Effects of once-monthly minodronate versus risedronate in osteoporosis patients with rheumatoid arthritis: a 12-month randomized head-to-head comparison.

A head-to-head comparison of once-monthly oral bisphosphonates minodronate (MIN) and risedronate (RIS) in patients with rheumatoid arthritis (RA) demonstrated that MIN has the same effect as RIS on increase in bone mineral density (BMD) and a stronger effect on inhibition of bone resorption than RIS, suggesting that MIN is a promising treatment option for osteoporosis patients with RA. INTRODUCTION: To evaluate the effect of once-monthly oral MIN in patients with RA, a prospective, randomized, open-label, head-to-head comparison with once-monthly oral RIS was conducted. METHODS: A total of 83 patients with RA were randomly assigned to either once-monthly oral MIN 50 mg (n = 42) or once-monthly oral RIS 75 mg (n = 41). Serial BMD and bone turnover markers were measured and compared between the treatment groups. RESULTS: BMD (lumbar spine, total hip, femoral neck) increased significantly after 12 months of treatment with MIN (3.8, 2.0, and 2.2%, respectively, P < 0.05) and RIS (3.6, 1.9, and 1.9%, respectively, P < 0.05). There were no significant differences between the treatment groups. Percent changes of bone turnover markers from baseline to 12 months in the MIN group were significantly greater than those in the RIS group (TRACP-5b: - 36.3 vs - 19.3%, P < 0.05; NTX: - 27.1 vs - 17.3%, P < 0.05; BAP: -30.2 vs -19.4%, P < 0.05). CONCLUSIONS: The present study of RA patients demonstrated that MIN has the same effect as RIS on increase in BMD and a stronger effect on inhibition of bone resorption than RIS. The results suggest that MIN is a promising treatment option for osteoporosis patients with RA.

Effect of femoral canal shape on mechanical stress distribution and adaptive bone remodelling around a cementless tapered-wedge stem.

OBJECTIVES: In total hip arthroplasty (THA), the cementless, tapered-wedge stem design contributes to achieving initial stability and providing optimal load transfer in the proximal femur. However, loading conditions on the femur following THA are also influenced by femoral structure. Therefore, we determined the effects of tapered-wedge stems on the load distribution of the femur using subject-specific finite element models of femurs with various canal shapes. PATIENTS AND METHODS: We studied 20 femurs, including seven champagne flute-type femurs, five stovepipe-type femurs, and eight intermediate-type femurs, in patients who had undergone cementless THA using the Accolade TMZF stem at our institution. Subject-specific finite element (FE) models of pre- and post-operative femurs with stems were constructed and used to perform FE analyses (FEAs) to simulate single-leg stance. FEA predictions were compared with changes in bone mineral density (BMD) measured for each patient during the first post-operative year. RESULTS: Stovepipe models implanted with large-size stems had significantly lower equivalent stress on the proximal-medial area of the femur compared with champagne-flute and intermediate models, with a significant loss of BMD in the corresponding area at one year post-operatively. CONCLUSIONS: The stovepipe femurs required a large-size stem to obtain an optimal fit of the stem. The FEA result and post-operative BMD change of the femur suggest that the combination of a large-size Accolade TMZF stem and stovepipe femur may be associated with proximal stress shielding.Cite this article: M. Oba, Y. Inaba, N. Kobayashi, H. Ike, T. Tezuka, T. Saito. Effect of femoral canal shape on mechanical stress distribution and adaptive bone remodelling around a cementless tapered-wedge stem. Bone Joint Res 2016;5:362-369. DOI: 10.1302/2046-3758.59.2000525.

IκB kinase ß inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma.

BACKGROUND: Nuclear factor (NF)-κB is a transcription factor that regulates cytokine and chemokine production in various inflammatory diseases, including bronchial asthma. IκB kinase (IKK) ß is important for NF-κB activation in inflammatory conditions, and is possibly related to airway remodelling. Thus, inhibition of the IKKß-NF-κB pathway may be an ideal strategy for the management of airway remodelling. OBJECTIVE: We examined the effects of a newly synthesized IKKß inhibitor, IMD-0354, in a chronic allergen exposure model of bronchial asthma in mice. METHODS: A chronic mouse model was generated by challenge with house dust mite antigen (Dermatophagoides pteronyssinus). IMD-0354 was administrated intraperitoneally in therapeutic groups. Lung histopathology, hyperresponsiveness and the concentrations of mediators and molecules in supernatants of lung homogenates were determined. RESULTS: NF-κB activation was inhibited by prolonged periods of IMD-0354 administration. IMD-0354 reduced the numbers of bronchial eosinophils. IMD-0354 also inhibited the pathological features of airway remodelling, including goblet cell hyperplasia, subepithelial fibrosis, collagen deposition and smooth muscle hypertrophy. Inhibition of these structural changes by IMD-0354 was the result of the suppressing the production and activation of remodelling-related mediators, such as TGF-ß, via inhibition of IKKß. IMD-0354 inhibited IL-13 and IL-1ß production, and it restored the production of IFN-γ. It also ameliorated airway hyperresponsiveness. CONCLUSION: IKKß plays crucial roles in airway inflammation and remodelling in a chronic mouse model of asthma. A specific IKKß inhibitor, IMD-0354, may be therapeutically beneficial for treating airway inflammation and remodelling in chronic asthma.

Effect of immunoglobulin G (IgG) interchain disulfide bond cleavage on efficacy of intravenous immunoglobulin for immune thrombocytopenic purpura (ITP).

Intravenous immunoglobulin (IVIG) has been used widely to treat immune thrombocytopenic purpura (ITP), but the mechanisms of its action remain unclear. We investigated the affinity for Fcγ receptors (FcγRs) and the thrombocytopenia-ameliorating effect of S-sulfonated gammaglobulin (SGG) and S-alkylated gammaglobulin (AGG), in comparison with unmodified gammaglobulin (GG), in a mouse ITP model. Cleavage of immunoglobulin (Ig)G interchain disulfide bonds by either S-sulfonation or S-alkylation did not decrease the affinity for FcγRIIA (CD32A) and FcγRIIB (CD32B), but did decrease the affinity for FcγRIA (CD64A) and FcγRIIIA (CD16A), presumably because of changes in H-chain configuration. The interchain disulfide bond cleavage decreased the affinity much more for mouse FcγRIV than for mouse FcγRIIB. The ability of AGG to ameliorate ITP was greatly diminished, while SGG, whose disulfide bonds are reconstituted in vivo, was as effective as GG. These results suggest that the interchain disulfide bonds are important for therapeutic effect. It is also suggested that the interaction of IVIG with the inhibitory receptor FcγRIIB is insufficient for effective amelioration of ITP and that, at least in this model, direct binding of IVIG to FcγRIIIA is also required.

Little impact of donor/recipient major mismatch for neutrophil-specific antigen NA2 on neutrophil recovery after allogeneic SCT.

The Fcgamma receptor IIIb (FcgammaRIIIb), a receptor for the Fcgamma region of IgG, is specifically expressed on neutrophils. It has two allelic polymorphisms, NA1 and NA2, which are highly immunogenic and act as targets in alloimmune or autoimmune neutropenia. Thus, neutrophil antigens (NA) compatibility of donor/recipient pairs might be expected to affect the engraftment of neutrophils after allogeneic SCT (allo-SCT). Here, the impact of NA compatibility of 17 patients and their donors undergoing allo-SCT with a myeloablative regimen was determined. Leukocyte depletion filters were used for all transfusions before and post-SCT; most patients received G-CSF after transplant. Major mismatches for NA1 and NA2 were present in 1 and 7 patient/donor pairs, respectively. These eight patients receiving NA major-mismatched allo-SCT were compared with nine patients who received NA compatible allo-SCT. Engraftment of neutrophils and the incidence of post-engraftment neutropenia were found to be identical in the two groups. Despite the limitations in statistical power because of the small number of patients analyzed, these observations suggest that the major mismatching for NA2 antigen has little impact on the engraftment of neutrophils after myeloablative allo-SCT, at least in patients transfused using leukocyte depletion filters and receiving G-CSF after transplantation.

Hybrid lethality in interspecific hybrids between Nicotiana tabacum and N. suaveolens: evidence that the Q chromosome causes hybrid lethality based on Q-chromosome-specific DNA markers.

Hybrid seedlings from the cross Nicotiana tabacum x N. suaveolens express lethality at 28 degrees C. We carried out a cross between monosomic lines of N. tabacum lacking the Q chromosome and N. suaveolens by test-tube pollination and ovule culture at 28 degrees C. To suppress hybrid lethality, hybrid seedlings obtained were transferred to 36 degrees C immediately after germination and cultured. We determined whether Q-chromosome-specific DNA markers were detected among hybrid seedlings. When hybrid seedlings cultured at 36 degrees C were transferred to 28 degrees C, hybrid seedlings in which Q-chromosome-specific DNA markers were detected expressed hybrid lethality, while hybrid seedlings in which Q-chromosome-specific DNA markers were not detected did not express hybrid lethality. From these results, we concluded that the presence of the Q chromosome of N. tabacum is related to hybrid lethality observed in crosses between N. tabacum and N. suaveolens. This is the first report that clearly demonstrates the relationship between a certain chromosome and hybrid lethality in the genus Nicotiana using chromosome-specific DNA markers. Additionally, we confirmed that the Q chromosome belongs to the S subgenome because Q-chromosome-specific DNA markers were detected only in N. sylvestris.

Molecular cloning and gene expression of endoplasmic reticulum stress proteins in Japanese monkey, Macaca fuscata.

BACKGROUND: Immunoglobulin heavy-chain binding protein (BiP), calreticulin (Crt), and protein disulfide isomerase (PDI), are major resident endoplasmic reticulum (ER) stress proteins which are involved in diverse roles relating to successful folding, assembly, intracellular localization, and degradation of other proteins. METHODS: In this study, we molecular cloned cDNAs for BiP, Crt, and PDI from Japanese monkey (Macaca fuscata), and analyzed tissue-specific expression of respective genes. RESULTS AND CONCLUSIONS: The lengths of protein-coding regions of these cDNAs for BiP, Crt and PDI are 1965, 1254, and 1533 bp, respectively. Each protein has a signal peptide and a KDEL motif in N- and C-terminal parts respectively, showing its intracellular localization to be the lumen of the ER. These stress proteins are highly conserved, showing that their similarities among mammals are more than 90% in the level of amino acid. The expression of the genes for stress proteins differed among the monkey tissues examined. BiP and PDI gene expression was predominant in secretory tissues such as liver and kidney, and brain tissues. But Crt gene expressed rather ubiquitously in a variety of tissues.

Large haematoxylin-stainable keratohyaline granules in solar keratoses: immunohistochemical comparison using anti-Ted-H-1 antibody and antiloricrin antibody.

BACKGROUND: Our previous study showed that large keratohyaline granules (KHG) in molluscum contagiosum that stained with haematoxylin also reacted with anti-Ted-H-1 monoclonal antibody (mAb), but not with antifilaggrin mAb or antiloricrin polyclonal antibody (pAb). This finding indicated that the Ted-H-1 antigenic protein is a haematoxylin-stainable protein in KHG. OBJECTIVES: To clarify the identity of the major component protein of the large KHG in solar keratosis, another disorder in which large KHG are observed. METHODS: An enzyme immunohistochemical study was performed using antifilaggrin mAb, anti-Ted-H-1 mAb and antiloricrin pAb. Immunofluorescent double staining and immunoelectron microscopic analyses were performed using anti-Ted-H-1 mAb and antiloricrin pAb. RESULTS: Antifilaggrin mAb, anti-Ted-H-1 mAb and antiloricrin pAb reacted with normal KHG in nonlesional skin of solar keratosis, while only anti-Ted-H-1 mAb reacted with the large KHG in the lesions of solar keratosis. Antifilaggrin mAb did not react with large KHG. Antiloricrin pAb reacted with the cell membrane of the stratum granulosum, but not with large KHG. CONCLUSIONS: These findings suggest that the haematoxylin-stainable protein in the large KHG would be a Ted-H-1 antigen protein which was neither filaggrin nor loricrin.

Prevalence of atopic dermatitis in Japanese elementary schoolchildren.

BACKGROUND: Although there have been several reports on the prevalence of atopic dermatitis (AD) in Japanese schoolchildren based on questionnaires, there has been no nation-wide study of the frequency of this condition diagnosed by dermatologists in regular health check-ups of schoolchildren. OBJECTIVES: The objective of this work was to evaluate precisely the prevalence of AD in elementary schoolchildren in Japan based on regular health check-ups by dermatologists. METHODS: In 2001/2, elementary schoolchildren: first graders (age 6-7 years) and sixth graders (age 11-12 years) were examined by dermatologists in eight prefectures of Japan (Hokkaido, Iwate, Tokyo, Gifu, Osaka, Hiroshima, Kochi and Fukuoka). In each prefecture, public elementary schools were randomly selected from urban and rural districts. We planned to examine about 700 schoolchildren in each of urban first, urban sixth, rural first and rural sixth grades from the eight areas, a total of 22 400 children (700 x 4 x 8). AD was diagnosed by the dermatologists based on the Japanese Dermatological Association criteria for the disease. RESULTS: The point prevalence of AD was 11.2% overall (2664 of 23 719) ranging from 7.4% (Iwate) to 15.0% (Fukuoka) in the eight areas. Seventy-four per cent, 24%, 1.6% and 0.3% of those afflicted were in the mild, moderate, severe and very severe groups, respectively. Overall, the prevalence of first graders was slightly higher than that of sixth graders (11.8% vs. 10.5%, P < 0.01). There was no apparent difference in prevalence between urban and rural districts, or between boys and girls. CONCLUSIONS: The prevalence of AD in Japanese elementary schoolchildren was about 10%, three-quarters of those being mildly affected. This is the first nation-wide study made of Japanese elementary schoolchildren examined by dermatologists to evaluate the frequency of AD.

Comparison of post-translational modifications of alpha A-crystallin from normal and hereditary cataract rats.

In order to investigate the relationship between lens opacities and the various modifications of lens proteins, we analyzed and compared the properties of lens proteins of 85-day old normal Wistar rats and the hereditary cataract model, ICR/f rats. The present study identified many differences between normal and mutant lens proteins. In the ICR/f mutant rats, the relative amounts of gamma-crystallin decreased and high molecular weight (HMW) protein increased. Racemization and isomerization of Asp-151 of alpha A-crystallin was observed in the mutant ICR/f rats, and Met-1 of alpha A-crystallin was oxidized to methionine sulfoxide. These modifications were not found in the age-matched normal rats. These tendencies are consistent with aged and cataractous human lenses.

Epinastine inhibits eosinophil chemotaxis and adhesion molecules in atopic dermatitis.

PURPOSE: To investigate the effects of epinastine on eosinophil chemotaxis and changes in eosinophil adhesion molecules induced by epinastine and three other antiallergic agents, using eosinophils of atopic dermatitis (AD) patients. RESULTS: Epinastine reduced eosinophil chemotaxis toward eotaxin when the eosinophils had been prestimulated with interleukin (IL)-5, but given alone it did not alter eosinophil chemotaxis toward IL-5. CD11b expression was inhibited when peripheral blood was prestimulated with IL-5, but eosinophil adhesion molecule expression was not altered. CONCLUSIONS: Epinastine suppresses allergic inflammation not only through its strong antihistamine and antimediator effects, but also by inhibiting eosinophilic chemotaxis and the expression of adhesion molecules involved in chemotaxis, especially CD11b.

Therapeutic guidelines for the treatment of generalized pustular psoriasis (GPP) based on a proposed classification of disease severity.

Generalized pustular psoriasis (GPP) is a rare but notoriously recalcitrant cutaneous diseases. Therefore, there have been few reports of more than ten patients with GPP who were treated at the same institution. The severity of this disease and its response to each therapeutic modality vary among patients. In some GPP is life-threatening, but in others it may show a benign, chronic course for a long period of time. Before starting treatment, a knowledge of the therapeutic efficacy and side effects of each drug used in the treatment of GPP is necessary. In our multicenter study, we compared the effectiveness of and adverse reactions to several systemically administered drugs. Following the development of a unique classification of the disease severity based on scoring the clinical symptoms and the laboratory findings, we propose here therapeutic guidelines for the treatment of GPP.

A variable number of tandem repeats in the serotonin transporter gene does not affect the antidepressant response to fluvoxamine.

A variable number of tandem repeats (VNTR) in the second intron of the serotonin transporter gene (STin2) has been studied in association with the susceptibility to affective disorders. Recently, it was reported that selective serotonin reuptake inhibitors were more effective in patients with major depressive disorder having the homozygous allele pair (12-copy/12-copy) of VNTR in the STin2 than in ones having other allele combinations. As the study had methodological problems, further studies are needed to confirm the above finding. Therefore, the authors investigated whether the allelic variation of VNTR in the STin2 was associated with the antidepressant response to fluvoxamine in 66 patients with major depressive disorder. Fluvoxamine was prescribed up to 200 mg/day in the dosing protocol for 6 weeks. The present study showed no significant association between the polymorphism of VNTR in the STin2 and the treatment response to fluvoxamine.

Relationship between the self-incompatibility and cAMP level in Lilium longiflorum.

The elongation of pollen tubes in Lilium longiflorum cv. Hinomoto after self-incompatible pollination stopped halfway, but that after cross-compatible pollination (cross with cv. Georgia) did not. The elongation of pollen tubes after self-pollination was enhanced by exogenous cAMP and by pertussis toxin or cholera toxin, which activates adenylate cyclase. The level of endogenous cAMP in pistils after self-pollination was approximately one half of that after cross-pollination. Furthermore, the activity of adenylate cyclase in pistils after self-pollination was also approximately one half of that after cross-pollination. By contrast, cAMP phosphodiesterase in pistils after self-pollination was approximately 2 times as high as that after cross-pollination. A possible correlation between self-incompatibility and the low level of endogenous cAMP in lily pistils is discussed on the basis of these results.

Immunohistochemical detection for nuclear beta-catenin in sporadic basal cell carcinoma.

BACKGROUND: Despite the increasing incidence of basal cell carcinoma (BCC), its pathogenesis has remained largely unknown. Recently, it was reported that genes involved in tissue morphogenesis, such as sonic hedgehog or patched, were found to be mutated in BCC, suggesting the involvement of those molecules in the pathogenesis of this tumour. Furthermore, there is evidence that the Wnt-mediated signalling pathway may be one of the downstream targets of sonic hedgehog-mediated signalling, which has led us to focus on molecular events on the Wnt pathway in BCC. Among the signal transducers involved in the Wnt pathway, it is clear that beta-catenin plays a pivotal role in the promotion of morphogenesis and cell growth. In respect to this, it has been reported that, in particular circumstances, as in colorectal cancers, beta-catenin migrates to the nuclei, where it exerts an ability to activate the transcription of various genes. OBJECTIVES: To investigate the cellular distribution of beta-catenin in skin tumours, in particular, in BCC. METHODS: Twenty skin biopsy specimens derived from BCC, 10 from inflammatory skin diseases and five from squamous cell carcinomas were immunostained with an antibody directed against beta-catenin. RESULTS: Fourteen of the 20 BCC samples tested showed nuclear localization of beta-catenin, while none of the other samples gave rise to positive nuclear staining. CONCLUSIONS: Nuclear localization of beta-catenin is a characteristic feature of BCC; this suggests its tumorigenic role in this tumour. This gives us a further insight into the molecular pathogenesis of BCC.