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Biomedical subjects

J M Jacobs

Publications and source records attributed to J M Jacobs.

At least 109 records · Page 6Linked to original sources
PubMed1982

Improved myelination in nerve grafts from the leucodystrophic twitcher into trembler mice: evidence for enzyme replacement.

The possibility of the treatment of globoid cell leucodystrophy in the twitcher mouse by enzyme replacement was investigated using nerve grafts from affected animals into trembler hosts. The trembler mouse has no known enzyme deficiency but its peripheral nerves are hypomyelinated due to a Schwann cell abnormality and this defect represents a marker used in the present study to exclude the possibility of migration of Schwann cells from the host into the graft. Twitcher grafts were examined after periods ranging from 1 to 4 months. At all stages myelin sheaths were well formed and did not show signs of degeneration. Moreover the interstitial oedema, characteristic of the twitcher nerve, was greatly diminished in amount and no globoid cells were seen. These results were compared with previous studies done in vivo and in vitro in other types of lysosomal storage disease. We concluded that the improvement of the conditions of the myelin in the transplant is possibly due to enzyme replacement from the host.

Animals↗
PubMed1982

The pathogenesis of globoid cell leucodystrophy in peripheral nerve of the mouse mutant twitcher.

The twitcher mouse is affected by a disease with pathological features resembling those of human globoid cell leucodystrophy (Krabbe's disease): it also has an identical enzyme deficiency. The progress of the disease has been studied in peripheral nerves. Myelin sheaths develop normally until about the 15th day when the rate of myelination declines. Demyelination, first affecting paranodal regions is seen from the 10th-11th day before clinical signs appear. Krabbe-type inclusions are seen in macrophages and Schwann cells a few days later. Demyelination becomes extensive with increasing age, affecting fibres of all sizes, and axons rapidly remyelinate. Axons are not involved but quantitative studies show that they remain smaller than normal. Changes in twitcher nerves are compared to those in the neuropathy in human Krabbe's disease.

Animals↗
PubMed1982

Changes in peripheral nerve fibres distal to a constriction.

Continued constriction of the tibial nerve of the rabbit by a ligature was accompanied by a reduction in maximal motor conduction velocity distal to the ligature, and by a reduction in axonal and total fibre diameter. From the presence of paranodal demyelination and distal fibre degeneration in severely affected nerves, it is suggested that in some instances the change in axonal calibre was part of a progressive distal atrophy which could lead to secondary demyelination and ultimately to "dying-back" of the affected axons.

Animals↗
PubMed1982

Assay for enzymatic protoporphyrinogen oxidation, a late step in heme synthesis.

Detailed directions are given for the spectrophotometric and fluorometric assays for protoporphyrinogen oxidation in rat liver mitochondria and other tissues. Linearity of the two assays with enzyme concentration is demonstrated. Some possible assay modifications and sources of error are mentioned. The fluorometric assay appears more sensitive, while the spectrophotometric assay may be more useful for assaying a wider variety of tissues. By both methods, rat liver mitochondria exhibit enzymatic oxidation at the rate of approximately 10 nmol protoporphyrin produced per hour per milligram protein.

Animals↗
PubMed1982

Decrease in creatine kinase in human prostatic carcinoma compared to benign prostatic hyperplasia.

Many previous studies have shown that a proportion of patients with carcinoma of the prostate have increased activity of the creatine kinase (E.C. 2.7.3.2) isoenzyme designated BB in sera from their peripheral blood. We have analyzed tissues from prostatic hyperplasia of 22 patients and from prostatic carcinoma of 23 additional patients. Prostatic carcinomas contain less (p less than 0.001) creatine kinase activity (units/g) than do prostates with benign prostatic hyperplasia. The facts that (a) histochemical studies that we performed confirmed the observation reported previously by others that creatine kinase activity is found primarily in the epithelial elements of hyperplastic prostates and prostatic carcinomas, (b) the carcinomas that we examined had, on the average, a somewhat larger epithelial component than the hyperplastic prostates that we examined, and (c) prostate cancer was found to contain less creatine kinase activity than hyperplastic prostates suggest that the epithelial cells in prostate cancers contain less creatine kinase activity per cell than do those from hyperplastic prostates. The BB form of creatine kinase accounts for 98% of the activity in prostatic carcinoma and in prostates without cancer. Creatine kinase has been discussed as a possible marker for prostatic carcinoma, and we had hoped that it might be useful for the assay of tumor burden. Our data suggest that, if creatine kinase is to be useful in the monitoring of tumor burden, it will be useful only in the contexts of particular patients studied longitudinally since the creatine kinase activity varies enormously among different prostatic carcinomas.

Aged↗
PubMed1981

The measurement of motor cell volumes in rats.

The volumes of cell bodies and nuclei of rat motoneurons were calculated from reconstruction in araldite embedded spinal cord. The results were compared with those obtained by applying formulae to two-dimensional measurements. The results show that the volumes of reconstructed cells have comparable values when derived from transverse and longitudinal sections. These values differ quite remarkably from those obtained by applying the formulae of the sphere and of a non-rotational ellipsoid. The difference is thought to reflect shape and orientation of the cells in the spinal cord. Nuclei were found to have a spheroidal shape, with the major diameter parallel to the axis of the spinal cord. There is also a linear relationship between cells and nuclear volume (with values varying between 5 and 15). The results of this study suggest that once reconstruction studies have shown the basic parameters of the cells, a graphical method for cell volumes from equatorial area measurements gives more satisfactory results than other proposed methods.

Animals↗
PubMed1981

Peripheral nerve grafts in hereditary leukodystrophic mutant mice (twitcher).

The twitcher mouse is a mutant affected by a form of leukodystrophy which shows close similarities to human globoid cell (Krabbe's) leukodystrophy. Transmission is by an autosomal recessive gene twi. Progressive loss of myelin sheaths from both central and peripheral nervous systems and the presence of inclusion-laden macrophages are characteristic findings. Morphological features of the twitcher have been described by Duchen et al. Nerve iso- and allografting have been used to determine the roles of axon and Schwann cell in a number of mouse and human nerve abnormalities. Schwann cells in a graft proliferate and become associated with regenerating host axons which grow through the graft into the host distal stump. In the twitcher, peripheral nerve axons do not degenerate but are thinner than normal, although there is considerable axonal degeneration in the central nervous system. In 15-day-old mutants, inclusions have been found in Schwann cells associated with apparently normal myelin sheaths. Grafting experiments might show whether the phenotype of this mutant is fully expressed in the Schwann cell, or if axons are also involved. In previous experiments, survival of transplanted Schwann cells was achieved by the use of T cell-suppressed or nude mice. We report here that a twitcher nerve transplanted in immunologically unsuppressed animals reproduces all the characteristic features of leukodystrophy and conversely that Schwann cells from unaffected mice can produce normal myelin when associated with twitcher axons.

Animals↗
PubMed1981

The pathology of allyl chloride neurotoxicity in mice.

Allyl chloride is known to produce a neuropathy in man after occupational exposure to its vapour. The present study describes the neuropathy which develops in mice given allyl chloride by mouth. Mice were dosed three times weekly with 300 or 500 mg/kg allyl chloride for periods from 2-17 weeks. Functional disability was observed in some animals. Apart from evidence of focal kidney damage in 70% of dosed mice, pathological changes were restricted to the nervous system. Nerve fibre degeneration was found in many peripheral nerves and in roots, tending to be more marked distally and to affect more motor than sensory nerves. Degenerated fibres were also found in dorsal, ventral and lateral columns of the spinal cord. Males were more severely affected than females. Increased numbers of filaments were on early axonal change, occurring multifocally and apparently preceding axonal degeneration. No neuronal death was observed, but occasional anterior horn and dorsal root ganglion cells showed some morphological changes. Vacuolated lesions mainly due to swelling of astrocytes and their processes were found in the ventral horn in cervical and lumbar regions of spinal cord. Animals appeared to become tolerant to allyl chloride after continuous dosing. This neuropathy appears to be a central-peripheral distal type of axonopathy.

Allyl Compounds↗
PubMed1981

Separation of two populations of cells with gamma-glutamyl transpeptidase from carcinogen-treated rat liver.

Noninbred Sprague-Dawley rats were maintained on a choline-deficient diet containing 0.05% ethionine. After 10-13 weeks, livers were dispersed with collagenase, lysozyme, collagenase and hyaluronidase. Pronase, or a selected batch of trypsin. The highest yield of cells with histochemically demonstrable gamma-glutamyl transpeptidase (GGT) was obtained with trypsin. After velocity sedimentation in an isokinetic gradient of Ficoll in tissue culture medium, two modal populations of cells with histochemically demonstrable GGT were observed. The first mode contained cells that were morphologically different from hepatocytes and that may be oval cells. The second, more rapidly sedimenting modal population of cells with GGT was morphologically similar to hepatocytes as assessed with Wright's stain; the location of this population in the gradient was the same as the location of cells with the appearance of hepatocytes that lacked iron and that had decreased glucose 6-phosphatase. In multiple experiments, the purest fractions contained 71.7 +/- 3.5% cells (mean +/- SD) with the appearance of hepatocytes with histochemically demonstrable GGT.

Animals↗
PubMed1981

The neurotoxicity and antifertility properties of 6-chloro-6-deoxyglucose in the mouse.

6-chloro-6-deoxyglucose (24 mg/kg/day) produces infertility in male rats and marmosets. In the present study very high doses (480 mg/kg/day) were found not to impair the fertility of male mice. However, such doses induced the formation of vacuolated lesions in specific regions of central nervous system grey matter causing varying degrees of physical disability. A similar response has been obtained in marmosets. Astrocytes appear to be primarily affected with later involvement of nerve cells. The sites of lesions correspond closely to regions of high glucose utilization.

Animals↗
PubMed1981

A new neurological rat mutant "mutilated foot".

A new autosomal recessive mutant rat (mutilated foot) with a neurological disorder is described. Affected animals become ataxic and the feet, generally of the hind limbs, are mutilated. Quantitative studies show a severe reduction in numbers of sensory ganglion cells and fibres, including unmyelinated fibres. The numbers of ventral root fibres, particularly those of small diameter, are also reduced. Markedly decreased numbers of spindles are found in the limb muscles. These quantitative abnormalities are present in animals of all ages and appear to be congenital. No nerve fibre degeneration is found in the spinal cord of young animals, but progressive degeneration of ascending tracts is seen with increasing age. Mossy fibre degeneration in the cerebellum confirms that the spinocerebellar tract is affected. The neurological disease in this mutant shows many similarities to that found in human hereditary sensory neuropathy.

Animals↗
PubMed1980

The Twitcher mouse: an enzymatically authentic model of human globoid cell leukodystrophy (Krabbe disease).

The Twitcher is a new neurological mutant of mouse which shows clinical and histopathological features similar to those of human and canine globoid cell leukodystrophy (Krabbe disease). Brain and liver tissues of affected mice showed a profound deficiency of galactosylceramidase and lactosylceramidase I activities. A distinct group with intermediate enzyme activities could be identified among the phenotypically normal mice, consistent with their being heterozygotes. The Twitcher mouse is, therefore, not only a clinically and morphologically, but also an enzymatically, authentic model of human globoid cell leukodystrophy. This is the first enzymatically authentic murine model of human sphingolipidosis.

Animals↗
PubMed1980

Hereditary leucodystrophy in the mouse: the new mutant twitcher.

A new inherited neurological disease in the mouse (the mutant twitcher) has been studied. Transmission is by an autosomal recessive gene (twi). Affected animals are apparently normal at birth but develop a generalized tremor at about 3 weeks of age followed by progressive weakness and wasting. The disease is fatal by 3 months. The principal pathological changes affect the myelin of both central and peripheral nervous systems. Degeneration of myelin sheaths and the presence of multinucleated macrophages with PAS-positive cytoplasm are characteristic findings. Peripheral nerves show remyelination following demyelination. Electron microscopically the macrophages contain a variety of inclusions in which there are crystalline and multi-angular structures and twisted tubules. The abnormalities closely resemble those found in globoid cell leucodystrophy (Krabbe's disease) in man.

Animals↗
PubMed1979

Studies on the early changes in acute isoniazid neuropathy in the rat.

Large single doses if isoniazid by mouth (1--2g/kg) have been shown to produce in rats Wallerian degeneration visible with the light microscope from the third day onwards. By contrast, changes in axons are seen from 24 h onwards by electron microscopy. The earliest ultrastructural changes are associated with vacuoles appearing between axon and Schwann cells. These are large and focal, and often compress the axon. The adjacent axon may show changes in smooth ER, and in microtubular arrangement. Alterations in smooth membranes and in mitochondria are visible in Schwann cell cytoplasm, not necessarily related to the vacuole formation and axonal features. It is suggested that INH neuropathy is essentially a multifocal axonal lesion.

Acute Disease↗