GLCCI1 variant accelerates pulmonary function decline in patients with asthma receiving inhaled corticosteroids.

BACKGROUND: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation. METHODS: In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined. RESULTS: Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/µl) in the high serum periostin group. CONCLUSIONS: A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.

Impact of being overweight on outcomes of hematopoietic SCT: a meta-analysis.

The impact of being overweight on outcome after hematopoietic SCT (HSCT) is controversial. We performed meta-analyses to evaluate the impact of being overweight on acute graft-versus-host disease (aGVHD) risk and survival. Original data were obtained from MEDLINE, and studies that evaluated being overweight before transplantation in recipients as a risk factor for aGVHD or a prognostic factor for overall survival (OS) were extracted. Study-specific relative risks on the log scale comparing overweight with non-overweight patients were used to obtain a pooled RR with 95% confidence interval (CI). We identified 8 studies of aGVHD and 21 of OS. In allogeneic HSCT, the meta-analysis determined statistically significant associations of overweight recipients with aGVHD risk and OS. Meta-analysis of the 8 studies of aGVHD indicated that the RR for overweight to non-overweight patients was 1.186 (95% CI: 1.072-1.312). Regarding OS, meta-analysis of 11 allogeneic HSCT studies indicated that the RR for overweight to non-overweight patients was 1.163 (1.009-1.340). Our results indicate that being overweight before transplantation in recipients is associated with a high aGVHD rate and worse survival after allogeneic HSCT. Potential heterogeneity especially in adult/pediatric patients limits the interpretability of our finding. Further, well-designed large cohort studies are warranted.

Smoking attenuates the age-related decrease in IgE levels and maintains eosinophilic inflammation.

BACKGROUND: Epidemiological studies have shown that smoking increases the propensity for atopy and asthma. However, the effects of smoking on atopy and eosinophilic inflammation in asthmatics, including the elderly, remain unknown. OBJECTIVE: To determine the effects of smoking on serum immunoglobulin E (IgE) levels and eosinophilic inflammation in asthmatics of all ages. METHODS: The associations of serum IgE levels, blood eosinophil counts and fractional exhaled nitric oxide (FeNO) levels with smoking and age in steroid-naive asthmatics were cross-sectionally assessed (n = 307). Levels of sputum eosinophil and thymic stromal lymphopoietin (TSLP) that promotes Th2 inflammation were also analysed. Current smokers were excluded when analysing contributing factors of FeNO. RESULTS: Levels of serum IgE, blood eosinophil and FeNO decreased with increasing age in never-smokers, whereas decrease in serum IgE levels with increasing age was not observed in current smokers. In addition, current smoking was associated with higher blood eosinophil counts. In atopic asthmatics, age-related declines in serum IgE levels were less steep in ex-smokers than in never-smokers, and atopic ex-smokers with asthma showed higher blood eosinophil counts and higher FeNO irrespective of age. Lastly, sputum TSLP levels were associated with sputum eosinophil proportions and pack-years. Current and ex-smokers had higher TSLP levels than never-smokers. CONCLUSIONS AND CLINICAL RELEVANCE: In steroid-naive asthmatics, smoking may attenuate the age-related decrease in IgE levels and maintain eosinophilic inflammation, in which TSLP may be involved.

Reduced pH and chloride levels in exhaled breath condensate of patients with chronic cough.

BACKGROUND: Increased hydrogen and reduced chloride ionic environments of the airways are conducive to the stimulation of cough. However, the constituents of the local milieu of the airways of patients with chronic cough are unknown. METHODS: The pH and chloride levels in exhaled breath condensate and capsaicin cough threshold (C5) were measured in 50 patients with chronic cough and in 16 healthy controls. pH and chloride measurements were repeated after capsaicin challenge in those with cough. The cause of cough was asthma (n = 13), postnasal drip/rhinitis (n = 7), gastro-oesophageal reflux (n = 5), bronchiectasis (n = 5), but remained unidentified in 20. RESULTS: Compared with controls, patients with chronic cough had lower pH (mean 7.9 v 8.3, 95% CI of difference -0.5 to -0.2, p<0.0001), chloride levels (median 4 v 6 mmol/l, 95% CI -3.1 to -0.2, p = 0.007), and C5 (median 3.9 v 125 micro M, 95% CI -270.0 to -17.6, p = 0.002). The pH levels were different in the six subgroups including controls, and were reduced in all diagnostic subgroups of patients with cough compared with controls but did not differ between them. Chloride levels were significantly different in the six subgroups but were lower than controls in only the gastro-oesophageal reflux subgroup. There was a weak but significant correlation between chloride levels and C5 when all participants were analysed together, but not between pH and C5 or chloride levels. pH and chloride levels did not change after capsaicin challenge. CONCLUSIONS: The epithelial lining fluid of patients with chronic cough has a reduced pH and reduced chloride levels which could contribute to the enhanced cough reflex.

An immunoglobulin agent (IVIG) inhibits NF-kappaB activation in cultured endothelial cells of coronary arteries in vitro.

OBJECTIVE: Kawasaki disease (KD) is an acute febrile vasculitis of unknown etiology that may lead to cardiovascular disorders. High-dose intravenous immunoglobulin (IVIG) therapy is well established as a standard therapy for KD. Tumor necrosis factor-alpha (TNF-alpha) is responsible for the pathogenesis of acute KD. We examined whether or not IVIG inhibits TNF-alpha-induced activation of transcription factor NF-kappaB, a factor that is essential for the expression of proinflammatory cytokines, in human coronary artery endothelial cells (CAEC). METHODS: The inhibitory effect of IVIG on NF-kappaB activation induced by TNF-alpha was evaluated by Western blot analysis and ELISA. Moreover, the inhibitory effects of IVIG on IkappaBalpha degradation, interleukin-6 (IL-6) production, and E-selectin expression induced by TNF-alpha were evaluated by Western blot analysis, ELISA, and flow cytometry, respectively. RESULTS: Western blot analysis and ELISA demonstrated that IVIG inhibits NF-kappaB activation induced by TNF-alpha in CAEC. Moreover, IVIG inhibited IkappaBalpha degradation, IL-6 production, and E-selectin expression induced by TNF-alpha in CAEC. CONCLUSION: The data suggest that IVIG inhibits NF-kappaB activation induced by TNF-alpha in CAEC, thereby possibly modulating IL-6 production and E-selectin expression.

Maxillary sinus floor augmentation in rabbits: a comparative histologic-histomorphometric study between rhBMP-2 and autogenous bone.

The present study was designed to compare recombinant human bone morphogenetic protein-2 (rhBMP-2) impregnated on an absorbable collagen sponge (ACS) with particulate cancellous bone and marrow (PCBM) harvested from the iliac crest in an animal model of maxillary sinus floor augmentation. Bilateral sinus floor augmentation procedures were performed in 30 adult Japanese white rabbits. rhBMP-2/ACS or PCBM was grafted to each maxillary sinus. Animals were sacrificed at 2, 4, or 8 weeks after grafting, and bone formation in response to each implant was evaluated histologically and histometrically. Histometric results compared by analysis of variance revealed no statistically significant difference in the bone volume at augmented areas between the two types of implant (P > 0.05). Histologic evaluation documented that the trabeculae with a lamellar structure were embedded in fatty marrow at 8 weeks in both implant sites. These results suggest that sinus floor augmentation with rhBMP-2/ACS or PCBM induces comparable histologic and histometric evidence of bone formation in rabbits.

Co-localization of chicken DNA topoisomerase IIalpha, but not beta, with sites of DNA replication and possible involvement of a C-terminal region of alpha through its binding to PCNA.

Clones for DNA topoisomerase IIalpha and beta (topo-IIalpha and beta) were isolated from a cDNA expression library of chicken MSB-1 cells by immunoscreening. The deduced sequences of chicken topo-IIalpha and beta were about 80% identical for the N-terminal ATPase domain and the central core domain but only 37% for the C-terminal domain. Polyclonal antibodies were raised against C-terminal polypeptides specific to topo-IIalpha and beta. Indirect immunofluorescence with these antibodies to chicken embryonic fibroblasts demonstrated that topo-IIalpha was distributed in discrete intranuclear spots, which coincided with sites of DNA replication as indicated by incorporation of 5-bromo-2'-deoxyuridine, whereas topo-IIbeta was distributed rather uniformly within a nucleus. Examination of intranuclear distribution patterns of chimeric constructs between topo-IIalpha and beta suggested that a sequence region (residues 1280-1294) in the C-terminal domain of topo-IIalpha was effective in co-localization with sites of DNA replication. This region consists of a QTxhxF motif (x, any residue; h, hydrophobic residue) followed by a KR-rich sequence, which resembles those found in several proteins known to associate with proliferating cell nuclear antigen (PCNA) or targeted to the replication factory. An in vitro pull-down assay with glutathione-S-transferase-PCNA and (His)6-tagged truncated forms of topo-IIalpha demonstrated that polypeptides containing the above region (residues 1158-1553 or 1158-1294) bound to PCNA in vitro.

Serum eosinophil cationic protein levels measured during exacerbation of asthma: characteristics of patients with low titres.

BACKGROUND: Serum eosinophil cationic protein (ECP) levels reflect ongoing eosinophilic airway inflammation and are used as a marker for asthma activity. ECP levels, however, may not be elevated in some asthmatic patients, even when they are symptomatic. OBJECTIVE: To clarify the characteristics of patients with 'low' ECP titres despite asthma exacerbation. METHODS: Serum ECP levels were measured in 113 asthmatic patients during exacerbation. Patients were divided into two groups according to ECP titre: a high ECP group (H; ECP > or = 16.0 microg/L) and a low ECP group (L; ECP <16.0 microg/L). Twenty-two patients who had recently received systemic steroids were excluded and the clinical features of the remaining patients in H (n = 54) and L (n = 37 were compared. RESULTS: Gender, atopic or smoking status, disease severity, inhaled steroid or theophylline usage, peak expiratory flow (% personal best) and forced expiratory volume in 1 s (FEV1) (% predicted) did not significantly differ between the two groups. Patients in L were significantly older and had longer disease duration and lower serum IgE levels than those in H. Multivariate analysis combining age, disease duration and IgE levels showed that age and disease duration were independently associated with ECP level. Airway wall thickness, assessed in a subset of patients using computed tomography, was significantly larger in L. CONCLUSION: Serum ECP levels in asthmatic patients may not be elevated during exacerbation and thus may not be a useful marker in patients who are older, have longer disease duration or possibly have thicker airway walls. Mechanisms other than eosinophilic inflammation, such as airway remodelling, may be involved in asthma exacerbation in these patients.

Allergic granulomatous angiitis (Churg-Strauss syndrome) associated with allergic bronchopulmonary candidiasis.

We describe a case of Churg-Strauss syndrome (CSS) associated with allergic bronchopulmonary candidiasis (ABPC). A 61-year-old man who had been given a diagnosis of ABPC based on serologic and radiographic findings experienced pain and purpuric rash on the left leg accompanied with motor weakness. The diagnosis of CSS was made from skin, nerve and muscle biopsies. Although immunosuppressant and prednisolone were administered and resulted in transient improvement, candidal pneumonia was suspected to have developed 60 days after the administration and the patient finally died of respiratory failure. To our knowledge, this is the first case of CSS associated with ABPC.

Airway remodelling in cough-variant asthma.

Subepithelial-layer thickening, a pathological feature of airway remodelling, is present in cough-variant asthma. In bronchial biopsy samples we found mean subepithelial-layer thickness was 7.1 (SE 0.4) microm in patients with cough-variant asthma, 8.6 (0.4) microm in patients with classic asthma with wheezing, and 5.0 (0.2) microm in healthy controls. Thickness was significantly higher in patients with asthma than in controls, and was significantly greater in those with classic asthma than in those with cough-variant asthma. Early anti-inflammatory treatment might, therefore, be beneficial in cough-variant asthma, as recommended in classic asthma.

Receptor for hyaluronan-mediated motility and CD44 expressions in colon cancer assessed by quantitative analysis using real-time reverse transcriptase-polymerase chain reaction.

Receptor for hyaluronan (HA)-mediated motility (RHAMM) is a receptor for HA-mediated motility and its expression is correlated with malignancy of ras-transformed cells in that binding of HA to this receptor activates their migratory ability. CD44, a cell surface receptor for HA is also implicated in metastatic behavior of some cancer cells. In this study we examined the relationships of cancer progression with mRNA levels of RHAMM, CD44 (all forms), and exon 6 of CD44 using the real-time reverse transcriptase-polymerase chain reaction method in specimens of colon cancers at different diagnostic stages from 30 patients. Increased mRNA levels of RHAMM were observed in 29 specimens (97%), CD44s (all forms) in 21 specimens (70%), and its exon 6 in 19 specimens (63%) in comparison with those in the corresponding noncancerous tissue specimens. A statistically significant correlation between RHAMM expression and cancerous specimens at any of Dukes' stages A, B, and C was found, and the overexpression of CD44 mRNAs was confirmed in specimens at Dukes' stage C. Thus, our present study for the first time suggests that RHAMM expression may be a clinically useful indicator of colon cancer.

Autogenous bone grafts in the rabbit maxillary sinus.

OBJECTIVE: This study involving rabbits was undertaken to establish an experimental model for the sinus lift procedure and to clarify the repair of autogenous grafted bone in the maxillary sinus. STUDY DESIGN: A corticocancellous bone block was grafted into the maxillary sinus of each of 18 rabbits. Each animal was killed at 2, 4, or 8 weeks after grafting and then histologically evaluated. RESULTS: At 2 weeks, new bone formation was observed. There was no inflammation of the antral membrane. At 4 weeks, lamellar structures were observed in newly formed bone. At 8 weeks, newly formed cortical bone was observed under the elevated membrane and the medullary cavity was almost completely occupied by fat cells. CONCLUSIONS: There were no histologic complications after the sinus lift procedure. Histologic results indicated that newly continuous cortical bone was formed along the elevated membrane at 8 weeks. This animal model could be useful as a sinus lift model.

Histologic evaluation of clinically successful osseointegrated implants retrieved from irradiated bone: a report of 2 patients.

The present study described the histologic findings of 2 implants and surrounding tissues retrieved from human irradiated bone. For the treatment of a malignant tumor, 50 Gy of irradiation after implant placement and 60 Gy of irradiation before implant placement were provided for patients 1 and 2, respectively. In patient 1, the implant and surrounding tissues were removed from the frontal bone 24 months after implant placement because of the patient's death from a tumor recurrence. In patient 2, the implant and surrounding tissue were removed from a maxillectomy site 26 months after implant placement because of tumor recurrence. In each patient, new bone formation surrounding the implants was observed. The ratio of direct bone-implant contact along the threaded implant surface was 61.3% in patient 1 and 69.0% in patient 2. The ratio of the area occupied by mineralized bone in each thread was 75.8% in patient 1 and 81.2% in patient 2. These results indicate the potential of irradiated bone to achieve osseointegration of titanium implants.

[A case of miliary tuberculosis with brain tuberculoma, following intraocular tuberculosis].

A 52-year-old woman with visual loss of her left eye consulted a ophthalmology clinic. She was conducted left vitrectomy and administered corticosteroid under the diagnosis of uveitis of unknown cause. But her visual acuity was not improved. Although re-surgery was planned, pus retention was found in her left eye. After her left eye was resected, fever and general malaise appeared suddenly. Her chest X-ray film revealed diffuse micronodular opacities. Acid-fast bacilli were detected from her sputum and identified to be Mycobacterium tuberculosis. She was diagnosed miliary tuberculosis, and then antituberculous chemotherapy consisting of 4 drugs was started. Granulomatous inflammation destructing retina and numerous acid-fact bacilli were found in histologic examination of the resected eye. This case was thought to be miliary tuberculosis disseminated from intraocular tuberculosis. After 2 months of therapy, neurologic symptoms which might be caused by brain tuberucloma appeared and deteriorated rapidly. But by adding corticosteroid to antituberculous therapy, symptoms were diminished gradually.

Peri-implant soft tissue management through use of cultured mucosal epithelium.

OBJECTIVE: In implant therapy, peri-implant soft tissue management through use of mucosal grafting or skin grafting is necessary in some patients who do not have enough attached gingiva around the abutment. However, limitation of donor site size is a problem for the mucosal graft, and the different characteristics of skin, such as hair growth, are disadvantages in treatment that involves the use of skin graft. On the other hand, cultured epithelium fabricated with living mucosal cells has proved to be a good grafting material for any kind of mucosal defect. In this study, we used cultured mucosal epithelium for soft tissue management in implant therapy. STUDY DESIGN: In the first surgical procedure of the implant therapy, a small segment of oral mucosa was sampled from a patient. The cultured epithelium was fabricated and then stored until it was grafted in the second surgery. RESULTS: Twelve cases in which patients underwent peri-implant soft tissue management through use of cultured mucosal epithelium for implant therapy are presented, and the usefulness of this technique in the making of attached gingiva is analyzed. CONCLUSIONS: From this study it was concluded that cultured mucosal epithelium can serve as a proper material for peri-implant soft tissue management.

Eosinophilic inflammation in cough variant asthma.

Eosinophils are considered to play a central pathogenetic role in asthma. We previously reported that sputum eosinophilia was observed in patients with cough variant asthma (CVA), as well as in "classic" asthma with wheezing. This study was undertaken to further investigate the involvement of eosinophils in CVA. The serum eosinophil cationic protein (ECP) level, the percentage of eosinophils in bronchoalveolar lavage (BAL) fluid, and the number of eosinophils in bronchial biopsy specimen were examined in 14 patients with CVA, 21 with classic asthma, and in seven healthy controls. For the two asthmatic groups, the clinical severity was classified with scores of 1-3. Pulmonary function and bronchial responsiveness were not significantly different between the patients with classic asthma and those with CVA. BAL, tissue eosinophil and serum ECP were all significantly increased in both classic asthma and CVA when compared with the controls but were not different between classic asthma and CVA. In both groups of asthmatics, the clinical severity significantly correlated with serum ECP and tissue eosinophils. In conclusion, eosinophilic inflammation is involved in cough variant asthma as well as in classic asthma. Anti-inflammatory treatment may be essential in patients with CVA, as in those with classic asthma.

Experience with osseointegrated implants placed in irradiated tissues in Japan and the United States.

A survey was undertaken to analyze osseointegrated implants placed in irradiated maxillae and mandibles. It was found that nine centers in Japan and two centers in the United States had placed 228 implants in 44 patients. Of 228 implants, 59 were placed in the maxilla, 169 in the mandible. Three of 169 implants placed in irradiated mandibles were removed; 17 of 59 were removed from maxillae. One hundred nineteen implants were placed in the mandible without adjunctive hyperbaric oxygen treatment, of which only 2 were removed. From these results, it is suggested that osseointegrated implants can be placed in the irradiated mandibles of selected patients without hyperbaric oxygen treatment.