Predictors and moderators of outcomes in mindfulness-based cognitive therapy intervention for early breast cancer patients.

OBJECTIVES: To deliver mindfulness-based cognitive therapy (MBCT) efficiently, the present study aimed (1) to identify predictors and moderators of patients who benefit from MBCT for psychological distress and (2) to explore the initial treatment reaction to identify the optimal number of sessions that produce a significant clinical effect. METHODS: This is the secondary analysis of a randomized controlled trial of MBCT for breast cancer patients (N = 74). We classified the participants into remitters vs. non-remitters, and responder vs. non-responders, according to the total score of the Hospital Anxiety and Depression Scale at the end of the intervention. We conducted multivariate analyses to explore for predictors of response and remission. We adopted generalized estimating equations to explore the optimal number of sessions. RESULTS: Sociodemographic and clinical backgrounds did not have significant influence on the treatment outcomes of the MBCT. Better program adherence, which was represented as the participants' better attendance to the MBCT program, was a significant predictor of both remission and response [odds ratio (OR) = 1.90, 95% confidence interval (CI) 1.25-2.89, p = 0.003, and OR = 1.72, 95% CI 1.12-2.65, p = 0.013, respectively]. It was not until seventh session that the remission rate exceeded 50% and the response rate showed significance. SIGNIFICANCE OF RESULTS: Sociodemographic and clinical characteristics did not significantly influence the treatment outcomes, while homework minutes and class attendance had significant effects on treatment outcomes. This implies that MBCT is recommended to any cancer patient, if he/she is motivated to the program, regardless of their sociodemographic and clinical characteristics. Patients are encouraged to attend a standard MBCT program (eight sessions) and do the assigned homework as intensely as possible. Further studies with larger sample and objective measurements are desired.

Inter-professional and inter-departmental alcoholism rehabilitation program.

A 3-month alcoholism rehabilitation program at psychiatric hospitals is common in Japan for patients with alcohol use disorder (AUD). However, many AUD patients are often hospitalized for the treatment of digestive disorders due to alcohol-related liver diseases and pancreatitis. In this sense, AUD patients need to be better supported by professionals and departments in general hospitals. Here we analyzed the problems in alcohol-related medical care in Japan and examined the measures to be taken at general hospitals.

Mindfulness-Based Cognitive Therapy for Psychological Distress, Fear of Cancer Recurrence, Fatigue, Spiritual Well-Being, and Quality of Life in Patients With Breast Cancer-A Randomized Controlled Trial.

CONTEXT: Mindfulness-based interventions have been receiving growing attention in cancer care. OBJECTIVES: The purpose of this randomized controlled trial is to examine the effectiveness of mindfulness-based cognitive therapy (MBCT) for psychological distress (anxiety and depression), fear of cancer recurrence (FCR), fatigue, spiritual well-being, and quality of life (QOL) in Japanese ambulatory patients with Stage I-III breast cancer. METHODS: A total of 74 patients were randomly assigned to either an eight-week MBCT intervention group (n = 38) or a wait-list control group (n = 36). The primary outcome was psychological distress, measured on Hospital Anxiety and Depression Scale. The secondary outcomes were FCR (Concerns About Recurrence Scale-overall anxiety subscale), fatigue (Brief Fatigue Inventory), spiritual well-being (Functional Assessment of Chronic Illness Therapy-Spiritual), QOL (Functional Assessment of Cancer Therapy-General), and mindfulness skills (Five Facet Mindfulness Questionnaire). The participants were assessed at baseline (T0), Week 8 (T1), and Week 12 (T2). The results were analyzed using a intention-to-treat linear mixed model. RESULTS: The participants in the MBCT group experienced significantly better outcomes in their psychological distress (Cohen's d = 1.17; P < 0.001), FCR (d = 0.43; P < 0.05), fatigue (d = 0.66; P < 0.01), spiritual well-being (d = 0.98; P < 0.001), and QOL (d = 0.79; P < 0.001) compared with the control group. The difference remained significant at T2 (four weeks after completion of the intervention). CONCLUSION: MBCT was demonstrated to improve well-being that encompasses psychological, physical, and spiritual domains in Japanese patients with nonmetastatic breast cancer. The favorable effect was maintained up to four weeks after the completion of the intervention.

Feasibility study of mindfulness-based cognitive therapy for anxiety disorders in a Japanese setting.

OBJECTIVE: Mindfulness-based cognitive therapy (MBCT) could be a treatment option for anxiety disorders. Although its effectiveness under conditions of low pharmacotherapy rates has been demonstrated, its effectiveness under condition of high pharmacotherapy rate is still unknown. The aim of the study was to evaluate effectiveness of MBCT under the context of high pharmacotherapy rates. RESULTS: A single arm with pre-post comparison design was adopted. Those who had any diagnosis of anxiety disorders, between the ages of 20 and 74, were included. Participants attended 8 weekly 2-hour-long sessions followed by 2 monthly boosters. Evaluation was conducted at baseline, in the middle, at end of the intervention, and at follow-up. The State-Trait Anxiety Inventory (STAI)-state was set as the primary outcome. Pre-post analyses with mixed-effect models repeated measures were conducted. Fourteen patients were involved. The mean age was 45.0, and 71.4% were female. The mean change in the STAI-state at every point showed statistically significant improvement. The STAI-trait also showed improvement at a high significance level from the very early stages. The participants showed significant improvement at least one point in some other secondary outcomes. Trial registration Retrospectively registered at the University Hospital Medical Information Network on 1st August 2013 (ID: UMIN000011347).

Mindfulness-based cognitive therapy for Japanese breast cancer patients-a feasibility study.

OBJECTIVES: Mindfulness-based intervention has been receiving growing attention in cancer care. This study aimed to examine feasibility and to preliminary explore effectiveness of mindfulness-based cognitive therapy (MBCT) in Japanese breast cancer patients, and to explore possible modification of the program so that it fits better with this population. METHODS: Twelve participants with diagnosis of Stage I-III breast cancer received an eight session, weekly MBCT intervention in a group therapy format. The participants were followed up until 3 months after the completion of the program. RESULTS: All the participants completed the program with high attendance rate (mean number of attended sessions = 7.7). Significant improvement in anxiety (Hospital Anxiety and Depression Scale (HADS) - anxiety subscale; effect size Cohen's d = 0.88, P < 0.05), trauma-related psychological symptoms (Impact of Event Scale-revised; d = 0.64, P < 0.01) and quality of life (Functional Assessment of Cancer Therapy-Breast Cancer: FACT-B; d = 0.72, P < 0.01), and trend-level improvement in depression (HADS - depression subscale; d = 0.53, P = 0.054) were observed. Qualitative analyses suggested the program may be beneficial for alleviating fear of cancer recurrence and for increasing spiritual well-being. Some recommended modification of the program was indicated from the post-intervention interviews. CONCLUSIONS: Mindfulness-based cognitive therapy was well accepted by Japanese breast cancer patients and yielded favorable effect on their psychological status and quality of life. Further effectiveness study in a randomized-control design is warranted.

Early detection of colon cancer by increased serum level of Krebs von den Lungen-6 in a patient with dermatomyositis-associated interstitial pneumonia.

Krebs von den Lungen-6 (KL-6) is a high-molecular-weight glycoprotein which is elevated in serum of patients with interstitial pneumonia (IP). Serum KL-6 level is clinically used for the diagnosis of IP as well as the evaluation of its disease activity. KL-6 is originally identified when exploring novel soluble antigens in patients with lung cancer, and is known to be elevated in patients with several malignant tumors. The risk of malignant tumors is high in IP patients with polymyositis and dermatomyositis (PM/DM), and follow-up of KL-6 levels may allow earlier detection of such tumors. However, to date, there are only a few reports showing the usefulness of following-up serum KL-6 levels for finding malignant tumors in IP patients with PM/DM. Here, we described the first patient in whom increased serum KL-6 led to the diagnosis of colon cancer during follow-up of DM-associated IP.

Inhibition of metastasis of rhabdomyosarcoma by a novel neutralizing antibody to CXC chemokine receptor-4.

Rhabdomyosarcoma is the most common soft tissue sarcoma affecting children, and the overall cure rate of children with metastatic disease remains below 30%. The CXC chemokine receptor-4 (CXCR4)/stromal cell-derived factor-1 (SDF1) axis has been implicated in the promotion of metastatic potential in several tumors. In this study, we developed a novel anti-CXCR4 mAb, CF172, and investigated its antimetastatic activity against rhabdomyosarcoma cells in vitro and in vivo, to evaluate its potential as a therapeutic antibody to treat rhabdomyosarcoma. The CF172 molecule showed a specific binding reactivity against human CXCR4, as well as a specific neutralizing activity against CXCR4/SDF1 signal transduction. Using CF172, we determined that SJCRH30 rhabdomyosarcoma cells expressed high levels of CXCR4. In addition, CF172 was found to inhibit the SDF1-induced migration activity of SJCRH30 cells in vitro. Using xenograft models of SJCRH30 cells, we carried out in vivo efficacy studies for peritoneal and lymph node metastasis, which were clinically observed in rhabdomyosarcoma. These studies indicated that CF172 significantly decreased both types of metastasis of SJCRH30. In conclusion, we found that a novel anti-CXCR4 mAb, CF172, with specific reactivity against human CXCR4, prevented peritoneal metastasis and lymph node metastasis of rhabdomyosarcoma in animal models. These results suggest that CF172 is a potential antimetastasis therapeutic antibody for rhabdomyosarcoma treatment.

Predictive markers of capecitabine sensitivity identified from the expression profile of pyrimidine nucleoside-metabolizing enzymes.

Molecular markers predicting sensitivity to anticancer drugs are important and useful not only for selecting potential responders but also for developing new combinations. In the present study, we analyzed the difference in the sensitivity of xenograft models to capecitabine (Xeloda®), 5'-deoxy-5-fluorouridine (5'-DFUR, doxifluridine, Furtulon®) and 5-FU by comparing the mRNA levels of 12 pyrimidine nucleoside-metabolizing enzymes. Amounts of mRNA in the tumor tissues of 80 xenograft models were determined by real-time RT-PCR and mutual correlations were examined. A clustering analysis revealed that the 12 enzymes were divided into two groups; one group consisted of 8 enzymes, including orotate phosphoribosyl transferase (OPRT), TMP kinase (TMPK) and UMP kinase (UMPK), and was related to the de novo synthesis pathway for nucleotides, with mRNA expression levels showing significant mutual correlation. In the other group, 4 enzymes, including thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD), were involved in the salvage/degradation pathway of the nucleotides, and the mRNA levels of this group were dispersed more widely than that of the de novo group. Antitumor activity was assessed in 24 xenograft models for each drug. The antitumor activity of capecitabine and 5'-DFUR correlated significantly with the mRNA levels of TP and with the TP/DPD ratio, whereas the activity of 5-FU correlated significantly with OPRT, TMPK, UMPK and CD. In a stepwise regression analysis, TP and DPD were found to be independent predictive factors of sensitivity to capecitabine and 5'-DFUR, and UMPK was predictive of sensitivity to 5-FU. These results indicate that the predictive factors for sensitivity to capecitabine and 5'-DFUR in xenograft models may be different from those for 5-FU, suggesting that these drugs may have different responders in clinical usage.

Association of asthma education with asthma control evaluated by asthma control test, FEV1, and fractional exhaled nitric oxide.

BACKGROUND: Asthma education is an important adjunct for asthma control although the way asthma education affects asthma outcomes is poorly understood. The asthma control test (ACT), forced expiratory volume in 1 s (FEV(1)), and fractional exhaled nitric oxide (FeNO) have all been used as markers of asthma control. However, the use of FeNO as a surrogate marker remains controversial. OBJECTIVES: (i) To examine whether asthma education is associated with asthma control; (ii) to compare absolute levels and changes of ACT, FEV(1), and FeNO over a year; and (iii) to evaluate whether FeNO can be used as an additional marker of asthma control. METHODS: Fifty asthmatics with poor adherence (12 mild, 21 moderate, and 17 severe) received asthma education at study entry. Medications were unchanged for the first 3 months, and ACT, FEV(1), and FeNO measurements were recorded at entry, 3, 6, and 12 months. Asthma control was assessed at each visit and patients were categorized as either "stable" or "unstable" asthmatics according to the global initiative for asthma (GINA) guidelines. RESULTS: A significant decrease in FeNO and increase in ACT score were noted in the stable asthmatic group at 3 months (p < .001), and this persisted over 12 months. Significant correlations were seen between changes (Δ) in FeNO, ACT, and FEV(1) over time. However, significant correlations between the absolute levels were not maintained over 12 months. A decrease of ≥18.6% in FeNO and a ≥3-point increase in ACT score (sensitivity: 80% and 73.3% and specificity: 83.3% and 87.5%, respectively) were associated with stable asthma control although the absolute levels were not. CONCLUSIONS: Asthma education may be useful to achieve stable control. In addition, changes rather than absolute levels of FeNO and ACT may be better markers of asthma control.

Four cases of Trousseau's syndrome associated with lung adenocarcinoma.

Cancer patients are at high risk of venous thromboembolism (VTE), and the combination of these two conditions is well known as Trousseau's syndrome. Here we present four cases of Trousseau's syndrome associated with advanced lung adenocarcinoma. In addition to fibrinogen degradation products (FDP) and D-dimer, the levels of mucin-producing markers, such as KL-6, were elevated. There is a possibility that mucin production may be associated with cancer-related VTE.

Angiogenesis inhibitors identified by cell-based high-throughput screening: synthesis, structure-activity relationships and biological evaluation of 3-[(E)-styryl]benzamides that specifically inhibit endothelial cell proliferation.

Proliferation of endothelial cells is critical for angiogenesis. We report orally available, in vivo active antiangiogenic agents which specifically inhibit endothelial cell proliferation. After identifying human umbilical vein endothelial cell (HUVEC) proliferation inhibitors from a cell-based high-throughput screening (HTS), we eliminated those compounds which showed cytotoxicity against HCT116 and vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitory activity. Evaluations in human Calu-6 xenograft model delivered lead compound 1. Following extensive lead optimization and alteration of the scaffold we discovered 32f and 32g, which both inhibited the proliferation and tube formation of HUVEC without showing inhibitory activity against any of 25 kinases or cytotoxicity against either normal fibroblasts or 40 cancer cell lines. Upon oral administration, 32f and 32g had good pharmacokinetic profiles and potent antitumor activity and decreased microvessel density (MVD) in Calu-6 xenograft model. Combination therapy with a VEGFR inhibitor enhanced the in vivo efficacy. These results suggest that 32f and 32g may have potential for use in cancer treatment.

Validation study of asthma screening criteria based on subjective symptoms and fractional exhaled nitric oxide.

BACKGROUND: In the latest Global Initiative for Asthma guideline, neither sputum eosinophilia nor fractional exhaled nitric oxide (FeNO) have been evaluated prospectively as an aid in asthma diagnosis, but these measurements are being evaluated for potential use in determining optimal treatment. OBJECTIVE: To report criteria for screening asthma using subjective symptoms and FeNO levels and results of a prospective validation study using these criteria. METHODS: Sixty-one outpatients with recurrent cough, wheezing, or dyspnea underwent measurements of FeNO levels, pulmonary function, methacholine airway responsiveness, and inflammatory cells in induced sputum. The sensitivity, specificity, and concordance achieved using the FeNO-based criteria (at least 1 of the following subjective symptoms: recurrent cough, wheezing, or dyspnea and/or FeNO level ≥ 40 ppb) were analyzed and compared with the values obtained using conventional asthma diagnostic criteria, which includes subjective symptoms with any 2 of the following conditions: airway hyperresponsiveness, reversible airflow limitation, and eosinophilia in induced sputum. RESULTS: Of the 61 patients, 41 were diagnosed as having asthma by the conventional criteria, and 33 were diagnosed as having asthma by the FeNO-based criteria, which showed a sensitivity of 78.6%, a specificity of 89.5%, and a concordance rate of 0.62. Nine of 42 patients were misdiagnosed as not having asthma by FeNO-based criteria (mean [SD] FeNO level, 23.9 [8.0] ppb). Seven of 9 patients were diagnosed as having nonatopic asthma according to IgE levels. CONCLUSIONS: Asthma may be accurately diagnosed in daily practice on the basis of subjective symptoms and FeNO levels, particularly in atopic patients.

[Differences of fractional exhaled nitric oxide (FeNO) levels performed using two different analyzers].

The measurement of fractional exhaled nitric oxide (FeNO) is going to become more wide-spread as a noninvasive marker for diagnosing and controlling bronchial asthma. In Japan, both stationary and portable FeNO analyzers are now available. However, the difference between these analyzers has not been fully examined. Therefore, the aim of this study is to determine whether there is a difference between a stationary FeNO analyzer (NA623NP, CHEST inc. Tokyo, Japan) and a portable analyzer (NIOX MINO, Aerocrine, Solna, Sweden). One hundred subjects (17 non-treated asthma cases, 45 asthma cases treated with inhaled corticosteroids, 21 with other respiratory disorders, 17 healthy subjects) were enrolled in the study. All the subjects were non- or ex-smokers. There was a strong positive correlation between FeNO (CHEST) and FeNO (MINO) (r = 0.970, p < 0.001). However, when FeNO levels between FeNO (CHEST) and FeNO (MINO) were compared in all subjects and each subject group, the levels of FeNO (MINO) were significantly lower than those of FeNO (CHEST) (p < 0.05). Finally, the following conversion equation was calculated: FeNO (CHEST) = FeNO (MINO) x 1.278 + 3.065. From these results, the following conclusion was drawn: when FeNO is measured by different analyzers, there might be differences between devices. Therefore, the conversion equation could help clinicians and researchers to compare data obtainable by these two analyzers.

Clinical usefulness of fractional exhaled nitric oxide for diagnosing prolonged cough.

BACKGROUND: Prolonged cough is one of the troublesome symptoms commonly seen in daily practice. Especially, detection of allergic cough such as bronchial asthma (BA), cough variant asthma (CVA) and eosinophilic bronchitis without asthma (EB) is important because the prevalence of these disorders are high. We previously reported fractional exhaled nitric oxide (FeNO) can be a non-invasive marker of allergic airway inflammation. We examined whether FeNO could be applicable for the proper diagnosis of prolonged cough. METHOD: About 71 consecutive subjects complaining prolonged cough who gave informed consent for the study were enrolled. FeNO, pulmonary function tests, bronchial hyperresponsiveness (BHR), IgE, and eosinophils in induced sputum and peripheral blood were measured. Final diagnosis of the subjects was 30 with BA, 18 with CVA, 8 with EB, and 15 with other respiratory disorders (Others). RESULT: FeNO had significant correlations with non-specific IgE, mite-specific IgE, FEV/FVC, BHR, and eosinophils. The level of cedar-specific IgE was significantly higher in subjects with EB than CVA. FeNO levels in BA and CVA were significantly higher than those in EB and Others. The optimal cutoff level of FeNO was 38.8 ppb with sensitivity of 79.2% and specificity of 91.3% for distinguishing BA and CVA from EB and Others. CONCLUSION: FeNO could be used as a diagnostic marker of prolonged cough, especially for the differential diagnosis BA and CVA from EB and others.

Toll-like receptor 4 signal transduction inhibitor, M62812, suppresses endothelial cell and leukocyte activation and prevents lethal septic shock in mice.

Sepsis occurs when microbes activate toll-like receptors (TLRs) stimulating widespread inflammation and activating coagulation cascades. TLR4 signal transduction has been recognized as a key pathway for lipopolysaccharide (LPS)-induced activation of various cells and an attractive target for treatment of sepsis. We found a new benzisothiazole derivative, M62812 that inhibits TLR4 signal transduction. This compound suppressed LPS-induced upregulation of inflammatory cytokines, adhesion molecules and procoagulant activity in human vascular endothelial cells and peripheral mononuclear cells. The half maximal inhibitory concentrations in these assays ranged from 1 to 3 microg/ml. Single intravenous administration of M62812 (10-20 mg/kg) protected mice from lethality and reduced inflammatory and coagulatory parameters in a murine d-galactosamine-sensitized endotoxin shock model. M62812 (20 mg/kg) also prevented mice from lethality in a murine cecal ligation and puncture model. These results suggest that inhibition of TLR4 signal transduction can suppress coagulation as well as inflammation during sepsis and may be clinically beneficial in sepsis treatment.

An ESR contrast agent is transported to rat liver through organic anion transporter.

Carboxy PROXYL is a useful extracellular paramagnetic contrast reagent in electron spin resonance (ESR) and magnetic resonance imaging (MRI). Active transfer of the probe was investigated using an in situ liver model in rats. Carboxy PROXYL, a nitroxyl spin probe, was perfused into in situ liver perfusion system from Wistar rats. Concentration of nitroxyl form of the spin probe in effluent increased gradually after introducing perfusate with the spin probe and reached a plateau. The disappearance of Carboxy PROXYL from the perfusate was 40%, which could not be explained with its partition coefficient. Administration of non-selective inhibitors of organic anion transporters, p-aminohippuric acid and penicillin G, inhibited competitively and in a dose dependent manner the transfer of Carboxy PROXYL into rat liver in situ, resulting in increases of Carboxy PROXYL in the effluent. The results demonstrate that there is an active transfer system of an ESR contrast reagent into in situ rat liver through organic anion transporters.

Enhanced cementum formation in experimentally induced cementum defects of the root surface with the application of recombinant basic fibroblast growth factor in collagen gel in vivo.

BACKGROUND: Therapies using biologically active, soluble factors such as growth factors or cytokines have been investigated for potential clinical use in regenerating lost periodontal tissue due to periodontitis. Basic fibroblast growth factor (bFGF, FGF-2) is a multifunctional growth factor that has a variety of effects including induction of proliferation and morphogenesis in a wide range of cells and tissues including periodontal ligament tissue. METHODS: In this study, we examined the effects of bFGF on the regeneration of cementum and periodontal ligament in experimentally induced partial defects in a beagle dog model. bFGF in a collagen gel was applied to the defects and root surfaces, and the teeth were replanted. RESULTS: Eight weeks post-surgery, formation of cementum on denuded dentin was enhanced by application of 0.1, 1, or 5 microg of bFGF in a collagen gel compared to collagen gel containing vehicle. Histological analyses revealed that at 4 weeks post-surgery, random periodontal ligament fibers had bound to dentin, but were attached only to denuded dentin to which 0.1, 1, or 5 microg of bFGF in collagen gel had been applied. At 8 weeks post-surgery, we observed the formation of dense fibers bound to alveolar bone and newly synthesized cementum in teeth treated with 1 microg of bFGF. CONCLUSION: These results suggest that basic fibroblast growth factor in a collagen gel is a suitable therapy for damaged periodontal ligament and could lead to readily achievable methods of treatment for periodontal disease.

Inhibitory effects of (-)-epigallocatechin gallate on the mutation, DNA strand cleavage, and DNA adduct formation by heterocyclic amines.

Green tea is known to be a potential chemopreventive agent against cancer. In this study, we investigated the inhibitory activities of tea extracts, and in particular the polyphenolic component (-)-epigallocatechin gallate (EGCG), against heterocyclic amine-induced genotoxicity. The tea extracts displayed inhibition of 2-hydroxyamino-6-methyldipyrido[1,2-a,3',2'-d]imidazole (Glu-P-1(NHOH))-induced mutagenicity. This inhibition can be accounted for by the presence of EGCG in the extracts. The mutagenic effect of Glu-P-1(NHOH), which induces single-strand cleavage in supercoiled circular DNA under neutral conditions, was inhibited by EGCG. Using the Drosophila repair test, a test for gross DNA damage, and DNA adduct detection by (32)P-postlabeling, we showed that EGCG prevented 2-amino-3,8-dimethylimidazo[4,5-f]quinoline-induced DNA damage and adduct formation in insect DNA. EGCG was found to accelerate the degradation of Glu-P-1(NHOH) in vitro. This observation suggested that the inhibition by EGCG is associated with an accelerated degradation of metabolically activated heterocyclic amines.

Inhibition of BMP-induced ectopic bone formation by an antiangiogenic agent (epigallocatechin 3-gallate).

Epigallocatechin 3-gallate (EGCG), which is one of the components of green tea, was recently shown to inhibit endothelial cell growth in vitro and angiogenesis in vivo [5]. We have previously shown that bone and cartilage formation by bone morphogenetic protein (BMP) is highly dependent on the geometry of the carrier (vasculature-inducing or -inhibiting geometry [2]. To verify the function of angiogenesis in the BMP induction system, we examine in this article whether inhibition of angiogenesis enhances chondrogenesis and suppresses osteogenesis. Fibrous glass membrane used as a BMP carrier was mixed with 1.2 micrograms rhBMP-2 and 1-10 micrograms of EGCG and was implanted into rats subcutaneously. As the dose of EGCG increased, alkaline phosphatase activity and calcium content were decreased, whereas the type II collagen content was increased. The results clearly indicated that inhibition of vascularization enhanced chondrogenesis and suppressed osteogenesis.

Pleiotrophin regulates bone morphogenetic protein (BMP)-induced ectopic osteogenesis.

We previously isolated pleiotrophin (PTN) from bovine bone as a protein and showed that it stimulated osteoblastic growth and differentiation. Further details of its function, however, have not been fully clarified. The aim of this paper was to elucidate the effects of PTN on bone morphogenetic protein (BMP)-induced ectopic osteogenesis. Recombinant human BMP (rhBMP)-2 (1.2 microg) was combined with a fibrous glass membrane, which had been established as an effective carrier. Various amounts of the purified bovine PTN (5, 10, 50, and 100 microg) or rhPTN (5 and 10 microg) were added to the rhBMP-2/carrier composites and implanted into rats subcutaneously as reported. It was found that the amount of bone induced in the system increased with the addition of 10 microg of either purified PTN or rhPTN. However, the amount of bone decreased with the addition of 50 or 100 microg of purified PTN dose-dependently, as judged by both alkaline phosphatase activity and calcium content in the retrieved implants. It was concluded that purified PTN or rhPTN, at ratios of concentration of 10-100 microg of PTN to 1.2 microg of rhBMP-2 in the carrier, regulated the ectopic bone-inducing activity of rhBMP-2.