Studies on hypoxia. VII. Changes in lymphocytes and transitional cells in the bone marrow during prolonged rebound.
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Animals↗
Biomedical subjects
H B Jones
Publications and source records attributed to H B Jones.
A METHOD OF DISTRIBUTING BETA-RADIATION TO THE RETICULO-ENDOTHELIAL SYSTEM AND ADJACENT TISSUES.
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Journal Article↗
Blood-brain barrier integrity and host responses in experimental metastatic brain tumours.
The effect of brain implants of Walker 256 carcinosarcoma tumour cells on the integrity of the blood-brain barrier was examined in rats using labelled albumin, horseradish peroxidase and trypan blue. Barrier integrity was intact within 1 hour of implantation but was gradually reduced within the tumour after 3.5 days. This was related to alterations in the fine structure of the tumour capillaries. Dissociated tight junctions were apparent within the tumour centre, but no fenestrated endothelium or gap junctions were observed by electron microscopy.
Animals↗
The case for perfusion fixation of large tissue samples for ultrastructural pathology.
We present the case for the perfusion fixation of large, freshly isolated tissue samples of liver and lung from dog, rat, and mouse. Individual lobes of liver and lung were fixed by vascular perfusion using a technique that is simple and quick to perform and results in a reproducibly high standard of ultrastructural preservation compared to immersion fixation. A major advantage to the use of this technique lies in the ability to provide tissue samples for diagnostic ultrastructural pathology and toxicological pathology while avoiding the need for whole-organ or whole-body perfusion fixation. This advantage therefore permits the use of fresh tissue from the same organ for other investigative purposes (e.g., drug metabolism studies and pharmacokinetics), thereby allowing correlation of structure and function. The advantages of perfusion fixation compared to immersion fixation are discussed, and potential applications for tissue preparation of postmortem specimens and also for scanning electron microscopy are indicated.
Animals↗
Comparison between the early changes in isoniazid intoxication and the chromatolytic response to nerve ligation in spinal ganglion cells of the rat.
The early effects of acute isoniazid intoxication and the early responses of the neuron to axotomy have been compared in lumbar spinal ganglion cells in the rat. The cells were studied by light and electron microscopy during the 4 days after a single oral dose (2g/kg) of isoniazid and for four days after application of a tight ligature to the sciatic nerve at the level of the sciatic notch. After axotomy a greater proportion of cells showed changes visible by light and electron microscopy than after INH. Small dark neurons were affected more rapidly and more severely by both insults than the large light cells as evidenced principally by changes in their ribosomal organization. Large light cells showed little response to INH. The first response to axotomy was visible about 12 h after injury. The response to INH began 24 h after the single oral dose. The early cell responses to INH therefore apparently precede axon degeneration which is first seen 72 h later and are thus probably a direct toxic effect.
Animals↗
The early evolution of neurofilamentous accumulations due to 2,5-hexanediol in the optic pathways of the rat.
Rats were given 2,5-hexanediol in their water for more than 5 weeks. The changes in the optic pathways were studied both qualitatively and quantitatively. Increase in 10-nm filaments within axons was noticeable from 10 days onwards in the superior colliculus and in the brachium of the superior colliculus. From then onwards there was a steady increase in the number of affected axons, and their gross enlargement occurred. The proportion of affected fibres in the brachia was in fact few, but all fibres were of retinotectal origin. Less than half of those in the superior colliculus that were swollen were of retinal origin. Measurement of axon diameter versus myelin sheath thickness showed gross relative thinning of the latter. Axon degeneration did not occur but there was increasing ultrastructural evidence of impairment of transport of organelles both centrifugally and centripetally as the filamentous masses accumulated.
Animals↗
The evolution of intracellular responses to acrylamide in rat spinal ganglion neurons.
Acrylamide (30 mg or 50 mg/kg/day, 5 days each week) was injected intraperitoneally into rats for up to 4 weeks. Lumbar spinal ganglia, spinal cord and lumbrical muscle spindles were examined by light and electron microscopy at various times during this period. The first abnormalities in spinal ganglion neurons were seen at 7 days when an apparent increase in numbers of mitochondria, some being hypertrophic, were found in a few large light cells. This was 10 days before any significant Wallerian degeneration was found in muscle spindle sensory fibres. Mitochondrial changes became more marked with time and were later associated with RER disruption, loss of neurofilaments and peripheral displacement of the nucleus thus mimicking chromatolysis of the axon reaction. All these changes began, however, before axon degeneration. Evidence of increased satellite cell activity was maximal at 21 days. These changes are discussed in the light of the possibility that calcium entry into the cell may be seriously increased early in the intoxication as a direct result of the presence of acrylamide and that many of these cellular features are secondary responses to such an event. Distal degeneration of axons seems likely to be secondary to the perikaryal changes.
Acrylamide↗
Evolution of the intracellular changes in neurons caused by trimethyltin.
Rats have been given a single dose of trimethyltin (10 mg/kg) and the intracellular events have been followed particularly in hippocampus, cerebral cortex, cerebellum and spinal ganglion cells. The earliest change visible occurs 12 h after this dose and is found to be dense membrane-bound bodies, probably derived from branching tubulo-vesicular smooth endoplasmic reticulum formations. These occur in close connection with rought endoplasmic reticulum and polyribosomes and appear also to have some association with the Golgi complex. At 24 h there is a general vacuolation of Golgi cisterns and SER membranes, and the membrane-bound dense body formation is greatly increased. SER abnormalities are particularly conspicuous in Purkinje cells. In spinal ganglion cells, while vacuolation of Golgi cisterns is intense, dense bodies are inconspicuous and are replaced by increased autophagosomes, often of great complexity. By 48 h vacuolation of Golgi cisterns has waned, but accumulation of dense bodies and secondary lysosomes has steadily increased. In spinal ganglion cells autophagosomes only are increased as the Golgi vacuolation declines. At later times steady increases of lysosomal dense bodies is seen generally accompanied in hippocampal pyramidal cells and dentate fascia cells by abundant cell death. The suggestion is put forward that the Golgi complex may be the seat of the critical metabolic lesion and disturbances to protein transfer and protein synthesis follow. No explanation for the selective loss of hippocampal h1-5 (CA1-CA4 except Sommer's sector) pyramidal cells and of small dentate fascia neurons can be derived from these conclusions.
Amygdala↗
Histopathological and ultrastructural changes in the juxtaglomerular apparatus of the rat following administration of ZENECA ZD6888 (2-ethyl-5,6,7,8-tetrahydro-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)- methoxy]quinoline), an angiotensin II antagonist.
Male and female Alderley Park rats were treated for 26 wk with ZENECA ZD6888, an angiotensin II (AII) antagonist, at doses of 25, 50, and 250 mg/kg/day and the kidneys examined by light and electron microscopy. Nephropathy (tubular degeneration and regeneration), thickening of the basal lamina, mononuclear cell infiltration, and hypertrophy and hyperplasia of the juxtaglomerular apparatus were seen by light microscopy. Ultrastructurally, juxtaglomerular cell granules were increased in number and displayed substantial structural heterogeneity. In some cells, granules contained paracrystalline inclusions while others consisted predominantly of myelinic debris. Evidence of conversion of arteriolar smooth muscle cells into juxtaglomerular cells and their degeneration was also obtained by electron microscopy. The juxtaglomerular changes were treatment- and dose-related and were attributed to an exaggerated pharmacological action of the compound, that is, ZD6888-mediated blockade of AII receptors leading to competitive inhibition of the AII-mediated release of renin. The resemblance between the findings seen in the present study following administration of an AII antagonist and those due to angiotensin-converting enzyme inhibitors reported by others was striking.
Angiotensin II↗
Disturbance of macrophage and monocyte function in the dog by a thromboxane receptor antagonist: ICI 185,282.
ICI 185,282 is a specific thromboxane receptor antagonist developed by ZENECA Pharmaceuticals for potential use in the treatment of inflammatory disease. During safety evaluation in dogs, multifocal granulomatous infiltrates occurred in multiple organs at high dose levels. These consisted predominantly of enlarged histiocytic cells. We reported a 28-day investigative study in which Millipore filters overlaid with carbon were implanted subcutaneously. Histological assessment of the developing foreign body granulomatous tissue response and evaluation of in vitro migration of peripheral blood monocytes were performed. The development of epithelioid macrophages with altered behavior, modification of fibroplasia, and increased monocyte infiltration at the implant site resulted from administration of ICI 185,282. This was accompanied by enhanced migration of isolated peripheral blood monocytes in vitro. We believe that the granulomatous infiltrates that occurred during toxicological assessment in dogs may be a result of a drug-induced disturbance in macrophage response to concurrent subclinical inflammations or alteration in the normal disposition of tissue macrophages, i.e., they were a result of an atypical response to a concurrent stimulus for macrophage activity.
Administration, Oral↗
Characterization of coronary arterial lesions in the dog following administration of SK&F 95654, a phosphodiesterase III inhibitor.
Drugs that inhibit the low-Km, cGMP-inhibitable form of phosphodiesterase III (PDE III) are associated with arterial lesions in the extramural coronary arteries of dogs following oral and intravenous administration at high doses. Acute coronary arterial lesions have been investigated following administration to the dog of SK&F 95654, a potent PDE III inhibitor, and the progression of the lesion defined. Groups of 3 male beagle dogs received a single 2-hr infusion of SK&F 95654 at 8 mg/kg/hr and the characteristics of the coronary arterial lesions were evaluated at 1, 3, 10, and 34 days postdosing by light, scanning, and transmission electron microscopy. At 24 hr postdosing, the arterial lesion was characterized by segmental or circumferential necrosis of medial smooth muscle cells and hemorrhage; adventitial hemorrhage was also noted, particularly in the right atrial artery. Ultrastructural evaluation showed extensive medial necrosis, characterized by loss of smooth muscle cells and their replacement by cellular debris with ingress of erythrocytes, platelets, and inflammatory cells into the media. Associated with medial changes, significant endothelial effects were observed consisting of widening of intercellular boundaries, loss of normal elongated cellular appearance, and the attachment of numerous leukocytes and platelets. During the 10-34-day postdosing period, substantial repair of the arterial lesions occurred such that by day 34 all sections of extramural coronary artery were normal. The lesions induced in the dog are consistent with a hemodynamic effect induced by the pharmacological action of SK&F 95654.
3',5'-Cyclic-AMP Phosphodiesterases↗