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Biomedical subjects

R M Garruto

Publications and source records attributed to R M Garruto.

At least 55 records · Page 3Linked to original sources
PubMed1991

Potentiation in the neurotoxic induction of experimental chronic neurodegenerative disorders: N-butyl benzenesulfonamide and aluminum chloride.

Repeated monthly intracisternal inoculations of N-butyl benzenesulfonamide induced a chronic, slowly progressive myelopathy in young adult New Zealand white rabbits that was manifested by hyperreflexia, spasticity, hypertonia, gait impairment and altered tonic immobility responses. The neuropathological features consisted of scattered neuroaxonal spheroids, fusiform distention of the intramedullary portions of the spinal cord ventral roots and, as defined by microtubule-associated protein-2 (MAP 2) immunoreactivity, an initial distention and subsequent loss of dendritic processes in neurons of the nucleus motoris lateralis with the perikaryon of these cells remaining intact. A similar chronic progressive myelopathy was induced by repeated low dose intracisternal inoculations of aluminum chloride in New Zealand white rabbits. However, the neuropathological changes were more extensive and consisted of dendritic, axonal and perikaryal inclusions of phosphorylated and nonphosphorylated neurofilament localized to spinal motor neurons in the nucleus motoris medialis, substantia grisea intermedia and select brainstem nuclei with only minimal involvement of the nucleus motoris lateralis. The co-administration of these two neurotoxins over the course of 8 months induced striking behavioral changes as well as a fulminant myelopathy. This was accompanied by a loss of neuronal perikarya in the nucleus motoris accompanied by a loss of neuronal perikarya in the nucleus motoris lateralis and topographically extensive neocortical neurofilamentous degeneration. These features suggest that potentiation occurs when the two toxins are co-administered, a view supported by an estimation of the co-neurotoxicity coefficient (CNC greater than 1). Our results have implications for understanding human neurodegenerative disorders in which potentiation of insults may occur, producing a clinical and neuropathological disease state not expected from either agent alone.

Aluminum↗
PubMed1991

Evaluation of magnesium, calcium and aluminum metabolism in rats and monkeys maintained on calcium-deficient diets.

The epidemiology of amyotrophic lateral sclerosis (ALS) in the Western Pacific indicates that low concentrations of calcium (Ca) and magnesium (Mg) and high levels of aluminum (Al) in soil and water in these foci are etiologically important. To determine the biochemical derangements and metal deposition induced by chronic dietary deficiencies of Ca, we maintained experimental animals on several regimens. Male Wistar rats, weighing 100g, were fed either a standard diet, low Ca diet, low Ca-Mg diet, or low Ca-Mg diet with high Al for 90 days. Ca, Mg and Al content was determined in central nervous system (CNS) tissues and bone using inductively coupled plasma emission spectrometry (ICP). In separate studies, five male Japanese macaques (Macaca fuscata), weighing 3.5 to 5 kg, were fed alternately with diets, normal in Ca, low in Ca, low in Mg, low in Ca-Mg, or low in Ca-Mg with added Al for four-week periods. Serum Ca, Mg, Al, parathyroid hormone (PTH), bone Gla-protein (BGP) and alkaline phosphatase (ALP) were measured after feeding each dietary regimen. Ca and Mg levels in lumbar vertebrae and femur were significantly reduced and bone Al levels were significantly increased in rats fed diets deficient in Ca alone or diets low in Ca-Mg with or without added Al. Al content in bones was also higher in rats fed the Ca deficient diets. In monkeys fed the low Ca-Mg diet with added Al, reduced levels of serum Ca and Mg, serum PTH, BGP, and ALP were apparent. Our data support the conjecture that deranged bone mineralization induced by chronic dietary deficiency of Ca accelerates mobilization of Ca and Mg from bone and deposition in brain.

Aluminum↗
PubMed1991

Aluminum deposition in the central nervous system of patients with amyotrophic lateral sclerosis from the Kii Peninsula of Japan.

Chronic dietary deficiency of calcium (Ca) and magnesium (Mg) with excessive intake of aluminum (Al) and manganese (Mn) has been implicated in the pathogenesis of high incidence amyotrophic lateral sclerosis (ALS) in the Western Pacific. We report two cases of ALS from the Kii Peninsula of Japan with markedly elevated concentrations of Al in central nervous system (CNS) tissues. Six pathologically verified cases of ALS and five neurologically normal controls were studied. Levels of Al, Ca and phosphorus (P) were determined simultaneously by neutron activation analysis (NAA), and Mg concentration was measured by inductively coupled plasma emission spectrometry (ICP) in 26 CNS regions. Al concentrations in the precentral gyrus, internal capsule, crus cerebri and spinal cord were significantly increased in two ALS patients, compared with those of controls. Mean Al concentrations of the 26 CNS regions in these two patients were also higher than those of controls and of the four other ALS cases (p less than 0.01). By contrast, Mg concentrations in the 26 CNS regions were markedly reduced in the ALS cases, compared with controls (p less than 0.01), and the Ca/Mg ratios were significantly increased in the ALS cases (p less than 0.01). Our data indicate that high-incidence ALS in the Western Pacific may result from Ca-Mg dysmetabolism with resultant deposition of Al.

Aged↗
PubMed1991

Neuron-specific thresholds of aluminum toxicity in vitro. A comparative analysis of dissociated fetal rabbit hippocampal and motor neuron-enriched cultures.

Mature dissociated motor neuron-enriched and hippocampal neuron cultures derived from fetal New Zealand white rabbits were continuously exposed to 1, 10, 25, 50, or 100 microM AlCl3 in a chemically defined medium for 14 days. Motor neuron-enriched cultures exposed to low concentrations (1 or 10 microM) of AlCl3 remained viable for the entire experiment but developed perikaryal and neuritic inclusions composed of phosphorylated neurofilament. Similar inclusions developed in cultures exposed to 25 and 50 microM AlCl3, but motor neurons did not survive beyond 10 days exposure. The 100 microM AlCl3-supplemented medium induced cell death within 72 hours without development of inclusions. In contrast, hippocampal neurons exposed to 1, 10, or 25 microM AlCl3 developed no morphological changes or inclusions. Although hippocampal cultures exposed to 50 or 100 microM AlCl3 developed perinuclear and proximal neuritic inclusions of phosphorylated neurofilament after 10 days, they remained viable. These in vitro morphological observations demonstrate a 10-fold greater sensitivity of spinal motor neurons to aluminum toxicity when compared with hippocampal neurons and suggest that the earlier observations of neuron-specific thresholds of aluminum toxicity in vivo are related to unique regulatory mechanisms of neurofilament biosynthesis and catabolism within distinct neuronal cell populations.

Aluminum↗
PubMed1991

Aluminum-induced chronic myelopathy in rabbits.

Young adult New Zealand white rabbits, inoculated intracisternally once monthly with 100 micrograms AlCl3, developed progressive hyperreflexia, hypertonia, gait impairment, weight loss, muscle wasting and abnormal righting reflexes over the course of 8 months. No overt encephalopathic features were present. In spinal motor neuron perikarya, dendrites and axonal processes, argentophilic globular inclusions were extensive. Additionally, neurofibrillary tangle-like argentophilic inclusions were consistently present in the gigantocellularis, reticularis, raphe and trapezoid nuclei, but rarely present in the dorsal and ventral subiculum, parasubiculum and anterior thalamus, and never found in the cerebral cortex, substantia nigra, locus ceruleus, or cerebellum. All neuronal inclusions were immunoreactive with monoclonal antibodies recognizing phosphorylated and nonphosphorylated high and intermediate weight neurofilament proteins (SMI 31, SMI 32). Also, some spinal motor neuron inclusions were immunoreactive with a monoclonal antibody recognizing an 'age-related' phosphorylation state of neurofilament (SMI 34). Ultrastructurally, the inclusions consisted of straight or interwoven skeins of 10 nm filaments. This study demonstrates unique variability in the phosphorylation state of aluminum-induced neurofilamentous inclusions in a predominantly motor system degeneration induced by chronic low dose AlCl3.

Aluminum↗
PubMed1990

The temporal expression of amyloid precursor protein mRNA in vitro in dissociated hippocampal neuron cultures.

The subunit protein of the neurofibrillary tangle, the core protein of the neuritic plaque, and the amyloid of the cerebrovasculature in Alzheimer disease and normal aging is a unique 42-amino acid protein (amyloid beta-protein), suggesting a common origin for these pathological entities. However, the expression of the amyloid precursor protein mRNA (APP mRNA) from which the amyloid beta-protein is derived varies between specific neuronal populations. To determine the conditions under which neuronal synthesis of amyloid beta-protein might contribute to the formation of these structures, we have studied the temporal pattern of APP mRNA expression in developing fetal rabbit hippocampal neurons in vitro. Using in situ hybridization with a biotinylated riboprobe transcribed from a cDNA which includes the region encoding the amyloid beta-protein, we have observed a developmentally specific pattern of APP mRNA hybridization during neuronal maturation in vitro.

Alzheimer Disease↗
PubMed1990

Human T lymphotropic virus type I infection in Papua New Guinea: high prevalence among the Hagahai confirmed by western analysis.

A serologic survey for human T lymphotropic virus type I (HTLV-I) infection was conducted on nearly half of the entire 260-member Hagahai population, a hunter-horticulturist group occupying the northern banks of the Yuat River Gorge in Madang Province of Papua New Guinea. For comparison, sera from two neighboring groups, the Pinai and Haruai, were tested. As determined by enzyme-linked immunosorbent assay (ELISA) and verified by Western immunoblot, IgG antibodies against HTLV-I were detected in 17 of 120 Hagahai, giving an HTLV-I seroprevalence of 14%, which is as high as that found in HTLV-I-endemic regions such as southwestern Japan and the Caribbean basin. Infection tended to cluster in family groups and was more common with increasing age. The majority of ELISA-positive (45/61) Hagahai sera were indeterminate, with 62% (28/45) exhibiting reactivity to three or more gag-encoded proteins. The clinical significance of the high frequency of indeterminate HTLV-I Western immunoblots is unknown, but it is not unlike that encountered in other Melanesian populations. Whether this reflects incomplete specific reactivity to HTLV-I or the existence of HTLV-I-related retroviruses in Papua New Guinea is being investigated.

Age Factors↗
PubMed1989

Bone mass in Guamanian patients with amyotrophic lateral sclerosis and parkinsonism-dementia.

Bone mass, as assessed by measurements of total subperiosteal diameter and medullary width of the second metacarpal bone on hand-wrist radiographs, was evaluated for 31 Guamanian patients (15 males, 16 females) with amyotrophic lateral sclerosis (ALS), 67 patients (39 males, 28 females) with parkinsonism-dementia (PD), and 66 (34 males, 32 females) nonaffected Guamanian controls. Comparisons between the two disease groups and between each disease group and the nonaffected controls were made taking into account the sex, age, and disability status of each participant. At all ages, ALS patients of both sexes had significantly lower percent cortical areas (PCA) than did nonaffected controls. The ALS males also had significantly lower PCA than PD males, although no significant differences were observed between female ALS and PD patients. The PD patients of either sex had a lower PCA when compared to controls, but the differences were not statistically significant. The observed differences in PCA were due solely to increased medullary width, suggesting that the diminished cortical bone thickness resulted from greater bone resorption rather than differential bone growth. Longitudinal studies support the cross-sectional findings of accelerated bone loss among ALS patients. It is not possible to determine from the present data whether the observed differences in PCA of the second metacarpal of the ALS patients are due to atrophy of the first interosseous muscle, to a generalized resorption process inherently associated with the development and progression of ALS, or to factors not accounted for by the present analysis.

Adult↗
PubMed1989

Immunocytochemical characterization of neurofibrillary tangles in amyotrophic lateral sclerosis and parkinsonism-dementia of Guam.

Cryostat-cut sections of formalin-fixed and unfixed hippocampus from 23 Guamanian Chamorros with clinically and neuropathologically verified amyotrophic lateral sclerosis (ALS) (8 cases) and parkinsonism-dementia (PD) (15 cases) and from 12 neurologically normal Guamanians (5 with and 7 without neurofibrillary degeneration) were evaluated by the immunoperoxidase technique, using monoclonal antibodies against phosphorylated neurofilament, human fetal microtubule-associated protein tau, and paired helical filaments. On immunostaining, all three antibodies showed intracellular tangles in the hippocampal neurons of patients with ALS, patients with PD, and in neurologically normal Guamanians with neurofibrillary pathology, but the correlation of immunostaining between these antibodies was not absolute. Extracellular or ghost tangles were immunostained only with the antibody against paired helical filaments. Our immunocytochemical data indicate that the antigenic composition of neurofibrillary tangles in Guamanian ALS and PD is similar to that of Alzheimer's disease, suggesting a common pathogenetic pathway for neurofibrillary tangle formation in these neurodegenerative disorders.

Adult↗
PubMed1989

Low-calcium, high-aluminum diet-induced motor neuron pathology in cynomolgus monkeys.

Long-term epidemiological studies indicate that environmental factors play a causative role in high-incidence amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD) in the western Pacific. An increased risk for disease is acquired in youth and remains for life. The low concentrations of calcium and magnesium and high levels of aluminum in the soil and drinking water, along with the relative isolation of these populations, constitute an unusual environmental feature common to all three high-incidence foci. Studies of mineral deposition in brain tissue of Guamanian ALS and PD patients, as well as of neurologically normal Guamanians with neurofibrillary degeneration, demonstrate accumulations of calcium, aluminum and silicon in neurofibrillary tangle-bearing neurons. In an attempt to duplicate the low calcium and high aluminum and manganese in soil and drinking water in these foci, we maintained juvenile cynomolgus monkeys for 41 to 46 months on a low-calcium diet with or without supplemental aluminum and manganese. Experimental animals exhibited mild calcium and aluminum deposition and degenerative changes, compatible with those of early ALS and PD, in motor neurons of the spinal cord, brain stem, substantia nigra and cerebrum. Neuropathological findings included chromatolysis, aberrant perikaryal accumulation of phosphorylated neurofilament, neurofibrillary tangles, axonal spheroids, and basophilic and hyaline-like inclusions consisting of abnormal cytoskeletal elements by electron microscopy. The magnitude and extent of these lesions far exceeded those found in normal aged monkeys.

Aluminum↗