Using a quality of life (QoL)-monitor: preliminary results of a randomized trial in Dutch patients with early breast cancer.

PURPOSE: The diagnosis and treatment of cancer negatively affect patients' physical, functional and psychological wellbeing. Patients' needs for care cannot be addressed unless they are recognized by healthcare providers (HCPs). The use of quality of life (QoL) assessments with feedback to HCPs might facilitate the identification and discussion of QoL-topics. METHODS: 113 patients with stage I-IIIB breast cancer treated with chemotherapy were included in this randomized controlled trial. Patients were randomly allocated to receive either usual care, or usual care with an intervention consisting of a QoL-monitor assessing QoL, distress and care needs before every chemotherapy cycle visit. Patients completed questionnaires regarding QoL, illness perceptions, self-efficacy, and satisfaction with communication. From the 2nd visit onwards, patients in the intervention arm and their HCPs received a copy of the QoL overview and results were shown in patients' medical files. Audio-recordings and patients' self-reports were used to investigate effects on communication, patient management and patient-wellbeing. A composite score for communication was calculated by summing the number of QoL-topics discussed during each consultation. RESULTS: Use of the QoL-monitor resulted in a higher communication score (0.7 topics increase per visit, p = 0.04), especially regarding the disease-specific and psychosocial issues (p < 0.01). There were no differences in patient management, QoL, illness perceptions or distress. Patients in the experimental arm (n = 60) had higher scores on satisfaction with communication (p < 0.05). CONCLUSIONS: Use of a QoL-monitor during chemotherapy in patients with early breast cancer might result in a more frequent discussion of QoL-topics, associated with high levels of patients' satisfaction.

Transition of Spleen Volume Long After Pediatric Living Donor Liver Transplantation for Biliary Atresia.

PURPOSE: After undergoing the Kasai procedure for biliary atresia (BA), most patients develop severe splenomegaly that tends to be improved by liver transplantation. However, fluctuations in splenic volume long after transplantation remain to be elucidated. PATIENTS AND METHODS: Seventy-one consecutive patients who had undergone pediatric living donor liver transplantation (LDLT) for BA were followed up in our outpatient clinic for 5 years. They were classified into 3 groups according to their clinical outcomes: a good course group (GC, n = 41) who were maintained on only 1 or without an immunosuppressant, a liver dysfunction group (LD, n = 18) who were maintained on 2 or 3 types of immunosuppressants, and a vascular complication group (VC, n = 11). Splenic and hepatic volumes were calculated by computed tomography in 464 examinations and the values compared before and after the treatment, especially in the VC group. RESULTS: Splenic volume decreased exponentially in the GC group, with splenic volume to standard spleen volume ratio (SD) being 1.59 (0.33) 5 years after liver transplantation. Splenic volume to standard spleen volume ratios were greater in the VC and LD groups than in the GC group. Patients in the VC group with portal vein stenosis developed liver atrophy and splenomegaly, whereas those with hepatic vein stenosis developed hepatomegaly and splenomegaly. Interventional radiation therapy tended to improve the associated symptoms. CONCLUSIONS: Fluctuations in splenic volume long after pediatric LDLT for BA may reflect various clinical conditions. Evaluation of both splenic and hepatic volumes can facilitate understanding clinical conditions following pediatric LDLT.

Cross-cultural comparison of breast cancer patients' Quality of Life in the Netherlands and Japan.

PURPOSE: Cultural differences are hypothesized to influence patients' Quality of Life (QoL) reports. However, there is a lack of empirical cross-cultural studies comparing QoL of patients with cancer. This study aims to compare QoL of women with breast cancer in the Netherlands and Japan, and to investigate the association of QoL with sociodemographic, clinical, and psychological variables (illness perceptions). METHODS: Dutch (n = 116) and Japanese (n = 148) women with early breast cancer undergoing chemotherapy completed the EORTC QLQ-C30 and Brief Illness Perception Questionnaire immediately before their second cycle of chemotherapy. RESULTS: Dutch women reported poorer Physical, Role, Emotional, and Cognitive functioning than Japanese women. Additionally, illness perceptions were significantly different in Japan and the Netherlands, but these did not vary across treatment type. In Japan, QoL of women receiving AC-chemotherapy was better than that of women receiving FEC-chemotherapy, whereas in the Netherlands, QoL did not vary as a function of chemotherapy. Illness perceptions about symptom severity, adverse consequences, and emotional representations were negatively related to most domains of patients' QoL in both countries. Adding illness perceptions as covariates to the ANOVA analyses rendered the effects of country and treatment type on QoL non-significant. CONCLUSIONS: Comparing Dutch and Japanese women with early breast cancer revealed important differences in treatment modalities and illness perceptions which both appear to influence QoL. Perceptions about cancer have been found to vary across cultures, and our study suggests that these perceptions should be considered when performing cross-cultural studies focusing on patient-reported outcomes.

Antibacterial Nucleoside Natural Products Inhibiting Phospho-MurNAc-Pentapeptide Translocase; Chemistry and Structure-Activity Relationship.

The continued emergence of drug-resistance to existing antibacterial agents represents a severe and ongoing public health concern, which demands the discovery of new antibiotics. However the number of novel classes of antibacterial drugs launched in the clinic has been remarkably slow since the 1960s, and it is urgent to develop novel antibacterial agents to fight against drug-resistant bacterial pathogens. Peptidoglycan is a component of the bacterial cell wall, which consists of a repeated N-acetylmuramic acid (MurNAc) and Nacetylglucosamine (GluNAc) polymer cross-linked with polypeptides, and is a good target for antibacterial drug discovery. Among enzymes responsible for its biosynthesis, phospho-MurNAc-pentapeptide translocase (MraY) is a novel and promising target. Many nucleoside natural products, which strongly inhibit MraY, have been found in nature. This review will summarize the synthesis and biological properties of selected MraY inhibitory nucleoside natural products and their analogues synthesized in our laboratory and by others.

Highly expressed cytoplasmic FcεRIß in human mast cells functions as a negative regulator of the FcRγ-mediated cell activation signal.

BACKGROUND: We recently reported that the interaction between Lyn and FcεRIß is indispensable for FcεRI-mediated human mast cell (MC) activation and that FcεRIß functions as an amplifier of FcεRI-mediated activation signal. Some of FcεRIß in cytoplasm appeared not to be co-localized with FcεRIα. The function of FcεRIß in the cytoplasm remains unknown. METHODS: The localization of FcεRIß and FcεRIα in giant papillae specimens from patients with allergic keratoconjunctivitis and of FcεRIß, FcεRIα, and Lyn in cultured human MCs was examined using confocal microscopy. FcεRIß was overexpressed using an adenovirus vector system. Mediators were measured by enzyme immunoassays or enzyme-linked immunosorbent assays. RESULTS: In the subepithelial region, FcεRIß was mainly localized in the cell membrane of MCs. In the perivascular region, FcεRIß expression was scattered throughout the cytoplasm and in the cell membrane of MCs. Overexpression of FcεRIß in MCs mainly increased its cytoplasmic expression and slightly up-regulated cell surface FcεRI expression. However, overexpression of FcεRIß in MCs resulted in down-regulation of the tyrosine phosphorylation levels of FcεRIß and Syk and down-regulation of the Ca(2+) influx soon after FcεRI aggregation and then resulted in down-regulation of degranulation, PGD2 synthesis, and production of a set of cytokines. This negative regulatory effect may be due to inhibition of the redistribution of Lyn to small patches within the plasma membrane. CONCLUSION: Cytoplasmic FcεRIß, which is not co-localized with FcεRIα, may function as a negative regulator, as it can capture important signalling molecules such as Lyn.

Heterogeneity of internal tandem duplications in the c-kit of dogs with multiple mast cell tumours.

Mast cell tumours are one of the most common neoplasms in dogs. Mutations in the proto-oncogene c-kit, especially internal tandem duplications of exon 11, are considered to play a crucial role in mast cell tumourigenesis. In this report, two cases that suffered from multiple mast cell tumours containing an internal tandem duplication in the primary lesion but not in the secondary lesions are described. This finding indicates the existence of heterogenous c-kit gene mutations in each site of multiple mast cell tumours. Additionally, these results raise the possibility that the contribution of internal tandem duplications in the malignant transformation of mast cells is quite limited. It is proposed that, for clinicians, genetic analysis of several regions of multiple mast cell tumours is necessary for predicting prognosis and tumour response to KIT inhibitors.

Stem cell factor contributes to tumorigenesis of mast cells via an autocrine/paracrine mechanism.

Mastocytosis is a disease accompanied by the abnormal expansion and accumulation of mast cells. Although the D816V mutation is detected in most cases of systemic mastocytosis, the mutation is rarely observed in other forms of mastocytosis, such as cutaneous mastocytosis and mast cell leukemia/sarcoma, for which the mechanism of tumorigenesis remains unknown. In this study, we demonstrated a novel mechanism of mast cell tumorigenesis via SCF autocrine/paracrine release. SCF was highly expressed in a WT KIT-expressing HRMC line, contributing to the phosphorylation of KIT. Neutralization of external SCF using a neutralizing antibody or suppression of SCF production by RNA interference inhibited the growth of HRMC cells, indicating the essential role of SCF in cell proliferation. To the best of our knowledge, this is the first report to determine the significant contribution of SCF autoproduction to neoplastic proliferation of mast cells. These results indicate the possibility that targeting SCF production may become a novel treatment for mast cell malignancies.

Clinical outcomes of recipients with aplastic bone disease after renal transplantation.

OBJECTIVES: We expect that if chronic renal failure (CRF) is improved after renal transplantation (RTx), dialysis osteopathy bone lesions would also recover to normal. Nevertheless, it is controversial whether bone lesions really improve after RTx. In this study, we evaluated whether pathological dialysis osteopathy improved after RTx. MATERIALS AND METHODS: The 84 patients who had undergone living related RTx had also undergone a bone biopsy (Bx) since January 2004, including 13 (16.0%) with a diagnosis of aplastic osteopathy. They included 7 men and 6 women. The average hemodialysis (HD) period was 40.3 months. The immunosuppression was tacrolimus (FK); mycophenalate mofetil (MMF) and steroid. We examined Ca, P, intact-PTH (i-PTH), metabolic bone markers, and bone density (DXA) before and 1 year after RTx. In addition, a Bx was performed after having osteal labeling twice before Bx. In addition 2 cases (15.3%) also underwent a Bx after RTx. RESULTS: All cases survive with well functioning renal grafts. The mean levels of Ca and P before RTx were 8.7 mg/mL and 6.6 mg/dL, respectively. The mean i-PTH level was 137.8 pg/mL before RTx and of alkaline phosphatase (ALP) was 202.1 U/L before RTx. The total density and % age match of DXA before RTx averaged 398.7 mg/ccm and 96.7%, respectively. The mean bone volume fraction (BV/TV: Bone Volume/Tissue Volume) before RTx was 17.2%. The mean osteoid volume (OV/TV) before RTx was 2.7%. The mean fibrosis volume (Fb.V/TV) before RTx was 0%. The mean bone formation rate (BFR/BV) before RTx was 2.1 %/y. Two cases were also pathologically diagnosed as renal osteodystrophy at 1 year after RTx: 1 case was mixed type, and another was osteomalacia, which was accompanied by a lumbar compression fracture (Fx) during the clinical course. CONCLUSIONS: Bone metabolism in patients with aplastic ROD histologically improved at 1 year after RTx, presumably due to good renal transplant function. However, it is unknown whether both hypophosphatemia and decrease of FGF-23 improved bone However, patients with aplastic ROD were not completely normalized histologically at 1 year after RTx.

A novel NF-κB inhibitor improves glucocorticoid sensitivity of canine neoplastic lymphoid cells by up-regulating expression of glucocorticoid receptors.

Lymphoid neoplasms including lymphoma and leukemia are one of the most life-threatening disorders in dogs. Many lymphoid malignancies are well-treated with glucocorticoid (GC); however, GC resistance sometimes develops and its mechanism remains uncertain. Since constitutive activation of nuclear factor-κB (NF-κB) has been reported to play roles in lymphoid malignancies, we examined whether inhibition of NF-κB activity with a synthetic inhibitor IMD-0354 affected GC sensitivity of canine neoplastic lymphoid cells, CL-1 and GL-1. Dexamethasone failed to inhibit proliferation of these cells, in which low expression of glucocorticoid receptors (GR) was identified. In the presence of IMD-0354, GR expressions in CL-1 and GL-1 were increased, consequently dexamethasone inhibited their proliferation. These results indicated that GR expression might be down-regulated by spontaneous activation of NF-κB, resulting in GC resistance. Taken together, interference of NF-κB activity may have the synergistic effect in combination chemotherapy with GC for treatment against lymphoid malignancies.

Static bone cavity in the condylar neck and mandibular notch of the mandible.

This study presents the radiographic findings of two cases of static bone cavity in the inferior aspect of the condylar neck and mandibular notch of the mandible. On plain CT, a soft tissue mass was observed in each cavity. The submandibular gland and the other glands were not found in each cavity. On contrast-enhanced CT, the soft tissue in the cavity in the inferior aspect of the condylar neck had marked linear enhancement and dilated vasculature structure was observed in the cavity. On the contrast-enhanced MRI, the soft tissue in the cavity of the mandibular notch had marked enhancement and flow void was detected in the cavity. In the inferior aspect of the condylar neck, the cavity size had enlarged radiographically over a period of three years. Vascular lesions were found in the cavity located in the inferior aspect of the condylar neck and mandibular notch of the mandible by both CT and MRI. The vascular lesion might explain the enlargement of the static bone cavity.

Corticosteroid enhances TNF-alpha-mediated leukocyte adhesion to pulmonary microvascular endothelial cells.

BACKGROUND: Some severe asthma patients are characterized by elevated levels of tumor necrosis factor alpha (TNF-alpha) and neutrophilic inflammation in the airways. Although such phenotypic changes in asthma might contribute to corticosteroid refractoriness, the role of TNF-alpha in the process remains unclear. TNF-alpha exerts its biological effects mainly by acting on the vascular endothelium, and thereby upregulates leukocyte recruitment into inflamed tissues. The aim of this study was to investigate the effects of dexamethasone (DEX) on the TNF-alpha-mediated responses of human microvascular endothelial cells from lung blood vessels (HMVEC-LBl) in vitro. METHODS: HMVEC-LBl were cultured with TNF-alpha in the presence and absence of DEX. The effects of DEX on various TNF-alpha-mediated responses, such as the expressions of chemokines and cellular adhesion molecules, leukocyte adhesion were determined. RESULTS: TNF-alpha significantly induced growth-related oncogene alpha (GRO-alpha), interleukin 8 (IL-8), regulated on activation, normal T-cell expressed and secreted (RANTES) and interferon-inducible protein 10 (IP-10) productions and cell surface expressions of intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) on HMVEC-LBl. TNF-alpha-induced GRO-alpha and IL-8 were slightly attenuated by DEX treatment (reaches to 89% and 79%, respectively), whereas expressions of IP-10, ICAM-1 and VCAM-1 were significantly enhanced by the same treatment (up to 172%, 152% and 139%, respectively). Correspondingly, in vitro adhesion of eosinophils and neutrophils to TNF-alpha-treated HMVEC-LBl were significantly enhanced by DEX. CONCLUSIONS: Some proinflammatory effects of DEX, a corticosteroid, were found in TNF-alpha-mediated in vitro reactions of pulmonary microvascular endothelial cells, i.e. chemokine productions and leukocyte adhesion. These in vitro results may explain, at least in part, the corticosteroid refractoriness accompanied by a marked increase in TNF-alpha production that is seen in severe asthmatic patients.

Inhibition of HIF-1alpha by the anticancer drug TAS106 enhances X-ray-induced apoptosis in vitro and in vivo.

In a previous study, we showed that a novel anticancer drug, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (TAS106, ECyd) increased the antitumour efficacy of X-irradiation. However, its effects on hypoxic cells in tumours remain unclarified. Here, we show that TAS106 enhances the induction of apoptosis in X-irradiated human gastric adenocarcinoma MKN45 and MKN28 cells under hypoxia in vitro. At the same time, the accumulation of HIF-1alpha observed under hypoxia was shown to be decreased to the level of normoxia in the presence of 0.1 microM TAS106. To study the function of HIF-1alpha protein in apoptosis of hypoxic cells, we employed an HIF-1alpha reductive approach using its specific antisense oligodeoxynucleotide. The reduction of HIF-1alpha gene expression dramatically enhanced X-ray-induced apoptosis in hypoxic cells. In in vivo experiments in which MKN45 cells were transplanted into severe combined immunodeficient (SCID) mice, TAS106 (0.5 mg kg(-1)) suppressed HIF-1alpha expression and subsequently reduced the area of the hypoxic region in the tumour and enhanced the induction of apoptosis in the hypoxic region when combined with 2 Gy of X-irradiation. These results suggest the possibility that TAS106 acts as a potent radiosensitiser through the inhibition of HIF-1alpha expression and can be a useful agent against radiotherapy-resistant hypoxic cells in solid tumours.

Renal amyloidosis associated with extracapillary glomerulonephritis and vasculitis in a patient with inflammatory bowel disease treated with infliximab.

A 70-year-old woman with an 11-year history of indeterminate inflammatory bowel disease developed rapidly progressive glomerulonephritis (RPGN) 3 months after the initiation of infliximab therapy. A renal biopsy showed Congo red-positive homogenous deposits in the mesangial area, glomerular capillary walls and arterial walls. Cellular and fibrocellular crescents were observed in 7 of 28 functioning glomeruli. There were findings of active tubulointerstitial nephritis and vasculitis of the small arteries. On electron microscopy, amyloid fibrils were observed in the deposits. Immunohistochemistry showed positive staining for amyloid A (AA) protein. After cessation of infliximab therapy, she was treated with methylprednisolone pulse therapy followed by oral prednisolone therapy. Thereafter, her RPGN was improved. This is a rare case of co-existent focal extracapillary glomerulonephritis with vasculitis and AA renal amyloidosis. Considering the temporal association of drug use with new onset of RPGN in our patient, we suggest a causal link between infliximab and RPGN due to extracapillary glomerulonephritis and vasculitis.

Association of free fatty acids (FFA) and tumor necrosis factor-alpha (TNF-alpha) and insulin-resistant metabolic disorder.

The roles of free fatty acids (FFA), tumor necrosis factor-alpha (TNF-alpha), and adiponectin in the development of the insulin-resistant metabolic disorder in several subjects have been studied. A total of 70 Japanese male subjects were selected according to the following three sets of criteria: subjects in group A had, (1) a fasting plasma glucose (FPG)>or=110 to <140 mg/dl, (2) a triglyceride (TG) level>or=150 mg/dl, (3) a systolic blood pressure (SBP)>or=140 and/or diastolic blood pressure (DBP)>or=90 mmHg, and (4) a body mass index (BMI)>or=25 kg/m2 (age=53.4+/-8.5 years, BMI=27.0+/-1.3 kg/m2, n=16). Subjects in group B had, (1) FPG<110 mg/dl, (2) TG<150 mg/dl, (3) SBP<140 and DBP<90 mmHg, and (4) BMI>or=25 kg/m2 (age=47.2+/-10.3 years, BMI=26.6+/-1.31 kg/m2, n=38). Subjects in group C had, (1) FPG<110 mg/dl, (2) TG<150 mg/dl, (3) SBP<140 and DBP<90 mmHg, and (4) 20>or=BMI<22 kg/m2 (age=50.4+/-9.3 years, BMI=20.9+/-0.6 kg/m2, n=16). The homeostasis model assessment of insulin resistance in group A (2.7+/-1.4) was significantly higher (p<0.0001) than in groups B (1.6+/-0.7) and C (0.9+/-0.5). FFA in group A (1.17+/-0.57 mEq/l) was significantly higher than in groups B (0.62+/-0.23 mEq/l) and C (0.48+/-0.16 mEq/l) (p<0.0001). Serum TNF-alpha in group A (1.36+/-0.62 pg/ml) was significantly higher than in groups B (0.95+/-0.35 pg/ml; p=0.003) and C (0.76+/-0.09 pg/ml; p=0.0013). No significant differences in the serum level of adiponectin were observed between groups A and B or between groups B and C. The results suggest that FFA and possibly TNF-alpha levels are closely related to the development of insulin resistance in subjects with metabolic disorders.

Improvement of criteria for refractory cytopenia with multilineage dysplasia according to the WHO classification based on prognostic significance of morphological features in patients with refractory anemia according to the FAB classification.

In the criteria of refractory cytopenia with multilineage dysplasia (RCMD) according to the WHO (World Health Organization) classification, the frequency threshold concerning dysplasia of each lineage was defined as 10%. To predict overall survival (OS) and leukemia-free survival (LFS) for patients with refractory anemia (RA) according to the French-American-British (FAB) classification, we investigated prognostic factors based on the morphological features of 100 Japanese and 87 German FAB-RA patients, excluding 5q-syndrome. In the univariate analysis of all patients, pseudo-Pelger-Huet anomalies >or=10% (Pelger+), micromegakaryocytes >or=10% (mMgk+), dysgranulopoiesis (dys G) >or=10% and dysmegakaryopoiesis (dys Mgk) >or=40% were unfavorable prognostic factors for OS and LFS (OS; P<0.001, LFS; P<0.001). The prognostic effects of the morphological features were similar in both Japanese and German patients. However, dys Mgk >or=10% was not correlated with OS and LFS. In the multivariate analysis, mMgk+ and dys Mgk>or=40% were adverse prognostic factors for OS for all patients, and dys G >or=10% and dys Mgk>or=40% were adverse prognostic factors for LFS for all patients. On the basis of the present analysis, we propose the following modified morphological criteria for RCMD. Modified RCMD should be defined as FAB-RA, excluding 5q-syndrome with dys G >or=10%, dys Mgk>or=40% or mMgk+.

Synthesis of complex nucleoside antibiotics.

Herbicidin B and fully prtected tunicaminyluracil, which were undecose nucleoside antibiotics, were synthesized using a samarium diiodide (SmI2) mediated aldol reaction with the use of alpha-phenylthioketone as an enolate. The characteristics of the SmI2-mediated aldol reaction are that the enolate can be regioselectively generated and the aldol reaction proceeds under near neutral condition. This reaction is proved to be a powerful reaction for the synthesis of complex nucleoside antibiotics. The synthesis of caprazol, the core structure of caprazamycins, was conducted by the strategy including beta-selective ribosylation without using a neighboring group participation and the construction of a diazepanone by a modified reductive amination. Our synthetic route would provide a range of key analogues with partial structures to define the pharmacophore, which can be a lead for the development of more effective anti-bacterial agents.

Suppressing effects of bisphenol A on the secretory function of ovine anterior pituitary cells.

We investigated the action of bisphenol A (BPA) on cellular GH release and content, cell number, GHmRNA expression, and concentrations of cellular cyclic AMP ([cAMP]c) and calcium ion ([Ca2+]c) in primary cultured ovine anterior pituitary cells. The following results were found: (1) BPA as well as nonylphenol (NP) at 10(-6) to 10(-3) M significantly and concentration-dependently suppressed basal and GHRH-stimulated GH release, and the cellular GH content, (2) BPA suppressed the cell number in a time- and concentration-dependent manner, (3) 10(-4)M BPA suppressed GHmRNA expression to 68% of control (BPA-free), and abolished GHRH (10(-8) M)-induced increases in [cAMP]c and [Ca2+]c. From these findings we conclude that BPA possesses a suppressing action on GH synthesis and release, and this suppressing action is probably related to impairment of cellular signal transduction systems in ovine anterior pituitary cells.

Orthodontic treatment of a case of Becker muscular dystrophy.

Becker muscular dystrophy, similar to Duchenne muscular dystrophy, is a X-chromosomal linked anomaly characterized by progressive muscle wasting and weakness. Duchenne-type is known to have severe openbite with a steep mandibular plane, but there are no studies that describe the occlusal and skeletal patterns of the Becker-type. Here, we report the orthodontic treatment of a Becker muscular dystrophy patient. In the correction of his severe skeletal open bite general anesthesia or orthognathic surgery was not an option. Multiloop edgewise archwires were employed for orthodontic treatment. After 3 years and 8 months the open bite was corrected. During the retention period contact between the anterior teeth was maintained 8 months after active treatment despite a marked relapse tendency.