise (occurrence of IOP >21 mmHg) and the incidence of newly developed glaucoma. RESULTS: Eighty-nine eyes were included, with 62 attack eyes in group A and 27 fellow eyes in group B. Group A (14 eyes, 22.58%) had a higher cumulative rate of IOP rise than group B (3 eyes, 11.11%) at 12 months (p = 0.001). Newly developed glaucoma was not observed in group B; however, 6 patients in group A developed glaucoma during the 12-month follow-up period (p < 0.001). CONCLUSIONS: The attack eyes treated with phacoemulsification showed a significantly higher prevalence of IOP rise and newly developed glaucoma than fellow eyes that received phacoemulsification. These findings suggest that there is a possibility of IOP rise and development of glaucoma even when angle closure and successful IOP control have apparently been achieved after phacoemulsification.

Periorbital changes associated with prostaglandin analogs in Korean patients.

BACKGROUND: Prostaglandin analogs (PGAs) are commonly used to treat glaucoma because of their powerful intraocular pressure lowering effect. However, various periorbital changes associated with the use of PGAs have been reported. We investigated the incidence of periorbital changes in Korean patients who were treated with PGAs, and analyzed clinical factors associated with superior sulcus deepening. METHODS: This study included 58 glaucoma patients who were treated with latanoprost, travoprost, or bimatoprost unilaterally. Face photographs were collected, and periorbital changes such as superior sulcus deepening, eyelid pigmentation, ptosis, lid retraction, dermatochalasis, and redness were evaluated by two oculoplastic specialists. For each patient, the contralateral eye served as a control. The frequency of ptosis, dermatochalasis, pigmentation, erythema, and superior sulcus deepening were analyzed. Demographic and ocular factors were compared between patients who showed superior sulcus deepening and those who did not. RESULTS: Thirty-one patients (53.4%) showed one or more periorbital changes associated with PGAs. The most common change was superior sulcus deepening (24.1%), followed by eyelid pigmentation (19.0%), eyelid erythema (19.0%), dermatochalasis (10.3%), eyelid retraction (5.2%), and ptosis (3.4%). The age of the patient and the duration of PGA administration was significantly correlated with superior sulcus deepening (p = 0.007, p = 0.002, respectively). CONCLUSIONS: Periorbital changes are frequently seen in patients who use PGAs, and superior sulcus deepening is the most common change in Korean patients. Long-term use of PGAs and old age were associated with superior sulcus deepening.

An effective strategy to prevent allopurinol-induced hypersensitivity by HLA typing.

PURPOSE: This study was conducted to evaluate the usefulness of human leukocyte antigen (HLA) typing in preventing allopurinol-induced severe cutaneous adverse reactions (SCARs) through the application of an allopurinol tolerance induction protocol or prescription of other alternative medications in high-risk patients. METHODS: HLA typing was performed in patients with chronic renal insufficiency who needed allopurinol. HLA-B*58:01-negative patients were prescribed the usual dose of allopurinol. For HLA-B*58:01-positive patients, administration of either allopurinol based on a 28-day tolerance induction protocol or alternative medications was initiated. Hypersensitivity reactions were surveyed for 90 days and compared with the result of a previous retrospective cohort study. RESULTS: Among a total of 401 study subjects, no SCARs were noted in HLA-B*58:01-positive patients with application of the tolerance induction protocol (n = 30) or alternative medications (n = 16), nor were any SCARs observed in HLA-B*58:01-negative patients who started allopurinol at the usual dose (n = 355). Compared with the previous retrospective cohort study, a significant reduction in SCARs was observed in HLA-B*58:01-positive patients (0 vs. 18%; P = 0.002). CONCLUSION: This study shows the usefulness of HLA-B*58:01 screening in identifying patients at high risk for the development of allopurinol-induced SCARs and suggests that application of a tolerance induction protocol or alternative medications could be an effective strategy to prevent allopurinol-induced SCARs in HLA-B*58:01-positive patients.

Peroxiredoxin-2 represses melanoma metastasis by increasing E-Cadherin/ß-Catenin complexes in adherens junctions.

In melanoma, transition to the vertical growth phase is the critical step in conversion to a deadly malignant disease. Here, we offer the first evidence that an antioxidant enzyme has a key role in this transition. We found that the antioxidant enzyme peroxiredoxin-2 (Prx2) inversely correlated with the metastatic capacity of human melanoma cells. Silencing Prx2 expression stimulated proliferation and migration, whereas ectopic expression of Prx2 produced the opposite effect. Mechanistic investigations indicated that Prx2 negatively regulated Src/ERK activation status, which in turn fortified adherens junctions function by increasing E-cadherin expression and phospho-Y654-dependent retention of ß-catenin in the plasma membrane. In murine melanoma cells, Prx2 silencing enhanced lung metastasis in vivo. Interestingly, the natural compound gliotoxin, which is known to exert a Prx-like activity, inhibited proliferation and migration as well as lung metastasis of Prx2-deficient melanoma cells. Overall, our findings reveal that Prx2 is a key regulator of invasion and metastasis in melanoma, and also suggest a pharmacologic strategy to effectively decrease deadly malignant forms of this disease.

Interaction of HLA-DRB1*09:01 and *04:05 with smoking suggests distinctive mechanisms of rheumatoid arthritis susceptibility beyond the shared epitope.

OBJECTIVE: Although HLA-DRB1 shared epitope (SE) alleles and HLA-DRB1*09:01 have repeatedly been shown to be associated with susceptibility to rheumatoid arthritis (RA), the effect of each allele on levels of anticyclic citrullinated peptide autoantibodies (anti-CCP) and interaction with cigarette smoking in RA remains to be fully defined. We investigated whether HLA-DRB1 risk alleles influence anti-CCP levels and whether each allele interacts with smoking in anti-CCP-positive or -negative RA. METHODS: All patients with RA (n = 1924) and controls (n = 1119) were Korean. The HLA-DRB1 4-digit genotyping was performed by standard PCR-sequencing based typing method. OR and biologic interactions as departures from additivity or multiplicity were analyzed by logistic regression. RESULTS: SE alleles were significantly associated with increased anti-CCP levels. Conversely, HLA-DRB1*09:01 was associated with reduced levels, in both SE-positive and SE-negative patients. Each of SE alleles interacted significantly with smoking, whereas HLA-DRB1*09:01 did not. Interactions between the 2 most significant risk alleles, HLA-DRB1*04:05 and HLA-DRB1*09:01, (attributable proportion = 0.68, 95% CI 0.46-0.89, multiplicity p = 0.012) significantly increased RA susceptibility regardless of anti-CCP and smoking status. Smoking increased the risk for RA by significant interaction with the heterozygote HLA-DRB1*04:05/*09:01. CONCLUSION: HLA-DRB1*09:01 differs from SE alleles with regard to anti-CCP levels and interaction with smoking, suggesting a distinct mechanism of HLA-DRB1*09:01 in the pathogenesis of RA that may bypass anti-CCP formation. Also, a significant increase of the HLA-DRB1*04:05/ *09:01 heterozygote in RA susceptibility may be attributable to the synergistic contribution of 2 different pathways in which 2 alleles participate independently.

Overview of ocular complications in patients with electrical burns: an analysis of 102 cases across a 7-year period.

BACKGROUND: Ocular complications from electrical burns are uncommon. Thus far, there has been no systematic review on ocular electrical trauma with emphasis on patients' ophthalmic complications and visual symptoms. Herein, we retrospectively analyzed records of patients with electrical injuries to summarize the ophthalmic characteristics and explore their relationships with visual symptoms. METHODS: We collected the medical records of 102 patients who consulted from 557 electrical burn patients between 2004 and 2010. Ophthalmic, systemic and demographic factors associated with electrical burns were identified in the patient who underwent the ophthalmic consultations. Two sets of comparisons were used to determine the demographic and systemic factors that were related to ophthalmic complications and the subjective outcome of visual impairment. RESULTS: There were 53 eyes (29 patients) with ophthalmic complication were identified. Corneal epithelial erosion was the most common ocular electrical injury and the primary reason for subjective visual symptoms. Electrical burns affecting the head and neck were significantly related to subjective symptoms of visual disturbances. CONCLUSION: Present study indicates that earlier involvement of ophthalmologists in the case of any patient who has suffered a facial burn is advisable. Appropriate management would be helpful to prevent future complications and alleviate visual symptoms.

Antituberculosis drug-induced hypersensitivity syndrome and its association with human leukocyte antigen.

Antituberculosis drug (ATD)-induced hypersensitivity syndrome (HSS) is a serious adverse reaction to ATDs, but much remains to be determined regarding its characteristics and genetic risk factors. In this study, we have collected cases of ATD-induced HSS and their clinical features, and investigated the associations of ATD-induced HSS with human leukocyte antigen (HLA). Subjects with ATD-induced HSS and ATD-tolerant controls were recruited through analysis of a multicenter adverse drug reaction registry in Korea. HLA allele frequencies were compared between subjects with ATD-induced HSS (n = 14) and two control groups: ATD-tolerant controls (n = 166) and the general population (n = 485). The number of enrolled subjects with ATD-induced HSS (n = 14) was comparable to those of patients with HSS induced by other common drugs such as allopurinol during the recruitment period. The frequency of Cw*0401 was much higher in the cases (50.0%) compared with ATD-tolerant controls (12.7%, Pc = 0.0204, OR = 6.90) and the general population (12.8%, Pc = 0.0132, OR = 6.82). Our results suggest that ATD is an important causative agent inducing HSS with distinct clinical features. The strong association of Cw*0401 with the risk for ATD-induced HSS suggests immunological involvement in the development of this syndrome.

Use of PCR with sequence-specific primers for high-resolution human leukocyte antigen typing of patients with narcolepsy.

BACKGROUND: Narcolepsy is a neurologic disorder characterized by excessive daytime sleepiness, symptoms of abnormal rapid eye movement (REM) sleep, and a strong association with HLA-DRB1*1501, -DQA1*0102, and -DQB1*0602. Here, we investigated the clinico-physical characteristics of Korean patients with narcolepsy, their HLA types, and the clinical utility of high-resolution PCR with sequence-specific primers (PCR-SSP) as a simple typing method for identifying DRB1*15/16, DQA1, and DQB1 alleles. METHODS: The study population consisted of 67 consecutively enrolled patients having unexplained daytime sleepiness and diagnosed narcolepsy based on clinical and neurological findings. Clinical data and the results of the multiple sleep latency test and polysomnography were reviewed, and HLA typing was performed using both high-resolution PCR-SSP and sequence-based typing (SBT). RESULTS: The 44 narcolepsy patients with cataplexy displayed significantly higher frequencies of DRB1*1501 (Pc= 0.003), DQA1*0102 (Pc=0.001), and DQB1*0602 (Pc=0.014) than the patients without cataplexy. Among patients carrying DRB1*1501-DQB1*0602 or DQA1*0102, the frequencies of a mean REM sleep latency of less than 20 min in nocturnal polysomnography and clinical findings, including sleep paralysis and hypnagogic hallucination were significantly higher. SBT and PCR-SSP showed 100% concordance for high-resolution typing of DRB1*15/16 alleles and DQA1 and DQB1 loci. CONCLUSIONS: The clinical characteristics and somnographic findings of narcolepsy patients were associated with specific HLA alleles, including DRB1*1501, DQA1*0102, and DQB1*0602. Application of high-resolution PCR-SSP, a reliable and simple method, for both allele- and locus-specific HLA typing of DRB1*15/16, DQA1, and DQB1 would be useful for characterizing clinical status among subjects with narcolepsy.

Peroxiredoxin II is an essential antioxidant enzyme that prevents the oxidative inactivation of VEGF receptor-2 in vascular endothelial cells.

Cellular antioxidant enzymes play crucial roles in aerobic organisms by eliminating detrimental oxidants and maintaining the intracellular redox homeostasis. Therefore, the function of antioxidant enzymes is inextricably linked to the redox-dependent activities of multiple proteins and signaling pathways. Here, we report that the VEGFR2 RTK has an oxidation-sensitive cysteine residue whose reduced state is preserved specifically by peroxiredoxin II (PrxII) in vascular endothelial cells. In the absence of PrxII, the cellular H(2)O(2) level is markedly increased and the VEGFR2 becomes inactive, no longer responding to VEGF stimulation. Such VEGFR2 inactivation is due to the formation of intramolecular disulfide linkage between Cys1199 and Cys1206 in the C-terminal tail. Interestingly, the PrxII-mediated VEGFR2 protection is achieved by association of two proteins in the caveolae. Furthermore, PrxII deficiency suppresses tumor angiogenesis in vivo. This study thus demonstrates a physiological function of PrxII as the residential antioxidant safeguard specific to the redox-sensitive VEGFR2.

Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans.

BACKGROUND: Although the US FDA recommends screening for HLA-B*1502 allele in most of Asian ancestry before initiating carbamazepine therapy, the HLA associations with carbamazepine hypersensitivity in non-Chinese Asian populations remain unclear. This study investigated the association between the HLA class I genotype and carbamazepine-induced severe cutaneous adverse reaction (SCAR) in Koreans. METHODS: Twenty-four patients who had developed carbamazepine-induced SCAR (7 Stevens-Johnson syndrome (SJS), 17 drug hypersensitivity syndrome (HSS)), 50 carbamazepine-tolerant controls from the Korean Pharmacogenetic Adverse Drug Reaction Research Network and data of 485 Korean general population from a previously published study were recruited. HLA-A, -B, and -C genotyping was performed by direct DNA sequence analysis. RESULTS: Only one of the seven SJS patients was positive for the B*1502 allele, but the frequency of B*1511 was much higher in the patients with CBZ-SJS than in the CBZ-tolerant control patients (P=0.011, P(c)=not significant; OR=18.0(2.3-141.2)). The frequencies of A*3101 in carbamazepine-induced HSS and SCAR were significantly higher than those in carbamazepine-tolerant controls (P(c)=0.011, OR=8.8(2.5-30.7) and P(c)=0.013, OR=7.3(2.3-22.5), respectively). The frequencies of B*1511 in carbamazepine-SJS and A*3101 in carbamazepine-HSS/SCAR were significantly higher than those in the general population. CONCLUSIONS: HLA-B*1502 does not seem to be an effective predictive marker for carbamazepine-induced SCAR, while HLA-B*1511 and A*3101 was associated with carbamazepine-induced SJS and HSS/SCAR respectively in the Korean population.

Refined information on alleles belonging to the C*07:01/07:06/07:18 group in the Korean population.

Alleles of the C*07:01/07:06/07:18 group is distinguished by polymorphisms in exons 5-6. In a previous study, we focused on exons 2-3 of the gene and showed that 6.8% of Koreans express alleles in this group. In this study, we identified allelic and haplotypic diversities of the C*07:01/07:06/07:18 group in Koreans. Among 118 C*07:01/07:06/07:18-positive, unrelated, healthy samples, 96.6% were C*07:06 and 3.4% were C*07:01. Each allele was exclusively associated with a specific set of other alleles consisting of the conserved haplotypes A*01:01-C*07:01-B*08:01-DRB1*03:01-DQB1*02:01 (100%) and A*33:03-C*07:06-B*44:03-DRB1*07:01-DQB1*02:02 (95.6%), respectively. None carried C*07:18. With the continuous discovery of novel alleles, periodic updates with testing for newer alleles will be useful to support related research and clinical settings in each population.

HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency.

BACKGROUND: Although allopurinol is a very effective urate-lowering drug for complicated hyperuricemia, in some patients, it can induce severe cutaneous adverse reactions (SCARs). Recent investigations suggest that HLA-B*5801 is a very strong marker for allopurinol-induced SCARs, especially in the population with a high frequency of HLA-B*5801. Korea is one of the countries with a high frequency of HLA-B*5801 which is the only subtype of HLA-B58 in the Korean population. Objective. This study was conducted to find out the incidence of allopurinol-induced hypersensitivity on patients with chronic renal insufficiency (CRI) according to HLA-B58 and the clinical implications of HLA-B58 as a risk marker for the development of allopurinol-induced hypersensitivity. METHODS: We retrospectively reviewed the medical records of patients with CRI who took allopurinol and carried out serologic human leukocyte antigen (HLA) typing for kidney transplantation between January 2003 and May 2010. RESULTS: Among a total of 448 patients with CRI, 16 (3.6%) patients experienced allopurinol hypersensitivity. Nine of these patients (2.0%) were diagnosed with SCARs (two Stevens-Johnson syndrome and seven allopurinol hypersensitivity syndrome) and seven patients (1.6%) had simple maculopapular rashes. The HLA-B58 allele was present in all patients with allopurinol-induced SCARs, while the frequency of HLA-B58 was only 9.5% in allopurinol-tolerant patients (P < 0.05). The incidence of allopurinol-induced SCARs in CRI shows a wide disparity according to HLA-B58 [18% in HLA-B58 (+) versus 0% in HLA-B58 (-)]. Among patients without HLA-B58, most (98.2%) of the CRI patients were tolerant to allopurinol and only 1.8% experienced simple rashes after taking allopurinol. CONCLUSIONS: In this study, the incidence of allopurinol-induced SCARs was considerably high in CRI patients with HLA-B58. This finding indicates that the presence of HLA-B58 may increase the risk of allopurinol-induced SCARs. Screening tests for HLA-B58 in CRI patients will be clinically helpful in preventing severe allopurinol hypersensitivity reactions.

Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans.

Recent investigations suggest genetic susceptibility of allopurinol-induced severe cutaneous adverse reactions (SCARs). However, the strength of association was variable according to phenotypes and ethnic backgrounds. To explore genetic markers for allopurinol-induced SCARs in Koreans, we genotyped human leukocyte antigen (HLA) class I alleles of 25 cases of allopurinol-induced SCARs (20 cases of drug-induced hypersensitivity syndrome and five cases of Stevens-Johnson syndrome/toxic epidermal necrolysis) and 57 patients tolerant to allopurinol. Frequencies of B*5801 [92.0 vs. 10.5%, P(c)=2.45×10(-11), odds ratio (OR)=97.8], Cw*0302 (92.0 vs. 12.3%, P(c)=9.39×10(-11), OR=82.1), and A*3303 (88.0 vs. 26.3%, P(c)=3.31×10(-6), OR=20.5) were significantly higher in SCARs compared with tolerant controls. In contrast, A*0201 was not found in SCARs patients despite relatively high frequency in tolerant controls (29.8%). We found strong positive association of HLA-B*5801 and negative association of HLA-A*0201 with the development of allopurinol-induced SCARs in the Korean population.

Peroxiredoxin II restrains DNA damage-induced death in cancer cells by positively regulating JNK-dependent DNA repair.

The 2-Cys peroxiredoxins (Prx) belong to a family of antioxidant enzymes that detoxify reactive oxygen and nitrogen species and are distributed throughout the intracellular and extracellular compartments. However, the presence and role of 2-Cys Prxs in the nucleus have not been studied. This study demonstrates that the PrxII located in the nucleus protects cancer cells from DNA damage-induced cell death. Although the two cytosolic 2-Cys Prxs, PrxI and PrxII, were found in the nucleus, only PrxII knockdown selectively and markedly increased cell death in the cancer cells treated with DNA-damaging agents. The increased death was completely reverted by the nuclearly targeted expression of PrxII in an activity-independent manner. Furthermore, the antioxidant butylated hydroxyanisole did not influence the etoposide-induced cell death. Mechanistically, the knockdown of Prx II expression impaired the DNA repair process by reducing the activation of the JNK/c-Jun pathway. These results suggest that PrxII is likely to be attributed to a tumor survival factor positively regulating JNK-dependent DNA repair with its inhibition possibly sensitizing cancer cells to chemotherapeutic agents.

Increased expression of L-amino acid transporters in balloon cells of tuberous sclerosis.

OBJECTS: Tuberous sclerosis complex (TSC) is a dysgenetic syndrome involved in multiple organs, and the pathognomonic cortical tuber act as an epileptic substrate. The amino acid transport system L (LAT) is a major nutrient transport system, and LAT1 is highly expressed in malignant tumors to support tumor cell growth. To study the life-long epilepsy from the cortical tuber, the expression of LAT1 in balloon cells and dysplastic neurons of the cortical tuber is investigated. MATERIALS AND METHODS: LAT1 expression was investigated by LAT1 mRNA using reverse transcription-polymerase chain reaction and immunohistochemical staining with anti-human LAT1 antibody in nine patients with TSC and three control brains. CONCLUSION: LAT1 mRNA was detectable only in fresh-frozen tissues of TSC, and it was upregulated in the cortical tuber lesion. While the LAT1 immunopositivity of control brains was limited in the capillary endothelial cells in the gray matter, increased LAT1 immunopositivity was noted in balloon cells of the cortical tubers in addition to the capillary endothelial cells as shown in control brains. Linear and strong immunopositivity along the cell membrane and cytoplasm of the balloon cells, and weakly granular immunopositivity in their cytoplasm were noted. Increased expression of LAT1 in the balloon cells is important for the active transport of large neutral amino acids into the balloon cells, and that the biologic process may play an important role in the active protein synthesis with metabolic maintenance of balloon cells in cortical tubers of patients with TSC.

[New HLA nomenclature (2010) and its clinical application in Koreans].

Human leukocyte antigen (HLA) gene region encodes a set of HLA molecules functioning critical roles in immune response. Each HLA gene locus shows extensive polymorphism with ever-increasing number of alleles. The HLA nomenclature system for alleles defined by DNA typing was first established in 1987 and has been revised several times. Recently, it has been revised again with a new frame that can accommodate ever-increasing number of new alleles. The new system has also introduced the novel suffixes, P and G, to simplify reporting of ambiguous strings of alleles in typing reports. This review introduces the HLA nomenclature system-2010 in conjunction with its clinical application in Koreans.

HLA-B*5901 is strongly associated with methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis.

AIMS: The carbonic anhydrase inhibitor methazolamide infrequently causes Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). An association between these diseases and the HLA-B59 serotype has been suggested in case reports. This study examined the disease-associated B*59 allele and investigated the association of these diseases with other HLA class I alleles. METHODS: We performed high-resolution HLA-A, -B and -C genotyping in five patients with methazolamide-induced SJS/TEN using a PCR-sequencing-based typing method and analyzed the association between HLA-class I alleles and occurrence of methazolamide-induced SJS/TEN. RESULTS: B*5901 and Cw*0102 alleles were observed in all patients and A*2402 was observed in four patients. The B*5901 allele showed the strongest association with methazolamide-induced SJS/TEN (p < 0.001; odds ratio: 249.8; 95% CI: 13.4-4813.5), followed by Cw*0102 (p = 0.004; odds ratio: 22.1; 95% CI: 1.2-414.3), when compared with the general population as a control. The frequency of the patients carrying B*5901, Cw*0102 and A*2402 simultaneously was significantly higher than that in the general population (p < 0.001; odds ratio: 110.1; 95% CI: 11.7-1038.6). CONCLUSION: A strong association was observed between HLA-B*5901 and methazolamide-induced SJS/TEN in Korean patients. HLA-B*5901 may be a useful screening marker for predicting methazolamide-induced SJS/TEN in patients of Korean and Japanese ancestry.

Cytosolic Hsp60 is involved in the NF-kappaB-dependent survival of cancer cells via IKK regulation.

Cytoplasmic presence of Hsp60, which is principally a nuclear gene-encoded mitochondrial chaperonin, has frequently been stated, but its role in intracellular signaling is largely unknown. In this study, we demonstrate that the cytosolic Hsp60 promotes the TNF-alpha-mediated activation of the IKK/NF-kappaB survival pathway via direct interaction with IKKalpha/beta in the cytoplasm. Selective loss or blockade of cytosolic Hsp60 by specific antisense oligonucleotide or neutralizing antibody diminished the IKK/NF-kappaB activation and the expression of NF-kappaB target genes, such as Bfl-1/A1 and MnSOD, which thus augmented intracellular ROS production and ASK1-dependent cell death, in response to TNF-alpha. Conversely, the ectopic expression of cytosol-targeted Hsp60 enhanced IKK/NF-kappaB activation. Mechanistically, the cytosolic Hsp60 enhanced IKK activation via upregulating the activation-dependent serine phosphorylation in a chaperone-independent manner. Furthermore, transgenic mouse study showed that the cytosolic Hsp60 suppressed hepatic cell death induced by diethylnitrosamine in vivo. The cytosolic Hsp60 is likely to be a regulatory component of IKK complex and it implicates the first mitochondrial factor that regulates cell survival via NF-kappaB pathway.

Smoking increases rheumatoid arthritis susceptibility in individuals carrying the HLA-DRB1 shared epitope, regardless of rheumatoid factor or anti-cyclic citrullinated peptide antibody status.

OBJECTIVE: Smoking is associated with rheumatoid arthritis (RA) in individuals with the HLA-DRB1 shared epitope (SE). SE alleles have been shown to be predominantly associated with anti-cyclic citrullinated peptide (anti-CCP)-positive RA. These risk factors have not been identified for anti-CCP-negative RA. The aim of this study was to investigate whether SE-containing HLA-DRB1 alleles, smoking, or the combination of these factors contributes to the development of RA, depending on the presence or absence of serologic markers, in a Korean population. METHODS: All of the patients with RA (n =1,482) and all of the control subjects (n = 1,119) were Korean. Four-digit HLA-DRB1 typing was performed by a conventional polymerase chain reaction-sequence-based typing method. Information about smoking history was obtained through a questionnaire. The patients with RA were tested for anti-CCP antibodies and rheumatoid factor (RF). RESULTS: The SE alleles had significant effects on anti-CCP antibody and RF formation. The DRB1*0901 allele was associated with the presence of anti-CCP antibodies (odds ratio [OR] 2.49) and RF (OR 2.09). SE alleles and smoking were associated with both anti-CCP-positive and anti-CCP-negative RA. The combination of smoking and double copies of the SE allele increased the risk of anti-CCP-positive RA 36.11-fold and increased the risk of anti-CCP-negative RA 12.29-fold, compared with the risk among nonsmokers not carrying SE alleles. Interactions between SE alleles and smoking were observed for both anti-CCP-positive and RF-positive RA, although the associations of RF-positive RA could be consequences of the underlying anti-CCP antibody status. CONCLUSION: We demonstrated that the combination of SE alleles and smoking is associated with RA susceptibility regardless of anti-CCP antibody or RF status, but that the combination shows stronger effects in anti-CCP-positive/RF-positive patients with RA than in anti-CCP-negative/RF-negative patients with RA. The SE-smoking interactions were present in anti-CCP-positive and RF-positive RA.