RETRACTED: P444 Shared decision making for switching from oral mesalazine tablets to granules in low adherent inflammatory bowel disease patients.

BACKGROUND: Oral mesalazine effectively induces and maintains remission in inflammatory bowel diseases (IBD) patients. However, adherence to the drug regimen is low. Shared decision-making (SDM) is considered effective in promoting treatment adherence in IBD patients. We used SDM to switch non-adherent IBD patients from oral mesalazine tablets to granules and checked the new adherence rates. METHODS: The IRB of our hospital approved this observational study named 'Evaluation of improvement of adherence by changing oral mesalazine to Pentasa granule in low adherent inflammatory bowel disease patients, IMPACT-PG'. We used the Morisky Medication Adherence Scale (MMAS-8, where an MMAS-8 score of ≥6 indicates good adherence) to assess adherence to oral mesalazine. We met with low adherence patients and explained the benefits and characteristics of mesalazine granules and tablets; we then gave them a choice between continuing with the same pH-dependent mesalazine tablets (with a 20% weight/volume decrease) and switching to oral mesalazine granules (2 g in one stick, 2 g once or twice a day). Primary endpoint was adherence rate in IBD patients with granule or with tablet at 6 months, and secondary endpoint was adherence rate at 12 months. Contributing factors to good adherence to the oral regimen were also examined. The adherence rate was analysed using chi-square test, and contributing factors were determined by multivariate analysis using SPSS ver24. RESULTS: One hundred and eighty-three patients (126 UC and 57 Crohn's colitis patients) were enrolled and examined adherence by MMAS-8 score. Good adherence ratio was 42.6% (78 of 183). Both higher age and low frequency of medication were significantly more common in adherent patients than in non-adherent patients. Odds ratios of age and the frequency of daily medication were 1.057 (95% CI 1.029-1.086; p < 0.0001) and 0.407 (95% CI 0.218-0.759; p = 0.005), respectively. SDM was performed to the 105 low adherence patients. 67% of the low adherence patients (70 of 105) preferred mesalazine granules. Five patients were dropped out until 6 months, as well as 13 patients were dropped out until 12 months. Remission rates at 0, 6, and 24 months were not significantly different between granule and tablet groups. Adherence rates at 6 [67% (44/66) vs. 32% (11 of 34)] and at 12 [72% (43 of 60) vs. 44% (14 of 32)] months were significantly higher in the granule group than in the tablet group. CONCLUSIONS: SDM was effective for switching patients from a mesalazine tablet to a granule regimen, and adherence rates were improved in IBD patients.

Immunosuppressive effect of ER-38925, a retinoic acid receptor subtype α-selective agonist, in mouse models of human graft-vs-host disease.

Graft-vs-host disease (GVHD) is a devastating disorder that determines the prognosis of patients who receive a bone marrow transplant. GVHD is caused by donor cells responding to host disparate MHC alleles. In this report, we demonstrate that ER-38925, a newly discovered retinoid agonist with selectivity to retinoic acid receptor subtype α (RAR-α), is a potent immunosuppressive agent in mouse models of human GVHD. In a mouse model of lethal acute GVHD (aGVHD), ER-38925 prolonged the lifespan of the recipient mice in a dose-dependent manner. Its effect at 1 mg/kg was almost comparable to that of cyclosporin A at 30 mg/kg. ER-38925 profoundly prevented the development of antiallogeneic cytotoxic T lymphocyte (CTL) response in the mouse model of aGVHD at 0.1 and 0.3 mg/kg. It strongly inhibited in vitro proliferation of alloantigenstimulated donor T lymphocytes, and RAR-α seemed to play an exclusive role in this effect since inhibition by all-trans retinoic acid, which can activate all subtypes of RAR, was completely reversed by an RAR-α selective antagonist. Moreover, it significantly inhibited the elevation of serum IL-12 and IFN-γ and LPS-induced serum TNF-α elevation, all of which are known to be crucial disease-exacerbating factors in this model and human GVHD, in the mouse model of aGVHD. These results suggest that ER-38925 prevents the development of aGVHD through substantial inhibition of anti-allogeneic responses of donor T lymphocytes. In addition, in vivo administration of ER-38925 also blocked serum anti-DNA autoantibody production in a mouse model of human chronic GVHD. This is the first report to clearly show the remarkable immunosuppressive effects of an RAR-α selective agonist in mouse models of human GVHD. These findings may allow an RAR-αselective agonist like ER-38925 to serve as a novel therapy to prevent both acute and chronic types of human GVHD.

Age-related changes in the intramuscular distribution of melanocytes in the Silky fowl.

1. The characteristics of melanocyte distribution in skeletal muscles in the Silky fowl were investigated in association with growth. 2. Pectoralis (PT) and iliotibialis lateralis (ITL) muscles from 1-, 3-, 5-, 10-, 20- and 30-week-old Silky males were weighed and collagen type I was detected in frozen sections immunohistochemically. 3. Melanocytes were observed in the collagen type I-immunopositive endomysium and perimysium in both muscles. 4. Image analysis indicated that the total area occupied by melanocytes in histological sections sharply decreased from 0.61% to 0.16% in PT muscle and from 1.67% to 0.33% in ITL muscle at 1 to 3 weeks, and then gradually decreased. The melanocyte area was larger in ITL muscle than in PT muscle until 10 weeks of age. 5. We concluded that the proportion of intramuscular melanocytes in the Silky fowl differs between types of muscles in the early stages of development, and it decreases with growth.

Facial lichen striatus: successful treatment with tacrolimus ointment.

We report a 22-year-old Japanese woman with facial lichen striatus (LS). The distribution of the lesions corresponded to that of Blaschko's lines. Histology of the lesional skin showed an inflammatory cell infiltrate around hair follicles and eccrine glands. Treatment of the linear lesions with tacrolimus ointment once or twice daily resulted in a dramatical improvement in a short time. LS is a T-cell-mediated inflammatory disease and tacrolimus ointment may be an effective alternative treatment for this disease especially when the lesions are located on the face.

Coexistence of beta2 microglobulin and lambda light chain in amyloid fibrils of dialysis-unrelated plasma cell dyscrasia-associated systemic amyloidosis.

BACKGROUND: Systemic amyloidosis occurs as a result of amyloid deposition in various tissues. The amyloid fibrils in systemic amyloidosis have been reported to originate from immunoglobulin light chains. OBJECTIVE: We studied the composition of amyloid fibrils from two patients with plasma cell-associated systemic amyloidosis (PASA). METHODS: A double immunofluorescence study of the lesional skin of PASA was undertaken. Amyloid proteins were extracted with distilled water from one case of PASA. RESULTS: The double immunofluorescence study showed that anti-lambda light chain and anti-beta2 microglobulin antibodies mostly reacted with the same area of amyloid deposit. Amyloid deposits from two patients with PASA who had never undergone haemodialysis showed a positive reaction with the antibodies for beta2 microglobulin as well as immunoglobulin lambda light chain. By the use of immunoblot assay of amyloid fibril proteins, polypeptides immunoreactive with antigamma light chain antibody (29 kDa) and with anti-beta2 microglobulin antibody (12 kDa) were detected. CONCLUSIONS: These results indicate that beta2 microglobulin is a component of amyloid fibrils in PASA.

Expression of the 67-kDa elastin receptor in perforating skin disorders.

BACKGROUND: Perforating skin dermatoses include elastosis perforans serpiginosa (EPS), reactive perforating collagenosis, Kyrle's disease and perforating folliculitis. In addition to these four diseases, an acquired form of perforating dermatosis associated with diabetes mellitus and/or chronic renal failure has been reported for which the term acquired perforating dermatosis (APD) was proposed. The molecular mechanism of transepidermal elimination of dermal components in perforating skin dermatoses remains unclear. We recently demonstrated that the 67-kDa elastin receptor can be detected in the epidermis eliminating altered elastic fibres in EPS, suggesting that the elastin-keratinocyte interaction may play a role in transepidermal elimination in EPS. OBJECTIVES: To determine whether the 67-kDa elastin receptor is involved in other perforating diseases. METHODS: Paraffin-embedded skin specimens from new cases of EPS (n = 2), APD (n = 15) and perforating granuloma annulare (PGA; n = 2) were studied immunohistochemically using a specific antibody to the 67-kDa elastin receptor. In one case of EPS, two different sites from a single lesion, a central atrophic area and a peripheral keratotic area, were studied. RESULTS: Expression of the elastin receptor was detected in the epidermis surrounding the elastic materials in both cases of EPS. The elastin receptor was not detected in the central inactive area, whereas it was expressed strongly in the peripheral keratotic active area. The elastin receptor was also detected in three of 15 cases of APD in which a few elastic fibres were found in the eliminated dermal materials. In one case of APD, the elastin receptor was not detected in spite of the presence of a few elastic fibres in the eliminated materials. The elastin receptor was not detected in either case of PGA. CONCLUSIONS: Expression of the elastin receptor in EPS was seen in both cases studied and was dependent on the stage of the lesion. Expression of the elastin receptor in APD appeared to be related to the amount of elastic fibres in the eliminated materials. Thus, expression of the elastin receptor in perforating skin disorders may depend on the stage of the lesion and/or the content of elastic fibres in the dermal materials being eliminated.

Outcomes in patients with ischemic cerebrovascular disease.

An analysis was conducted to determine at discharge the outcomes associated with risk factors in 246 patients with ischemic cerebrovascular disease who were admitted within 48 hours after the onset of the disease. Statistical analysis in this study disclosed that atrial fibrillation was a significant risk factor contributing to the worse outcomes among the subtypes of the ischemic cerebrovascular disease.

Immunohistochemical detection of lipid peroxidation products, protein-bound acrolein and 4-hydroxynonenal protein adducts, in actinic elastosis of photodamaged skin.

Acrolein and 4-hydroxy-2-nonenal (HNE) are both byproducts of a lipid peroxidation reaction. Actinic elastosis in photodamaged skin of aged individuals is characterized by the accumulation of fragmented elastic fibers in the sun-exposed areas. To study whether a lipid peroxidation reaction is involved in the accumulation of altered elastic fibers in actinic elastosis, skin specimens obtained from sun-damaged areas were immunohistochemically examined using the antibodies against acrolein and HNE. Both antibodies were found to react with the accumulations of elastic material. Double immunofluorescence labeling demonstrated that acrolein/elastin and HNE/elastin were colocalized in the actinic elastosis. Western blot analysis showed that the polypeptide with a molecular weight of 62 kDa reacted with anti-acrolein, anti-HNE and anti-elastin antibodies. The results suggest that acrolein and HNE may be associated with actinic elastosis.

In vitro and in vivo expression of protoporphyrin IX induced by lipophilic 5-aminolevulinic acid derivatives.

We estimated the expression level of protoporphyrin IX (PpIX) induced by lipophilic 5-aminolevulinic acid (ALA) derivatives and observed its histological distribution by fluorescence microscopy. In vitro PpIX expression in Hepe2 cells was the highest when induced by ALA pentyl ester. This level was 2.8-fold higher than that induced by ALA after 4 h incubation and 2.5-fold higher than that after 24 h incubation. The differences between ALA pentyl ester and ALA were significant at both time points (P<0.01). In HeLa cells, ALA butyl ester showed the highest induction of PpIX, which was 2.6-fold higher than ALA after 4 h incubation and 3.5-fold higher after 24 h incubation. The differences were significant at both time points (P<0.01). In mice with squamous cell carcinoma, the in vivo expression of PpIX in the tumors was highest with ALA methyl ester, which was 1.3-fold higher than ALA. The difference was significant (P<0.01). The expression of PpIX by means of fluorescence microscopy was highest by ALA methyl ester. Under in vitro conditions, PpIX expression was efficiently induced by long chain ALA esters, while better in vivo PpIX induction was obtained with short chain ALA esters. In this study, ALA methyl ester was found to be the best among the ALA derivatives in inducing PpIX expression in vivo, and would be more effective in treatment of skin cancers than ALA.

Coordinate expression of membrane type-matrix metalloproteinases-2 and 3 (MT2-MMP and MT3-MMP) and matrix metalloproteinase-2 (MMP-2) in primary and metastatic melanoma cells.

Expression of MMP-2 in melanoma cells has been demonstrated to be involved in the degradation of extracellular matrix during melanoma growth and to correlate with later melanoma metastasis. MMP-2 is considered to be activated by membrane-associated matrix metalloproteinases (MT-MMPs). To know whether MT-MMPs are involved in the activation of MMP-2 in melanoma cells, immunohistochemical studies were performed in primary and metastatic melanoma by use of the antibodies for MT1-MMP, MT2-MMP and MT3-MMP. Expression of MT1-MMP, MT2-MMP, MT3-MMP and MMP-2 in nevocellular nevus (n = 5), dysplastic nevus (n = 2) and juvenile melanoma (n = 3) was undetectable or detected in only a few cells. Superficial spreading melanoma (SSM) (n = 3) and acral lentiginous melanoma (ALM) (n = 3) showed a moderate expression of MT1 approximately 3-MMP. In nodular melanoma (NM) (n = 2) and metastatic melanoma (n = 3), MT1 approximately 3-MMP was more intensely expressed. Double immunofluorescence demonstrated a consistent colocalization of MT2-MMP/MMP-2 and MT3-MMP/MMP-2 in the NM and metastatic melanoma cells. The colocalization of MT2,3-MMP and MMP-2 in nodular and metastatic melanoma cells suggests that MT-MMPs and MMP-2 co-operate in the invasive and metastatic process of melanoma cells.

Reticular erythematous mucinosis syndrome with an infiltration of factor XIIIa+ and hyaluronan synthase 2+ dermal dendrocytes.

We report a patient with reticular erythematous mucinosis (REM) syndrome. Content of hyaluronan in lesional skin was approximately 2.9-fold higher than in the patient's uninvolved skin, but its synthetic activity in fibroblasts explanted from lesional skin remained unchanged. Immunohistochemical study using antifactor XIIIa (anti-FXIIIa) antibody demonstrated that the number of FXIIIa+ cells in the lesional skin was significantly increased compared with those in the patient's uninvolved skin and in normal control skin samples (P < 0.01). As hyaluronan is considered to be synthesized by hyaluronan synthase (HAS), which is composed of three genetically distinct isoforms (HAS1, HAS2 and HAS3), the cells responsible for the accumulation of hyaluronan in lesional skin were immunohistochemically examined using antibodies for HAS1, HAS2 and HAS3. The specific antibody for HAS2 was found to react with some populations of FXIIIa+ cells in the involved skin, and the number of HAS2+ cells was significantly increased in the involved skin (P < 0.01). The results suggest that accumulation of hyaluronan in REM may be related to populations of FXIIIa+/HAS2+ dermal dendrocytes rather than to dermal fibroblasts.

Effects of suplatast tosilate on airway inflammation and airway hyperresponsiveness.

Suplatast tosilate (IPD) is a Th2 cytokine inhibitor that lowers the titer of the IgE antibody through specific inhibition of the production of IL (interleukin)-4 and IL-5 by T cells and inhibits tissue infiltration by eosinophils. In this clinical trial, suplatast tosilate (300 mg/day) was administered orally for 4 weeks to 25 patients (13 patients with atopic asthma, 12 patients with nonatopic asthma) whose bronchial asthma was staged in step 1 or step 2 according to the Guidelines for Prevention and Management of Bronchial Asthma, 1998. Before and after administration, the parameters of airway inflammation, that is, peripheral blood eosinophils count, serum level of eosinophil cationic protein (ECP), ECP level in induced sputum, airway hyperresponsiveness (Dmin), and morning peak expiratory flow (PEF), were measured. The peripheral blood eosinophil count, serum level of ECP, and ECP level in induced sputum decreased significantly. Of these parameters, the ECP level in induced sputum was the most sensitive. Furthermore, suplatast tosilate significantly inhibited Dmin. These results were especially significant in patients with atopic asthma. Suplatast tosilate was considered to have inhibited airway eosinophilic inflammation through decreases in peripheral blood eosinophils counts and in ECP levels in induced sputum, which resulted in inhibition of airway hyperresponsiveness.

Trp122 and Trp134 on the surface of the catalytic domain are essential for crystalline chitin hydrolysis by Bacillus circulans chitinase A1.

From the 3D-structural analysis of the catalytic domain of chitinase A1, two exposed tryptophan residues (W122 and W134) are proposed to play an important role in guiding a chitin chain into the catalytic cleft during the crystalline chitin hydrolysis. Mutation of either W122 or W134 to alanine significantly reduced the hydrolyzing activity against highly crystalline beta-chitin microfibrils. Double mutation almost completely abolished the hydrolyzing activity. On the other hand, the hydrolyzing activity against either soluble or amorphous substrate was not reduced. These mutations slightly impaired the binding activity of this enzyme. These results clearly demonstrated that the two exposed aromatic residues play a critical role in hydrolyzing the chitin chain in crystalline chitin.

Photodynamic therapy of acne vulgaris with topical delta-aminolaevulinic acid and incoherent light in Japanese patients.

BACKGROUND: Photodynamic therapy (PDT) is useful for treatment of epidermal neoplasia but may also have a role in the treatment of inflammatory dermatoses. OBJECTIVES: To study the effect of PDT in patients with acne. METHODS: Three men and 10 women who suffered from intractable acne vulgaris were treated using PDT with topical delta-aminolaevulinic acid (ALA) and polychromatic visible light. Twenty per cent ALA in an oil-in-water emulsion was applied to the lesions for 4 h with a light-shielding dressing. The lesions were then exposed to polychromatic visible light at 600-700 nm using a halogen light source of energy intensity 17 mW cm-2 and a total energy dose of 13 J cm-2. RESULTS: All patients had apparent improvement of facial appearance and reduction of new acne lesions at 1, 3 and 6 months following PDT treatment. The adverse effects were discomfort, burning and stinging during irradiation, oedematous erythema for 3 days after PDT, epidermal exfoliation from the fourth to the 10th day, irritation and hypersensitivity to physical stimulation for 10 days after PDT, and pigmentation or erythema after epidermal exfoliation; the treated lesions returned to normal skin conditions within 1 month. CONCLUSIONS: PDT was beneficial in the treatment of acne. As a photoactivating light source, polychromatic visible light was thought to be better for use with acne patients than laser light because of its cost-effectiveness, uniform illumination and time-efficiency in treating large areas.

Existence of retinoic acid-receptor-independent retinoid X-receptor-dependent pathway in myeloid cell function.

We previously reported that ER-27191 (4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)anthra[1,2-b]pyrrol-3-yl]benzoic acid) is a potent antagonist of retinoic acid receptor (RAR), and ER-35795 ((2E,4E,6E)-7-[1-(1-methylethyl)-8-chloro-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-2,4,6-nonatrienoic acid) is a novel retinoid X receptor (RXR)-specific agonist. By using these compounds, we investigated whether distinct RAR-dependent and RXR-dependent pathways operate to mediate the diverse activities of retinoids, particularly, the effects of the RXR pathway on cellular function. ER-27191 completely antagonized HL60 cell differentiation induced by all-trans-retinoic acid (atRA). However, the differentiation induced by the ER-35795 was not antagonized at all by the RAR antagonist, but was inhibited by an RXR homodimer antagonist (LGD100754, (2E,4E,6Z)-7-(3-n-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-3-methylocta-2,4,6-trienoic acid). Its agonistic action on RXR/RAR heterodimer, on the other hand, was neutralized by the RAR antagonist. During HL60 cell differentiation, atRA induced RARbeta mRNA, while the RXR had no effect. Interestingly, a functional RXR-pathway was also seen in lipopolysaccharide-induced inhibition of mouse splenocyte proliferation. These results strongly suggest the existence of a pharmacological RXR-dependent pathway that is activated by a ligand that can bind to RXR.

The needs of children and adolescents with cancer for information and social support.

Research has indicated that information and social support may have helped children and adolescents with cancer to cope with their illness and lead normal lives. However, recent researchers have reported that youths with cancer express a clear interest in receiving more information and social support. This study reviewed research on information and social support for children and adolescents with cancer to understand their needs. Young patients with cancer showed high uncertainty about cancer. Besides, adolescents with cancer were more in conflict with their parents than healthy youths. Discussions on future plans or death are difficult for young people with cancer. They also are frequently absent from school over time. Moreover, they want to make healthy friends. To fulfill the needs of these youths, nurses should be aware not only of individualized information and social support, but also of these factors from an ecologic perspective. Further qualitative research is required to identify the needs of youths with cancer and resolve these issues.

[Clinical utility and safety of diagnostic thoracoscopy].

The increasing use of thoracoscopy performed under local anesthesia has made contributions to the diagnosis of pleural disease with effusion. During the past 7 years, we have performed 100 such thoracoscopy procedures using a flexible fiberoptic bronchoscope. On the basis of our clinical findings, we are able to discuss the utility and safety of this procedure. The causes of pleural effusion were carcinomatous pleurisy in 72 cases, tuberculosis pleurisy in 15 cases, infection without tuberculosis in 4 cases, malignant pleural mesothelioma in 8 cases and one case of asbestosis. The success rate of thoracoscopic pleural biopsies were 97% for carcinomatous pleurisy, 100% for malignant pleural mesothelioma and 86% for tuberculosis pleurisy. This procedure was performed with no serious effect on blood pressure, oxygen saturation, monitored ECG or BGA data, and with no serious complications. Therefore, we concluded that this method is very useful for the diagnosis of pleural effusions and has few complications.

[Clinical significance of serum KL-6 in pulmonary sarcoidosis].

We investigated whether the level of serum KL-6 could be an activity marker for pulmonary sarcoidosis. In 33 patients with pulmonary sarcoidosis, the relationships between serum KL-6 levels and diagnostic imaging, serum angiotensin-converting enzyme (ACE) levels, serum lysozyme levels, steroid therapy, and prognosis were evaluated. There were no significant differences in the level of serum KL-6 when the patients were divided on the basis of radiographic findings, but the level of serum KL-6 was markedly elevated in some patients with stage-II pulmonary sarcoidosis. There was a significant correlation between serum KL-6 levels and the following two parameters: serum ACE and lysozyme levels. Among patients with a high initial level of serum KL-6, pulmonary sarcoidosis tended to become exacerbated within one year. Steroid therapy significantly decreased the level of serum KL-6, suggesting that the level of serum KL-6 could be an activity indicator for pulmonary sarcoidosis. Immunohistochemical staining by anti-KL-6 antibody revealed that KL-6 was localized in proliferating type-II alveolar epithelial cells.

Elafin is induced in epidermis in skin disorders with dermal neutrophilic infiltration: interleukin-1 beta and tumour necrosis factor-alpha stimulate its secretion in vitro.

BACKGROUND: Elafin, an elastase inhibitor produced by keratinocytes, is overexpressed in the subcorneal region of skin affected by psoriasis, a major feature of which is epidermal infiltration by neutrophil leucocytes. OBJECTIVES: We studied the expression of elafin in the epidermis in other skin disorders characterized by dermal neutrophil infiltration and in skin disorders with dermal lymphocyte infiltration. PATIENTS/METHODS: We examined biopsies from the lesional skin of patients with Behçet's syndrome, Sweet's syndrome, pyoderma gangrenosum, cutaneous allergic vasculitis and acute bacterial infection (cellulitis), and from the skin of patients with chronic prurigo, discoid lupus erythematosus and psoriasis. We performed in vitro experiments using cultured keratinocytes treated with mediators such as interleukin (IL)-1 beta, tumour necrosis factor (TNF)-alpha, IL-6, neutrophil elastase and interferon (IFN)-gamma. RESULTS: Anti-elafin antibody showed a strong reaction with the subcorneal region of the epidermis in patients with Behçet's syndrome, Sweet's syndrome, pyoderma gangrenosum, cutaneous allergic vasculitis and acute bacterial infection (cellulitis), but showed no reaction in skin from patients with dermal lymphocyte infiltration such as is seen in chronic prurigo and discoid lupus erythematosus. The in vitro experiments demonstrated that treatment with IL-1 beta and TNF-alpha resulted in 2.6-fold and 4-fold stimulation of elafin secretion, respectively, whereas IL-6, neutrophil elastase and IFN-gamma caused no significant changes in elafin release. CONCLUSIONS: These results suggest that inflammatory mediators such as IL-1 beta or TNF-alpha secreted by dermal neutrophils may be involved in overexpression of elafin in keratinocytes; this could protect the epidermis from degradation by dermal neutrophil infiltration.