Superior mesenteric artery is more important than inferior mesenteric artery in maintaining colonic mucosal perfusion and integrity in rats

Mucosal hemodynamics (by reflectance spectrophotometry) and mucosal damage (by histologic examination) following acute colonic ischemia were evaluated in different anatomic locations in the colon of anesthetized rats. The reflectance spectrophotometer provides an index of mucosal hemoglobin concentration (IHB) and an index of oxygen saturation of hemoglobin (ISO₂). The patterns of ischemia without congestion (IHB, ISO₂) during superior mesenteric artery occlusion, and ischemia with congestion (IHB, ISO₂) during portal vein occlusion, previously demonstrated in the stomach and duodenum, are also applicable to the colon. The significant linear correlations between changes (as percent of baseline) in IHB, ISO₂, and hydrogen gas clearance suggest that changes in these indices are adequate indicators of changes in colonic mucosal perfusion. Superior mesenteric artery ligation produced significant reductions in both indices, and an increase in damage in the mucosa of the cecum, transverse colon, splenic flexure, and left colon, but not the rectum. Inferior mesenteric artery ligation produced only slight reduction in these indices and minimal damage only in the mucosa of the splenic flexure. These results support the hypothesis that the superior mesenteric artery is more important than the inferior mesenteric artery in maintaining colonic perfusion and colonic mucosal integrity in the rat.Supported by the American Society for Gastrointestinal Endoscopy Career Development Award (H850208, H870212), Veterans Administration Medical Research Funds; and in part by research grants (0162-01, 0162-02; 0291-01) from the Smokeless Tobacco Research Council, Inc.; and by funds provided by the Cigarette and Tobacco Surtax Fund of the State of California through the Tobacco Related Disease Research Program of the University of California.     

Clonal structural chromosome aberrations in fibrous dysplasia

Cytogenetic analysis of short-term cultures from a case of monostotic fibrous dysplasia in a 14-year-old girl revealed multiple clonal structural rearrangements with evidence of clonal evolution. The karyotype was 46,XX,del(3)(q27),add(10)(q22), add(12)(p13)/46,idem,t(3;8)(p21;q13),add(10)(q26),der(15)del(15)(q15q22)ins(15;?)(q15;?)/46,idem,-X, + 2,t(3;8),add(10),der(15). The finding of clonal structural aberrations suggests that fibrous dysplasia is a neoplastic lesion which develops as the result of somatic mutations.     

Chromosome analysis of 20 breast carcinomas: Cytogenetic multiclonality and karyotypic-pathologic correlations

Short-term cultures from 20 breast carcinomas were analyzed cytogenetically. A normal female chromosome complement was found in 4 cases. Clonal chromosome aberrations were detected in 16 tumors. In 10 tumors, multiple cytogenetic clones were found; in 2 cancers the clones were related, reflecting clonal evolution, but in the remaining 8 tumors the clones were cytogenetically unrelated, indicating clonal heterogeneity in the origin of the tumor parenchyma. Correlation analysis between karyotypic and pathologic parameters indicated that cases with complex karyotypes and/or cytogenetically unrelated clones, when compared with cases with a single simple karyotypic abnormality, were generally of higher histologic malignancy grade, had more mitoses in the histologic sections, and also more often had carcinoma in situ lesions in the same breast. © 1993 Wiley-Liss, Inc.     

Frequent rearrangement of chromosomal bands 1p22 and 11q13 in squamous cell carcinomas of the head and neck

We report the finding of clonal structural chromosome abnormalities in short-term cultures from 15 squamous cell carcinomas of the head and neck region. When the distribution of chromosomal breakpoints in these 15 tumors and in the 16 head and neck carcinomas previously described are assessed, a marked clustering is seen at bands 1p22 and 11q13, which are rearranged in eight and nine tumors, respectively. No other band was involved in aberrations in more than five tumors. Cytogenetic evidence of gene amplification was seen in four tumors, three times in the form of homogeneously staining regions (twice located in 11q13), and in one tumor as double minutes. Among the candidate genes for such amplification are BCLI, INT2, and HSTI, all of which map to 11q13, and NRAS, which maps to 1p22. All these oncogenes have previously been shown to be amplified in subsets of head and neck carcinomas. We conclude that bands 1p22 and 11q13 are nonrandomly involved in chromosomal rearrangements in head and neck carcinomas and suggest that activation of oncogenes located in these bands may proceed via cytogenetic mechanisms.     

Hemodynamic profile of arpromidine and its F2-substituted derivatives in comparison to impromidine in congestive heart failure

There is considerable evidence that congestive heart failure (CHF) is paralleled by a decrease in the number of sarcolemmal β-receptors due to excessive levels of circulating endogenous catecholamines [1, 2]. In contrast, the myocardial H₂-receptor system is not affected. The first clinically available specific H₂-receptor agonist impromidine proved to be a potent inotrope in patients with CHF which were insensitive to catecholamine stimulation [3, 4]. Though the overall results of these initial studies were beneficial, the narrow therapeutic range, high costs of synthesis and the arrhythmogenic potential of impromidine limited its broad clinical application in large scale clinical trials. Recently developed phenylpyridylalkylguanidines [5] were investigated underin vitro andin vivo conditions in the guinea pig under physiologic and pathophysiologic conditions using impromidine as reference. Compounds tested were arpromidine and the difluorinated analogues BU-E-75 and BU-E-76, all guanidine-type H₂-agonists with additional H₁-antagonistic properties due to a pheniramine like moiety. In the isolated perfused heart, all three new compounds were more potent in increasing cardiac contractile force and coronary flow but less effective on heart rate and less arrhythmogenic. The same could be established underin vivo conditions where BU-E-76 was more potent than BU-E-75, arpromidine and impromidine, respectively, in augmenting LV dp/dt, LVP, cardiac output and systemic blood pressure, but all compounds were revealed to have less chronotropic and arrhythmogenic potential. In the vasopressin-induced acute heart failure model, BU-E-76 and BU-E-75 normalized within minutes all contractile parameters in contrast to arpromidine and impromidine. It is thus concluded that these new H₂-receptor agonists may represent a promising therapeutic improvement for treatments of CHF patients, with a cardiovascular profile superior to impromidine and conventional catecholamines.

     

Dissecting karyotypic patterns in renal cell carcinoma: an analysis of the accumulated cytogenetic data

Molecular cytogenetic analysis frequently shows human papillomavirus (HPV) integration near translocation breakpoints in cervical cancer cells. We have recently described a cluster of HPV18 integrations in the distal end of the common fragile site FRA8C at 8q24 in primary cervical carcinoma samples. Chromosome band 8q24 contains the MYC gene (alias c-MYC), FRA8C, and FRA8D. The MYC gene is frequently deregulated--usually by translocation or amplification--in various tumor types. In the present study, we performed a molecular cytogenetic analysis of HPV18 integration patterns and the 8q24 translocation in a primary cervical carcinoma and in HeLa cells using combined binary ratio-fluorescence in situ hybridization. Our aim was to determine how the chromosomal breaks involved in these events relate physically to the MYC gene; whether they map to the FRA8C site, the FRA8D site, or both; and how they correlate with the occurrence of DNA flexibility domains. The 8q24 translocation breakpoints mapped between stretches of integrated HPV18 sequences in the distal end of FRA8C. This region contained DNA helix flexibility clusters, several of which mapped in the vicinity of HPV integration sites and translocation breakpoints in cervical carcinomas. DNA helix flexibility clusters were also found near known MYC translocation breakpoints in Burkitt lymphomas (BL), but most BL breakpoints mapped clearly outside FRA8C. Our data revealed that FRA8C is involved in HPV integration and chromosomal translocations in cervical carcinoma; however, this fragile site is not involved in classical MYC translocations in most BLs. In the context of the familial nature of cervical cancer, FRA8C may be considered a candidate susceptibility region for cervical carcinoma.     

Acute changes in short-term plasticity at synapses with elevated levels of neuronal calcium sensor-1

Short-term synaptic plasticity is a defining feature of neuronal activity, but the underlying molecular mechanisms are poorly understood. Depression of synaptic activity might be due to limited vesicle availability, whereas facilitation is thought to result from elevated calcium levels. However, it is unclear whether the strength and direction (facilitation versus depression) of plasticity at a given synapse result from preexisting synaptic strength or whether they are regulated by separate mechanisms. Here we show, in rat hippocampal cell cultures, that increases in the calcium binding protein neuronal calcium sensor-1 (NCS-1) can switch paired-pulse depression to facilitation without altering basal synaptic transmission or initial neurotransmitter release probability. Facilitation persisted during high-frequency trains of stimulation, indicating that NCS-1 can recruit 'dormant' vesicles. Our results suggest that NCS-1 acts as a calcium sensor for short-term plasticity by facilitating neurotransmitter output independent of initial release. We conclude that separate mechanisms are responsible for determining basal synaptic strength and short-term plasticity.