Primary hepatic low-grade B-cell lymphoma of MALT-type associated with Helicobacter pylori infection

Primary marginal zone B-cell lymphoma of mucosa associated tissue (MALT) type in the liver is extremely rare, and the etiology of this disease is yet to be clarified. We present the first report of a primary hepatic low-grade lymphoma of MALT-type associated with Helicobacter pylori (H. pylori) infection. A 64-year-old man was referred to our hospital for the treatment of early gastric carcinoma. He underwent distal gastrectomy with regional lymph node dissection. In the operation, several small nodules were recognized at the surface of the liver, and one of these hepatic nodules was resected as biopsy. The hepatic lesion exhibited a nodular growth pattern consisting of centrocyte-like cells and intermediate lymphocytes, which were stained with CD20 and CD79a, but not with CD43 or CD45RO. The neoplastic cells form lymphoepithelial lesions infiltrating bile ducts. From these findings the liver lesion was diagnosed as marginal zone B-cell lymphoma of MALT type. Histological examinations of resected stomach and residual stomach showed H. pylori infection. There is a strong association between the presence of H. pylori in the stomach and in the bile, and therefore, the H. pylori may be related to the etiology of primary hepatic MALT type lymphoma.     

Expression of mouse osteoclast K-Cl Co-transporter-1 and its role during bone resorption.

To assess the role of Cl- transport during osteoclastic bone resorption, we studied the expression and function of K+/Cl- co-transporters (KCCs). KCC1 and chloride channel-7 were found to be expressed in mouse osteoclasts. The KCC inhibitor, R(+)-butylindazone (DIOA), KCC1 antisense oligo-nucleotides, and siRNA suppressed osteoclastic pit formation. DIOA also decreased Cl- extrusion and reduced H+ extrusion activity. These results show that KCC1 provides a Cl- extrusion mechanism accompanying the H+ extrusion during bone resorption. INTRODUCTION: Mice with deficient chloride (Cl-) channels, ClC7, show severe osteopetrosis, resulting from impairment of Cl- extrusion during osteoclastic bone resorption. However, the expression and functional role of Cl- transporters other than ClC7 in mammalian osteoclasts is unknown. The aim of this study was to determine expression of K+/Cl- co-transporters (KCCs) and their functional role for bone resorption in mouse osteoclasts. MATERIALS AND METHODS: Mouse osteoclasts were derived from cultured bone marrow cells with macrophage-colony stimulating factor (M-CSF) and RANKL or from co-culture of bone marrow cells and primary osteoblasts. We examined the expression of Cl- transporters using RT-PCR, immunochemical, and Western blot methods. The effects of Cl- transport inhibitors on H+ and Cl- extrusion were assessed by measuring intracellular H+ ([H+]i) and Cl- ([Cl-]i). The effects of inhibitors, antisense oligo-nucleotides, and siRNA for Cl- transporters on bone resorption activities were evaluated using a pit formation assay. RESULTS AND CONCLUSIONS: Mouse osteoclasts express not only ClC7 but also K+/Cl- co-transporter mRNA. The existence of KCC1 in the cell membrane of mouse osteoclasts was confirmed by immunochemical staining and Western blot analysis. KCC inhibitors and Cl- channels blockers increased [Cl-]i and [H+]i in resorbing osteoclasts, suggesting that the suppression of Cl- extrusion through KCC and Cl- channels leads to reduced H+ extrusion activity. The combination of both inhibitors greatly suppressed these extrusion activities. KCC inhibitors and Cl- channel blockers also decreased osteoclastic bone resorption in our pit area essay. Furthermore, KCC1 antisense oligo-nucleotides and siRNA suppressed osteoclastic pit formation as well as treatment of ClC7 inhibitors. These results indicate that K+/Cl- co-transporter-1 expressed in mouse osteoclasts acts as a Cl- extruder and plays an important role for H+ extrusion during bone resorption.     

Comparison of myocardial perfusion imaging by thallium-201 single-photon emission computed tomography with SUNY4001 (adenosine) and exercise--crossover clinical trial at multi-center

We compared the ischemic diagnosis ability and adverse events of 201Tl myocardial perfusion imaging with SUNY4001 (adenosine) stress to that with exercise (ergometer) stress both on random crossover trial. Thirty one known or suspected chronic stable angina patients who are able to exercise and 10 healthy volunteers were enrolled for the trial. The early and delayed images were obtained by SPECT imaging. The concordance of diagnoses [ischemia vs. no ischemia] between the two types of stresses was 97.3% (36/37) [Kappa: 0.9068]. The sensitivity and specificity based on the exercise test were 100% (6/6) and 96.8% (30/31) respectively. The incidence of adverse events caused by SUNY4001 and the exercise were 44.7% (17/38) and 52.6% (20/38), respectively. Major adverse events caused by SUNY4001 were BP decrease, flushing and headache. And those by exercise were ST decrease, dyspnea and chest pain. None of the adverse events required the intervention or caused life-threatening complication in the trial. The trial showed that the ischemic diagnosis ability and safety of 201Tl scintigraphy with SUNY4001 stress are almost equal to those of the exercise stress that is considered as the standard stress method. We concluded that 201Tl imaging with SUNY4001 is safe and useful for detecting ischemic heart disease, especially for patients unable to exercise adequately.     

Improvement of carcinoembryonic antigen-specific prodrug gene therapy for experimental colon cancer

BACKGROUND: Improvement of tumor-specific gene expression is very important for achieving successful effects in prodrug gene therapy for advanced cancer with metastatic lesions. We used the Cre/loxP system for enhancing carcinoembryonic antigen (CEA)-specific prodrug gene therapy of cytosine (CD)/5-fluorocytosine (5-FC) for the treatment of a colon cancer model accompanied with liver metastases. METHODS: Orthotopic colon cancer models were developed. Seven days later, adenovirus vector (3 x 10(9) pfu)was injected into the abdominal cavity, and 5-FC was administered for the next 10 days. RESULTS: In these models, the double administration of AxCEANCre expressing Cre recombinase under the control of the CEA promoter, and AxCALNLCD expressing the CD gene under the control of the CAG promoter by the Cre-mediated switching system, completely inhibited liver metastases, and significantly reduced primary tumor volume compared to the administration of Mock or AxCEACD (P <.001). The survival periods of the mice treated with AxCEANCre and AxCALNLCD were longer than mice treated with Mock or AxCEACD, and longer than the mice treated with AxCACD (P <.05). CONCLUSIONS: The enhanced CEA-specific prodrug gene therapy using the Cre/loxP system was useful for the treatment of advanced colon cancer with liver metastases, implicating clinical application.     

Early glycemic control reduces large-for-gestational-age infants in 250 Japanese gestational diabetes pregnancies

Our objective was to test if tight glycemic control versus loose glycemic control in gestational diabetic patients and a gestational age of < 32 weeks influence fetal growth, fetal distress, and neonatal complication. We performed a retrospective study with 250 gestational diabetes mellitus in Japanese women. Two groups were categorized according to the timing at which good maternal glycemic control was attained at < 32 weeks and kept so until delivery (group 1) and > 32 weeks or never until delivery (group 2). In these two groups, neonatal growth (large-for-gestational age: LGA; appropriate- : AGA; and small- : SGA), neonatal complications (hypoglycemia, jaundice, polycythemia, and cumulative incidence), and incidence of fetal distress were compared. The chi2 test, unpaired t test, one-way analysis of variance (ANOVA) and multiple logistic regression analyses were used for statistical analyses. Maternal age, height, prepregnancy body mass index (BMI), gestational age at delivery were not different between the groups. In group 2 (> 32 weeks), LGA, macrosomia (> 4 kg), neonatal hypoglycemia was significantly increased compared with those in group 1. Incidence of SGA, fetal distress, and neonatal jaundice were not different between the groups. Multiple logistic regression analysis for LGA showed significant relation to timing of maternal glycemic control. We concluded that good glycemic control should be attained at < 32 weeks and maintained until delivery to reduce LGA infants and neonatal hypoglycemia in gestational diabetes mellitus. This management did not appear to decrease SGA infants or fetal distress.     

Theoretical analysis of T-wave polarity based on a model of cardiac electrical activity

The effect of the gradient of transmembrane action potential duration through the ventricular wall on T-wave polarity and QRS-T angle was investigated using a mathematical model of the electrical activity of the heart which incorporates the characteristic electrophysiological properties of the left ventricular wall. Two models, a rectangular solid model and a concave model, were constructed to simulate a part of the left ventricular wall. The ventricular gradient was defined as a linear decrease (beta msec/cm) of the action potential duration from the endocardium to epicardium. The theoretically-obtained relationship between the QRS-T angle and the ventricular gradient revealed that the transmural gradient (beta) was 10--40 msec/cm when the QRS-T angle was within the normal range. The positive T wave was obtained at the observation point which would correspond to the precordial lead when the transmural gradient was more than 30 msec/cm. The amplitude of the simulated T-wave increased with the ventricular gradient. Thus, our mathematical models can provide the quantitative relationship between the transmural ventricular gradient and T-wave polarity and are compatible with further simulation study for various pathological conditions.     

Availability, fermentability, and energy value of resistant maltodextrin: modeling of short-term indirect calorimetric measurements in healthy adults

BACKGROUND: Determination of the metabolizable (ME) and net metabolizable (NME) energy of total carbohydrate requires estimation of its available (AC) and fermentable (FC) carbohydrate content. Modeling of indirect calorimetric observations (respiratory gas exchange) and breath hydrogen would appear to make it possible to estimate noninvasively these nutritional quantities and the approximate time-course of availability. OBJECTIVE: We assessed the time-course of metabolism and energy availability from resistant maltodextrin (RMD) by modeling of respiratory gases after a single oral dose. DESIGN: Seventeen healthy adults (13 M, 4 F; aged 25-46 y) were randomly assigned to treatments (water, maltodextrin, or RMD) in a multiple-crossover, single-blinded trial with > or = 7 d washout. We monitored 8-h nitrogen-corrected oxygen and carbon dioxide exchanges and breath hydrogen. All treatment groups took low-carbohydrate meals at 3 and 6 h. RESULTS: Indirect calorimetry alone provided only qualitative information about the nutritional values of carbohydrate. In contrast, modeling of gaseous exchanges along with the use of central assumptions showed that 17 +/- 2% of RMD was AC and 40 +/- 4% was FC. As compared with 17 kJ gross energy/g RMD, mean (+/- SE) energy values were 7.3 +/- 0.6 kJ ME/g and 6.3 +/- 0.5 kJ NME/g. The fiber fraction of RMD provided 5.2 +/- 0.7 kJ ME/g and 4.1 +/- 0.6 kJ NME/g. CONCLUSIONS: Modeling with the use of this noninvasive and widely available respiratory gas-monitoring technique yields nutritional values for carbohydrate that are supported by enzymatic, microbial, and animal studies and human fecal collection studies. Improvement in this approach is likely and testable across laboratories.     

Streptococcal preparation OK-432 promotes the capacity of dendritic cells (DCs) to prime carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocyte responses induced with genetically modified DCs that express CEA

Cancer immunotherapy using dendritic cells (DCs) adenovirally transduced with the whole tumor-associated antigen (TAA) gene is an effective approach. Streptococcal preparation OK-432 is useful for stimulating DCs in terms of maturation. In this study, we established carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes (CTLs) using in vitro stimulation with adenovirally modified human DCs that express CEA. We investigated whether OK-432 stimulation could be more effective in inducing CEA-specific CTLs compared with other typical stimuli. DCs adenovirally transduced with the CEA gene were cultured under various conditions with tumor necrosis factor (TNF)-alpha, lipopolysaccharide (LPS), or OK-432. A cytotoxicity assay using peripheral blood mononuclear cell (PBMC)-derived CTLs was performed in a 4 h-51Cr release assay. OK-432 stimulated immature DCs to acquire a mature phenotype and to produce significant amounts of T-helper 1 cytokines. In all groups (immature DCs, TNF-alpha/DCs, LPS/DCs, OK-432/DCs), CEA-specific CTLs were generated. OK-432-stimulated DCs (HLA-A24) induced the most potent cytotoxic activity against CEA-expressing targets (A24) but not against controls. OK-432/DCs were able to induce markedly potent CTLs specific to target cells pulsed with CEA652 peptide (HLA-A24-restricted peptide), although others failed to induce potent CTLs. In conclusion, the CTL induction protocol using adenovirally modified DCs that express CEA after maturation with OK-432 showed a potent antitumor activity against CEA-expressing target cells, and is therefore promising for clinical applications as a cancer vaccine therapy.