Autoradiographic assessment of blood flow heterogeneity in the hamster heart

OBJECTIVE: Provide regional flow measurement in the hearts of small mammals using a new, higher-resolution technique based on the deposition of a molecular marker. METHODS: We determined the instantaneous extraction and retention of the "molecular microsphere" radiolabeled desmethylimipramine in retrogradely perfused hamster hearts. In a separate series of experiments, autoradiography was used to measure regional myocardial deposition densities in hamster hearts of about 0.5 g with spatial area resolution of 16 x 16 microns. RESULTS: Radiolabeled desmethylimipramine is almost 100% extracted during a single transcapillary passage and is retained in the tissue for many minutes. Autoradiographic images demonstrated a spatial flow heterogeneity with standard deviations of 31 +/- 4% of the mean flow (N = 5) in 16 x 16 x 20-micronm3 voxels. This is equivalent to the projections made using fractal relationships from cruder observations obtained with microspheres in the hearts of baboons, sheep, and rabbits. CONCLUSIONS: Autoradiography using a molecular deposition marker provides quantitative information on myocardial flow heterogeneities with resolution at the size of cardiac myocytes. Because the regions resolved are smaller than the volume of regions supplied by single arterioles, the results must slightly exaggerate the true heterogeneity of regional flows.     

Static and fatigue failure properties of thoracic and lumbar vertebral bodies and their relation to regional density

This study investigated (1) whether a characterization of the macroscopic architecture within the vertebral centrum would improve predictions of vertebral strength, (2) if regions in the centrum where least bone loss with age occurs are more predictive of vertebral strength, and (3) whether different patterns of the macroscopic architecture are predictive of static as compared to fatigue strength. To characterize the vertebral macroscopic architecture, a regional bone mineral density (rBMD) technique was used that estimated the cancellous density distribution (in 18 specific regions of the vertebral centrum) for vertebrae T7-L4, from spines of 20 female cadavers. Static and fatigue failure properties of whole vertebrae were obtained, and predictive models of static and fatigue failure properties of whole vertebrae were examined. We found that (1) vertebral failure properties were better predicted by combinations of vertebral regional cancellous density (multiple linear regressions) rather than by any individual region of cancellous density alone (simple linear regressions); (2) models using regions of density that demonstrated minimum decline with age [from the data of Flynn and Cody (Calcif. Tissue Int. 53, S170-S175 (1993))] resulted in better correlations with ex vivo vertebral static failure properties than models using density regions that showed maximum decline with age, and (3) static and fatigue characteristics required different density regions to reach significance. (A comparison of models predictive of static and fatigue failure properties revealed that anterior density regions were most often included in predictive models of the static properties while posterior regions were more predictive of the fatigue properties).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cervical meningoceles and myelocystoceles: a unifying hypothesis

We initiated a pilot study of adjuvant hepatic arterial infusion chemotherapy (AHAIC) using 5-fluorouracil (5-FU) and leucovorin. Hepatic arterial infusion ports were placed in 15 consecutive patients undergoing curative resection of colorectal liver metastases. The chemotherapy regimen consisted of a weekly infusion of 5-FU (12 mg m 2 per day) and leucovorin (200 mg m 2 per day) for 12 months. The mean follow-up was 22 months (range 3-62 months, SD 21-37 months). There were no clinical or biological complications related to chemotherapy, except for sharp epigastric burns in four patients immediately after 5-FU infusions. Catheter irreversible occlusions led to early cessation of the treatment in three patients. Four of the 15 evaluable patients developed recurrent disease. The site of relapse was the liver in two patients and extra-hepatic sites in the two remaining patients. Three of these four patients died of their recurrent disease. These results suggest that 5-FU and leucovorin can be combined for AHAIC in a long duration regimen with a very low rate of side-effects. This protocol could be safely employed in a prospective randomized study in combination with 5-FU systemic infusions.     

Chronic treatments with 5-HT1A agonists attenuate posthypoxic myoclonus in rats

Following 10 min cardiac arrest and resuscitation, male Sprague-Dawley rats developed posthypoxic myoclonus. This phenomenon peaked at 14 days and disappeared by 60 days after cardiac arrest. From previous results, the 5-hydroxytryptamine (5-HT) system was implicated in the pathogenesis of the disease. In the present study, we investigated the involvement of 5-HT1A receptors in posthypoxic myoclonus in rats. Single injections of 5-HT1A agonists, buspirone (5 and 10 mg/kg body wt.) or 8-OH-DPAT (1, 2, and 4 mg/kg), had no effect on either the intensity or time course of the disease. In contrast, multiple injections (twice a day for 7 or more days) of buspirone (10 mg/kg) or 8-OH-DPAT (4 mg/kg) significantly attenuated the myoclonus scores of animals (p < 0.05). The results indicate that chronic stimulation of 5-HT1A receptors in the brain may accelerate endogenous compensatory mechanisms and shorten the time course of the disease.     

Kinesin mutations cause motor neuron disease phenotypes by disrupting fast axonal transport in Drosophila

Previous work has shown that mutation of the gene that encodes the microtubule motor subunit kinesin heavy chain (Khc) in Drosophila inhibits neuronal sodium channel activity, action potentials and neurotransmitter secretion. These physiological defects cause progressive distal paralysis in larvae. To identify the cellular defects that cause these phenotypes, larval nerves were studied by light and electron microscopy. The axons of Khc mutants develop dramatic focal swellings along their lengths. The swellings are packed with fast axonal transport cargoes including vesicles, synaptic membrane proteins, mitochondria and prelysosomal organelles, but not with slow axonal transport cargoes such as cytoskeletal elements. Khc mutations also impair the development of larval motor axon terminals, causing dystrophic morphology and marked reductions in synaptic bouton numbers. These observations suggest that as the concentration of maternally provided wild-type KHC decreases, axonal organelles transported by kinesin periodically stall. This causes organelle jams that disrupt retrograde as well as anterograde fast axonal transport, leading to defective action potentials, dystrophic terminals, reduced transmitter secretion and progressive distal paralysis. These phenotypes parallel the pathologies of some vertebrate motor neuron diseases, including some forms of amyotrophic lateral sclerosis (ALS), and suggest that impaired fast axonal transport is a key element in these diseases.