We have studied the three-dimensional arrangement of ventricular muscle cells and the associated extracellular connective tissue matrix in dog hearts. Four hearts were potassium-arrested, excised, and perfusion-fixed at zero transmural pressure. Full-thickness segments were cut from the right and left ventricular walls at a series of precisely located sites. Morphology was visualized macroscopically and with scanning electron microscopy in 1) transmural planes of section and 2) planes tangential to the epicardial surface. The appearance of all specimens was consistent with an ordered laminar arrangement of myocytes with extensive cleavage planes between muscle layers. These planes ran radially from endocardium toward epicardium in transmural section and coincided with the local muscle fiber orientation in tangential section. Stereological techniques were used to quantify aspects of this organization. There was no consistent variation in the cellular organization of muscle layers (48.4 +/- 20.4 microns thick and 4 +/- 2 myocytes across) transmurally or in different ventricular regions (23 sites in 6 segments), but there was significant transmural variation in the coupling between adjacent layers. The number of branches between layers decreased twofold from subepicardium to midwall, whereas the length distribution of perimysial collagen fibers connecting muscle layers was greatest in the midwall. We conclude that ventricular myocardium is not a uniformly branching continuum but a laminar hierarchy in which it is possible to identify three axes of material symmetry at any point.
Mcl-1, an antiapoptotic member of
the Bcl-2 family of proteins,
is a validated and attractive target for cancer therapy. Overexpression
of Mcl-1 in many cancers results in disease progression and resistance
to current chemotherapeutics. Utilizing high-throughput screening,
compound 1 was identified as a selective Mcl-1 inhibitor
and its binding to the BH3 binding groove of Mcl-1 was confirmed by
several different, but complementary, biochemical and biophysical
assays. Guided by structure-based drug design and supported by NMR
experiments, comprehensive SAR studies were undertaken and a potent
and selective inhibitor, compound 21, was designed which
binds to Mcl-1 with a Ki of 180 nM. Biological
characterization of 21 showed that it disrupts the interaction
of endogenous Mcl-1 and biotinylated Noxa-BH3 peptide, causes cell
death through a Bak/Bax-dependent mechanism, and selectively sensitizes
Eμ-myc lymphomas overexpressing Mcl-1, but not Eμ-myc
lymphoma cells overexpressing Bcl-2. Treatment of human leukemic cell
lines with compound 21 resulted in cell death through
activation of caspase-3 and induction of apoptosis.
Some investigators have suggested that the marked activity of flavone acetic acid (FAA) against advanced solid tumors in mice results from an indirect effect. This study indicates that the critical effect of FAA is irreversible inhibition of tumor blood flow. Perfusion of sc Colon 38 tumors, assessed with H33342 as a fluorescent stain for functional blood vessels, was reduced to 50% of controls within 3 hours of an ip injection of 1.2 mmol of FAA/kg and was completely inhibited by 24 hours. A double-label fluorescence technique demonstrated a significant decrease in blood flow in both sc Colon 38 and im EMT-6/Ak tumors as early as 15 minutes after iv treatment with 1.2 mmol of FAA/kg, with progressively enlarging zones of perfusion failure. The rate of cell death in totally ischemic EMT-6 tumors was shown to be sufficiently rapid to represent a major component of the observed antitumor effect of FAA if the flavonoid acts via inhibition of blood flow. Further, avascular EMT-6/Ak multicellular spheroids growing in the mouse peritoneum are relatively resistant to killing by FAA administered iv or ip, despite extensive infiltration with host immune cells. These results indicate that inhibition of tumor blood flow by FAA is a necessary component of its antitumor activity against solid tumors.
The spatial relations between bacteria and the affected tissues can indicate pathogenic mechanisms. This study was undertaken to define the spatial relation of Helicobacter pylori to the human gastric mucosa. Antibodies against gastric mucus and ruthenium red were used to stabilise the glycoprotein structure of the mucus and glycocalyces in antral biopsy specimens from eight patients infected with H pylori. The location of organisms and ultrastructural features were assessed using systematic scanning and transmission electron microscopy: 92 (2)% (mean (SE)) of H pylori were in the pit mucus, and 7 (3)% were in the surface mucus; 60 (12)% of H pylori were close to epithelial cells, with only 5 (2)% located near the epithelial intercellular junctions. Fine shown by the use of ruthenium red" in the preparation of samples.The research described in this paper used systematic microscopy to determine the relation of H pylori to the gastric epithelium in infected human gastric biopsy specimens, in which the glycoprotein structure of the mucus and of the glycocalyces had been stabilised.
Methods
SUBJECTS AND SAMPLESBiopsy specimens from the gastric antrum of eight subjects infected with H pylori were studied. The subjects were selected from patients with dyspeptic symptoms attending the endoscopy clinic at Auckland Hospital. Only patients not receiving treatment for dyspeptic symptoms, who gave informed consent, and from whom the additional specimens could be obtained with reasonable comfort, were included in this study.Three antral biopsy specimens (one for urease detection, one for histopathological assessment, and one for electron microscopy) were obtained from each subject from the region within 5 cm of the pyloric valve.
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