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Background Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker for acute kidney injury. This study was conducted to determine the clinical implications of perioperative plasma NGAL levels for renal function after living donor nephrectomy. Methods Between July 2013 and May 2014, 112 donors underwent live donor nephrectomy at our institution. Donor plasma NGAL levels were measured perioperatively for 6 months. The relationship between perioperative plasma NGAL and recovery of renal function was analyzed. Renal function was estimated with the Modification of Diet in Renal Disease formula. Results Mean preoperative NGAL was 62.1 ± 29.5 ng/mL. Plasma NGAL was most elevated 1 week postoperatively (218 ± 95.5 ng/mL), and stabilized after 1 month (122.9 ± 45.3 ng/mL). Preoperative plasma NGAL was not correlated with donor age or preoperative estimated glomerular filtration rates (eGFR), but was negatively correlated with 6-month eGFR (r = −0.458, P < .001). During the observation period, plasma NGAL at 1 week was most correlated with 6-month eGFR (r = −0.554, P < .001). An ROC curve analysis showed that age, preoperative eGFR, and 1-week postoperative plasma NGAL were highly predictive of developing of chronic kidney disease (CKD), defined as eGFR

Syndrome pattern (SP) is a core concept of Chinese medicine (CM) and is used to diagnose and treat patients based on an overall analysis of symptoms and signs. This study aimed to systematically review randomized controlled trials (RCTs) using the SP concept and to demonstrate how the SP concept could be applied to the study design of parallel RCTs, considering a gold standard of clinical research. After conducting a brief systematic review by way of a PubMed search, we analyzed how the SP concept was applied to the design of RCT in a CM herbal medicine trial. We then formulated possible research questions, applied the SP concept to answer the research questions, and suggested possible RCT designs to be used for conducting future trials. Fourteen RCTs were included in our systematic review, and three key points of the SP concept were formulated for the design of parallel RCTs: the time point of SP diagnosis between before and after randomization; the relationship between the international classification of diseases (ICD) and SP for the inclusion of target population; and the proper diagnostic method of SP. In this study, we formulated three possible research questions and then suggested perspectives for five possible RCT models arrived at using SP concepts. Future trials applying SP concept to RCTs should overcome the shortcomings of past SP trials, moving CM forward from experience-based to evidence-based medicine.

Langerhans cells (LCs) are epidermal dendritic cells with incompletely understood origins that associate with hair follicles for unknown reasons. Here we show that in response to external stress, mouse hair follicles recruited Gr-1(hi) monocyte-derived precursors of LCs whose epidermal entry was dependent on the chemokine receptors CCR2 and CCR6, whereas the chemokine receptor CCR8 inhibited the recruitment of LCs. Distinct hair-follicle regions had differences in their expression of ligands for CCR2 and CCR6. The isthmus expressed the chemokine CCL2; the infundibulum expressed the chemokine CCL20; and keratinocytes in the bulge produced the chemokine CCL8, which is the ligand for CCR8. Thus, distinct hair-follicle keratinocyte subpopulations promoted or inhibited repopulation with LCs via differences in chemokine production, a feature also noted in humans. Pre-LCs failed to enter hairless skin in mice or humans, which establishes hair follicles as portals for LCs.

PURPOSE Dendritic cell (DC) vaccination for melanoma was introduced because melanoma carries distinct tumor-associated antigens. The purpose of this study was to investigate the efficacy and safety of DC vaccination for melanoma in Korea. MATERIALS AND METHODS Five patients with stage IV and one with stage II were enrolled. Autologous monocyte-derived DCs (MoDCs) were cultured and pulsed with tumor-lysate, keyhole limpet hemocyanin, and cytokine cocktail for mature antigen-loaded DC. DC vaccination was repeated four times at 2-week intervals and 2-4×10⁷ DC were injected each time. RESULTS Reduced tumor volume was observed by PET-CT in three patients after DC vaccination. Delayed type hypersensitivity responses against tumor antigen were induced in five patients. Tumor antigen-specific IFN-γ-producing peripheral blood mononuclear cells were detected with enzyme-linked immunosorbent spot in two patients. However, the overall clinical outcome showed disease progression in all patients. CONCLUSION In this study, DC vaccination using tumor antigen-loaded, mature MoDCs led to tumor regression in individual melanoma patients. Further standardization of DC vaccination protocol is required to determine which parameters lead to better anti-tumor responses and clinical outcomes.

Summary Missense mutations in the C-terminal B30.2 domain of pyrin cause familial Mediterranean fever (FMF), the most common Mendelian autoinflammatory disease. However, it remains controversial as to whether FMF is due to the loss of an inhibitor of inflammation or to the activity of a proinflammatory molecule. We generated both pyrin-deficient mice and "knockin" mice harboring mutant human B30.2 domains. Homozygous knockin, but not pyrin-deficient, mice exhibited spontaneous bone marrow-dependent inflammation similar to but more severe than human FMF. Caspase-1 was constitutively activated in knockin macrophages and active IL-1β was secreted when stimulated with lipopolysaccharide alone, which is also observed in FMF patients. The inflammatory phenotype of knockin mice was completely ablated by crossing with IL-1 receptor-deficient or adaptor molecule ASC-deficient mice, but not NLRP3-deficient mice. Thus, our data provide evidence for an ASC-dependent NLRP3-independent inflammasome in which gain-of-function pyrin mutations cause autoinflammatory disease.

Behçet's disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behçet's disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behçet's disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 x 10(-8)). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 x 10(-18), odds ratio = 1.45, 95% CI 1.34-1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 x 10(-9), OR = 1.28, 95% CI 1.18-1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production.

Dendritic cell (DC) immunotherapy is a strong candidate for the treatment of incurable cancers especially malignant melanoma. Nevertheless, the proper guideline of DC immunotherapy does not exist. The absence of the guideline is also an obstacle to clinical trials of DC immunotherapy. So we conducted this study in order to develop an effective DC preparation method for immunotherapy in mouse malignant melanoma. Mouse bone marrow-derived DC were stimulated with tumour antigen alone or tumour antigen plus a cocktail (anti-CD40 antibody +TNF-alpha+ IL-1beta) for 8, 24 or 48 h and the characteristics of these DC, such as surface molecules (CD40, CD80, CD86, MHC class II, CCR7), cytokines(IL-12, IFN-gamma, and IL-10), DC-induced T cell proliferation in vitro, and the production of IFN-gamma by those cells, were evaluated. Mice with melanoma were then treated with DC stimulated with tumour antigen alone and tumour antigen plus cocktail for 8 or 48 h. The tumour size and survival rate of these mice were then evaluated. (1) Beneficial clinical effects such as a reduction of tumour size and an increased survival rate were best observed in the group treated with DC stimulated for 8 h with tumour antigen plus cocktail. (2) The single prominent characteristic of DC stimulated for 8 h with tumour antigen plus cocktail was an elevated IL-12 secretion. The cytokine IL-12 was not secreted by other DC. Consequently, proper production of IL-12 was found to be an important requirement for DC used in immunotherapy of mouse melanoma.

ROS are produced in dendritic cells (DCs) during antigen presentation in contact hypersensitivity (CHS). As a result, ROS cause a number of nonenzymatic protein modifications, including carbonylation, which is the most widely used marker of oxidative stress. 2,4,6-Trinitrobenzene sulfonic acid (TNBS) is a well-characterized contact allergen that results in the formation of ROS. However, proteins that are carbonylated in DCs in response to TNBS have not been identified. To study ROS-dependent protein carbonylation in response to TNBS, we used the well-established mouse DC line, XS-106. We focused on the effects of TNBS on oxidation by examining selected oxidative markers. We identified TNBS-induced ROS and myeloperoxidase (MPO) proteins and demonstrated that the increase in ROS resulted in IL-12 production. The increase in oxidation was further confirmed by an oxidation-dependent increase in protein modifications, such as carbonylation. In fact, TNBS strongly induced carbonylation of mitochondrial adenosine triphosphate (ATP) synthase in XS-106 DCs, as determined by MALDI-TOF analysis and 2-D Western blotting. ROS production and protein carbonylation were confirmed in human monocyte-derived DCs (Mo-DCs). Furthermore, glutathione (GSH) decreased ROS and protein carbonylation in Mo-DCs. Carbonylation of ATP synthase in DCs may contribute to the pathophysiology of CHS.

The dendritic cell (DC) is a potentially promising tool for cancer immunotherapy. To date, however, DC-based immunotherapy has not yielded data with which firm conclusions can be drawn. In the present study, we tested the dose-dependant enhancement of the anti-tumor effect induced by DCs. When large numbers of DCs were used, tumor growth was suppressed up to 41% when compared to control mice. Survival of the animals was prolonged to 54 days compared to the 33-day survival the control mice. The delayed-type hypersensitivity (DTH) response induced was 26-fold higher than in the controls. Larger numbers of DCs also led to higher expansion of IFN-gamma-secreting-CD8(+) T cells. Furthermore, the secretion of IL-12p70 and IFN-gamma by spleen cells were enhanced in proportion to the dosage. However, the level of IL-4 secreted from spleen cells was negligible compared to the level of IFN-gamma that was released. These results indicate that DCs induce Th1-dominant immune response and that more DCs could lead to better immunological results, a finding which was consistent with our therapeutic results.

Hypertrichosis lanuginosa acquisita (HLA) is an unusual condition which is characterized by subtle and progressive development of multiple, long, thin, unmedullated hairs ("lanugo hairs") distributed preferentially on the face. Most cases are associated with malignant tumors or non-malignant condition such as porphyria cutanea tarda, AIDS, anorexia nervosa, thyrotoxicosis, or secondary to topical or systemic drugs (e.g. cyclosporine, phenytoin, diazoxide, minoxidil). We have recently experienced a rare case of hypertrichosis lanuginosa acquisita associated with autoimmune hepatitis. To our best knowledge, this is the first report of hypertrichosis lanuginosa acquisita associated with autoimmune hepatitis. Our observation expands the spectrum of diseases associated with this uncommon disorder.

Objectives Acupuncture is commonly used as a complimentary treatment for pain management. However, there has been no systematic review summarizing the current evidence concerning the effectiveness of acupuncture for acute postoperative pain after back surgery. This systematic review aimed at evaluating the effectiveness of acupuncture treatment for acute postoperative pain (≤1 week) after back surgery. Methods We searched 15 electronic databases without language restrictions. Two reviewers independently assessed studies for eligibility and extracted data, outcomes, and risk of bias. Random effect meta-analyses and subgroup analyses were performed. Results Five trials, including 3 of high quality, met our inclusion criteria. The meta-analysis showed positive results for acupuncture treatment of pain after surgery in terms of the visual analogue scale (VAS) for pain intensity 24 hours after surgery, when compared to sham acupuncture (standard mean difference −0.67 (−1.04 to −0.31), P = 0.0003), whereas the other meta-analysis did not show a positive effect of acupuncture on 24-hour opiate demands when compared to sham acupuncture (standard mean difference −0.23 (−0.58 to 0.13), P = 0.21). Conclusion Our systematic review finds encouraging but limited evidence for the effectiveness of acupuncture treatment for acute postoperative pain after back surgery. Further rigorously designed clinical trials are required.

Internal radiotherapy with the intratumoral injection of the beta-emitting radionuclide, Holmium (Ho)-166, into B16 melanoma resulted in a reduction in size and growth rate; however, complete remission was not always achieved. Therefore, additional dendritic cell (DC) therapy was investigated to determine whether it could improve therapeutic results. Malignant melanoma was induced in mice by inoculating B16F10 cell line subcutaneously. Fifty-four mice were divided into four groups: (1) non-treated (group I, n = 11), (2) treated with Ho-166 (group II, n = 16), (3) treated with immature DCs (group III, n = 8), and (4) treated with immature DCs after Ho-166 injection (group IV, n = 19). Changes in tumor size, survival rates, and immunologic profiles were observed. Nineteen days after Ho-166 or PBS injection, mean tumor sizes in the four groups were 6044 +/- 1046, 1658 +/- 523, 3871 +/- 921, and 444 +/- 167 mm(3), respectively. We observed a significant decrease in tumor size (P0.05) and an increase in survival in group IV. When the B16F10 cell line was reinjected into the contralateral backs of survivors, much slower growth was observed in group IV (P0.05). Both tumor-specific CTL and natural killer cell activities and the infiltration of inflammatory cells into tumor tissues were found to be elevated in group IV. In addition, strong immune responses as determined by in vitro T cell proliferation, ELISA and ELISPOT assay were induced in group IV. Our results suggest that a combination of internal radiotherapy using Ho-166 and immature DCs could be used either to treat unresectable melanoma or as an adjuvant therapy after surgery.

Mature dendritic cells (DCs) were generated by culturing human peripheral blood monocytes for 7 days and, then, treating them with a cytokine cocktail for 2 days. The viability of the mature DCs (Day 9) obtained was approximately 60-70%, and this gradually declined when they were recultured in X-VIVO 15 media containing 2% human plasma (40% viability after 3 days of reculture). DC death accelerated on withdrawing plasma from the culture (20% viability after 3 days). However, the addition of tumor necrosis factor-alpha (TNF-alpha) to the medium completely restored DC viability in the absence of plasma. Such a protective effect was not afforded by other cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1alpha (IL-1alpha), IL-4, IL-6 and prostaglandin E2 which are used for the maturation of DCs. These results indicate that TNF-alpha is specifically required to maintain the viability of mature DCs. The withdrawal of plasma rapidly (within 15 min) elevated cellular levels of reactive oxygen intermediates (ROIs), which have been proposed to regulate the ability of DCs to control inflammatory reactions. The possibility that ROIs act as mediators of DC death was eliminated by the observation that scavengers of ROIs, such as catalase, N-acetylcysteine, glutathione, failed to prolong DC life span in the absence of plasma. Interestingly, TNF-alpha was found to almost completely abolish the production of ROIs induced by plasma withdrawal. To summarize, our results suggest that TNF-alpha controls not only the inflammatory functions of DCs but also their survival.

Epididymitis is a rare manifestation of Behçet's disease but its clinical significance is still not fully understood. We evaluated the clinical significance of epididymitis in patients with Behçet's disease.Of 780 male patients attending our clinics between 1985 and 2002 who were diagnosed with Behçet's disease by international criteria or who had the complete or incomplete type of Behçet's disease by Japanese criteria 36 were identified with epididymitis. Clinical data on these patients were reviewed.The 36 patients were categorized into the complete (13 or 36.1%) and incomplete (23 or 63.9%) types of Behçet's disease with an average age at onset of 27.4 years. The frequency of individual symptoms were oral ulcers and cutaneous involvement in all 36 cases (100%), genital ulcers in 32 (88.9%), arthritis in 18 (50.0%), ocular involvement in 17 (47.2%), central nervous system involvement in 2 (5.6%), gastrointestinal ulcer in 1 (2.8%) and a positive pathergy test in 4 (11.1%). A significantly higher number of patients with epididymitis had genital ulcers (p0.05), cutaneous involvement (p0.001), arthritis (p0.05), central nervous system involvement (p0.05) and a positive pathergy test (p0.05) compared with the other 744 with Behçet's disease without epididymitis who served as controls.To our knowledge there has been no controlled study of the clinical significance of epididymitis in Behçet's disease. Our results suggest a tendency toward severe Behçet's disease manifestations in patients with epididymitis, prompting physicians to evaluate closely and meticulously treat such patients.

ejd.2012.1797 Auteur(s) : Hye Min Lee1, Young Hun Cho2, Dae Won Koo1, Joong Sun Lee1 sun_lee@eulji.ac.kr 1 Department of Dermatology, Eulji University Hospital, Dunsan 2-dong, 302-799 Seo-gu Daejeon, Korea 2 Department of Dermatology, KAIST Clinic, 301-805 Daejeon, Korea 82-42-611-3037 A 59-year-old Korean woman presented with a 3-month history of severe pruritic erythematous papules, plaques, and blisters on the whole body. The symptoms appeared several days after contact with a Rhus tree. She [...]

The precise contribution(s) of skin dendritic cells (DCs) (epidermal Langerhans cells (LCs) and dermal dendritic cells (dDCs)) to graft-versus-host-disease (GvHD) in the skin has not been well delineated. We therefore developed an intradermal (id) injection model whereby CD8+ T (OT-I) cells that express ovalbumin (OVA)-peptide-specific T-cell receptors (Vα2/Vβ5) are delivered directly to the dermis of transgenic (Tg) mice expressing OVA targeted to the epidermis under a keratin 14 (K14) promoter. To determine the relative contribution of LCs to the GvHD reaction, we have generated K14-OVA x Langerin-diphtheria-toxin-receptor (Langerin-DTR) Tg mice to conditionally ablate LCs in the epidermis. Additionally, to identify the role of dDCs in the reaction we generated K14-OVA Tg chimeras using β2-microglobulin-deficient (b2m) congenic donor bone marrow cells. These mice were chimerized with donor b2m-derived MHC II high cells in the spleen (> 98%), LN (> 98%), and dermis (> 90%), whereas the majority of epidermal LCs remained recipient derived (> 95%). The dDCs in these mice do not have the capacity to present OVA to OT-I cells, whereas the LCs maintain their antigen-presenting functions, as previously reported. Following id injection of OT-I cells, the K14-OVA Tg mice developed localized skin GvHD on day 7 regardless of the level of OVA expression in the epidermis. Local injection of OT-I cells into the b2m→K14-OVA chimeric mice and LC-depleted K14-OVA x Langerin-DTR double Tg mice resulted in skin GvHD by day 7, comparable to normal K14-OVA Tg mice. Unexpectedly, OT-I cell injection into diptheria toxin (DT)-treated b2m→K14-OVA x Langerin-DTR Tg mice also resulted in skin GvHD. Thus, in vivo, even in the absence of both LCs in the epidermis and dDCs that can present OVA peptide in association with MHC I molecules, GvHD ensued. Furthermore, in vitro, OVA-expressing epidermal cells depleted of LCs (> 98% depletion) induced OT-I cell priming but did not induce a detectable allogeneic epidermal lymphocyte reaction. These results indicate that keratinocytes can function as accessory cells to induce the priming of naive autoreactive T cells in the skin.

The precise contribution(s) of skin dendritic cells (DCs) to immune responses in the skin has not been well delineated. We developed an intradermal (i.d.) injection model in which CD8+ T (OT-I) cells that express ovalbumin (OVA) peptide-specific TCRs (Valpha2/Vbeta5) are delivered directly to the dermis of transgenic (Tg) mice expressing OVA in the epidermis. After i.d. injection, these mice reliably develop skin graft-versus-host disease (GVHD) by day 7. To determine the relative contribution of Langerhans cells (LCs) to the ensuing GVHD-like reaction, we generated K14-OVA x Langerin-diphtheria-toxin-receptor (Langerin-DTR) Tg mice to allow conditional ablation of LCs in the epidermis. To delineate the role of dermal DCs (dDCs) in the reaction, we also generated K14-OVA Tg chimeras using beta(2)-microglobulin-deficient (beta(2)m) congenic donor bone marrow cells. Dermal DCs in these mice cannot present OVA to autoreactive T cells (OT-I cells), whereas the LCs are antigen presentation-competent. Unexpectedly, OT-I cell injection into diphtheria toxin (DT)-treated beta(2)m --K14-OVA x Langerin-DTR Tg mice resulted in skin GVHD. Thus, in vivo, both LC and dDC appear to be dispensable for the induction of keratinocyte-directed, CD8-mediated effector immune responses. Furthermore and surprisingly, OVA-expressing epidermal cells depleted of LCs that could not initiate allogeneic epidermal lymphocyte reactions activated naive OT-I cells in vitro. These results indicate that keratinocytes may function as accessory cells competent to prime naive skin-reactive T cells.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://network.nature.com/group/jidclub.