IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type-2 inflammatory endotype.

BACKGROUND: Genetic markers of susceptibility to asthma exacerbations in adults remain unclear. OBJECTIVE: To identify genetic markers of asthma exacerbations, particularly in patients with type-2 inflammatory endotype. METHODS: In this observational study of patients enrolled in the Kinki Hokuriku Airway disease Conference multicenter study, frequency of exacerbations requiring systemic corticosteroids during 2 years after enrolment and associated risk factors was determined. For genetic marker analysis, interleukin-4 receptor α (IL4RA) rs8832 and a disintegrin and metalloprotease 33 (ADAM33) S_2 (rs528557), T_1 (rs2280091), T_2 (rs2280090), and V_4 (rs2787094) variants were included. Elevated serum periostin levels at enrolment (≥95 ng/mL, defined as type-2 inflammatory endotype) were considered in the analysis. RESULTS: Among 217 patients who were successfully followed up for 2 years after enrolment, 60 patients showed at least one asthma exacerbation during the 2 years. Airflow limitation (%FEV1 <80%) and recent exacerbations but not genetic variants were identified as risk markers of exacerbations. A total of 27 patients showed type-2 inflammatory endotype (serum periostin ≥95 ng/mL at enrolment) and subsequent exacerbations; risk factors in these patients were airflow limitation (odds ratio, 6.51; 95% confidence interval (CI): 2.37-18.6; P=.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95% CI: 1.47-11.0; P=.007), and A allele of ADAM33 T_2 (odds ratio, 2.81; 95% CI: 1.05-7.67; P=.04) by multivariate analysis. In addition, GG genotype of IL4RA rs8832 was associated with type-2 endotype, whereas A allele of ADAM33 T_2 was associated with mixed type of eosinophilic/type-2 and neutrophilic inflammations. CONCLUSIONS AND CLINICAL RELEVANCE: IL4RA and ADAM33 variants may be risk markers of asthma exacerbations in type-2 inflammatory endotype. Precise endotyping may facilitate the identification of genetic risk markers of asthma exacerbations.

Combined effects of starvation and butyrate on autophagy-dependent gingival epithelial cell death.

BACKGROUND AND OBJECTIVE: Bacteria in the dental biofilm surrounding marginal gingival grooves cause periodontal diseases. Numerous bacteria within the biofilm consume nutrients from the gingival crevicular fluid. Furthermore, some gram-negative bacteria in mature dental biofilms produce butyrate. Thus, gingival epithelial cells in close proximity to mature dental biofilms are at risk of both starvation and exposure to butyrate. In the present study, we determined the combined effects of starvation and butyrate exposure on gingival epithelial cell death and the underlying mechanisms. MATERIAL AND METHODS: The Ca9-22 cell line was used as an in vitro counterpart of gingival epithelial cells. Cell death was measured as the amount of total DNA in the dead cells using SYTOX Green dye, which penetrates through membranes of dead cells and emits fluorescence when it intercalates into double-stranded DNA. AMP-activated protein kinase (AMPK) activity, the amount of autophagy, and acetylation of histone H3 were determined using western blot. Gene expression levels of microtubule-associated protein 1 light chain 3b (lc3b) were determined using quantitative reverse transcription-polymerase chain reaction. RESULTS: Butyrate-induced cell death occurred in a dose-dependent manner whether cells were starved or fed. However, the induction of cell death was two to four times higher when cells were placed under starvation conditions compared to when they were fed. Moreover, both starvation and butyrate exposure induced AMPK activity and autophagy. While AMPK inactivation resulted in decreased autophagy and butyrate-induced cell death under conditions of starvation, AMPK activation resulted in butyrate-induced cell death when cells were fed. Combined with the results of our previous report, which demonstrated butyrate-induced autophagy-dependent cell death, the results of this study suggest that the combination of starvation and butyrate exposure activates AMPK inducing autophagy and subsequent cell death. Notably, this combination markedly induced LC3B production and the induction was attenuated by AMPK inhibition. LC3B knockdown, in turn, significantly decreased butyrate-induced cell death. Therefore, AMPK-dependent LC3B induction apparently plays an important role in butyrate-induced cell death. There was a lack of correspondence between the levels of AMPK activation and LC3B induction; this may reflect the histone deacetylase-inhibitory capacity of butyrate on histone proteins. CONCLUSION: Taken together, starvation and butyrate exposure promote autophagy via AMPK signaling, while the histone deacetylase-inhibitory effects of butyrate alter chromatin to transcriptionally active state, resulting in strong LC3B induction and subsequent cell death. These findings may help improve the understanding of the cellular processes underlying periodontal disease initiation.

Stability of cervical esophagogastrostomy via hand-sewn anastomosis after esophagectomy for esophageal cancer.

The aim of the present study is to evaluate the outcome of hand-sewn esophagogastric anastomosis during radical esophagectomy for esophageal cancer. The outcomes of 467 consecutive esophageal cancer patients who underwent cervical esophagogastric anastomosis using interrupted and double-layered sutures after radical esophagectomy via right thoracotomy or thoracoscopic surgery were retrospectively reviewed. Anastomotic leakage, including conduit necrosis, occurred in 11 of 467 patients (2.4%); 7 of 11 (63.6%) cases experienced only minor leakage, whereas the other four (36.4%) patients had major leakage that required surgical or radiologic intervention, including two patients of conduit necrosis. Anastomotic leakages were more frequently observed after retrosternal reconstruction compared with the posterior mediastinal route (P < 0.0001). The median time to healing of leakage was 40 days (range: 14-97 days). Two patients (2/467, 0.4%) died in the hospital due to sepsis caused by the leakage and conduit necrosis. Twelve patients (2.6%) developed anastomotic stenosis, which was improved by dilatation in all patients. Hand-sewn cervical esophagogastric anastomosis is a stable and highly safe method of radical esophagectomy for esophageal cancer.

Clinical Features and Outcomes of Diffuse Alveolar Hemorrhage During Antithrombotic Therapy: A Retrospective Cohort Study.

PURPOSE: Antithrombotic therapy could trigger diffuse alveolar hemorrhage (DAH), and there are several case reports of DAH that occurred during antithrombotic therapy (DAH-AT). However, little is known about the clinical features and outcomes of DAH-AT. The purpose of this study was to clarify the features and mortality of DAH-AT. METHODS: 76 consecutive patients with DAH who were admitted to our hospital between January 2003 and April 2014 were retrospectively reviewed to identify the clinical features and outcomes of DAH-AT. The primary outcome was 90-day mortality. RESULTS: Of the 76 patients with DAH, 39 patients (51 %) had DAH-AT, and 37 patients (49 %) had DAH that occurred with no antithrombotic therapy (DAH-NAT). Of the patients with DAH-AT, 25 (64 %) were taking aspirin, 14 (36 %) were taking warfarin, 5 (13 %) were taking clopidogrel sulfate, and 4 (10 %) were taking cilostazol. Pre-existing cardiac disease was present in 23 (59 %) DAH-AT cases and 5 (14 %) DAH-NAT cases. Logistic regression analysis was used to assess the effect of antithrombotic therapy on the mortality of DAH patients, and no significant difference in survival was seen with antithrombotic therapy (OR 1.18, 95 % CI 0.38-3.78). CONCLUSIONS: Antithrombotic therapies had no effect on the 90-day mortality of DAH patients.

Observation of motion of colloidal particles undergoing flowing Brownian motion using self-mixing laser velocimetry with a thin-slice solid-state laser.

We achieved a highly sensitive method for observing the motion of colloidal particles in a flowing suspension using a self-mixing laser Doppler velocimeter (LDV) comprising a laser-diode-pumped thin-slice solid-state laser and a simple photodiode. We describe the measurement method and the optical system of the self-mixing LDV for real-time measurements of the motion of colloidal particles. For a condensed solution, when the light scattered from the particles is reinjected into the solid-state laser, the laser output is modulated in intensity by the reinjected laser light. Thus, we can capture the motion of colloidal particles from the spectrum of the modulated laser output. For a diluted solution, when the relaxation oscillation frequency coincides with the Doppler shift frequency, fd, which is related to the average velocity of the particles, the spectrum reflecting the motion of the colloidal particles is enhanced by the resonant excitation of relaxation oscillations. Then, the spectral peak reflecting the motion of colloidal particles appears at 2×fd. The spectrum reflecting the motion of colloidal particles in a flowing diluted solution can be measured with high sensitivity, owing to the enhancement of the spectrum by the thin-slice solid-state laser.

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.

Room-temperature quantum emission from interface excitons in mixed-dimensional heterostructures.

The development of van der Waals heterostructures has introduced unconventional phenomena that emerge at atomically precise interfaces. For example, interlayer excitons in two-dimensional transition metal dichalcogenides show intriguing optical properties at low temperatures. Here we report on room-temperature observation of interface excitons in mixed-dimensional heterostructures consisting of two-dimensional tungsten diselenide and one-dimensional carbon nanotubes. Bright emission peaks originating from the interface are identified, spanning a broad energy range within the telecommunication wavelengths. The effect of band alignment is investigated by systematically varying the nanotube bandgap, and we assign the new peaks to interface excitons as they only appear in type-II heterostructures. Room-temperature localization of low-energy interface excitons is indicated by extended lifetimes as well as small excitation saturation powers, and photon correlation measurements confirm antibunching. With mixed-dimensional van der Waals heterostructures where band alignment can be engineered, new opportunities for quantum photonics are envisioned.

Resonant exciton transfer in mixed-dimensional heterostructures for overcoming dimensional restrictions in optical processes.

Nanomaterials exhibit unique optical phenomena, in particular excitonic quantum processes occurring at room temperature. The low dimensionality, however, imposes strict requirements for conventional optical excitation, and an approach for bypassing such restrictions is desirable. Here we report on exciton transfer in carbon-nanotube/tungsten-diselenide heterostructures, where band alignment can be systematically varied. The mixed-dimensional heterostructures display a pronounced exciton reservoir effect where the longer-lifetime excitons within the two-dimensional semiconductor are funneled into carbon nanotubes through diffusion. This new excitation pathway presents several advantages, including larger absorption areas, broadband spectral response, and polarization-independent efficiency. When band alignment is resonant, we observe substantially more efficient excitation via tungsten diselenide compared to direct excitation of the nanotube. We further demonstrate simultaneous bright emission from an array of carbon nanotubes with varied chiralities and orientations. Our findings show the potential of mixed-dimensional heterostructures and band alignment engineering for energy harvesting and quantum applications through exciton manipulation.

Long-term changes in airway-wall thickness on computed tomography in asthmatic patients.

BACKGROUND: Effects of long-term treatment with inhaled corticosteroids (ICSs) on airway-wall thickness in patients with asthma remain unknown. OBJECTIVES: To determine whether airway-wall thickness consistently decreases after long-term ICS treatment, and to analyze factors contributing to long-term airway-wall changes in asthmatics. METHODS: A retrospective analysis of long-term changes in airway-wall thickness using computed tomography was performed in 14 patients with asthma. Wall area corrected by body surface area (WA/BSA) was examined at baseline, 12 weeks after the commencement of ICSs (second measurement), and at least 2 years (mean +/- SEM. 4.2 +/- 0.5) after the second measurement (third measurement). Mean +/- SEM changes in WA/BSA from the second to the third measurements were analyzed. RESULTS: The mean change in WA/BSA was not significant between the second and the third measurements (-0.27 +/- 0.59 mm2/m2/y). Overall, the changes were significantly associated with disease duration but not with other clinical indices. When the 14 patients were divided into 2 groups using a cutoff value of 0.32 mm2/m2/y for the mean change in WA/BSA, for the 5 patients whose WA/BSA exceeded this cutoff, daily ICS doses were not reduced and both forced expiratory volume in the first second (FEV1) and forced vital capacity decreased significantly. For the remaining 9 patients, daily ICS doses were reduced and long-term FEV1 values did not change. CONCLUSIONS: Despite long-term treatment with ICSs, airway-wall thickness did not consistently decrease. One possible mechanism underlying poor response to long-term treatment may be long-standing asthma.

Administration of an angiotensin-converting enzyme inhibitor improves vascular function and urinary albumin excretion in low-risk essential hypertensive patients receiving anti-hypertensive treatment with calcium channel blockers. Organ-protecting effects independent of anti-hypertensive effect.

Concomitant administration of calcium channel blockers (CCBs) and angiotensin-converting enzyme inhibitors (ACEIs) to hypertensive patients at high risk for cardiovascular disease can prevent cardiovascular disease occurrence, but the effects of this treatment on renal and vascular function in low-risk hypertensive patients are unknown. The current study was an open-label prospective study. Hypertensive patients with no history of cardiovascular disease who had not met their blood pressure (BP) goals with CCB treatment were administered perindopril and followed for 6 months. Both home and office BP were significantly lowered by perindopril administration. The morning/evening (M/E) ratios calculated from home BP were 1.31 and 1.05 for systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively. When the patients were divided into two groups based on the presence or absence of an anti-hypertensive response, urinary albumin excretion, and cardio ankle vascular index were significantly reduced by perindopril administration in all the subjects, irrespective of the presence or absence of anti-hypertensive reaction. In low-risk hypertensive patients, perindopril improves renal and vascular function probably via its persistent anti-hypertensive effects and the concomitant effects of CCB.

T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6.

This study investigates the molecular mechanisms underlying the induction of and protection from T cell activation-associated hepatic injury. When BALB/c mice were given a single intravenous injection of concanavalin A (Con A) (> or = 0.3 mg/mouse), they developed acute hepatic injury as assessed by a striking increase in plasma transaminase levels within 24 h. Histopathologically, only the liver was injured while moderate infiltration of T cells and polymorphonuclear cells occurred in the portal areas and around the central veins. The induction of hepatic injury was dependent on the existence as well as the activation of T cells, as untreated BALB/c nu/nu mice or BALB/c mice pretreated with a T cell-specific immunosuppressive drug, FK506, failed to develop disease. Significant increases in the levels of various cytokines in the plasma were detected before an increase in plasma transaminase levels. Within 1 h after Con A injection, tumor necrosis factor (TNF) levels peaked, this being followed by production of two other inflammatory cytokines, interleukin 6 (IL-6) and IL-1. Passive immunization with anti-TNF but not with anti-IL-1 or anti-IL-6 antibody, conferred significant levels of protection. Moreover, administration of rIL-6 before Con A injection resulted in an IL-6 dose-dependent protection. A single administration of a given dose of rIL-6 completely inhibited the release of transaminases, whereas the same regimen induced only 40-50% inhibition of TNF production. More than 80% inhibition of TNF production required four consecutive rIL-6 injections. These results indicate that: (a) TNFs are critical cytokines for inducing T cell activation-associated (Con A-induced) hepatitis; (b) the induction of hepatitis is almost completely controlled by rIL-6; and (c) rIL-6 exerts its protective effect through multiple mechanisms including the reduction of TNF production.

Butyrate, a bacterial metabolite, induces apoptosis and autophagic cell death in gingival epithelial cells.

BACKGROUND AND OBJECTIVE: Butyrate is produced by some types of anaerobic periodontal bacteria. Millimolar concentrations of butyrate are found in mature dental plaque from periodontitis patients. Although butyrate reportedly has a variety of effects in many mammalian cells, its effect on gingival epithelial cells is not well known. In this study, we investigated the effect of butyrate on gingival epithelial Ca9-22 cell death. MATERIAL AND METHODS: Death of Ca9-22 cells was assessed after treating the cells with or without butyrate. A SYTOX Green dye, which exhibits strong green fluorescence once it enters dead cells through ruptured cell membranes, was used for cell death detection. Phosphatidylserine redistribution was measured using fluorescein isothiocyanate-labeled annexin V. The activity of caspase-3 was measured as the amount of cleaved substrate peptide. Anti-apoptotic bcl-2 mRNA expression was measured using real-time RT-PCR. Western blotting and fluoromicroscopic analysis with anti-microtubule-associated protein 1 light chain 3 (LC3) antibodies were performed for detection of autophagy. RESULTS: Stimulation with millimolar concentrations of butyrate for 48 h induced Ca9-22 cell death. The stimulation also caused increased caspase-3 activity, phosphatidylserine redistribution and bcl-2 down-regulation, suggesting butyrate-induced apoptosis. However, the pan-caspase inhibitor, Z-VAD-FMK, did not inhibit cell death completely. This implies the existence of other types of cell death. In addition, markers of autophagy, namely, the conversion of LC3-I to LC3-II and increased LC3 accumulation, were observed. Moreover, inhibition of autophagy by 3-methyladenine suppressed the butyrate-induced cell death, suggesting that butyrate could induce cell death through autophagy. CONCLUSION: These data suggest that butyrate induces apoptosis and autophagic cell death.

Insulin-like growth factor-binding protein-2 and -3 in gingival crevicular fluid.

BACKGROUND AND OBJECTIVE: Insulin-like growth factor-binding proteins (IGFBPs) are crucial regulators of insulin-like growth factor (IGF). They enhance or inhibit IGF functions, but also exhibit IGF-independent effects. In a previous study, we detected, qualitatively, IGFBP-2 and -3 in gingival crevicular fluid using a cytokine antibody array. Here we extended these results using an ELISA to determine the concentrations of IGFBP-2 and -3 in gingival crevicular fluid. In addition, we explored whether the expression of IGFBP-2 and IGFBP-3 correlates with periodontal disease severity. MATERIAL AND METHODS: Gingival crevicular fluid samples from 92 sites of 12 patients affected with periodontal disease and from 100 sites of 19 healthy volunteers, were collected, divided into two groups and analyzed by ELISA for IGFBP-2 and -3 expression. The potential correlation among probing depth, gingival index and the concentrations of IGFBP-2 and -3 was analyzed. RESULTS: Positive correlations were observed between the concentration of IGFBP-2 and probing depth and gingival index, but not for IGFBP-3. The IGFBP-2 concentrations at bleeding on probing-positive sites and at sites with a probing depth of ≥ 4 mm were higher than at bleeding on probing-negative sites and at sites with a probing depth of ≤ 3 mm. CONCLUSION: These results indicate that IGFBP-2 is a potential novel marker for periodontal disease progression. As IGFBP-2 modulates bone metabolism and cell migration, IGFBP-2 in the gingival crevicular fluid may reflect periodontal disease activity.

Phase I/II study of sequential therapy with irinotecan and S-1 for metastatic colorectal cancer.

BACKGROUND: Both irinotecan (CPT-11) and S-1 are active against colorectal cancer; however, as S-1 is a prodrug of 5-fluorouracil (5-FU), 5-FU and its metabolites might inhibit the antitumour effect of CPT-11. Therefore, we designed a sequential combination, in which CPT-11 infusion was given on day 1 and S-1 was given orally at 80 mg m(-2) per day on days 3-16 every 3 weeks. METHODS: Twelve patients entered the phase I study, and the recommended doses were determined as a CPT-11 dose of 150 mg m(-2) and an S-1 dose of 80 mg m(-2). RESULTS: In all, 36 patients entered the phase II study, of whom 4 and 16 had complete and partial responses. The overall response rate was 55.6% (95% confidence interval, 38.1-72.1%), and median progression-free survival was 7.7 months (95% confidence interval, 4.8-12.6 months). Grade 3 neutropenia was the most common haematological toxicity and occurred in 6.5% of 215 treatment courses. Grade 3 non-haematological toxicities included anorexia (1.4%) and diarrhoea (0.9%). There was no grade 4 toxicity of any kind. CONCLUSION: Our results suggest that this regimen is convenient, safe and promising, compared with conventional regimens for patients with metastatic colorectal cancer.

Spatial and polarization entanglement of lasing patterns and related dynamic behaviors in laser-diode-pumped solid-state lasers.

To provide the underlying physical mechanism for formations of spatial- and polarization-entangled lasing patterns (namely, SPEPs), we performed experiments using a c-cut Nd:GdVO(4) microchip laser with off-axis laser-diode pumping. This extends recent work on entangled lasing pattern generation from an isotropic laser, where such a pattern was explained only in terms of generalized coherent states (GCSs) formed by mathematical manipulation. Here, we show that polarization-resolved transverse patterns can be well explained by the transverse mode-locking of distinct orthogonal linearly polarized Ince-Gauss (IG) mode pairs rather than GCSs. Dynamic properties of SPEPs were experimentally examined in both free-running and modulated conditions to identify long-term correlations of IG mode pairs over time. The complete chaos synchronization among IG mode pairs subjected to external perturbation is also demonstrated.

Ten-year experience of totally laparoscopic liver resection in a single institution.

BACKGROUND: Recent developments in liver surgery include the introduction of laparoscopic liver resection. The aim of the present study was to review a single institution's 10-year experience of totally laparoscopic liver resection (TLLR). METHODS: Between May 1997 and April 2008, 82 patients underwent TLLR for hepatocellular carcinoma (HCC) (37 patients), liver metastases (39) and benign liver lesions (six). Operations included 69 laparoscopic wedge resections, 11 laparoscopic left lateral sectionectomies and two thoracoscopic wedge resections. Nine patients underwent simultaneous laparoscopic resection of colorectal primary cancer and synchronous liver metastases. RESULTS: Median operating time was 177 (range 70-430) min and blood loss 64 (range 1-917) ml. Median tumour size and surgical margin were 25 (range 15-85) and 6 (range 0-40) mm respectively. One procedure was converted to a laparoscopically assisted hepatectomy. Three patients developed complications. Median postoperative stay was 9 (range 3-37) days. The overall 5-year survival rate after surgery for HCC and colorectal metastases was 53 and 64 per cent respectively. CONCLUSION: TLLR can be performed safely for a variety of primary and secondary liver tumours, and seems to offer at least short-term benefits in selected patients.

Evaluation of the effect of 4 months of risedronate therapy on femoral strength using femoral strength analysis tools.

The effect of risedronate (2.5 mg once daily) on femoral strength was evaluated using Advanced Hip Assessment (AHA) for the first time in Japan. In total, 104 patients with primary osteoporosis and available data on bone mineral density (BMD; lumbar spine/proximal femur), urinary NTx (cross-linked N-telopeptides of type I collagen) and AHA-based parameters collected before and after 4 months of risedronate therapy were included in the analyses. Change and percentage change from baseline in these parameters were determined. Percentage change in femur strength index was 7.9 +/- 21.1% and 5.5 +/- 18.0% for the right and left femurs, respectively; both increases were statistically significant. Cross-sectional moment of inertia, cross-sectional area and mean neck width in the femoral neck region of interest also increased significantly in both femurs. Percentage change in lumbar spine BMD (L2 - L4) was 3.0 +/- 3.7%, and proximal femoral BMD was 1.1 +/- 3.1% and 0.7 +/- 3.2% in the right and left femurs, respectively, all showing a significant increase from baseline. Percentage change in urinary NTx was -41.5 +/- 30.5%, which was a significant decrease. Using AHA, this study showed that, in patients with primary osteoporosis, risedronate improved BMD and bone quality, thereby enhancing femoral strength as early as 4 months after treatment initiation.

Butyric acid induces apoptosis in inflamed fibroblasts.

Butyric acid, an extracellular metabolite from periodontopathic bacteria, induces apoptosis in murine and human T- and B-cells, whereas intact gingival fibroblasts isolated from healthy humans are resistant to butyric-acid-induced apoptosis. We examined the susceptibility of inflamed gingival fibroblasts isolated from adult persons with periodontitis to butyric-acid-induced apoptosis. Butyric acid significantly suppressed the viability of inflamed gingival fibroblasts and induced apoptosis in a dose-dependent manner. The incubation of inflamed gingival fibroblasts with butyric acid induced DNA fragmentation and apoptotic changes such as chromatin condensation, hypodiploid nuclei, and mitochondrial injury. Furthermore, butyric-acid-induced apoptosis in inflamed gingival fibroblasts was reduced by caspase-3/7, -6, -8, and -9 inhibitors. Thus, inflamed gingival fibroblasts from adult persons with periodontitis appear to be highly susceptible to mitochondria- and caspase-dependent apoptosis induced by butyric acid, compared with healthy gingival fibroblasts.

Sputum levels of transforming growth factor-beta1 in asthma: relation to clinical and computed tomography findings.

BACKGROUND: Transforming growth factor (TGF) beta1 is considered to play central roles in the pathogenesis of airway remodeling in asthma. This notion is based primarily on the results of experimental studies; clinical evidence is limited. OBJECTIVES: To ascertain the involvement of TGF-beta1 in asthma. METHODS: We studied 27 patients with moderate-to-severe, but stable, asthma treated with inhaled corticosteroids and 8 healthy controls. Helical computed tomography scans were acquired at full inspiration. Airway wall thickness (WT) was assessed on the basis of wall area corrected for body surface area (WA/BSA) and absolute WT corrected for BSA (WT/square root of BSA) according to a validated method. Induced sputum concentrations of TGF-beta1 were measured by enzyme-linked immunosorbent assay. Pulmonary function was evaluated. RESULTS: Indices of expiratory airflow were significantly lower in the asthmatic patients than in the controls. WA/BSA, WT/square root of square root of BSA, and sputum concentrations of TGF-beta1 were significantly higher in the asthmatic patients. Sputum TGF-beta1 concentrations correlated positively with WA/BSA and WT/square root of BSA and negatively with forced expiratory volume in 1 second in both asthmatic and control subjects. CONCLUSIONS: Levels of TGF-beta1 in induced sputum are elevated in asthmatic patients despite treatment with inhaled corticosteroids and are associated with airflow obstruction and airway wall thickening. TGF-beta1 is involved in the pathogenesis of airway remodeling and resultant functional impairment and it may be a target for specific medical treatment.