Search

Background: Identification of sensitized allergens for patients with respiratory allergy is an important step in disease care and environmental allergen control. The Japanese archipelago belongs to various climate categories due to its length from north to south which transverse the subarctic in the north to the subtropical in the south, suggesting substantial regional differences in dominant environmental allergens. However, few studies have assessed the regional differences in the prevalence of sensitization to environmental allergens. Methods: We requested three major clinical testing laboratories to provide us with summarized results of antigen-specific IgE-antibody (Ab) measurements. These measurements were collected for clinical purposes throughout Japan from 2002 through 2011. The prevalence of positivity for IgE-Ab against 19 environmental allergens was calculated for each prefecture in order to evaluate regional differences. Results: Test data on specific IgE-Ab of 19,969,753 orders were analyzed. The prevalence of positivity for house dust mites was high and the regional difference was low, whereas apparent regional differences were found for pollen, insects, and fungi. The prevalence of positivity for Japanese cedar was low in Hokkaido and Okinawa, while those to alder was highest in Hokkaido. Higher prevalence for insects was observed in southern areas (Okinawa and prefectures in Kyusyu). Conclusions: Findings of this study clearly demonstrated regional differences in the prevalence of sensitization to environmental allergens in Japan and the study also provides useful information for the clinician when deciding which allergens should preferentially be measured for IgE-Ab after considering regional difference. Keywords: Allergic rhinitis, Asthma, Environmental allergen, IgE antibody, Regional differences

Four patients with non-small-cell lung cancer(NSCLC), diagnosed with cN2 stage III A disease, by using CT and FDG-PET/ CT imaging, received 2 or 3 courses of platinum-based combination chemotherapy.The patients achieved partial response after chemotherapy and underwent surgery.Complete tumor resection was performed via upper lobectomy for 3 patients, but in 1 patient, interlobar metastatic lymph nodes remained after middle and lower bilobectomy.Two courses of postoperative chemotherapy were administered to 3 patients, but 1 patient could not receive postoperative chemotherapy due to complications.One patient, in whom lymph node metastasis completely disappeared after induction chemotherapy, is still alive and without disease recurrence for 7 years.Another patient, with the presence of only one intralobar metastatic lymph node after chemotherapy, died of brain and meningeal metastases, 3 years after surgery.Two other patients, with multiple pN2 lymph nodes after chemotherapy, died of early intrathoracic local relapse, indicating that prognosis is influenced by response to chemotherapy, especially in patients with poor N-downstaging.Improvements in response to induction therapy by using intensive chemotherapeutic regimens, concurrent radiotherapy, and strict patient selection, limited to N-downstaged cases, are needed for successful surgery outcomes in patients with cN2 stage III A NSCLC who have received induction therapy.

Tumor necrosis factor (TNF)-α plays a crucial role in the pathogenesis of ischemia/reperfusion-induced renal injury. We demonstrated recently that the preischemic treatment with resiniferatoxin, a transient receptor potential vanilloid 1 (TRPV1) agonist, attenuates renal TNF-α mRNA expression, and improves ischemia/reperfusion-induced renal injury in rats. In the present study, we investigated effects of treatment with SA13353, a novel orally active TRPV1 agonist, on ischemia/reperfusion-induced renal injury in rats. Ischemic acute kidney injury (AKI) was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in vehicle-treated AKI rats markedly decreased at 24 h after reperfusion. Treatment with SA13353 (3, 10, and 30 mg/kg, p.o.) 30 min before ischemia dose-dependently attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of AKI rats revealed severe renal damage, which were significantly suppressed by the SA13353 treatment. In renal tissues exposed to ischemia/reperfusion, TNF-α and cytokine-induced neutrophil chemoattractant-1 mRNA expressions were augmented, but these alterations were attenuated by the treatment with SA13353. On the other hand, ischemia/reperfusion-enhanced renal interleukin-10 mRNA expression and its plasma concentration were further augmented by SA13353 treatment. These results demonstrate that the orally active TRPV1 agonist SA13353 prevents the ischemia/reperfusion-induced AKI. This renoprotective effects seem to be closely related to the inhibition of inflammatory response via TRPV1 activation.

Background: Chronic rhinosinusitis (CRS) is classified into eosinophilic CRS (ECRS) and non-ECRS. The objectives of this study were to evaluate lower airway inflammation by measuring the fractional concentration of exhaled nitric oxide (FeNO) and to examine the effects of endoscopic sinus surgery (ESS) on FeNO in patients with ECRS compared to non-ECRS. Methods: CRS patients with nasal polyps (23 with ECRS and 22 with non-ECRS) were enrolled into this study. ECRS was diagnosed based on the definition proposed by the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) study group. Several clinical markers including blood eosinophil counts, percent of eosinophils in white blood cells (WBC), number of eosinophils in nasal polyps, JESREC scores, total IgE, FeNO, and Lund-Mackay paranasal sinus CT scores were compared between ECRS and non-ECRS. These markers were also tested before and 2 months after ESS. Results: FeNO was significantly higher in patients with ECRS than in non-ECRS patients. When all CRS patients were tested, a significant correlation was found between FeNO and eosinophilic markers including blood eosinophil counts, percent of eosinophils in WBC, number of eosinophils in nasal polyps, and JESREC scores. FeNO showed a significant correlation with Lund-Mackay scores only in ECRS patients. Blood eosinophil counts, percent of eosinophils in WBC, and FeNO decreased after ESS only in ECRS patients. Conclusions: ECRS patients had lower airway inflammation as revealed by an elevated FeNO, which was parallel to the Lund-Mackay CT scores. ESS decreased the blood eosinophils and FeNO, leading to an improvement of the occult pulmonary dysfunction in ECRS patients.

A 78-year-old woman developed second, third, and fourth lung tumors at intervals of 1-3 years after left upper lobectomy for primary lung cancer. The tumors were controlled with radiofrequency ablation(RFA)or conventionalconformalradiotherapy for 9 years postoperatively. For the treatment of second primary lung cancer or lung metastasis after surgical resection of the primary lung cancer, reoperation is not recommended because of the impaired respiratory reserve. Thus, local therapy such as radiotherapy or RFA is applied in some cases. Among these, stereotactic body radiotherapy(SBRT)is a feasible option because of its good local control and safety, which is comparable with surgery. On the other hand, for cases of multiple lesions that are not suitable for radiotherapy or combination therapy, RFA could be an option because of its short-term local control, easiness, safety, and repeatability. After surgery for primary lung cancer, a second lung tumor could be controlled with highly effective and minimally invasive local therapy if it is recognized as a local disease but is medically inoperable. Therefore, longterm postoperative follow-up for primary lung cancer is beneficial.

Interleukin (IL)-1β activates various signal transduction pathways including p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and Akt in human fibroblast-like synoviocytes (HFLS).We investigated the effects of an Akt inhibitor, a phosphatidylinositol 3-kinase (PI3K) inhibitor, and Akt RNAi knockdown on IL-1β-induced protein phosphorylation in HFLS to clarify the role of the PI3K/Akt signaling pathway in the phosphorylation of the inhibitor of κB (IκB)α and heat shock protein 27 (HSP27).A multiplex suspension array system was used for the detection of phosphorylated proteins.IL-1β induced biphasic phosphorylation of IκBα, with the first phase occurring 10 min after IL-1β stimulation, and this was augmented by treatment with Akt inhibitor IV. However, this phenomenon was not observed after treatment with LY-294002, a PI3K inhibitor. Furthermore, Akt inhibitor IV suppressed ERK2 phosphorylation, whereas LY-294002 and Akt RNAi had no effect. In contrast, Akt inhibitor IV, LY-294002, and Akt RNAi augmented HSP27 phosphorylation.Modulation of different stages of the PI3K/Akt pathway may differentially affect the phosphorylation of IκBα and HSP27 in HFLS.

The transient receptor potential vanilloid-1 (TRPV1) cation channel is a receptor that is activated by heat, acidosis and a variety of chemicals, including capsaicin. With these properties, TRPV1 has emerged as a polymodal nocisensor of nociceptive afferent neurons. As many proalgesic pathways converge on TRPV1 and it is upregulated and sensitized by inflammation and injury, TRPV1 is thought to be a central transducer of hyperalgesia and a prime target for the pharmacological control of pain. However, there is conflicting evidence to date as to whether TRPV1 agonists promote or inhibit inflammation. We recently demonstrated that SA13353 [1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea], a novel TRPV1 agonist, inhibits tumor necrosis factor-α production through the activation of capsaicin-sensitive afferent neurons and reduces the severity of symptoms of kidney injury, lung inflammation, arthritis and encephalomyelitis in disease models. These results suggest that TRPV1 agonists may act in an anti-inflammatory manner in vivo in certain inflammatory diseases.

SA14867 ((+)-3-Acetyl-6-chloro-2-[2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline O,O'-diacetyl-L-tartrate), a selective kappa-opioid receptor agonist, was synthesized and its antinociceptive and antipruritic effects were investigated. In a functional binding assay, SA14867 showed approximately more than 31,000 and 2200 fold higher affinity for the kappa-opioid receptor than for the mu- and delta-opioid receptors, respectively. SA14867 inhibited acetic acid-induced writhing and formalin test results after oral administration. The ED(50) values of SA14867 for acetic acid-induced writhing and for formalin test first phase and second phase were 1.9, 9.4, and 6.4 mg/kg, respectively. These values were smaller than those of asimadoline, U-50488H, and tramadol. SA14867 also showed antinociceptive effects in silver nitrate-induced arthritis that were as strong as U-50488H, tramadol, and morphine, and were stronger than asimadoline. The ED(50) value of SA14867 for hyperalgesia of arthritis was approximately 10 mg/kg. In addition, SA14867 showed antipruritic effects on 5-hydroperoxyeicosatetraenoic acid (HPETE) and substance P-induced pruritic models at 1 to 3 mg/kg. SA14867 also attenuated scratching reactions in a morphine-induced pruritic model in monkeys. Some of the inhibitory effects of SA14867 on nociceptive and pruritic models were attenuated by a kappa-opioid receptor antagonist, nor-BNI. These results suggest that SA14867 is a potential antinociceptive and antipruritic drug.

The combined effects of bucillamine (Buc) and etanercept (ETN) on a rat model of type II collagen (CII)-induced arthritis (CIA) after treatment onset were investigated. In the combination treatment, rats received Buc 30 mg/kg orally administered once daily from the onset of arthritis or from 4 days after the onset of arthritis and ETN 0.3 mg/kg subcutaneously administered once on the day of onset. The effects of monotherapy with Buc and ETN, respectively, and of Buc + ETN combination therapy on the resulting polyarthritis were evaluated by histopathological analyses and measurements of hindpaw volumes, serum anti-collagen antibody and immunoglobulin levels, and cytokine levels. The Buc + ETN therapeutic combination reduced hindpaw swelling, synovial proliferation, bone destruction, new bone formation, and inflammatory cell infiltration in CIA. Montherapy with Buc showed a tendency to ameliorate these symptoms, while monotherapy with ETN reduced hindpaw swelling at 4 days after administration but did not maintain treatment efficacy toward the end of the experimental period. Histopathological findings did not reveal any efficacy of the ETN therapy. ETN alone increased the serum immunoglobulin levels, while its combination with Buc reduced these levels. Similar results were obtained for serum anti-CII antibody titers. The Buc + ETN combination treatment also reduced serum interleuking (IL)-1alpha and granulocyte macrophage colony-stimulating factor and tended to reduce serum IL-1beta and IL-6 levels. These results suggest that a combination therapy of Buc and ETN may be effective for the treatment of rheumatoid arthritis (RA).

We investigated the role of leukotriene (LT) B(4) in 5-lipoxygenase metabolite- and allergy-induced itch-associated responses using SA6541, an LTA(4) hydrolase inhibitor. Itch-associated responses were induced by intradermal injection of 5-hydroperoxyeicosatetraenoic acid (HPETE), a precursor of 5-lipoxygenase metabolites, and passive cutaneous anaphylaxis in ICR mice. By screening molecules related to arachidonic acid metabolism or pruritus, SA6541 was found to be a specific inhibitor of LTA(4) hydrolase. Pharmacokinetic studies confirmed the specificity of SA6541 at an oral dose of 100 mg/kg in mice. 5-HPETE induced scratching behavior, which was inhibited by SA6541 (100 mg/kg). However, SA6541 (100 mg/kg) hardly attenuated the 5-HPETE-induced increase in vascular permeability. Moreover, SA6541 (100 mg/kg) partially attenuated scratching behavior, but did not affect the increase in vascular permeability caused by passive cutaneous anaphylaxis. On the other hand, ketotifen fumarate, a histamine H1 antagonist, strongly inhibited the scratching behavior and the increase in vascular permeability caused by passive cutaneous anaphylaxis. These results suggest that LTB(4) is an endogenous itch mediator in the skin and is involved in the pruritus response in allergic reactions.

To identify the molecular mechanisms of bucillamine activity, global gene expression analysis and pathway analysis were conducted using IL-1 beta-stimulated human fibroblast-like synovial cells (FLS).Normal human FLS were treated with IL-1 beta in the presence or absence of 10 and 100 microM bucillamine for 6 h. Total RNA was extracted and global gene expression levels were detected using a 44 k human whole genome array. Data were analyzed using Ingenuity pathway analysis.Numerous pathways were activated by IL-1 beta stimulation. At both concentrations, bucillamine suppressed nine signal pathways stimulated by IL-1 beta.Bucillamine effectively inhibited fibroblast growth factor (FGF) signaling and tight junction signaling activated by IL-1 beta in FLS. Suppression of these signal pathways may correlate with the pharmacologic mechanisms of bucillamine. In particular, the suppression of FGF signaling by bucillamine is remarkable because the activation of FGF signaling may be involved in rheumatoid arthritis pathology.

We studied synthetic modifications of N-mercaptoacylamino acid derivatives to develop a new class of leukotriene A(4) (LTA(4)) hydrolase inhibitors. S-(4-Dimethylamino)benzyl-l-cysteine derivative 2a (SA6541) showed inhibitory activity against LTA(4) hydrolase (IC(50), 270nM) and selectivity over other metallopeptidases except angiotensin-converting enzyme (ACE, IC(50), 520nM). Modification at the para-substituent of the phenyl ring of compound 2a improved LTA(4) hydrolase inhibitory activity as well as selectivity over ACE. Finally, we obtained S-(4-cyclohexyl)benzy-l-cysteine derivatives 11l and 16i as potent and selective LTA(4) hydrolase inhibitors.

Purpose: To expect disease-modified anti-rheumatic drugs (DMARDs) combination therapy on rheumatoid arthritis (RA), combination effect of bucillamine (Buc) and methotrexate (MTX) on type II collagen-induced arthritis model (CIA) was investigated. IgM production from B lymphocytes was examined to understand one of the mechanisms of combination effects.Methods: Rat CIA was induced by bovine type II collagen (CII) sensitization. Buc 3 mg/kg was orally administrated once daily for 21 days from the day of sensitization. MTX 0.2 mg/kg was orally administrated on three times a week for three weeks as the mimic of the clinical dose. IgM production from B lymphocytes was examined with the stimulation of IL-2 and Staphylococcus aureus, and Buc or MTX were treated in vitro.Results: Buc and MTX combination additively reduced the hind paw swelling and bone destruction in CIA. α1-acidic glycoprotein, one of the inflammation markers in serum, and anti-CII antibody titer were also decreased. Buc and MTX combination additively reduced Staphylococcus aureus and IL-2 induced IgM production from B lymphocytes in vitro.Conclusion: This study provides the first evidence that Buc exerts additive effect with MTX in CIA rats. Regulating B cell function by Buc and MTX may contribute to their additive effects on rat CIA to some degree.

We retrospectively evaluated the clinical outcomes of 192 consecutive patients with local recurrence after complete resection of non-small cell lung cancer NSCLC). The initial local recurrent site was the resection stump in 5 patients the chest wall in 3 patients, mediastinum in 1 patient, and diaphragm in 1 patient), and the hilar and/or mediastinal lymph node (HMLN) in 17 patients. The sites of distant metastasis were the lungs in 10 patients, pleura in 4 patients, brain in 7 patients, liver in 5 patients, bone in 4 patients, and other sites in 4 patients. Treatments after initial recurrence included surgery in 2 patients, radiotherapy in 5 patients, chemotherapy in 9 patients, and chemo-radiotherapy in 5 patients. Only 1 patient received supportive care. The response to radiotherapy was a complete response (R) in 1 patient, partial response (PR) in 5 patients, stable disease (SD )in 3 patients, and progressive disease (PD )in 1 patient. The best response of all lines of chemotherapy was CR in 3 patients, PR in 4 patients, SD in 3 patients, and PD in 4 patients. The median post-recurrence survival (PRS) time with local recurrence was better than that with distant metastasis (23 vs 14 months); however, the best PRS was obtained in patients with recurrence in the lungs (29 months). A CR for more than 2 years was obtained in 1 patient after surgery, in 1 patient after radiotherapy, and in 2 patients after chemotherapy. Although local recurrence of resected NSCLC can be potentially controlled by using local treatments - such as surgery and radiotherapy - or systemic chemotherapy, curative aggressive treatment should be considered when required.

呼吸器疾患にとって咳嗽は最も代表的な症状の1つである。咳嗽は本来気道内の喀痰や異物を喀出するための生態防御反射であるため，安易に薬物によってとめる必要性はない。しかし，持続する病的な咳嗽は，体力を消耗させ，QOLの低下につながるため可能な限り原因を明らかにさせ，特異的でかつ適切な治療を施すべきである。しかし，咳嗽，特に慢性咳嗽の鑑別診断は多彩であり，決して容易ではない。多くの鑑別疾患の中から1つの疾患を導き出すには，ポイントをついた詳細な問診と身体所見の評価そして適切なタイミングでの検査が必要である。決して効果の認められない同一の鎮咳薬を長期間処方すべきではない。臨床上の注意点として，一般内科医は慢性咳嗽の鑑別疾患に一般の鎮咳薬の効果が認められないアレルギーが関与する咳嗽の認識を強くもつ必要がある。また，どうしても原因がわからないときや，咳嗽が徐々に悪化するときは，躊躇せず専門医へ移送するべきである。

We investigated the effects of marimastat, an inhibitor of TNF-alpha converting enzyme and matrix metalloproteinases, and anti-TNF-alpha antibodies on a murine model for sepsis, and on arthritis in human TNF-alpha transgenic mice. Marimastat (25-200 mg/kg) inhibited lipopolysaccharide (LPS)-induced soluble TNF-alpha production in mice in a dose-dependent manner. At an oral dose of 200 mg/kg, marimastat almost completely inhibited LPS-induced soluble TNF-alpha production, but only slightly delayed LPS lethality. On the other hand, anti-TNF-alpha antibodies completely abolished LPS-induced morbidity. In addition, anti-TNF-alpha antibodies, but not marimastat (200 mg/kg/day), inhibited the development of arthritis in human TNF-alpha transgenic mice. These results suggest that cell surface TNF-alpha may be important in the pathogenesis of murine models for sepsis and arthritis.

The effects of mitogen-activated protein (MAP) kinase inhibitors or phosphodiesterase (PDE) inhibitors on interleukin (IL)-1-induced cytokines production in synovium-derived cells were investigated. Human synoviocyte (HS) or synovial sarcoma (SW982) stimulated by IL-1beta (100 ng/ml) produced various cytokines including IL-6, IL-8, GROalpha, VEGF, basic FGF and tumor necrosis factor alpha (TNFalpha) in vitro. SB202190 or SB203580, an inhibitor of p38 MAP kinase, inhibited all cytokines production in both cells. PD98059, an inhibitor of MAP kinase kinase (MEK), inhibited IL-6, IL-8 and basic FGF production in HS and all cytokines production except basic FGF in SW982. However, many of its effects were weaker than those of SB202190 or SB203580. Quazinone, an inhibitor of cyclic GMP-inhibited PDE, scarcely affected cytokines production in both cells. Rolipram or R0201724, an inhibitor of cyclic AMP-specific PDE, inhibited IL-8 and basic FGF production in HS and TNFalpha production in SW982, however, it enhanced the other cytokines production in SW982. These results suggest that the activation of MAP kinase cascade may be important for IL-1-induced cytokines production in synovium-derived cells. On the other hand, the role of cyclic AMP may be dependent on cell and cytokine types.

We investigated the effects of S-(4-dimethylaminobenzyl)-N-[(2S)-3-mercapto-2-methylpropionyl]-L- cysteine (SA6541), a potent leukotriene A4 hydrolase inhibitor. on early phase of carrageenan-induced dermatitis model. Carrageenan injection induced edema and neutrophil influx in the mouse ear. SA6541 inhibited edema formation and neutrophil influx. SA6541 also inhibited leukotriene B4 production but not prostaglandin E2 production in the mouse ear. On the other hand, indomethacin inhibited edema formation but not neutrophil influx. Indomethacin also inhibited prostaglandin E2 production but not leukotriene B4 production. Combination therapy with SA6541 and indomethacin strongly inhibited edema formation in comparison with treatment with either agent alone. These results suggest that leukotriene B4 may be important in the pathogenesis of dermatitis.

The effects of tachykinins on prostaglandin E2 (PGE2)-induced intraocular inflammation were investigated. PGE2 (0.01% or 0.1%) instillation induced iridal hyperemia and protein leakage into the aqueous humor in rabbits, but caused minimal miosis. Intravitreally injected substance P (SP) or neurokinin A (NKA), on the other hand, did not induce protein leakage into the aqueous humor in normal rabbits, but they (SP 10 micrograms/eye or NKA 50 micrograms/eye) did induce long-lasting miosis. The miotic activity of SP was about fivefold stronger than that of NKA. Intravitreally injected SP (10 micrograms/eye) but not NKA (50 micrograms/eye) increased PGE2 concentration in the aqueous humor in normal rabbits. In addition, SP (10 micrograms/eye) or NKA (50 micrograms/eye) markedly enhanced protein leakage into the aqueous humor induced by PGE2 instillation. Pretreatment with indomethacin partially blocked the enhancing effect of SP on protein leakage, while it did not block that of NKA. These results suggest that SP or NKA may enhance intraocular inflammation in vivo. However, the mechanisms of these effects of SP and NKA may be different. The enhancing effect of SP in eye inflammation may be partially due to an increased turnover of arachidonic acid into PGE2 caused by activation of the enzyme cyclooxygenase.

A woman in her seventies presented with bilateral hilar and mediastinal lymphadenopathy with high fluorodeoxyglucose (FDG) uptake by positron emission tomography (PET)-computed tomography (CT), small lung nodules, and uveitis. Mediastinoscopic biopsy yielded a histological finding of epithelioid granuloma and a diagnosis of sarcoidosis. A nodule, 1 cm in diameter, in the right middle lobe with moderate FDG uptake was deemed to be a sarcoidosis lesion. Steroid therapy for uveitis resulted in shrinkage of the hilar and mediastinal lymph nodes; however, 1 year later the nodule in the right middle lobe had enlarged to 2 cm in diameter. Right middle lobectomy was performed, and a histological diagnosis of lung squamous cell carcinoma was made. Six months later, right pretracheal lymphadenopathy with high FDG uptake was noted and was proved to be a metastatic squamous cell carcinoma by endobronchial ultrasound-guided transbronchial needle aspiration( EBUS-TBNA). After 7 courses of chemotherapy with docetaxel, the target lesion shrank and its abnormal FDG uptake disappeared. Small-sized lung cancer could be missed when complicated by sarcoidosis because the latter produces a background of multiple lesions, so careful diagnostic imaging and follow-up should be performed in patients diagnosed as having sarcoidosis.

Objective and Design: We reported previously that the betamethasone derivative betamethasone dipropionate behaves as an anti-glucocorticoid in rat endotoxin-induced uveitis (EIU). In the present study, we produced EIU in guinea pigs and investigated the effects of betamethasone dipropionate on the EIU.¶Material: Male Hartley guinea pigs were used.¶Treatment: Glucocorticoids were instilled into the eye.¶Method: To elicit EIU, lipopolysaccharide (LPS) was injected into the anterior chamber of the eye. Cell numbers in the aqueous humor after LPS injection were determined by flow cytometry. Prostaglandin E2 (PGE2) production after LPS injection into the anterior chamber was also examined.¶Results: Intracameral injection of LPS (1 μg/eye) induced cell infiltration into the anterior chamber and PGE2 production. Betamethasone dipropionate inhibited cell infiltration and PGE2 production more strongly than betamethasone. These results suggest that betamethasone dipropionate is a potent glucocorticoid in guinea pigs.¶Conclusions: Structure-activity relationships of glucocorticoids in the guinea pig EIU model may differ from those in the rat EIU model.

The anti-inflammatory effects of betamethasone and its derivatives (betamethasone 21-phosphate, betamethasone 21-acetate, betamethasone 17-valerate, clobetasol 17-propionate and betamethasone dipropionate) on endotoxin-induced uveitis (EIU) in rats was investigated. Among the compounds examined, betamethasone, betamethasone 21-phosphate, betamethasone 21-acetate and clobetasol 17-propionate strongly inhibited cell infiltration into the aqueous humor in the EIU by instillation into the eye in a dose-dependent manner (0.01–1.0%) and by systemic administration (1 mg kg−1). On the other hand, betamethasone 17-valerate and betamethasone dipropionate showed only weak inhibitory effects or enhancment of cell infiltration by instillation into the eye (0.01–1.0%) and by systemic administration (1 mg kg−1). Combined systemic administration of betamethasone dipropionate and betamethasone reduced the inhibitory effect of betamethasone on cell infiltration and gene expression of IL-1β. In anin vitrointerleukin-8 (IL-8) release assay, betamethasone showed stronger inhibition of the IL-8 release from rat peritoneal exudate cells (PEC) than betamethasone dipropionate, and simultaneous addition of betamethasone dipropionate with betamethasone reduced the inhibitory effect of the latter. These results suggest that the betamethasone derivative betamethasone dipropionate might behave as an anti-glucocorticoid in rats.

While some potential biomarkers for ocular diseases have been reported, it is difficult to select a single biomarker that is most important in each ocular disease. After reviewing multiple biomarker studies conducted on small sample subgroups, we concluded that newer analysis techniques may result in different and more specific findings. While progress has been made in developing various omics studies, studies comparing tears of normal and diseased eyes are still lacking. Preliminary omics studies suggest the importance of further studies aimed at identifying potential ocular-associated lipid, non-lipid/protein, and protein biomarkers. In addition, combining potential biomarkers might be a good strategy for the diagnosis and assessment of ocular diseases.

For investigating the pathogenesis of DR, 2 main strategies are applied for the analysis of vitreous protein. The first strategy is antibody-based detection of vitreous cytokines. In previous studies of vitreous cytokines in DR, conventional enzyme-linked immunosorbent assay (ELISA) were used [4,5]. Recently, simultaneous analysis of the expression profiles of multiple cytokines and chemokines in the vitreous fluid was performed using an array system of antibody-coated beads [6]. Compared with the control group, interleukin (IL)-6, IL-8, IL-10, IL-13, interferon-inducible 10-kDa protein (IP-10), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 beta (MIP-1β), platelet-derived growth factor (PDGF), and VEGF levels in the vitreous fluid were significantly higher in the DR group. The second strategy is proteomic analysis of vitreous proteins [7-11]. Fluorescence-based difference gel electrophoresis (DIGE) combined with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) has enabled accurate quantitative comparisons of multiple proteins [12]. MALDI-TOF MS analysis of vitreous fluid detected approximately 1300 protein spots, and 25 of these intravitreal proteins were differentially expressed between DME and control groups. Hemopexin, beta-crystallin S, clusterin, and transthyretin were found to be specifically associated with DME. In a study using the same technique, 1242 protein spots were detected containing 19 differentially expressed intravitreal proteins between proliferative DR and control groups [13]. Differences in hemopoxin, clusterin, and pigment epithelium-derived factor (PEDF) levels were also observed between proliferative DR and control groups. Therefore, hemopexin expression was upregulated in DME and proliferative DR, whereas clusterin expression was downregulated in DME and proliferative DR and PEDF expression was downregulated only in proliferative DR. Hemopexin is an acute-phase plasma glycoprotein and is expressed in multiple cell lines derived from different tissues [14]. Importantly, increasing glucose concentrations in vitro increased hemopexin expression and modulated the reactive oxygen species levels in cells; these effects were partially reversed by addition of reduced glutathione. Clusterin is associated with protection from apoptosis of retinal cells [15]. In a mouse model of DR, clusterin reduced the leakage from vessels in the diabetic retina and restored expression of tight junction

The improvement of rheumatoid factor titers in patients with rheumatoid arthritis is one of the significant clinical effects of bucillamine (Buc). In this study, we investigated the effects of SA981, an active metabolite of Buc, and methotrexate (MTX) on CD40-mediated antibody production using mouse B-cell lymphoma, BCL1. SA981 significantly attenuated CD40-mediated antibody production in a concentration-dependent manner, but weakly affected cell proliferation. In contrast, MTX did not attenuate CD40-mediated antibody production until it had strongly inhibited cell proliferation at a concentration of 100 nM. CD40 signaling induced protein phosphorylation, including Akt phosphorylation, p38 mitogen-activated protein kinase (p38MAPK), and IκBα. SA981 at a concentration of 30 μM attenuated CD40-mediated Akt phosphorylation, but not p38MAPK or IκBα phosphorylation. MTX at a concentration of 100 nM did not affect CD40-mediated Akt, p38MAPK, or IκBα phosphorylation. Commercially available Akt inhibitor VIII significantly attenuated CD40-mediated IgM production at a concentration of 100 nM without significant inhibition of cell proliferation. These results suggest that SA981 inhibits CD40-mediated antibody production in mouse B-cell lymphoma, at least in part, by attenuation of Akt phosphorylation.

Glomerulonephritis is a renal disease characterized by inflammation of the glomeruli, i.e., small blood vessels, in the kidneys. It may present with isolated hematuria and/or proteinuria or as nephritic syndrome, acute renal failure, or chronic renal failure. Glomerulonephritis has several different pathological patterns that can be broadly grouped into non-proliferative and proliferative types. Non-proliferative types include minimal change glomerulonephritis, focal segmental glomerulosclerosis, and membranous glomerulonephritis. Proliferative types include IgA nephropathy, post-infectious glomerulonephritis, membranoproliferative/mesangiocapillary glomerulonephritis, and rapidly progressive glomerulonephritis (Miller et al., 2010). Of the many factors involved in the inflammatory response, cytokines are the most important factors that bind to their receptors and activate signal transduction pathways. Progress in our understanding of inflammatory signaling pathways has led to the identification of the involvement of nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs) such as p38, and Janus tyrosine kinase-signal transducer and activator of transcription (JAK-STAT) pathways (O’Neill, 2006). The NF-κB and p38 pathways are activated by the stimulation of interleukin1 (IL-1) and tumor necrosis factor (TNF). The principal signaling pathways activated by IL-1 and TNF are the NF-κB and stress-activated MAPK pathways, whereas the JAK-STAT pathway is activated by many other cytokines.

We examined the analgesic effect of the selective kappa opioid receptor agonist SA14867 and the balance of its antinociceptive and sedative effects. The ED 50 values of SA14867 after oral administration for acetic acid-induced writhing, first and second phases of the formalin test, and rotarod test in mice were 6.1, 9.3, 2.7, and 19.5 mg/kg, respectively. These values were smaller than those of the conventional kappa receptor agonists asimadoline and U-50488H. However, the balance of the antinociceptive and sedative effects of SA14867 was better than those of the other two drugs. Orally administered SA14867 (0.1–1 mg/kg) significantly improved the decreased pain threshold in a specific alternation of rhythm in an environmental temperature (SART)-stressed model by prophylactic and therapeutic treatment. Improvement in the decreased pain threshold of SA14867-treated animals was attenuated by the opioid receptor antagonist naloxone. Furthermore, orally administered asimadoline (10–100 mg/kg) improved the decreased pain threshold in a SART-stressed model, but the doses were close to those known to induce sedative effects. In addition, SA14867 (0.1–1 mg/kg) significantly inhibited the arthritis-induced decrease in the pain threshold. Subcutaneously administered morphine (0.1–1 mg/kg) improved the decreased pain threshold in a SART-stressed model; on the contrary, morphine did not inhibit the arthritis-induced decrease in the pain threshold. Moreover, orally administered SA14867 (0.1–1 mg/kg) strongly attenuated mechanical allodynia and thermal hyperalgesia in a sciatic nerve ligation model. These results suggest that SA14867 has analgesic effects on chronic pain and may serve as a new therapeutic agent for pain treatment.

A three substituted urea derivative, SA13353 (compound 1a), exhibited potent inhibitory activity against lipopolysaccharide (LPS)-induced TNF-alpha production. We focused on the 1,1-substituted moiety (R(1) and R(2)) of SA13353 and investigated substituent effects of this moiety on LPS-induced TNF-alpha production by oral administration in rats. The synthesis of the urea derivatives was performed rapidly in a one-pot manner using a manual synthesizer. Several compounds containing hydrophobic substituents at this moiety showed more potent inhibitory activities than SA13353.

We recently demonstrated that SA13353, a transient receptor potential vanilloid 1 (TRPV1) agonist, reduced the severity of the symptoms of kidney injury, arthritis, and encephalomyelitis in disease models. Here, we investigated the effects of orally administered SA13353 on leukocyte infiltration in lipopolysaccharide (LPS)-induced acute lung injury and ovalbumin-induced allergic airway inflammation. In LPS-induced lung injury, SA13353 attenuated neutrophil infiltration and the increase of TNF-α and CINC-1 levels. In allergic airway inflammation, SA13353 tended to inhibit leukocyte infiltration and attenuated the increase of IL-4 and IL-12p40. These results suggest that somatosensory TRPV1 may play an anti-inflammatory role in lung inflammation. Keywords:: SA13353, transient receptor potential vanilloid 1, lung inflammation

The effect of (9,11), (11,12)-didedoxa-9α, 11α -dimethylmethano-11,12-methano-13,14-dihydro-13-aza-14-oxo-15-cyclo-pentyl-16,17,18,19,20- pentanor-15-epi-TxA2 (ONO-3708) on 9,11-methanoepoxy-prostaglandin H2 (U-46619)-induced contraction of airway smooth muscle in the guinea pigs and human in vitro and bronchoconstriction in guinea pigs in vivo was investigated. In in vitro experiments, ONO-3708 inhibited the U-46619-induced contraction of isolated guinea pig and human tracheal smooth muscle in a dose related fashion (guinea pig; pA2=7.78, human; pA2=7.43). The contractions of guinea pig tracheal muscle caused by histamine and leukotriene D4 (LTD4) were not inhibited by ONO-3708. In in vivo experiments, intravenous injection of ONO-3708 at doses between 1 and 20 mg/kg inhibited the U-46619-induced inreased of airway insufflation pressure as measured by Konzett-Rossler method. In addition, ONO-3708 inhibited the U-46619-induced increase in airway reactivity to acetylcholine. These data suggest that ONO-3708 has possible therapeutic utility for asthma in which TxA2 participates.

We evaluated the effect of capsaicin, one of the transient receptor potential vanilloid receptor 1 (TRPV1) agonists, on ischemic acute renal failure (ARF) in rats. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 minutes followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in vehicle-treated ARF rats markedly decreased at 24 hours after reperfusion. Treatment with capsaicin (3, 10, and 30 mg/kg, orally) 30 minutes before ischemia dose-dependently attenuated ischemia/reperfusion-induced renal dysfunction. In renal tissues exposed to ischemia/reperfusion, neutrophil infiltration, renal superoxide production, and renal tumor necrosis factor (TNF)-alpha mRNA expression were augmented, but these alterations were attenuated by the treatment with capsaicin. On the other hand, ischemia/reperfusion-enhanced renal interleukin (IL)-10 mRNA expression and plasma concentrations of IL-10 were augmented by treatment with capsaicin in ARF rats. In addition, resiniferatoxin (20 microg/kg, subcutaneous), a more selective and potent TRPV1 agonist, showed a renoprotective effect on ischemia/reperfusion-induced renal injury, in a qualitatively similar way to cases seen with capsaicin. These results demonstrate that TRPV1 agonists prevent ischemia/reperfusion-induced renal dysfunction. These renoprotective effects seem to be closely related to the inhibition of inflammatory response via TRPV1.

We studied the synthetic modification of structurally similar N-mercaptoacyl- l -proline and (4R)-N-mercaptoacylthiazolidine-4-carboxylic acid to obtain potent leukotriene A4 (LTA4) hydrolase inhibitors. An N-mercaptoacyl group, (2S)-3-mercapto-2-methylpropionyl group, was effective for both scaffolds. Additional introduction of a large substituent such as 4-isopropylbenzylthio (3f), 4-tert-butylbenzylthio (3l) or 4-cyclohexylbenzylthio group (3m) with (S)-configuration at the C4 position of proline yielded much more potent LTA4 hydrolase inhibitors (IC50; 52, 31, and 34 nM, respectively) than captopril (IC50; 630,000 nM).

Tumor necrosis factor-alpha (TNF-alpha) is known to play a crucial role in the pathogenesis of rheumatoid arthritis. In the present study, we demonstrate the effects of SA13353 (1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea), a novel orally active inhibitor of TNF-alpha production, in animal models, and its mechanism of action on TNF-alpha production. SA13353 significantly inhibited lipopolysaccharide (LPS)-induced TNF-alpha production in a dose-dependent manner in rats. Moreover, SA13353 exhibited a binding affinity for the rat vanilloid receptor and increased neuropeptide release from the rat dorsal root ganglion neurons. However, its effects were blocked by pretreatment with the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine. The ability of SA13353 and capsaicin to inhibit LPS-induced TNF-alpha production was eliminated by sensory denervation or capsazepine pretreatment in vivo. Although they inhibited LPS-induced TNF-alpha production in mice, these effects were not observed in TRPV1 knockout mice. SA13353 provoked the release of neuropeptides without nerve inactivation, even when chronically administered to rats. These results suggest that SA13353 inhibits TNF-alpha production through activation of capsaicin-sensitive afferent neurons mediated via TRPV1 in vivo. Post-onset treatment of SA13353 strongly reduced the hindpaw swelling and joint destruction associated with collagen-induced arthritis in rats. Thus, SA13353 is expected to be a novel anti-arthritic agent with a unique mechanism of action.

We present a case of acute respiratory distress syndrome (ARDS) caused by allergic reactions to shiniseihaito. An 84-year-old woman showed acute interstitial pneumonia followed by ARDS after taking shiniseihaito for the treatment of rhinitis. The ARDS were markedly improved with corticosteroid therapy. This case was diagnosed as being induced by shiniseihaito because it was compatible with 4 of 5 of Camus's criteria. The stimulation index of the drug lymphocyte stimulation test with shiniseihaito increased after corticosteroid therapy had been tapered and suggested that the mechanism of acute interstitial pneumonia in this case was allergic reaction induced by shiniseihaito. This is the seventh reported case of drug induced lung injury by shiniseihaito. We recommend careful observation when this medicine is prescribed.

IL-17-producing Th (Th17) comprise a distinct lineage of pro-inflammatory Th that are major contributors to autoimmune diseases. Treatment with IL-6 and transforming growth factor beta (TGFbeta) induces naive CD4+ T cells to generate Th17, which also requires expression of the IL-6/TGFbeta target RORgammat. We reported that IL-6 transduces two signaling pathways via tyrosine redidues of the signal transducer gp130: one depends on signal transducers and activators of transcription (STAT)-3 activation and the other on Src homology region 2 domain-containing phosphatase 2 (SHP2)/Grb2 associated binder (Gab)/mitogen-activated protein kinase (MAPK) activation. Here, we showed that CD4+ T cells carrying a mutant gp130 that transduces the SHP2/Gab/MAPK pathway but not the STAT3-mediated one failed to develop into Th17, while CD4+ T cells whose mutant gp130 transduces the STAT3 signal only generated Th17, indicating that IL-6 acts directly on T cells through the tyrosine residues of gp130 required for STAT3 activation to promote the development of Th17. Moreover, we found that gp130-STAT3 pathway is essential for Th17 development and for the expression of RORgammat by using T cells specifically lacking gp130 and STAT3. Noteworthy is that the regulatory T cell (Treg) percentages and numbers were comparable between all mutant mice we tested in vivo, although we showed that IL-6-gp130-STAT3 pathway suppressed Treg development in vitro. Thus, we conclude that IL-6 acts directly to promote the development of Th17 by activating the T cell gp130-STAT3 pathway but has a minimum effect on Treg development at least in the steady state in vivo. Therefore, blockade of IL-6-gp130-STAT3 pathway in CD4+ T cells could be a good target for controlling unwanted Th17-mediated immune responses including autoimmune diseases.

A 39-year-old woman, who had a history of recurrent oral and genital ulcerations and folliculitis and had had a low-grade fever since December 2003, consulted our hospital on February 5, 2004. Chest radiography and computed tomography (CT) showed multiple pulmonary abscess-like opacities. She was admitted to the Department of Respiratory Medicine and Allergology, Kinki University School of Medicine on February 19, 2004. A transbronchial lung biopsy showed nonspecific inflammation with lymphocytic infiltration. The patient was discharged after she showed improvement with antibiotic therapy. She was readmitted to our hospital on October 3, 2006, because of recurrence of pulmonary abscess-like opacities. Bronchoalveolar lavage showed lymphocytosis (53%) but yielded no significant bacteria on culture. Behçet's disease was diagnosed on the basis of the three major symptoms (recurrent oral and genital ulcerations and folliculitis). The frequent recurrence of pulmonary lesions was suspected to be due to immunological impairment associated with Behçet's disease, and the pulmonary lesions and inflammatory reaction tests showed improvement after colchicine was administered. The patient was discharged on October 28, 2006. To our knowledge this is the third reported case of frequently recurrent multiple pulmonary abscess-like opacities in Behçet's disease.

A 38-year-old man with atopic dermatitis presented with right chest pain and dyspnea. Previously, he had received 2mg of betamethasone daily, to prevent rejection of the right transplanted cornea, for 24 days. His body temperature was 37.4 degrees C, peripheral leucocyte count measured 12,000/mm3, and C-reactive protein was 6.3 mg/dl. A computed tomogram of the chest revealed infiltration in the right lower lung field, and he was then treated for pneumonia. The second day he fell down one flight of stairs due to a syncopal attack and received a head injury. At this point his vital blood pressure was 102/55 mmHg, heart rate was 130/min and SpO2 under breathing room air was 76%. These findings indicated possible acute pulmonary thromboembolism. Enhanced computed tomography revealed pulmonary arteries occluded by massive thrombosis and anomalous inferior vena cava with azygous continuation. To decrease the risk of further cerebral bleeding, anti-coagulation therapy was administered with only 24,000 IU/day of heparin. Following treatment, the patient completely recovered. We reported this rare case of acute pulmonary thromboembolism accompanied by anomalous inferior vena cava with azygous continuation.

Recently, efforts in comprehensive pulmonary rehabilitation for COPD have been made, including education, physical therapy, occupational therapy, nutrition, nursing, medication and counseling. Each patient focuses on a different element. Supplying adequate nutrition, among others, is essential for comprehensive pulmonary rehabilitation, as well as survival. In this study, the utility of efficient nutritional supplement therapy before and after pulmonary physical therapy was investigated by adding an amino acid drink with a high Fisher ratio to comprehensive pulmonary rehabilitation. The subjects were eight patients with COPD with obstructive ventilation disorder as severe as 31.5 +/- 6% of FEV 1.0%. Pulmonary physical therapy was performed for eight weeks in a group administered one bottle of dietary supplement with a high Fisher ratio abundant in branched chain amino acids once daily (200 kCal/ 200 mL, Fisher ratio 40), and in another group without administration. Before and after the physical therapy, six-minute waking examination, QOL assessment (using CRQ), serum protein and serum Fisher ratio were comparatively examined between the two groups. After the eight weeks of pulmonary physical therapy, serum Fisher ratios were evidently reduced and serum protein measurements were also decreased in the group without dietary supplement abundant in branched chain amino acids. Accordingly, more amino acid is needed due to enhanced consumption of muscular protein during pulmonary physical therapy, during which nutrient ingestion including a sufficient amount of branched amino acid is necessary. It is an important element in continuing comprehensive pulmonary rehabilitation for a longer period.

The treatment of bronchial asthma with QVAR (hydrofluoroalkane-134a BDP; 3M Pharmaceuticals, St. Paul, MN, USA) is usually conducted without an inhalation assistance device. However, Japanese patients who experience difficulty in coordinating activation with inspiration of inhaled steroid drugs are instructed on the use of such a device. We therefore examined the necessity of using an inhalation assistance device (INSPIR-EASE, IE) and its effect on quality of life (QOL) in the treatment of patients with bronchial asthma taking QVAR. Hence, lung function and QOL associated with taking QVAR plus IE or QVAR alone were examined by a cross-over method in 44 bronchial asthma patients (STEP 2 or 3) over 20 years of age. In all patients, lung function tests conducted 12 weeks after start of treatment indicated significant improvements of forced expiratory volume in 1 second (FEV1) with QVAR alone compared with QVAR plus IE (p < 0.05). In patients less than 70 years of age, significant improvements of forced vital capacity (FVC) and nitric oxide (NO) were also observed with QVAR alone compared with QVAR plus IE (p < 0.05). Examination of QOL the Living with Asthma Questionnaire indicated that medication usage was significantly improved with QVAR alone compared with QVAR plus IE. Significant improvement of FEV1 was observed with QVAR alone compared with QVAR plus IE, and additionally in patients less than 70 years of age improvement of FVC and NO was also marked. This study confirmed the usefulness of QVAR alone in patients with bronchial asthma.

Our medical institution does not have a bacterial culture facility, requiring outsourcing of bacterial culture tests. Due to the time elapsed from the time of specimen collection to culturing, the identification of causative bacteria in respiratory tract infections tends to be difficult. We therefore used transport medium for sputum bacteria examinations. Expectorated purulent or purulent-mucous sputum specimens were collected from 32 patients with lower respiratory tract infection. We divided each of the sputum specimens into the two treatment groups: transport medium (Seedswab gamma2) ndar and stad disinfection container. Paired samples prepared from each patient were sent out for bacterial culture together. The time elapsed from collection to delivery to the lab were as follows: day 0 (same day, n = 14 patients), day 1 (n = 15), day 2 (n = 2), and day 3 (n = 1). The identified causative bacteria were Streptococcus pneumoniae (n = 6 patients), Haemophilus influenzae (n =5), Pseudomonas aeruginosa (n = 4), Staphylococcus aureus (n = 2), Moraxella catarrhalis (n = 2), Klebsiella pneumoniae (n = 1), and Streptococcus agalactiae (n = 1). Samples prepared by each of the two methods gave similar results. The utility of transport medium for examination of general bacteria for lower airway infection from sputum samples was not demonstrated. The rate of detection of bacteria decreased, when the transport of samples was delayed. Therefore, we need to send the sputum specimens as quickly as possible.