High-tension electrical injury to the heart as assessed by radionuclide imaging

To evaluate cardiac complications associated with electrical injury, 7 patients with high-tension electrical injury (6,600 V alternating current) underwent 201Tl and 123I-metaiodobenzylguanidine (MIBG) imaging in addition to conventional electrocardiographic and echocardiographic assessments. Electrocardiography showed transient atrial fibrillation, second degree atrioventricular block, ST-segment depression, and sinus bradycardia in each patient. Echocardiography showed mild hypokinesis of the anterior wall in only 2 patients, but 201Tl and 123I-MIBG myocardial scintigraphy showed an abnormal scan image in 6/7 and 5/6 patients, respectively. Decreased radionuclide accumulation was seen primarily in areas extending from the anterior wall to the septum. Decreased radionuclide accumulation was smaller in extent and milder in degree in 123I. MIBG than in 201Tl imaging. These results suggest that even in patients without definite evidence of severe cardiac complications in conventional examinations, radionuclide imaging detects significant damage due to high-tension electrical injury, in which sympathetic nerve dysfunction might be milder than myocardial cell damage.     

Primary signet ring cell carcinoma of the urinary bladder: a case report

Gross hematuria and urinary frequency caused a 71-year-old man to visit our hospital. A non-papillary tumor was identified on the posterior wall of the urinary bladder and the pathological diagnosis was signet ring cell carcinoma. Upper gastrointestinal endoscopy, computed tomographic scanning, barium enema revealed no involvement of other organs. Radical cystectomy and creation of an ileal conduit were performed. The histopathological stage was pT4N1M0. Apart from subacute ileus, the postoperative course was uneventful. Signet ring cell carcinoma of the bladder is a rare entity and we have identified 41 cases in the Japanese literature. This tumor usually has a poor prognosis. Our patient is currently free from disease at 5 months after the surgery.     

Intestinal neuronal dysplasia-like pathology in Ncx/Hox11L.1 gene-deficient mice

BACKGROUND/PURPOSE: Ncx/Hox11L.1-deficient (Ncx-/-) mice specifically created by the authors had mega-ileo-ceco-colon (mega-ICC) with a caliber change in the proximal colon. The authors studied the nerve distribution in the bowel of these Ncx-/- mice to determine the cause of their bowel dysmotility. METHODS: Four-week-old Ncx-/- mice (n = 10; 5 with mega-ICC, 5 without mega-ICC) were killed and the bowel harvested. Half of each specimen was snap frozen for AchE and NADPH-diaphorase histochemistry, and the other half were fixed with 10% formalin for H&E staining and immunohistochemistry using PGP9.5 antibody (a marker for neurons), C-kit antibody (a marker for intestinal pacemaker cells), and stem cell factor antibody (a marker for C-kit ligand). Age-matched wild-type normal mice (n = 5) served as controls. RESULTS: In the ileum, cecum, and proximal colon from all Ncx-/- mice (irrespective of the association of mega-ICC), typical findings of human intestinal neuronal dysplasia (IND) ie, obvious hyperganglionosis in neuronal plexuses on PGP9.5 immunohistochemistry, ectopic ganglia in the mucosal and muscular layers on AchE histochemistry, and ghostlike ganglia on NADPH-diaphorase histochemistry were found. Likewise, in normal caliber distal colon from these mice, the distribution of ganglion cells, C-kit, and stem cell factor was normal. In control specimens, there was no ectopic ganglia or hyperganglionosis. CONCLUSIONS: These findings suggest that the Ncx/Hox11L.1 gene is required for the proper innervation of the enteric nervous system in mice, and our deficient strain may be useful as a model for studying IND in humans.     

Mild alkalinization and acidification differentially modify the effects of lidocaine or mexiletine on vasorelaxation mediated by ATP-sensitive K+ channels

BACKGROUND: The previous study by the authors showed that the class Ib antiarrhythmic drug lidocaine impairs but mexiletine augments vasorelaxation mediated by adenosine triphosphate-sensitive K+ channels. Lidocaine and mexiletine have different values of the negative logarithm of the drug-proton dissociation constant, indicating that the ion channel-blocking effects of these drugs under different pH levels may vary. However, the role of pH in the effects of lidocaine and mexiletine on vasodilation mediated by K+ channels has not been studied. Therefore, the current study was designed to examine whether the inhibition and augmentation of vasorelaxation in response to an adenosine triphosphate-sensitive K+ channel opener, levcromakalim, by the clinically relevant concentrations of lidocaine or mexiletine are modified by mild alkalinization or acidification in the isolated rat aorta. METHODS: Rings of the rat aorta without endothelium were suspended for isometric force recording. Three types of modified Krebs-Ringer solutions (pH 7.2, 7.4, and 7.6) were prepared by changing the composition of NaCl and NaHCO3. During contractions in response to phenylephrine (3 x 10(-7) M), relaxations in response to levcromakalim (10(-8) to 10(-5) M) were obtained. Lidocaine (10(-5) to 10(-4) M), mexiletine (10(-5) to 10(-4) M), or glibenclamide (10(-5) M) was applied 15 min before addition of phenylephrine. RESULTS: Relaxations in response to levcromakalim, which are abolished by the selective adenosine triphosphate-sensitive K+ channel antagonist glibenclamide (10(-5) M), were not different among the three pH groups. In the normal Krebs-Ringer solution of pH 7.4, lidocaine significantly reduced these relaxations in a concentration-dependent fashion. Alkalinization of pH 7.6 augmented the inhibitory effect of lidocaine on these relaxations, whereas acidification of pH 7.2 substantially abolished this effect. In contrast, mexiletine pH independently augmented relaxations in response to levcromakalim. Glibenclamide (10(-5) M) abolished these relaxations in arteries treated with mexiletine (10(-4) M) in any pH group. CONCLUSIONS: These results suggest that even under conditions of such mild alkalosis or acidosis, vasorelaxation via adenosine triphosphate-sensitive K+ channels is dependent on pH in the presence of clinically relevant concentrations of lidocaine but not mexiletine.     

Successful transplantation of a cadaveric kidney with post-infectious glomerulonephritis

This report describes a successful renal Tx in a patient with chronic renal failure, caused by dysplastic kidneys, who received a cadaveric kidney with post-infectious glomerulonephritis. Sequential renal biopsies were performed at 12 h before Tx, and at 1 h and on days 8 and 58 post-Tx. Post-operative hematuria disappeared on day 9 and proteinuria on day 13. Normal graft function was observed within 1 month, with histologic resolution. Our study suggests that while the donor kidney facilitates deposition of certain immune reactants, this is a host (environmental) problem and when transplanted into a new host (new environment), the problem is no longer sustained.     

Chemotherapeutic efficacy of the protein-doxorubicin conjugates on multidrug resistant rat hepatoma cell line in vitro.

In vitro studies were initiated to study the antitumour effect of protein-doxorubicin (DXR) conjugate on the growth of the multidrug resistant rat ascites hepatoma cell line, AH66DR. The 50% inhibitory concentration (IC50) for DXR in AH66DR cell line was 16 mumol l-1 (AH66 parental cell line, AH66P, IC50 was 0.08 mumol l-1). Treatment of AH66P and AH66DR cells with various concentrations of DXR or conjugates at equivalent concentrations of DXR was performed. The two types of conjugates used were bovine serum albumin (BSA)-DXR conjugate and immunoglobulin G (IgG)-DXR conjugate. Both of these conjugates showed potent dose-dependent inhibition of cell growth against AH66DR cells as compared with the cells treated with DXR or other controls. The IC50 for BSA-DXR and IgG-DXR conjugates in AH66DR cell line was 0.05 (equivalent DXR) mumol l-1 and 0.07 (equivalent DXR) mumol l-1, respectively. These values were similar to that of the AH66P treated with DXR. Cellular uptake and accumulation of DXR or BSA-DXR conjugate was also quantitated in both cell lines. The cellular concentration of DXR in AH66DR cells was 2-fold lower than that of AH66P cells throughout the experiment. In contrast, by the treatment of AH66DR cells with BSA-DXR conjugate, the intracellular drug concentration increased as a function of time up to 24 h (639.1 +/- 41.8, equivalent DXR, ng 10(-5) cells) and reached the same drug level as AH66P cells treated with DXR (617.9 +/- 17.3 ng-5 cells). Ammonium chloride treatment inhibited the effects of the conjugates but did not inhibit the free drugs. Intracellular DXR was effluxed rapidly from AH66DR cells, but BSA-DXR conjugate remained in the cells at relatively high concentration for a long time. These results indicate that by chemically modifying DXR, such as by conjugation of the drug with proteins, it may be possible to overcome multidrug resistance.     

Prognostic impact of cathepsin B and matrix metalloproteinase-9 in pulmonary adenocarcinomas by immunohistochemical study

The expression of Cathepsin B (CB) and matrix metalloproteinase-9 (MMP-9) in extirpated tissues of adenocarcinomas in non-small cell lung cancer from 90 cases was investigated immunohistologically, and the correlations between the extent of the expression and the clinicopathological features were assessed for investigating the process of tumor metastasis. It is important to reveal the mechanisms of destruction of the basal membrane and infiltration of tumor cells at the primary lesion. Sections were obtained from 10%-formalin-fixed and paraffin-embedded tissues. They were reacted with an anti-human CB polyclonal antibody or an anti-human MMP-9 polyclonal antibody. Of 90 patients, 58 (64.4%) and 39 (48.3) cases were found to be positive for CB and MMP-9 expression, respectively. A significantly higher extent of the CB expression was observed in the tissues of patients who showed postoperative recurrence of the tumor (P = 0.013). Especially, a similar observation was obtained among early cases of T1N0 (P = 0.023). In contrast, no such tendency was demonstrated in the expression profile of MMP-9. Furthermore, the enzyme expressions were compared among different types of metastases. Patients with higher extents of CB expression tended to show significantly higher rates of hematogenous and intrapulmonary metastases (P = 0.023 and P = 0.010, respectively). However, there was no significant correlation between MMP-9 expression and the prognostic factor of the patients. Therefore, we suggested that evaluation of CB expression in the tumor tissue might be useful as a postoperative prognostic factor of pulmonary adenocarcinoma. Especially, early cancer of T1N0 cases showing higher expression of CB may need postoperative adjuvant chemotherapy.     

Avoidance of bone marrow suppression using A-5021 as a nucleoside analog for retrovirus-mediated herpes simplex virus type I thymidine kinase gene therapy

Gene therapy using the herpes simplex virus thymidine kinase (HSV-TK) gene combined with an anti-herpes drug, ganciclovir (GCV), has been applied for human diseases, especially for cancer treatment. However, bone marrow toxicity has been the most consistent adverse effect of GCV treatment in clinical settings. We evaluated the cytotoxic activity of a novel guanosine analog, (1'S,2'R)-9[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanin e (A-5021), against retrovirus-mediated HSV-TK gene-transduced human lung cancer cells. The bone marrow toxicity of A-5021 and GCV was studied by colony formation assay in both rodent and human bone marrow specimens. We demonstrated that A-5021 had potent cytotoxic activity equal to that of GCV against the retroviral vector-mediated HSV-TK gene-transduced lung cancer cell lines. Further, phosphorylated A-5021 could be transferred to neighboring cells, and this analog killed HSV-TK- neighboring cells, as was the case for GCV. In contrast, A-5021 did not exhibit an inhibitory effect on bone marrow progenitor cells and colony formation (the 50% inhibitory concentration of the colony-forming units in culture = >100 microg/mL in human bone marrow specimens and >66 microg/mL in rodent bone marrow specimens). These results indicate that A-5021 has potent cytotoxic activity as a nucleoside analog for gene therapy using HSV-TK gene, and can be used much more safely than GCV.     

Inhibition of autophagy by chloroquine makes chemotherapy in nasopharyngeal carcinoma more efficient

Objectives

A combination of platinum-based chemotherapy and radiotherapy is the standard treatment for nasopharyngeal carcinoma (NPC). However, the efficacy of chemotherapy has reached a plateau. Many autophagy studies suggest that autophagy can either promote or suppress to cancer progression. Thus, a role of autophagy in the acquisition of chemoradioresistance has recently been a notable event. Therefore, we examined the relationship between autophagy and chemotherapy in NPC.