Oncostatin M Maintains the Hematopoietic Microenvironment and Retains Hematopoietic Progenitors in the Bone Marrow

Bone marrow (BM) functions as the primary hematopoietic tissue throughout adult life by providing a microenvironment for the proliferation, differentiation, and retention of hematopoietic stem cells and progenitors. We describe novel roles for oncostatin M (OSM) in the BM hematopoietic microenvironment. Hematopoietic progenitor activity in OSM-deficient mice was reduced in BM but elevated in the spleen and peripheral blood. The level of circulating granulocyte colony-stimulating factor (G-CSF) was increased, whereas that of stromal cell-derived factor 1 (SDF-1) was decreased in OSM-deficient mice. Moreover, the ability of OSM-deficient BM stromal cells to support hematopoiesis in vitro was significantly reduced. These results indicate that OSM plays a unique role in hematopoiesis by maintaining the proper microenvironment for BM hematopoiesis; it also retains hematopoietic progenitors in BM by regulating G-CSF and SDF-1 levels.     

Hemorrhagic Cystitis in Adults after Unrelated Cord Blood Transplantation: A Single-Institution Experience in Japan

Hemorrhagic cystitis (HC) is the main complication after hematopoietic stem cell transplantation (SCT). Adenovirus (AdV) is the leading cause of late-onset HC after SCT in Japan. The incidence and outcome of HC were studied in 77 adults who underwent unrelated cord blood transplantation (CBT).Thirty-two patients developed HC in a median of 19 days (range, 11–170 days) after CBT. The cumulative incidence of HC was 41.8% at 1 year. Ten patients developed gross hematuria. The cumulative incidence of moderate-to-severe HC was 13.2% at 1 year. Only 1 patient developed severe HC;AdV was detected in a urine sample from that patient. AdV was also detected in a urine sample from another patient with moderate HC after CBT. AdV in both patients was identified as AdV type 11. The cumulative incidence of AdV-induced HC was 2.8% at 1 year. The incidence of AdV-induced severe HC after CBT may be relatively low among Japanese adults. The role of other viruses, including BK virus, in the pathogenesis of HC after CBT needs to be examined.     

A third-generation, long-acting, dihydropyridine calcium antagonist, azelnidipine, attenuates stent-associated neointimal formation in non-human primates

BACKGROUND: Calcium antagonists have been shown to reduce atherogenesis and improve clinical outcomes in atherosclerotic vascular disease. No study has so far, however, addressed the effects of calcium antagonists on stent-associated neointimal formation. We therefore investigated whether a third-generation calcium antagonist, azelnidipine, attenuates in-stent neointimal formation in non-human primates. METHOD: Male cynomolgus monkeys were fed a high cholesterol diet for 4 weeks, and were randomly assigned to three groups: a vehicle group and two other groups treated with azelnidipine at 3 and 10 mg/kg per day for an additional 24 weeks (n = 12 each). Multi-link stents were then implanted in the iliac artery. RESULTS: Azelnidipine at the high dose reduced neointimal thickness (0.25 +/- 0.02 versus 0.19 +/- 0.02 mm; P < 0.05). Azelnidipine also reduced local oxidative stress and monocyte chemoattractant protein 1 (MCP-1) expression. No difference was found between the three groups in the degrees of injury score, inflammation score, plaque neovascularization, or plasma lipid levels. Azelnidipine also reduced MCP-1-induced proliferation/migration of vascular smooth muscle cells in vitro. CONCLUSIONS: This study demonstrated for the first time that azelnidipine attenuates in-stent neointimal formation associated with the reduced expression of MCP-1 and smooth muscle proliferation/migration in the neointima. These data in non-human primates suggest potential clinical benefits of azelnidipine as a 'vasculoprotective calcium antagonist' in patients undergoing vascular interventions.     

Time course of systolic and diastolic blood pressure decreases during the preintubation period of anesthesia induction: modeling with a logistic function

Study ObjectiveTo investigate whether systolic (SBP) and diastolic blood pressure (DBP) decreases during the preintubation period could be expressed as 4-parameter logistic and cubic functions giving S-shaped curves.DesignProspective, clinical study.SettingOperating room of a metropolitan general hospital.PatientsSeven ASA physical status I and II patients scheduled for elective spinal surgery during general anesthesia.InterventionsAnesthesia was induced with fentanyl, propofol, and vecuronium injection followed by inhalation of sevoflurane.MeasurementsThe SBP and DBP data were recorded at all beats from fentanyl injection to direct laryngoscopy. The respective changes were analyzed using a logistic function: P(t) = p_L + (q_L − p_L)/(1 + exp{[4 m_L/(q_L − p_L)][k_L − t]}) and a cubic function: P(t) = at³ + bt² + ct + d, where parameter p_L is the upper asymptote, q_L is the lower asymptote, m_L is the slope at the inflection point, and k_L is the time to the inflection point and where a, b, and c are coefficients, and d are constants. Goodness of fit of the two functions was compared using a correlation coefficient and residual mean squares. Each parameter was compared with the corresponding observed data.Main ResultsLogistic correlation coefficient values for SBP and DBP decreases were larger than the cubic correlation coefficient values (0.990 [Z transformation: 2.64 ± 0.32] vs 0.981 [Z: 2.32 ± 0.37] and 0.977 [Z: 2.22 ± 0.33] vs 0.967 [Z: 2.05 ± 0.34], respectively; P < 0.05). Logistic residual mean squares values for SBP and DBP decreases were smaller than cubic residual mean squares values (20.6 vs 41.0 and 9.2 vs 13.7 mmHg², respectively; P < 0.05). There were significant correlations between p_L and SBP or DBP after anesthesia induction, between q_L and SBP or DBP before endotracheal intubation, and between k_L and time to maximal rate of the SBP or DBP decrease (dP/dt_min), but no significant correlation between m_L and dP/dt_min for SBP or DBP.ConclusionsTime courses of SBP and DBP decreases during the preintubation period of anesthesia induction are modeled effectively by a logistic function.     

Noninvasive quantitative assessment of oral tongue cancer by intraoral ultrasonography

BACKGROUND: To assess tissue characterization of oral tongue cancer and prediction of subclinical cervical lymph node metastasis, we investigated whether intraoral ultrasonography could be used in conjunction with a computer-aided diagnosis (CAD) system. METHODS: The study population comprised 109 patients with presurgical, clinical T1N0 or T2N0 oral tongue squamous cell carcinoma who underwent partial glossectomy. All the patients were examined by preoperative intraoral and postoperative ex vivo ultrasonography. To evaluate the ultrasonic images quantitatively, ultrasonographic parameters from tumor contour features were computed by using the proposed CAD system. The imaging results were correlated with histopathologic findings. RESULTS: Oral tongue cancer was clearly identified in all patients by intraoral ultrasonography. Ultrasonic images of oral tongue cancer reflected the histopathologic structures. Subclinical cervical lymph node metastasis was predicted by intraoral ultrasonography. In a logistic regression analysis using the proposed CAD system, the diagnostic sensitivity, specificity, and accuracy for prediction of subclinical lymph node metastasis were 87.2%, 84.3%, and 85.3%, respectively. CONCLUSIONS: Intraoral ultrasonography in conjunction with the proposed CAD system allows tissue characterization and prediction of subclinical cervical lymph node metastasis.     

Bacteria isolated from surgical infections and its susceptibilities to antimicrobial agents--special references to bacteria isolated between april 2003 and march 2004

Tendency of isolated bacteria from infections in abdominal surgery during the period from April 2005 to March 2006 were investigated in a multicenter study in Japan, and the following results were obtained. In this series, 384 strains including 18 strains of Candida spp. were isolated from 161 (70.3%) of 229 patients with surgical infections. One hundred and ninty-five strains were isolated from primary infections, and 171 strains were isolated from postoperative infections. From primary infections, aerobic Gram-negative bacteria and aerobic Gram-positive bacteria were predominant, while aerobic Gram-positive bacteria were predominant from postoperative infections. The isolation rate of aerobic Gram-positive bacteria, such as Enterococcus spp. and Staphylococcus aureus were higher from both types of infections. Among anaerobic Gram-positive bacteria, the isolation rate of Peptostreptococcus spp. was the highest from both types of infections. Among aerobic Gram-negative bacteria, Escherichia coli was the most predominantly isolated from primary infections, followed by Pseudomonas aeruginosa, Klebsiella spp. in this order, and from postoperative infections, E. coli was the most predominantly isolated, followed by Klebsiella pneumoniae and P. aeruginosa. Among anaerobic Gram-negative bacteria, the isolation rate of Bacteroides fragilis group was the highest from both primary and postoperative infections. In this series, we noticed no vancomycin-resistant Gram-positive cocci, nor multidrug-resistant P. aeruginosa. But cefazolin-resistant E. coli producing extended spectrum fl-lactamase was seen in 5.0 per cents. We should be carefully followed up the facts that the increasing isolation rates of B. fragilis group and Bilophila wadsworthia which were resistant to both penicillins and cephems.     

Paclitaxel-2′-Ethylcarbonate Prodrug Can Circumvent P-glycoprotein-mediated Cellular Efflux to Increase Drug Cytotoxicity

Purpose The aim of the study was to investigate whether 2′-ethylcarbonate-linked paclitaxel (TAX-2′-Et) circumvents P-glycoprotein (P-gp)-mediated cellular efflux and cytotoxicity enhanced by TAX-2′-Et activation within human culture cells transfected with a rabbit liver carboxylesterase (Ra-CES) cDNA. Materials and Methods TAX-2′-Et transport was characterized in a human colon carcinoma cell line (Caco-2) and paclitaxel (TAX)-resistant ovarian carcinoma cells (SKOV3/TAX60). Expression of P-gp, multidrug resistance protein (MRP) 2 and Ra-CES was detected by Western blotting. Cytotoxicity against Ra-CES-expressing cells and cellular amount of TAX produced were determined by MTT assay and using HPLC, respectively. Results Unlike rhodamine123 and TAX, TAX-2′-Et did not exhibit polarized transport in the Caco-2 cells in the absence or presence of verapamil. P-gp levels were expressed much higher in the SKOV3/TAX60 cells than in the Caco-2 cells. MRP2 protein was not detectable in the SKOV3/TAX60 cells. Uptake by the SKOV3/TAX60 cells was similar in quantity to the amount internalized by P-gp-negative SKOV3 cells. In the SKOV3/TAX60 cells, cellular uptake of TAX-2′-Et was not altered regardless of the absence or presence of verapamil. The cytotoxicity to the untransfected SKOV3 cells induced by TAX-2′-Et was significantly lower than that induced by TAX. In the Ra-CES-expressing SKOV3 line, the EC₅₀ value of TAX (10.6 nM) was approximately four-fold higher than that of TAX-2′-Et (2.5 nM). Transfection of Ra-CES into another TAX-resistant ovarian carcinoma cells (KOC-7c) conferred a high level of TAX-2′-Et cytotoxicity via prodrug activation. The intracellular levels of TAX produced from TAX-2′-Et in the Ra-CES-positive KOC-7c cells significantly increased compared with the levels seen in exposure of the untransfected KOC-7c cells to TAX. Conclusions TAX-2′-Et can circumvent P-gp-associated cellular efflux of TAX. TAX-2′-Et is converted into TAX by the Ra-CES, supporting its potential use as a theoretical GDEPT strategy for cancer cells expressing high levels of P-gp. The TAX-2′-Et prodrug efficiently increased the amount of intracellular TAX, which mediates tumor cell death.     

Pharmacological characterization of 5-Hydroxytryptamine-receptor subtypes in circular muscle from the rat stomach

5-Hydroxytryptamine (5-HT) modulates gastric motility and gastric emptying via a variety of 5-HT receptor subtypes. However, regional and functional differences among 5-HT receptor subtypes in the rat stomach are not fully investigated. Thus, we aimed to characterize 5-HT receptor subtypes involved in the 5-HT-induced contractions in the isolated antral, corporal and fundic circular muscles of the rat stomach by measuring the contractile force. 5-HT induced concentration-dependent contractions in the antrum, corpus and fundus. 5-HT-induced antral contractions were partly blocked by atropine and enhanced by tetrodotoxin (TTX). Neither atropine nor TTX affected the corporal or the fundic contractions to 5-HT. In the antrum, 5-HT-induced contractions were inhibited by methysergide, tended to be inhibited by ketanserin, enhanced by SB-203186, but were not affected by WAY-100635, GR127935, RS-127445, ondansetron, or SB-269970. In the corpus, 5-HT-induced contractions were inhibited by ketanserin or methysergide. In the fundus, 5-HT-induced contractions were blocked by methysergide or RS-127445, but were enhanced by cinanserin or SB-203186. It is thus concluded that contractile responses to 5-HT in the antrum are mediated by 5-HT receptors on both smooth muscle and neurons whilst in the corpus and fundus responses are mainly mediated by 5-HT receptors on smooth muscle. Moreover, the antrum presents the contractile 5-HT2A and 5-HT2B receptors and the relaxant 5-HT4 receptors. The corpus presents the contractile 5-HT2A receptors, and the fundus presents the contractile 5-HT2B receptors and the relaxant 5-HT2A and 5-HT4 receptors.