Localization of Ca2+-activated K+ channel,SK3, in fibroblast-like cells forming gap junctions with smooth muscle cells in the mouse small intestine

In the present study, we examined the expression and the localization of apamin-sensitive small conductance Ca(2+)-activated K(+) channels (SK channels) in the mouse intestine. SK3-immunoreactivity (IR) was detected in both ileum and colon. Double staining experiments showed that SK3-IR was colocalized with prolyl 4-hydroxylase (PH(alpha))-IR, but not with c-Kit-IR which are markers of fibroblast cells and the interstitial cells of Cajal (ICC), respectively. Although SK3-IR was colocalized with vimentin-IR, which is another marker of ICC, the reactivity of SK3-immunopositive cells was weaker than that of ICC. The SK3-immunopositive cells were similarly present in the intestine of c-Kit mutant mice (W/W(V)), in which ICC were absent, and its wild-type mice. The immuno-electron microscopic analysis indicated that SK3 was localized in the cells that had some similar morphological features to ICC, but obviously different from ICC. The SK3-immunopositive cells had gap junctions with the smooth muscle cells. The gap junctions were smaller than those between ICC and smooth muscle cells. These results indicate expression of SK3 in fibroblast-like cells, but not in ICC, and suggest participation of the cells in the intestinal motility.     

Rotational 3D-conformal radiation therapy (conformation therapy) combined with hormone therapy for the treatment of stage B2/C prostate cancer in Japanese men

BACKGROUND AND PURPOSE: In our institution, rotational 3D-conformal radiation therapy (also called conformation therapy) has been applied since the late 1970s to conform the target volume of high-dose radiation to the cancerous tissue while minimizing radiation to the surrounding normal tissues. This technique has been used most commonly to treat prostate cancers in combination with hormonal therapy. The results of Stage B2/C prostate cancer treated with this method were analyzed. PATIENTS AND METHODS: Between 1987 and 1997, 33 cases of prostate cancer were definitively treated with this method: 9 Stage B2 tumors and 24 Stage C tumors. Of these 33 tumors, 3 were well differentiated, 18 were moderately differentiated, and 12 were poorly differentiated. The average patient age was 75.6 years. The median pretreatment PSA value was 23.8 ng/ml. The total radiation dose ranged from 60 Gy to 70 Gy (average: 63.5 Gy) with conventional fractionation. Hormone therapy was administered permanently; the primary hormonal agent was diethylstilbestrol phosphate. RESULTS: The overall survival rate after 5 years was 58.2% and that after 10 years was 29.6%. The biochemical relapse-free rate after 5 years was 87.0% and that after 10 years was still 87.0%. There were 4 cases of biochemical failure, but no cases of death from prostate cancer. Stage, differentiation, and pretreatment PSA value were not prognostic factors. One of the 2 cases with delayed complications was a case of RTOG Grade 3 gastrointestinal complication. CONCLUSIONS: Rotational 3D-conformal radiation therapy combined with hormone therapy might be promising for the treatment of prostate cancer.     

Paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy in elderly patients

To evaluate the validity of administration of paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy in elderly patients with gynecologic cancer, we explored the efficacy and safety of these regimens. From October 1, 1998 to September 30, 2001, we administered paclitaxel and carboplatin with or without THP-ADR pursuant to the chart we prepared originally as first line chemotherapy in patients with gynecologic cancer. Eleven elderly patients (age > 70 years) and 62 younger patients (age < 70 years) were entered into the present study. Paclitaxel was administered as a 3-hour intravenous (i.v.) infusion at dosages of 135 to 180 mg/m2 immediately followed by carboplatin over 60 minutes at dosages of area under the curve (AUC) 3 to 5, administered intravenously or intraperitoneally. We observed grade 3/4 anemia more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin without THP-ADR (9% v.s. 47%, p < 0.0001). Grade 3/4 anemia (10% v.s. 22%, p = 0.02) and grade 3/4 thrombocytopenia (7% v.s. 22%, p = 0.007), febrile neutropenia (14% v.s. 44%, p = 0.02) also occurred more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin with THP-ADR. The overall response rates were equivalent among elderly and younger patients (69% and 78%), respectively. The regimen consisting of paclitaxel and carboplatin without THP-ADR was applied safely to elderly patients.     

Severe factor VII deficiency with recurrent intracranial haemorrhages owing to double heterozygosity for a splice site mutation of an IVS4 and a novel nonsense mutation in exon 8 (Gln211-->Term)

The purpose of the present study was to predict the response of malignant lymphomas (MLs) to chemotherapy using technetium-99m methoxyisobutylisonitrile (Tc-MIBI) scan and to compare it with the predictive ability of P-glycoprotein (P-gp) expression, multidrug resistance-related protein (MRP) expression and other prognosis factors. Twenty-five ML patients were enrolled in this study prior to initiation of chemotherapy. Images were obtained 10 min after intravenous injection of Tc-MIBI, interpreted visually and the tumour-to-background (T/B) ratios calculated. Immunohistochemical analyses were performed on sections of the biopsy specimens to determine P-gp and MRP expression. Chemotherapy response was evaluated in the first 1-2 years after completion of chemotherapy. The mean T/B ratio of the 15 patients with a good response (3.3 +/- 0.6) was significantly higher than that of the 10 patients with a poor response (1.2 +/- 0.1). All 15 patients with a good chemotherapy response had positive Tc-MIBI scan results and negative P-gp and MRP expression. All 10 patients with a poor response had negative Tc-MIBI scan results and either positive P-gp or MRP expression. Other prognosis factors showed no significant difference in the incidence of good and poor responses. Tc-MIBI scan results represent P-gp or MRP expression more accurately than other prognosis factors and predict the chemotherapy response in ML patients.     

Sudden cardiac death with left main coronary artery occlusion in a patient whose presenting ECG suggested Brugada syndrome

This article describes a patient who died suddenly during Holter ECG monitoring. A ventricular premature systole with an extremely short coupling interval of 240 ms was immediately followed by torsades de pointes, soon degenerating into ventricular fibrillation. Retrospective survey of the patient's medical records revealed an incomplete right bundle branch block (iRBBB) configuration with fluctuating saddle back-type ST elevation in leads V1 and V2, these suggesting Brugada syndrome. Autopsy showed complete thrombotic occlusion of the left main coronary artery.     

PTEN/MMAC1 Mutations in Hepatocellular Carcinomas: Somatic Inactivation of Both Alleles in Tumors

Allelic loss of loci on chromosome 10q occurs frequently in hepatocellular carcinomas. Somatic mutations of the PTEN/MMAC1 gene on this chromosome at 10q23 were recently identified in sporadic cancers of the uterus, brain, prostate and breast. To investigate the potential role of PTEN/MMAC1 gene in the genesis of hepatocellular carcinomas, we examined 96 tumors for allelic loss on 10q and also for subtle mutations anywhere within the coding region of PTEN/MMAC1 gene. Allelic loss was identified in 25 of the 89 (27%) tumors that were informative for polymorphic markers in the region. Somatic mutations were identified in five of those tumors: three frameshift mutations, a 1-bp insertion at codon 83–84 in exon 4 and two 4-bp deletions, both at codon 318–319 in exon 8; two C-to-G transversion mutation, both at -9 bp from the initiation codon in the 5'non-coding region of exon 1. No missense mutation was observed in this panel of tumors. In most of the informative tumors carrying intragenic mutations of one allele, we were able to detect loss of heterozygosity as well. These findings suggest that two alleles of the PTEN/MMAC1 gene may be inactivated by a combination of intragenic point mutation on one allele and loss of chromosomal material on the other allele in some of these tumors.     

Fibrinolytic Enzyme in Tracheobronchial Secretion of Rats: Existence of Plasminogen Activator

It is known that a plasminogen activator exists in the secretion of various organs, i.e., the existence of plasminogen activator in milk, tears, saliva, seminal fluids, urine and bile has been already demonstrated. However, the existence of the fibrinolytic enzyme in tracheobronchial secretions has not been known until this time. We found a new method to collect the tracheobronchial secretion of rats, and succeeded in detecting the fibrinolytic activity in the tracheobronchial secretions. Furthermore, it was found that the substance exhibiting the fibrinolytic activity in this secretion was not protease but plasminogen activator. In addition, some chemical properties of this plasminogen activator are presented, and the physiological and pathophysiological significances of it are discussed in this paper.     

Fibrinolysis-coagulation system in patients with cancer of the head and neck

Summary Five parameters of blood coagulation and fibrinolysis, viz., levels of fibrinogen, fibrinolytic activity of euglobulin, fibrinogen and/or fibrin-degradation products (FDP), antiplasmin activity, and antithrombin activity, were measured in patients with cancer of the head and neck, and the results were compared with those of healthy adults. The fibrinogen content in cancer was significantly increased (p<0.001), the fibrinolytic activity of euglobulin significantly enhanced (p<0.001), the antiplasmin activity significantly reduced (p<0.05), the antithrombin activity significantly reduced (p<0.001), and the FDP level slightly increased, although the difference was not significant. The importance of the coagulation and fibrinolytic system in cancer of the head and neck is discussed.     

The Outcome of Gastrointestinal Stromal Tumors (GISTs) After a Surgical Resection in Our Institute

PURPOSE: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract arising from Cajal's cells and expressing c-kit. In a consensus report, the clinical behavior of GISTs was categorized into risk classes according to the tumor size and mitotic count. We analyzed the risk categories based on GIST patients who underwent a surgical resection at our institute during a period of 15 years. METHODS: We evaluated the risk categories of GISTs and analyzed the outcome and risk categories retrospectively. We presented the MIB-1 score of the tumor instead of mitotic counts for the evaluation of cellular growth because of inaccuracies regarding the mitotic counts. RESULTS: Patients were classified into 4 cases of very low risk, 11 of low risk, 8 of intermediate risk, and 5 of high risk. Four high-risk patients showed recurrence as either liver metastasis or peritoneal dissemination. In addition, local recurrence occurred in one low-risk and one intermediate-risk patient each. CONCLUSION: Our cases confirmed the correlation between the risk categories and the prognosis. A complete resection with sufficient margin must be confirmed even in low-risk cases to prevent local recurrence. Since high-risk patients showed poor prognosis, the adjuvant treatment with chemotherapeutic regimens must therefore be further studied for high-risk patients.     

Climbing exercise enhances osteoblast differentiation and inhibits adipogenic differentiation with high expression of PTH/PTHrP receptor in bone marrow cells

We developed previously a mouse voluntary climbing exercise model as a physiological mechanical loading model and reported that climbing exercise increased bone formation, but its effect on adipogenesis is unknown. We assessed the effects of loading and PTH/PTHrP receptor (PTHR1) on bone marrow adipocyte differentiation in relation with osteoblast differentiation. 8-week-old C57BL/6J male mice were divided into ground control (GC) and climbing exercise (EX) group. Mice were housed in 100-cm towers and climbed up toward a bottle placed at the top of the cage to drink water. The values of bone volume and osteoblast number were significantly higher while those of marrow adipocyte volume and number were significantly lower in the 28dayEX group than 28dayGC group. The mRNA expression levels of adipocyte differentiation genes CCAAT/enhancer-binding proteins (C/EBP) beta and delta were lower in 4dayEX mice, while the adipocyte specific genes fatty acid binding protein (aP2) and phosphoenolpyruvate carboxykinase (PEPCK) expressions were lower in 7dayEX mice. In primary bone marrow cell cultures, the number of alkaline phosphatase-positive colony forming units-fibroblastic (ALP+ CFU-f) and Oil-red-O-positive cells were both increased in the 4dayEX group. Climbing exercise transiently increases both osteogenic and adipogenic potential in bone marrow stromal cells, and inhibits terminal adipocyte differentiation and promotes osteoblast differentiation. Immunoreactivity for the PTHR1 was intense on osteoblastic cell lineage in the endosteal tibial metaphysis. PTHR1 mRNA expression was increased in 4dayEX mice and PTHR1-positive cells were increased after 7 days in the experimental group. Ex vivo addition of PTHR1 antibody decreased and that of PTHrP(1-34) increased the number of ALP+ CFU-f in bone marrow cell cultures obtained at 4 days after the exercise, while the addition of PTHR1 antibody increased and PTHrP(1-34) decreased the number of Oil-red-O-positive cells. Our results indicate that climbing exercise enhanced osteoblast differentiation and inhibited terminal differentiation of adipocyte progenitors with high expression of PTHR1 in bone marrow cells.