Characteristic endoscopic findings of gastrointestinal malignant lymphomas other than mucosa-associated lymphoid tissue lymphoma.

Background and study aims: The gastrointestinal (GI) tract is the most common site of extra-nodal involvement for non-Hodgkin's lymphoma (NHL). The features of GI NHLs remain unclear. The aim of this study was to clarify endoscopic characteristics of GI NHLs. Patients and methods: We retrospectively analyzed the morphological characteristics of 63 GI malignant lymphomas other than mucosa-associated lymphoid tissue lymphoma. Lesions were diagnosed between 2005 and 2020. Macroscopic findings were classified into five subtypes: superficial (S); protruding without ulcer (P); protruding with ulcer (PU); fungating (F); and multiple nodules (MN). Results: Thirty-one lesions in the stomach were classified as S type in 3 cases (9.6%), P type in 6 (19%), PU type in 13 (42%), and F type in 9 (29%). In the stomach, the ulcerated phenotype was more frequent for diffuse large B-cell lymphoma (DLBCL) (89.5%) than for other histological types (41.7%; P = 0.01). In the intestine, 23 tumors were classified as S type in 4 cases (17%), P type in 1 (4%), PU type in 6 (26%), F type in 1 (4%), and MN in 11 (48%). Eleven of the 14 cases (78.6%) of intestinal follicular lymphoma lesions showed MN type. In the colon, eight tumors were classified as S type in 2 cases (25%), P type in 2 (25%), PU type in 1 (13%), and F type in 3 (38%). Conclusion: We have clarified the endoscopic features of GI NHL using macroscopic classifications. The ulcerated phenotype was the most frequent endoscopic finding for DLBCL.

Contribution of pharmacists with expertise in infectious diseases to appropriate individualized vancomycin dosing.

BACKGROUND/AIM: Dose adjustment of vancomycin (VCM) is important in improving clinical outcomes and avoiding adverse effects such as nephrotoxicity. Although pharmacist-managed VCM therapy has been reported to optimize treatment, there are no studies focused on pharmacist expertise to date. In this study, we compared the contribution of pharmacists trained for infectious diseases and general pharmacists to dose adjustment of VCM. PATIENTS AND METHODS: We retrospectively investigated VCM trough concentration after dose adjustment by both trained (n = 67) and general (without special training for infectious diseases; n = 85) pharmacists. We also compared the incidence of nephrotoxicity during VCM treatment in both groups. RESULTS: The rate of achieving therapeutic VCM trough concentration (10-20 µg/mL) was higher in the trained group than in the control group (80.6 vs. 54.1%, p < 0.001). No significant differences in incidence of nephrotoxicity were observed between the two groups (p = 0.744). Trained pharmacists could contribute more successfully to the achievement of therapeutic VCM concentration ranges without increasing the risk of nephrotoxicity.

Proteomic signatures and aberrations of mouse embryonic stem cells containing a single human chromosome 21 in neuronal differentiation: an in vitro model of Down syndrome.

Neurodegeneration in fetal development of Down syndrome (DS) patients is proposed to result in apparent neuropathological abnormalities and to contribute to the phenotypic characteristics of mental retardation and premature development of Alzheimer disease. In order to identify the aberrant and specific genes involved in the early differentiation of DS neurons, we have utilized an in vitro neuronal differentiation system of mouse ES cells containing a single human chromosome 21 (TT2F/hChr21) with TT2F parental ES cells as a control. The paired protein extracts from TT2F and TT2F/hChr21 cells at several stages of neuronal differentiation were subjected to two-dimensional polyacrylamide gel electrophoresis protein separation followed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry to identify the proteins differentially expressed between TT2F and TT2F/hChr21 cells. We provide here a novel set of specific gene products altered in early differentiating DS neuronal cells, which differs from that identified in adult or fetal brain with DS. The aberrant protein expression in early differentiating neurons, due to the hChr21 gene dosage effects or chromosomal imbalance, may affect neuronal outgrowth, proliferation and differentiation, producing developmental abnormalities in neural patterning, which eventually leads to formation of a suboptimal functioning neuronal network in DS.

Mutagens formed from beta-carbolines with aromatic amines.

Norharman, widely distributed in our environment such as cigarette smoke and cooked foods, is not mutagenic to Salmonella strains, but becomes mutagenic to Salmonella typhimurium TA98 and YG1024 with S9 mix in the presence of aromatic amines, including aniline and o-toluidine. Therefore, we have designated norharman as a "co-mutagen". Since, humans are simultaneously exposed to norharman and aromatic amines in daily life, it is important to clarify the mechanisms of its co-mutagenic action to further understanding of the potential genotoxic effects in humans. Regarding the mechanisms of this action of norharman with aniline, a mutagenic compound, 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole[aminophenylnorharman (APNH)] is produced by their interaction, and converted to the hydroxyamino derivative which eventually forms the DNA adduct, dG-C8-APNH through possible ultimate reactive forms with esterification, and this induces mutations. Also other aminophenyl-beta-carboline compounds, such as 9-(4'-amino-3'-methylphenyl)-9H-pyrido[3,4-b]indole[amino-3'-methylphenylnorharman (3'-AMPNH)], 9-(4'-amino-2'-methylphenyl)-9H-pyrido[3,4-b]indole [amino-2'-methylphenylnorharman (2'-AMPNH)], 9-(4'-aminophenyl)-1-methyl-9H-pyrido[3,4-b]indole[aminophenylharman (APH)] and 9-(4'-amino-3'-methylphenyl)-1-methyl-9H-pyrido[3,4-b]indole[amino-3'-methylphenylharman (AMPH)], have been found on reaction of norharman or harman with aniline or toluidine isomers. These compounds showed mutagenic and clastogenic actions in bacterial and mammalian cells. Among them, APNH demonstrated the most potent activity, and it was most extensively studied. When APNH was administered as a single dose to F344 rats, severe testicular toxicity was observed after 6 days. Moreover, liver preneoplastic lesions (GST-P-positive foci) in the liver clearly developed in animals fed 10-50 ppm of APNH in the diet for 4 weeks. Since, APNH was detected in 24 h urine of rats upon simultaneous administration with norharman and aniline by gavage, it is likely to be also produced from norharman and aniline in the human body. From these findings, it is suggested that aminophenyl-beta-carboline derivatives may be classified as one of the novel types of endogenous mutagens and carcinogens.

A new mouse model for Down syndrome.

Trisomy 21 (Ts21) is the most common live-born human aneuploidy and results in a constellation of features known as Down syndrome (DS). Ts21 is a frequent cause of congenital heart defects and the leading genetic cause of mental retardation. Although overexpression of a gene(s) or gene cluster on human chromosome 21 (Chr 21) or the genome imbalance by Ts21 has been suggested to play a key role in bringing about the diverse DS phenotypes, little is known about the molecular mechanisms underlying the various phenotypes associated with DS. Four approaches have been used to model DS to investigate the gene dosage effects of an extra copy of Chr 21 on various phenotypes; 1) Transgenic mice overexpressing a single gene from Chr 21, 2) YAC/BAC/PAC transgenic mice containing a single gene or genes on Chr 21, 3) Mice with intact/partial trisomy 16, a region with homology to human Chr 21 and 4) Human Chr 21 transchromosomal (Tc) mice. Here we review our new model system for the study of DS using the Tc technology, including the biological effects of an additional Chr 21 in vivo and in vitro.

Risk factors for development of postoperative hypertension.

One hundred and eighty-nine patients who underwent digestive tract surgery were studied to investigate risk factors for the development of postoperative hypertension. We examined factors related to maximum postoperative systolic blood pressure and postoperative hypertensive urgency, a sign of postoperative hypertension. Data collected included blood pressure, age, sex, body mass index (BMI), medical history, total water balance and grade of surgical stress. Maximum postoperative systolic blood pressure and incidence of postoperative hypertensive urgency were the dependent variables. Mean preoperative systolic blood pressure, age and BMI were significantly related to maximum postoperative systolic blood pressure and postoperative hypertensive urgency. In addition, the grade of surgical stress was significantly related to maximum postoperative systolic blood pressure. In analyses of multiple variables, the adjusted odds ratio for postoperative hypertensive urgency was 1.16 for every 1 mmHg increase in mean preoperative systolic blood pressure, 1.05 for every 1 year increase in age and 0.82 for every 1 kg/m2 increase in BMI. These findings may have important clinical implications for the prevention of postoperative hypertension.

Pharmacokinetic study of a gallium-porphyrin photo- and sono-sensitizer, ATX-70, in tumor-bearing mice.

The tissue distribution of a gallium-porphyrin photo- and sono-sensitizer, 7,12-bis(1-decyloxyethyl)-Ga(III)-3,8,13,17-tetramethylporphyrin-2,18-dipropionyldiaspartic acid, ATX-70, was pharmacokinetically examined in tumor-bearing mice. The drug was administered intravenously to CDF(1) mice implanted with Colon 26 carcinoma. Blood and tissue samples were collected for up to 72 h after administration. The drug concentration was determined by high-performance liquid chromatography (HPLC) with fluorescence detection. ATX-70 was found to accumulate in tumors at a relatively high concentration that peaked between 2 h and 6 h after administration. However, modest concentrations of ATX-70 also remained in healthy tissues for up to 6 h. We examined the distribution of ATX-70 in the tumor in comparison with other tissues from the viewpoint of minimizing possible side effects of laser or ultrasound exposure while maintaining the treatment effect. About 24 h after administration, the tumor / plasma concentration ratio peaked, and relatively high tumor / skin and tumor / muscle concentration ratios were seen.

Resting ultrasonic tissue characterization and dobutamine stress echocardiography for prediction of functional recovery in chronic left ventricular ischemic dysfunction.

This study was designed to assess the diagnostic accuracy of the percentage of resting systolic wall thickening (WT), dobutamine stress echocardiography (DSE), resting cyclic variation of integrated backscatter (IBS-CV), and low-dose dobutamine stress IBS-CV (DSE-IB) for the prediction of regional function recovery (RFR) in patients with chronic left ventricular (LV) ischemic dysfunction. The study also evaluated whether or not global LV function affected the diagnostic accuracy. All studies were conducted before percutaneous transluminal coronary angioplasty (PTCA) and RFR was assessed after PTCA (mean interval, 10 months) in 30 patients with chronic LV ischemic dysfunction. Patients were divided into 2 groups according to the LV ejection fraction (LVEF): group A, LVEF<40%, n=14; group B, LVEF> or =40%, n=16. Of a total of 480 segments, 37 initially demonstrating akinetic wall motion before PTCA were analyzed. The wall motion of 24 of the 37 segments improved on visual analysis after PTCA. In the prediction of RFR, resting WT, DSE, resting IBS-CV and DSE-IB had sensitivities of 79%, 79%, 92% and 62%, and specificities of 54%, 84%, 83% and 69%, respectively. In particular, the resting IBS-CV in group A, as well as DSE, was an excellent predictor of RFR (sensitivity, 100%; specificity, 86%; vs sensitivity, 82%; specificity, 78%; respectively). Therefore, both resting IBS-CV and DSE are useful predictors for RFR in patients with chronic LV ischemic dysfunction.

Large-scale evaluation of imprinting status in the Prader-Willi syndrome region: an imprinted direct repeat cluster resembling small nucleolar RNA genes.

Loss of paternal gene expression at the imprinted domain on proximal human chromosome 15 causes Prader-Willi syndrome (PWS), a complex multiple-anomaly disorder involving variable mental retardation, hyperphasia leading to obesity and infantile hypotonia with failure to thrive. Although numerous paternally expressed transcripts have been identified that reside in the candidate region, the individual contributions to the development of PWS have not been firmly established. Recent studies of mouse models carrying a cytogenetic deletion suggest that paternal deficiency of the SNRPN-IPW interval is critical for perinatal lethality of potential relevance to PWS. Here we determined the allelic expression profiles of a total of 118 cDNA clones using monochromosomal hybrids retaining either a paternal or maternal human chromosome 15. Our results demonstrated a preponderance of unusual transcripts lacking protein-coding potential that were expressed exclusively from the paternal copy of the critical interval. This interval was also found to encompass a large direct repeat (DR) cluster displaying a potentially active chromatin conformation of paternal origin, as suggested by enhanced sensitivity to nuclease digestion. Database searches revealed an unexpected organization of tandemly repeated consensus elements, all of which possessed well-defined box C and D sequences characteristic of small nucleolar RNAs (snoRNAs). Southern blot analysis further demonstrated a considerable degree of phylogenetic conservation of the DR locus in the genomes of all mammalian species tested, but not in chicken, Xenopus and Drosophila. These findings imply a potential direct contribution of the DR locus, representing a cluster of multiple snoRNA genes, to certain phenotypic features of PWS.

Localization of extracellular matrix and mitogen-activated protein kinase (MAPK) in aorta of streptozotocin treated Mongolian gerbils.

To evaluate the relationship among the extracellular matrix (ECM) and mitogen-activated protein kinase (MAPK) family for the vascular damages in hyperglycemia, we injected Mongolian gerbils intravenously with 150 mg/kg streptozotocin (STZ) and observed over the next one year the resulting aortic changes by immunohistochemical techniques. After STZ treatment, hyperglycemia was confirmed. At 4 weeks after STZ administration morphological observation revealed increased stromal components among the vascular smooth muscle cells (SMCs). Immunohistochemically, extracellular matrices such as fibronectin and laminin were localized in the aorta at 4 weeks and one year after STZ administration. The reaction products of MAPK in vascular SMCs were more increased at one year than at 4 weeks after STZ administration. After STZ administration, the increase of ECM and MAPK was observed in the aorta, which suggests these factors play important roles in the pathogenesis of macrovasculopathy in diabetes mellitus.

Characterization and overproduction of EcoO109I methyltransferase.

In order to characterize EcoO109I methyltransferase, a recombinant Escherichia coli clone that overproduces the enzyme was constructed. The coding region of M.EcoO109I was joined to the lac promoter of an expression vector, pUC118, and the resulting plasmid was introduced into E. coli HB101. M.EcoO109I was purified homogeneously from IPTG-induced cells, and was found to consist of a monomer subunit. M.EcoO109I uniquely methylates the inner deoxycytidylate residue in the sequence 5'-(A/G)GGNCC(C/T)-3' to produce 5-methylcytosine. The enzyme was most active at pH 8.0-8.5 and 50 degrees C. The enzyme activity was not affected by the addition of Mg2+ or EDTA.

Sonodynamically induced antitumor effect of Photofrin II on colon 26 carcinoma.

The sonodynamically induced antitumor effect of Photofrin II (PF), was evaluated in mice bearing colon 26 carcinoma. In order to find the optimum timing for ultrasonic exposure after the administration of PF, the PF concentrations in the plasma, skin, muscle, and tumor were measured. The antitumor effect was estimated by measuring the tumor size. Since the highest concentration of PF in the tumor was observed 24 h after administration, an ultrasonic exposure timing of 24 h after the intravenous administration of PF was chosen. When used alone, ultrasound showed a slight antitumor effect, which became increasingly significant as the dose of PF was increased, while use of PF alone showed no significant effect. From these results, it is concluded that PF significantly sensitizes solid tumors to ultrasound, demonstrating a synergistic antitumor effect.

Ultrasonically induced cell damage enhanced by photofrin II: mechanism of sonodynamic activation.

UNLABELLED: Ultrasonically induced cell damage and active oxygen generation with photofrin II (PF) were compared in the same in vitro insonation setup. MATERIALS AND METHODS: Sarcoma 180 cells suspended in air-saturated PBS were exposed to ultrasound for up to 60 seconds in the presence and absence of PF. The viability was determined by the Trypan Blue exclusion test. Ultrasonically induced active oxygen generation in the presence and absence of PF in air-saturated aqueous solutions of 50 mM 2,2,6,6-tetramethyl-4-piperidone was detected by electron spin resonance (ESR) spectrum. RESULTS: Significant enhancement of the rates of both ultrasonically induced cell damage and nitroxide generation was demonstrated with 20-80 micrograms/ml PF. Both rates correlated very well. The enhancement of both rates with PF was suppressed by 10 mM histidine. CONCLUSION: These results may suggest that ultrasonically generated active oxygen plays a primary role in ultrasonically induced cell damage in the presence of PF.

Sonodynamically induced antitumor effect of 4-formyloximethylidene-3-hydroxy-2-vinyl-deuterio-porphynyl(IX)-6,7-dia spartic acid (ATX-S10).

The sonodynamically induced antitumor effect of 4-formyloximethylidene-3-hydroxy-2-vinyl-deuterio-porphyn yl(IX)-6,7-diaspartic acid (ATX-S10) was investigated. Both in vitro and in vivo antitumor effects were tested in combination with ultrasound at 2 MHz. The rate of ultrasonically induced damage to isolated sarcoma 180 cells in air-saturated suspension was enhanced two-fold with 80 microM ATX-S10. This enhancement was significantly inhibited by histidine, which may suggest that it was mediated by ultrasonically induced oxidation. The coadministraion of 25 mg/kg ATX-S10 followed by ultrasonic exposure at 2 MHz stopped the growth of implanted colon 26 tumors at an intensity at which ultrasound alone showed only a slight antitumor effect.

A detailed linkage map of medaka, Oryzias latipes: comparative genomics and genome evolution.

We mapped 633 markers (488 AFLPs, 28 RAPDs, 34 IRSs, 75 ESTs, 4 STSs, and 4 phenotypic markers) for the Medaka Oryzias latipes, a teleost fish of the order Beloniformes. Linkage was determined using a reference typing DNA panel from 39 cell lines derived from backcross progeny. This panel provided unlimited DNA for the accumulation of mapping data. The total map length of Medaka was 1354.5 cM and 24 linkage groups were detected, corresponding to the haploid chromosome number of the organism. Thirteen to 49 markers for each linkage group were obtained. Conserved synteny between Medaka and zebrafish was observed for 2 independent linkage groups. Unlike zebrafish, however, the Medaka linkage map showed obvious restriction of recombination on the linkage group containing the male-determining region (Y) locus compared to the autosomal chromosomes.

Immunohistochemical localization of mitogen-activated protein kinase (MAPK) family and morphological changes in rat heart after ischemia-reperfusion injury.

The mitogen-activated protein kinase (MAPK) family is considered to be activated by stress, but the role of the MAPK family is still unknown in cardiac pathology. In the present study, not only the localization of MAPKs such as the extracellular responsive kinase (ERK), c-jun N-terminal kinase (JNK), and p38 MAPK (p38), but also ultrastructural changes were investigated in the ischemia-reperfusion model of Wistar rats. At 5, 10, 30, 60, and 180 min reperfusion after 30 min ischemia by occluding the coronary artery, the expression of these MAPKs was increased in blood vessels and cardiomyocytes by Western blotting and immunohistochemical methods. In addition, after ischemia reperfusion, various ultrastructural changes such as decreased glycogen granules, mitochondrial swelling, and myolysis were observed in the blood vessels and cardiomyocytes. These results suggest that protein kinases may regulate numerous biological processes, including the regulation of contraction and ion transport.

Effect of cyclobutane pyrimidine dimers on apoptosis induced by different wavelengths of UV.

Ultraviolet radiation within three different wavelength ranges, UVA (340-400 nm), UVB (290-320 nm) or UVC (200-290 nm), was shown to induce apoptosis in OCP13 cells, derived from the medaka fish. Morphological changes such as cell shrinkage and a decrease in the number of nucleoli appeared 4 h after UVA, UVB or UVC irradiation, although with different relative efficiencies. Doses required to induce apoptosis with similar efficiencies were about 2500-fold higher for UVA and 10-fold higher for UVB than for UVC. The following phenomena occurred after UVA irradiation but not after UVB or UVC irradiation. (1) Ultraviolet-A-induced cell detachment occurred with or without cycloheximide pretreatment. (2) Cells attached to plastic showed morphological changes such as rounding up of nuclei without a change in the cell distribution. (3) Morphological changes after UVA irradiation could not be evaded by photorepair treatment. (4) Morphological changes did not occur in cells attached to glass coverslips but only those in plastic dishes. (5) Apoptosis occurred without detectable increase of caspase-3-like activity. (6) Morphological changes were inhibited by N-acetylcysteine, a scavenger of active oxygen species. These results suggest the existence of two different pathways leading to apoptosis, one for long- (UVA) and the other for short- (UVB or UVC) wavelength radiation.

Ultrastructural changes and immunohistochemical localization of nitric oxide synthase, advanced glycation end products and NF-kappa B in aorta of streptozotocin treated Mongolian gerbils.

To evaluate the relationship among the induction of nitric oxide synthase (NOS), advanced glycation end products (AGEs) and NF-kappa B for vascular damage in hyperglycemia, we injected Mongolian gerbils intravenously with 150 mg/kg streptozotocin (STZ) and observed over the next one year the resulting aortic changes by immunohistochemical and electron microscopical techniques. After STZ treatment, hyperglycemia was confirmed and body weight transiently decreased. Morphological observation revealed no remarkable changs in vascular endothelial cells or vascular smooth muscle cells in the aorta at one week after STZ administration. After 4 weeks increased collagen fibrils were observed in the pericellular spaces of media. At one year after STZ administration, increased collagen fibrils and thickened elastic fibers were found around the vascular smooth muscle cells with vacuolization and increased cytoplasmic organellae compared with non-treated animals of the same age. Immunohistochemically endothelial constitutive NOS (ecNOS) was localized in the endothelium of the aorta of Mongolian gerbils. At one year after STZ administration, the reaction products of iNOS, AGEs and NF-kappa B in vascular endothelial cells and smooth muscle cells were much more greatly increased than at one week and 4 weeks. After STZ administration, the localization of NOS, AGEs and NF-kappa B was observed in the aorta, which suggests these factors play important roles in the pathogenesis of vasculopathy in diabetes mellitus.

Sonodynamically induced cell damage with 4'-O-tetrahydropyranyladriamycin, THP.

BACKGROUND: 4'-O-tetrahydropyranyladriamycin (THP) is a novel anthracycline derivative with cardiotoxicity significantly lower than ADM. In this study, the ultrasonically induced in vitro cell damaging effect of THP was investigated. MATERIALS AND METHODS: Sarcoma 180 cells suspended in air-saturated PBS were exposed to ultrasound for up to 60 s in the presence and absence of THP. The viability of the isolated cells was determined by staining of the cells with Trypan Blue dye. RESULTS: The rate of inducing cell damage with ultrasound was doubled with 80 microM THP, while no cell damage was observed with THP alone. CONCLUSION: The enhancement of ultrasonically induced in vitro cell damage was demonstrated with THP. This enhancement was significantly inhibited by histidine, which may suggest a sonochemical mechanism.