Utility of budgerigar/pigeon/parrot-specific IgG antibody with ImmunoCAP® in bird-related hypersensitivity pneumonitis caused by other bird species and duvet.

BACKGROUND: Bird-related hypersensitivity pneumonitis (BRHP) is an extrinsic allergic alveolitis caused by inhalation of bird antigens. Although the measurement of serum-specific IgG antibodies against budgerigar, pigeon, and parrot with ImmunoCAP® is available in Japan, the utility of the test for patients with causes by bird breeding other than these three species, including contact with wild birds/poultry/bird manure, and use of a duvet is unknown. METHODS: Of the 75 BRHP patients who participated in our previous study, 30 were included. Six cases were caused by bird breeding of species other than pigeon, budgerigar, and parrot, seven were in contact with wild birds/poultry/bird manure, and 17 were using a duvet. Bird-specific IgG antibodies were compared among the patients, 64 controls, and 147 healthy participants. RESULTS: In patients with BRHP caused by bird breeding, budgerigar and parrot-specific IgG levels were significantly higher than in disease controls. Only parrot-specific IgG was significantly higher than in disease controls in patients caused by duvet use. However, among patients with acute episodes (acute and recurrent type of chronic BRHP), IgG antibodies against all three species were significantly higher than those of disease controls caused by bird breeding and the use of a duvet. CONCLUSIONS: Bird-specific IgG antibody with ImmunoCAP® was useful for screening and diagnosing BRHP caused by other bird species and duvets.

NLRP3 inflammasome activation contributes to development of alopecia areata in C3H/HeJ mice.

Alopecia areata (AA) is an autoimmune non-scarring hair loss disease. Recently, several reports have suggested that innate immune systems such as interferon-α (IFN-α)-producing plasmacytoid dendritic cells and NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasomes play a role in the pathogenesis of AA. However, critical studies about their involvement in the initiation of AA have not yet been reported. Therefore, we investigated the expression of innate immune cytokines in serum and skin, and examined the effect of a selective NLRP3 inhibitor, MCC950, on AA in C3H/HeJ mice, induced by transferring cultured skin-draining lymph node cells. IFN-α production was upregulated in lesions of AA-affected mice, and interleukin-1ß in serum and skin was highly expressed before onset as well as postonset. Furthermore, MCC950 treatment prevented AA development and promoted hair growth in AA mouse models by reducing NLRP3 signalling and Th1/Tc1 chemokines and cytokines in the skin. These results suggest that NLRP3 inflammasome contributes to AA onset and chronicity, and NLRP3 inhibitor may be a potential therapeutic agent for AA.

Altered T cell subpopulations and serum anti-TYRP2 and tyrosinase antibodies in the acute and chronic phase of alopecia areata in the C3H/HeJ mouse model.

BACKGROUND: C3H/HeJ mouse models progress gradually in hair loss from acute to chronic phase and reflect the symptoms of patients with alopecia areata (AA). However, the underlying pathological characteristics alteration associated with disease progression and autoantigens remain unclear. OBJECTIVE: We aimed at elucidating the pathological differences between acute and chronic-AA in the C3H/HeJ mouse model. METHODS: We analyzed populations of PBMCs, skin-draining lymph node (SDLN) cells, and cutaneous cells of AA mice using flow cytometry. The cytokine and chemokine expressions in the serum and skin were determined using multiplex assay and qPCR. The antibody serum levels were determined using ELISA and the antigen-specific T cells were detected using the MHC class I tetramer. RESULTS: The CD8+NKG2D+ T and CD8+ TEM cell percentage in the chronic-AA SDLNs or among the unaffected and acute-AA mice PBMCs increased. The Th1 and CD4+ TEM cell percentage in the SDLNs and among PBMCs increased in the unaffected and AA mice. The percentage of CD8+ TEM/TRM cells and MHC class I expression increased in the lesions of acute-AA or the non-lesions and lesions of chronic-AA. The Th1 cells, dendritic cell-related cytokines, CD11c+ cells and MHC class II expression increased in the skin of AA mice. The antibody levels and TYRP2 and tyrosinase-specific CD8+ T cell percentages were upregulated in AA mice. CONCLUSION: These results suggest that the CD8+ and CD4+ T cell subpopulations, cytokine and chemokine expressions differ between the disease phases. Moreover, TYRP2 and tyrosinase are potential autoreactive targets in the AA mouse model.

Induction of alopecia areata in C3H/HeJ mice using cryopreserved lymphocytes.

BACKGROUND: Alopecia areata (AA) is an autoimmune disease resulting in non-scarring hair loss. Animal models are useful means to identify candidates for therapeutic agents. The C3H/HeJ mouse AA model induced via transferring cultured lymphoid cells isolated from AA-affected mice is widely used for AA research. However, this conventional method requires the continuous breeding of AA mice. OBJECTIVE: We aimed to establish a new method to generate AA model using the transfer of cryopreserved cells, which allows the rapid induction of a large number of AA mice when needed. METHODS: We cryopreserved lymph node cells soon after isolation from AA-affected mice and injected thawed-cultured cells into recipient mice. H&E staining, immunohistochemical staining, quantitative real-time PCR and ELISA were conducted to identify pathological characteristics. Flow cytometry was performed to reveal the profile of transferred cells. RESULTS: More than 90 % of recipient mice developed AA-like hair loss and showed inflammatory cell infiltration around anagen hair follicles, markedly increased mRNA expressions of interferon-γ, CXCL11, and granzyme B, and elevated interferon-α protein levels in the skin compared with naïve mice. Higher percentages of effector memory T cells and dendritic cells in transferred cells resulted in a higher incidence of AA. CONCLUSION: This is the first report to establish a method for generating AA mice using cryopreserved lymphocytes. These AA mice have similar pathological characteristics to AA mice generated with the conventional method and AA patients. This convenient and reproducible method is expected to be valuable for AA study.

Multi-Institutional Prospective Cohort Study of Patients With Pulmonary Hypertension Associated With Respiratory Diseases.

BACKGROUND: There is limited evidence for pulmonary arterial hypertension (PAH)-targeted therapy in patients with pulmonary hypertension associated with respiratory disease (R-PH). Therefore, we conducted a multicenter prospective study of patients with R-PH to examine real-world characteristics of responders by evaluating demographics, treatment backgrounds, and prognosis.Methods and Results:Among the 281 patients with R-PH included in this study, there was a treatment-naïve cohort of 183 patients with normal pulmonary arterial wedge pressure and 1 of 4 major diseases (chronic obstructive pulmonary diseases, interstitial pneumonia [IP], IP with connective tissue disease, or combined pulmonary fibrosis with emphysema); 43% of patients had mild ventilatory impairment (MVI), whereas 52% had a severe form of PH. 68% received PAH-targeted therapies (mainly phosphodiesterase-5 inhibitors). Among patients with MVI, those treated initially (i.e., within 2 months of the first right heart catheterization) had better survival than patients not treated initially (3-year survival 70.6% vs. 34.2%; P=0.01); there was no significant difference in survival in the group with severe ventilatory impairment (49.6% vs. 32.1%; P=0.38). Responders to PAH-targeted therapy were more prevalent in the group with MVI. CONCLUSIONS: This first Japanese registry of R-PH showed that a high proportion of patients with MVI (PAH phenotype) had better survival if they received initial treatment with PAH-targeted therapies. Responders were predominant in the group with MVI.

Screening and diagnosis of acute and chronic bird-related hypersensitivity pneumonitis by serum IgG and IgA antibodies to bird antigens with ImmunoCAP®.

BACKGROUND: Bird antigens are some of the most relevant antigens in hypersensitivity pneumonitis (HP). Possible sources of bird antigens are bird breeding, feather products and fertilizer with fowl droppings. For the screening and diagnosis of HP, the measurement of bird-specific antibodies should be standardized. The aim of this study was to clarify the utility of serum IgG (sIgG) and IgA (sIgA) antibodies to bird antigens in screening and diagnosing acute/chronic bird-related HP with ImmunoCAP® in multi-centre clinical research. METHODS: We executed a clinical performance test by conducting a multi-institutional study to measure the levels of sIgG/sIgA against pigeon, parrot and budgerigar antigens by the ImmunoCAP® system in 29 acute and 46 chronic bird-related HP patients. RESULTS: The levels of sIgG/sIgA against the bird antigens of the three species were significantly higher in subjects with acute bird-related HP and chronic bird-related HP with acute episodes (recurrent type) than in the control subjects. For sIgG, the optimal cutoff values by receiver operating characteristic (ROC) analysis were 24.6 mgA/L for pigeon, 14.0 mgA/L for parrot, and 8.7 mgA/L for budgerigar. By measuring multiple bird antigens and combining sIgG values of two species, the sensitivity and specificity for acute and recurrent-type chronic bird-related HP patients were 85-91% and 73-80%, respectively. For recurrent and insidious types of chronic bird-related HP, the sensitivity and specificity were 48-61% and 73-80%, respectively. CONCLUSIONS: Measurement of the levels of sIgG/sIgA against pigeon, budgerigar and parrot antigens by ImmunoCAP® was useful for screening and diagnosis in bird-related HP.

Thrombomodulin Alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. A Randomized, Double-Blind Placebo-controlled Trial.

Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombomodulin alfa, a recombinant human soluble thrombomodulin, has anticoagulant and antiinflammatory effects. Several clinical studies have shown that thrombomodulin alfa may improve survival of acute exacerbation.Objectives: To determine the efficacy and safety of thrombomodulin alfa compared with placebo in acute exacerbation of idiopathic pulmonary fibrosis.Methods: This randomized, double-blind placebo-controlled phase 3 study conducted at 27 sites in Japan involved patients with an acute exacerbation of idiopathic pulmonary fibrosis. Subjects were randomized 1:1 to receive placebo or thrombomodulin alfa (380 U/kg/d for 14 d by intravenous drip infusion). All subjects were treated with high-dose corticosteroid therapy. The primary endpoint was the survival proportion on Day 90.Measurements and Main Results: Of the 82 randomized subjects, 77 completed the study and were included in the full analysis set (thrombomodulin alfa, n = 40; placebo, n = 37). The survival proportions on Day 90 were 72.5% (29 of 40) in the thrombomodulin alfa group and 89.2% (33 of 37) in the placebo group, a difference of -16.7 percentage points (95% confidence interval, -33.8 to 0.4%; P = 0.0863). In the safety population (n = 80), bleeding adverse events occurred in the thrombomodulin alfa group (10 of 42; 23.8%) and the placebo group (4 of 38; 10.5%).Conclusions: Thrombomodulin alfa did not improve the 90-day survival proportion. The present results suggest that the use of thrombomodulin alfa for the treatment of acute exacerbation of idiopathic pulmonary fibrosis not be recommended.Clinical trial registered with www.clinicaltrials.gov (NCT02739165).

Anti-inflammatory effect of lanoconazole on 12-O-tetradecanoylphorbol-13-acetate- and 2,4,6-trinitrophenyl chloride-induced skin inflammation in mice.

BACKGROUND: Lanoconazole (LCZ) is a topical antifungal agent clinically used to treat fungal infections such as tinea pedis. LCZ has not only antifungal effects but also anti-inflammatory effects, which have the potential to provide additional clinical benefits. However, the characteristic features of the inhibitory effects of LCZ on skin inflammation remain unclear. OBJECTIVE: We evaluated the inhibitory effects of topical application of LCZ, and compared the effects of LCZ with those of other antifungal agents including liranaftate, terbinafine and amorolfine. METHODS: Each antifungal agent was topically applied on 12-O-tetradecanoylphorbol-13-acetate-induced irritant dermatitis and 2,4,6-trinitrophenyl chloride-induced contact dermatitis in mice (BALB/c). The ear thickness, myeloperoxidase activity and inflammatory mediator contents were evaluated. RESULTS: LCZ dose-dependently suppressed 12-O-tetradecanoylphorbol-13-acetate-induced irritant dermatitis, suppressed the production of neutrophil chemotactic factors such as keratinocyte-derived chemokine and macrophage inflammatory protein-2, and inhibited neutrophil infiltration to the inflammation site. Moreover, 1% LCZ reduced the ear swelling in mice with 2,4,6-trinitrophenyl chloride-induced contact dermatitis in accordance with the inhibition of interferon-γ production. The inhibitory potency of LCZ on these types of dermatitis in mice was stronger than that of other types of antifungal agents. CONCLUSION: The anti-inflammatory effects of LCZ were exerted through the inhibition of inflammatory mediator production. These effects may contribute to the relief of dermatitis symptoms in patients with tinea pedis.

The Analysis of Surgical Lung Biopsy and Explanted Lung Specimens Sheds Light on the Pathological Progression of Chronic Bird-related Hypersensitivity Pneumonitis.

Chronic hypersensitivity pneumonitis is an interstitial pneumonia caused by an immunological reaction to the chronic inhalation of an antigen. Little is known, however, about the pathological change of the pulmonary lesions. A 33-year-old man was diagnosed with chronic bird-related hypersensitivity pneumonitis based on the findings of a surgical lung biopsy and an inhalation provocation test. He underwent lung transplantation at 8 years after the diagnosis because of disease progression. We conclude that the analysis of the explant suggests that the presence of extensive fibrosis in the centrilobular and perilobular area with bridging fibrosis is a form of pathological progression of chronic hypersensitivity pneumonitis.

[Influence of Bases for External Medicines with Different Coatability and Water Retentivity on Wound Healing].

When selecting external medicines for the treatment of skin diseases, it is thought to be very important to consider differences in characteristics of their bases, because the bases may influence the clinical efficacy of the medicines. In this study, we investigated whether the differences in characteristics of three kinds of bases, white petrolatum, macrogol ointment, and aqueous gel affect wound healing. In vitro moisture permeability tests demonstrated that these bases have different characteristics in coatability and water retentivity, with the rank order of the intensity of coatability as white petrolatum>macrogol ointment>aqueous gel, and that of water retentivity as macrogol ointment>white petrolatum>aqueous gel. Similar rank order of these bases was observed for transepidermal water loss and stratum corneum water content in the dry skin on the abdomen of guinea pigs induced by topical application of acetone/ether mixture, followed by water. In addition, we found that treatment with macrogol ointment, but not white petrolatum or aqueous gel, significantly accelerated wound healing in rat skin, and that the contents of basic fibroblast growth factor and epidermal growth factor in the skin treated with macrogol ointment were significantly higher compared with non-treated skin. In conclusion, these results imply an important role of the bases of external medicines in the treatment of skin diseases.

Pleuroparenchymal fibroelastosis diagnosed by multidisciplinary discussions in Japan.

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a rare subset of idiopathic interstitial pneumonias. No large-scale clinical studies of PPFE have been published. The aim of the study was to clarify the clinical and physiological characteristics of PPFE in Japan METHODS: This was a retrospective, nationwide, and multicenter study in Japan. We reviewed 52 patients with PPFE, diagnosed after multidisciplinary discussions. RESULTS: Flat chest index, defined as the ratio of anteroposterior diameter to transverse diameter of thoracic cage at the level of 6th thoracic vertebra, correlated positively with body mass index (BMI) (r = 0.340, p = 0.013) and percentage of predicted value of forced vital capacity (FVC %pred) (r = 0.355, p = 0.012), and negatively with the ratio of residual volume to total lung capacity (RV/TLC) (r = -0.312, p = 0.042). RV/TLC correlated negatively with BMI (r = -0.746, p < 0.0001) and FVC %pred (r = -0.507, p = 0.0005), and positively with age, and physiological variables (GAP) scores (r = 0.332, p = 0.030). The median survival time and the cumulative 5-year survival rate were 96 months and 58%, respectively. Patients with KL-6 level >600 (U/mL) survived shorter than those with <600 (p < 0.001). CONCLUSION: Low BMI, decreased FVC and increased RV/TLC in PPFE may be related to the progression of flattened chest cage which impairs distension of chest cage at inspiration. Elevated serum levels of KL-6 suggest a poor prognosis of PPFE.

Immediate-type allergic and protease-mediated reactions are involved in scratching behaviour induced by topical application of Dermatophagoides farinae extract in NC/Nga mice.

Atopic dermatitis (AD)-like dermatitis can be induced by repeated topical application of an ointment containing Dermatophagoides farinae body (Dfb) extract in NC/Nga mice. This AD-like murine model also exhibits a biphasic increase in the number of scratching behaviour after topical application of Dfb ointment. In this study, we investigated the possible mechanisms underlying the scratching behaviour in each phase. An increase in the content of mast cell-derived mediators such as histamine and 5-hydroxytryptamine in the lesional skin and increased vascular permeability were observed in the early phase after the Dfb ointment application. Chlorpheniramine (H1 receptor antagonist) and cromoglycate (mast cell stabilizer) reduced the scratching behaviour in the early phase but not that in the later phase. Furthermore, the content of various endogenous pruritogens such as interleukin-31 and thymic stromal lymphopoietin in the lesional skin was increased 1 or 24 hours after the Dfb ointment application. Elevated expression of proteinase-activated receptor-2 (PAR-2) was also observed in the epidermis. Finally, gabexate (serine protease inhibitor) reduced the scratching behaviour in both phases, and anti-PAR2 antibody also showed a tendency to reduce both scratching behaviours. These findings suggest that immediate-type allergic reactions caused by mast cell degranulation and PAR-2 activation by proteases are involved in the scratching behaviour in this AD-like model.

House Dust Mites Induce Production of Endothelin-1 and Matrix Metalloproteinase-9 in Keratinocytes via Proteinase-Activated Receptor-2 Activation.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by skin barrier dysfunction and abnormal immune response. House dust mites (HDM) are a major source of allergens, some of which have cysteine and serine protease activities. Keratinocytes stimulated by HDM-derived proteases have been suggested to contribute to the pathogenesis of AD by producing various cytokines. However, whether keratinocytes contribute to the induction of pruritus in AD, especially by producing pruritus-related mediators upon stimulation with HDM-derived proteases, has not been fully elucidated. METHODS: We examined whether the production of endothelin-1 (ET-1), matrix metalloproteinase (MMP)-2, and MMP-9 in keratinocytes can be induced by stimulation with Dermatophagoides farinae extracts, and if so, whether pretreatment with a protease inhibitor or proteinase-activated receptor-2 (PAR-2) antagonist affects the production of these mediators in keratinocytes. RESULTS: Although MMP-2 levels were undetectable in the culture supernatants, the production of ET-1 and MMP-9 was increased upon stimulation with HDM extracts in a concentration- and time-dependent manner and suppressed by pretreatment of HDM extracts with serine protease inhibitor, but not with cysteine protease inhibitor. Mite-derived serine proteases also induced ET-1 and MMP-9 production in a concentration- and time-dependent manner. Moreover, pretreatment with a PAR-2 antagonist inhibited the production of ET-1 and MMP-9 in keratinocytes. CONCLUSION: These results suggest that the activation of PAR-2 on keratinocytes by HDM-derived serine proteases induces the production of ET-1 and MMP-9, and may contribute to the induction of pruritus in AD.

Clinical Course and Changes in High-Resolution Computed Tomography Findings in Patients with Idiopathic Pulmonary Fibrosis without Honeycombing.

Some patients with idiopathic pulmonary fibrosis (IPF) do not have honeycombing on high-resolution computed tomography (HRCT) at their initial evaluation. The clinical course and sequential changes in HRCT findings in these patients are not fully understood. We reviewed the cases of 43 patients with IPF without honeycombing on initial HRCT from institutions throughout Japan. All patients were diagnosed with IPF based on a surgical lung biopsy. Multidisciplinary discussions were held five times between 2011 and 2014, to exclude alternative etiologies. We evaluated the sequential changes in HRCT findings in 30 patients with IPF. We classified these 30 patients into three groups based on their HRCT patterns and clarified the clinical characteristics and prognosis among the groups. The patterns of all 30 patients on initial HRCT corresponded to a possible usual interstitial pneumonia (UIP) pattern which was described in the 2011 International Statement. On long-term follow-up (71.0±38.7 standard deviation [SD] months), honeycombing was seen in 16 patients (53%, the HoneyCo group); traction bronchiectasis or cysts without honeycombing was observed in 12 patients (40%, the NoHoneyCo group), and two patients showed no interval change (7%, the NoChange group) on HRCT. The mean survival periods of the HoneyCo and NoHoneyCo groups were 67.1 and 61.2 months, respectively (p = 0.76). There are some patients with IPF whose conditions chronically progress without honeycombing on HRCT. The appearance of honeycombing on HRCT during the follow-up might not be related to prognosis.

Biphasic increase in scratching behaviour induced by topical application of Dermatophagoides farinae extract in NC/Nga mice.

Atopic dermatitis (AD) is a chronic inflammatory skin disease accompanied by severe itching and eczematous lesion. In this study, we applied an ointment containing Dermatophagoides farinae body (Dfb) extract repeatedly on the dorsal skin of NC/Nga mice with barrier disruption to investigate the characteristics of this murine model of human AD. Following repeated topical application of Dfb ointment twice weekly for 2 weeks, the dermatitis score increased gradually, accompanied by an elevation of total immunoglobulin E level in plasma. Topical application of Dfb ointment also caused epidermal hyperplasia and accumulation of inflammatory cells in the lesional skin and increased expression of T-helper (Th) 1/Th2/Th17 cytokines in axillary lymph node cells. Furthermore, increased sprouting of intraepidermal nerve fibres was observed with an increase in the content of nerve growth factor and decrease in that of semaphorin 3A in the lesional skin. These findings suggest that the characteristics in this model were similar to those observed in patients with AD. Interestingly, it was observed for the first time that scratching behaviour increased in a biphasic fashion by topical application of Dfb ointment in addition to an increase in spontaneous scratching behaviour in this model. It is also suggested that further clarifying the underlying mechanisms of scratching behaviour in this model leads not only to elucidating the pathogenesis of AD but also to discovering novel therapeutic drugs for AD.

Anti-inflammatory activity of lanoconazole, a topical antifungal agent.

Topical antifungal agents which have anti-inflammatory effects have the potential to provide additional clinical benefits. Therefore, an anti-inflammatory activity of lanoconazole (LCZ), a topical antifungal agent, was investigated against in vitro and in vivo models of inflammation. The release of interleukin-8 (IL-8) from human epidermal keratinocytes stimulated by the addition of 100 µg ml(-1) ß-glucan of Saccharomyces cerevisiae was significantly inhibited by LCZ at the concentration of 10(-5) mol l(-1). The release of interferon-γ and IL-2 from human peripheral blood mononuclear cells stimulated by the addition of 30 and 100 µg ml(-1) phytohemagglutinin was significantly inhibited by LCZ at the concentrations of 10(-7) and 10(-6) mol l(-1), respectively. The increase in the ear thickness induced by topical application of 0.01% 12-O-tetradecanoyl phorbol-13-acetate and 1% 2,4,6-trinitrochlorobenzene (TNCB) after sensitisation with 3% TNCB were established as the mouse models of irritant and contact dermatitis, respectively. Application of 1% and 3% LCZ showed a significant anti-inflammatory activity against both the irritant and contact dermatitis models. These findings suggest that LCZ possesses an anti-inflammatory activity, which may be partially helpful in the treatment of dermatomycoses.

Long fasting is effective in inhibiting physiological myocardial 18F-FDG uptake and for evaluating active lesions of cardiac sarcoidosis.

BACKGROUND: F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a promising modality for detecting active lesions of cardiac sarcoidosis (CS). However, determining whether 18F-FDG uptake in the myocardium is physiological is challenging due to metabolic shift in myocardial cells. Although methods for inhibiting physiological myocardial 18F-FDG uptake have been proposed, no standard methods exist. This study therefore aimed to compare the effect of an 18-h fast (long fasting (LF)) with heparin loading plus a 12-h fast (HEP) before 18F-FDG PET scan. METHODS: We analyzed the effects of LF and HEP on the inhibition of physiological myocardial 18F-FDG uptake in healthy subjects (18 in HEP and 19 in LF) and in patients with known or suspected CS (96 in HEP and 69 in LF). In CS, the lower uptake of 18F-FDG in the myocardium was evaluated. A visual four-point scale was used to assess myocardial 18F-FDG uptake in comparison with hepatic uptake (1 lower, 2 similar, 3 somewhat higher, 4 noticeably higher). RESULTS: Myocardial 18F-FDG uptake was 1.68 ± 1.06 in LF and 3.17 ± 1.16 in HEP in healthy subjects (p < 0.0001), whereas it was 1.48 ± 0.99 in LF and 2.48 ± 1.33 in HEP in CS patients (p < 0.0001). Logistic regression and regression trees revealed the LF was the most effective in inhibiting myocardial 18F-FDG uptake. In addition, serum free fatty acid levels on intravenous 18F-FDG injection were a possible biomarker. CONCLUSIONS: LF is effective in inhibiting myocardial 18F-FDG uptake, and consequently, it could be useful for evaluating active lesions of CS in 18F-FDG PET images.

Usefulness of low-dose methotrexate monotherapy for treating sarcoidosis.

OBJECTIVE: Methotrexate (MTX) is a cytotoxic agent that is commonly employed as an alternative to corticosteroids to treat sarcoidosis, although the proper use and efficacy of MTX as a single agent remain unclear. METHODS: The clinical records of patients newly diagnosed with sarcoidosis who were admitted to our institution between 2000 and 2009 were reviewed. Among these patients, 26 received 7.5 mg of MTX per week as a single agent, and the independent effects of MTX were analyzed. RESULTS: Six of the 26 patients (23%) exhibited an improvement of sarcoidosis-related lesions. The skin lesions demonstrated a relatively higher response rate (37%) than the pulmonary lesions (9%). Ten of the 26 patients (39%) experienced adverse effects, mostly mild hepatotoxicity. No severe adverse effects, including irreversible hepatotoxicity, were observed. CONCLUSION: Although the efficacy of low-dose MTX monotherapy for sarcoidosis in this study was not high (23%), some patients exhibited definite improvements, and the drug proved to be safe, suggesting its possible benefits as a single agent for treating sarcoidosis.

Respiratory bronchiolitis and lung carcinoma.

BACKGROUND: Cigarette smoking is the primary causative factor for lung carcinoma and respiratory bronchiolitis (RB), particularly RB-associated interstitial lung disease (RB-ILD). However, the link between lung cancer and RB/RB-ILD remains undefined. We examined whether pathological fibrosis lesions exist simultaneously in patients with lung carcinoma because the fibrous lesions could be precancerous. METHODS: Clinical, radiological, and pathological features were consecutively evaluated in 67 current smokers, 22 ex-smokers, and 35 nonsmokers who underwent surgical resection for lung carcinoma. The presence of interstitial changes was evaluated by high-resolution computed tomography (HRCT). The pathological examination focused on RB, RB with fibrosis, and coexistent interstitial changes. RESULTS: RB with fibrosis was observed in 13/67 current smokers with centrilobular nodular and/or patchy ground-glass opacities patterns or emphysema on HRCT. RB without fibrosis was observed in 12/67 current smokers with a centrilobular pattern, emphysema, or a normal pattern on HRCT. The Brinkman smoking index was significantly higher in the RB with fibrosis group (1278±133) than in the RB without fibrosis group (791±131). No RB with/without fibrosis features were noted in nonsmokers or ex-smokers. Squamous cell carcinoma was observed in 11/13 patients with RB with fibrosis, whereas adenocarcinoma was observed in 7/12 patients with RB without fibrosis. CONCLUSIONS: Squamous cell carcinoma located in peripheral areas was primarily observed in patients with RB with fibrosis, whereas adenocarcinoma was primarily observed in patients with RB without fibrosis. Interstitial fibrosis with RB caused by continuous heavy cigarette smoking may increase the risk of developing squamous cell carcinoma.