HHV-6 AND CMV ANTIBODY STUDIES *Day 0 = date of transplant (or first or only sample for patients ... more HHV-6 AND CMV ANTIBODY STUDIES *Day 0 = date of transplant (or first or only sample for patients G and H). tIF titre; tIF assay, positive (+) = 80, negative (—) = < 20, NT = not tested; §optical density units, IgG positive = 0 20, IgM positive = 0 4. from the same source. If so, our data suggest that HHV-6 infection may be transmitted in graft tissue. Secondly, infection with one virus may reactivate another, latent, virus. Thirdly, we may simply be demonstrating cross-reactive antibodies, not yet reported. Whatever the explanation, there are important implications. For example, is co-infection, or infection plus reactivation, a more damaging clinical event than infection with a single agent? We are developing western blots for both viruses to find out whether the antibody rises we have demonstrated are directed against multiple proteins of both viruses, or against multiple proteins of one virus plus a cross-reactive protein antigen of the other one.
Among 20 consecutive autopsies of amyotrophic lateral sclerosis (ALS) occurring in Caucasians in ... more Among 20 consecutive autopsies of amyotrophic lateral sclerosis (ALS) occurring in Caucasians in Western Australia (WA), 85% were males. The median age of onset was 58.9 years and the average duration of illness was 2.4 years. Twenty-two randomly selected ALS occurring among natives in Guam also showed a male predominance of 75%, younger age of onset (median 48.5 years) and longer survival period (median 3.4 years). 45% of the WA patients presented with bulbar involvement at the time of first examination. These patients had the lowest median survival period of 1.5 years when compared with the other forms of ALS, the classic upper and lower motor system involvement and progressive muscular atrophy. Theneuropathologic lesions of ALS in WA and Guam were similar with the exception that neurofibrillary tangles were frequently present in the Guamanian brains. In 14%, neuronal loss, gliosis and frequency of tangles in the cerebral cortex especially in Ammon's horn, substantia nigra, and locus ceruleus, were sufficiently severe to indicate the coexistence of another disorder, Parkinsonism-Dementia Complex. This condition was not clinically recognized. In the WA cases only one patient had tangles in the brain and he had concurrent Alzheimers disease. While senile plaques were present in this patient they were usually absent in the Guamanian brains.
Repeated monthly intracisternal inoculations of N-butyl benzenesulfonamide induced a chronic, slo... more 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.
Human adaptability, as a field of inquiry within human biology, became defined during the researc... more Human adaptability, as a field of inquiry within human biology, became defined during the research activities of the International Biological Program (IBP) (1964-1974). During this period, research was focused on ecological, physiological, and genetic studies of human populations within the theoretical frameworks of adaptation and evolution. Other defining characteristics of the IBP human adaptability research were standardization of methods, multidisciplinary projects, international cooperation, and a concern with human health issues. Some observers suggest that this research contributed to the ongoing transformation of physical anthropology and related fields from a largely descriptive to an analytical science. During the 25 years between the end of the IBP and the present, a number of research trends have continued: Several new multidisciplinary projects were initiated and completed; a subfield of demography within human biology has matured; nutrition, infant and child growth, and health studies have proliferated; and molecular genetics and DNA analysis have superseded the earlier population genetics. International programs today are geared toward more practical and applied studies with less emphasis on basic science. Continuation of human adaptability research into the 21st century is likely to make contributions in 3 broad areas: population, environment, and health. Productive research is likely to contribute to these 3 areas in the following categories: reproduction, psychosocial stress, life span approaches to health, effects of losses in biodiversity on health, a human biology of poverty, emerging infectious diseases, epidemiology of modernization, evolutionary medicine, and aging. The success of much of this research in its contribution to knowledge will come from the integrated perspectives of a biobehavioral framework of inquiry.
Mature dissociated motor neuron-enriched and hippocampal neuron cultures derived from fetal New Z... more 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.
The strikingly high incidence of amyotrophic lateral sclerosis (ALS) and parkinsonism‐dementia (P... more The strikingly high incidence of amyotrophic lateral sclerosis (ALS) and parkinsonism‐dementia (PD), two uniformly fatal neurodegenerative disorders which often occur in the same families and occasionally in the same individual, was recognized on Guam more than three decades ago. Since the first systematic observations began, nearly 800 Guamanian Chamorro patients have been clinically diagnosed as having either disease. The original incidence rates for ALS and PD accounted for one in five deaths among Chamorros over ago 25. During the past 30 years, however, the incidence and mortality rates have dramatically declined and today the risk to Guamanian chamorros is only several‐fold higher than that for non‐Chamorro residents of the continental United States. The accumulating epidemiological and genetic data strongly suggest that environmental factors are primarily involved in the etiology and pathogenesis of these disorders. The high incidence focus of ALS and PD on Guam and similar, but less well‐studied, foci in West New Guinea and the Kii Peninsula of Japan represent natural paradigms of chronic degenerative disease that have provided new information and insights for understanding not only ALS and PD, but other neurological disorders such as classical ALS, Parkinson disease, Alzheimer disease, and early neuronal aging, insights that might otherwise not have been forthcoming from studies of low incidence sporadic disease in large cosmopolitan Western communities.
We report the distribution and imaging of calcium and aluminum in neurofibrillary tangle (NFT)-be... more We report the distribution and imaging of calcium and aluminum in neurofibrillary tangle (NFT)-bear- ing neurons within Sommer'S sector of the hippocampus in Guamanian patients with parkinsonism-dementia, using a method of computer-controlled electron beam x-ray micro- analysis and wavelength dispersive spectrometry. Calcium and aluminum were distributed in cell bodies and axonal processes of NFT-bearing neurons. The elemental images show that both calcium and aluminum deposits occur within the same NFT- bearing hippocampal neuron in this dementing disease, sug- gesting that these elements are involved in NFT formation. No prominent concentrations of calcium and aluminum were im- aged in non-NFT-containing regions within the pyramidal cell layer of the parkinsonism-dementia cases or in the control cas- es. These findings support the hypothesis that secondary hyperparathyroidisnm resulting from low environmental calci- um and magnesium in the high-incidence focus of amyotrophic lateral sclerosis and parkinsonism-dementia on Guam had led to abnormal deposition of calcium and aluminum in the cen- tral nervous system.
HHV-6 AND CMV ANTIBODY STUDIES *Day 0 = date of transplant (or first or only sample for patients ... more HHV-6 AND CMV ANTIBODY STUDIES *Day 0 = date of transplant (or first or only sample for patients G and H). tIF titre; tIF assay, positive (+) = 80, negative (—) = < 20, NT = not tested; §optical density units, IgG positive = 0 20, IgM positive = 0 4. from the same source. If so, our data suggest that HHV-6 infection may be transmitted in graft tissue. Secondly, infection with one virus may reactivate another, latent, virus. Thirdly, we may simply be demonstrating cross-reactive antibodies, not yet reported. Whatever the explanation, there are important implications. For example, is co-infection, or infection plus reactivation, a more damaging clinical event than infection with a single agent? We are developing western blots for both viruses to find out whether the antibody rises we have demonstrated are directed against multiple proteins of both viruses, or against multiple proteins of one virus plus a cross-reactive protein antigen of the other one.
Among 20 consecutive autopsies of amyotrophic lateral sclerosis (ALS) occurring in Caucasians in ... more Among 20 consecutive autopsies of amyotrophic lateral sclerosis (ALS) occurring in Caucasians in Western Australia (WA), 85% were males. The median age of onset was 58.9 years and the average duration of illness was 2.4 years. Twenty-two randomly selected ALS occurring among natives in Guam also showed a male predominance of 75%, younger age of onset (median 48.5 years) and longer survival period (median 3.4 years). 45% of the WA patients presented with bulbar involvement at the time of first examination. These patients had the lowest median survival period of 1.5 years when compared with the other forms of ALS, the classic upper and lower motor system involvement and progressive muscular atrophy. Theneuropathologic lesions of ALS in WA and Guam were similar with the exception that neurofibrillary tangles were frequently present in the Guamanian brains. In 14%, neuronal loss, gliosis and frequency of tangles in the cerebral cortex especially in Ammon's horn, substantia nigra, and locus ceruleus, were sufficiently severe to indicate the coexistence of another disorder, Parkinsonism-Dementia Complex. This condition was not clinically recognized. In the WA cases only one patient had tangles in the brain and he had concurrent Alzheimers disease. While senile plaques were present in this patient they were usually absent in the Guamanian brains.
Repeated monthly intracisternal inoculations of N-butyl benzenesulfonamide induced a chronic, slo... more 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.
Human adaptability, as a field of inquiry within human biology, became defined during the researc... more Human adaptability, as a field of inquiry within human biology, became defined during the research activities of the International Biological Program (IBP) (1964-1974). During this period, research was focused on ecological, physiological, and genetic studies of human populations within the theoretical frameworks of adaptation and evolution. Other defining characteristics of the IBP human adaptability research were standardization of methods, multidisciplinary projects, international cooperation, and a concern with human health issues. Some observers suggest that this research contributed to the ongoing transformation of physical anthropology and related fields from a largely descriptive to an analytical science. During the 25 years between the end of the IBP and the present, a number of research trends have continued: Several new multidisciplinary projects were initiated and completed; a subfield of demography within human biology has matured; nutrition, infant and child growth, and health studies have proliferated; and molecular genetics and DNA analysis have superseded the earlier population genetics. International programs today are geared toward more practical and applied studies with less emphasis on basic science. Continuation of human adaptability research into the 21st century is likely to make contributions in 3 broad areas: population, environment, and health. Productive research is likely to contribute to these 3 areas in the following categories: reproduction, psychosocial stress, life span approaches to health, effects of losses in biodiversity on health, a human biology of poverty, emerging infectious diseases, epidemiology of modernization, evolutionary medicine, and aging. The success of much of this research in its contribution to knowledge will come from the integrated perspectives of a biobehavioral framework of inquiry.
Mature dissociated motor neuron-enriched and hippocampal neuron cultures derived from fetal New Z... more 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.
The strikingly high incidence of amyotrophic lateral sclerosis (ALS) and parkinsonism‐dementia (P... more The strikingly high incidence of amyotrophic lateral sclerosis (ALS) and parkinsonism‐dementia (PD), two uniformly fatal neurodegenerative disorders which often occur in the same families and occasionally in the same individual, was recognized on Guam more than three decades ago. Since the first systematic observations began, nearly 800 Guamanian Chamorro patients have been clinically diagnosed as having either disease. The original incidence rates for ALS and PD accounted for one in five deaths among Chamorros over ago 25. During the past 30 years, however, the incidence and mortality rates have dramatically declined and today the risk to Guamanian chamorros is only several‐fold higher than that for non‐Chamorro residents of the continental United States. The accumulating epidemiological and genetic data strongly suggest that environmental factors are primarily involved in the etiology and pathogenesis of these disorders. The high incidence focus of ALS and PD on Guam and similar, but less well‐studied, foci in West New Guinea and the Kii Peninsula of Japan represent natural paradigms of chronic degenerative disease that have provided new information and insights for understanding not only ALS and PD, but other neurological disorders such as classical ALS, Parkinson disease, Alzheimer disease, and early neuronal aging, insights that might otherwise not have been forthcoming from studies of low incidence sporadic disease in large cosmopolitan Western communities.
We report the distribution and imaging of calcium and aluminum in neurofibrillary tangle (NFT)-be... more We report the distribution and imaging of calcium and aluminum in neurofibrillary tangle (NFT)-bear- ing neurons within Sommer'S sector of the hippocampus in Guamanian patients with parkinsonism-dementia, using a method of computer-controlled electron beam x-ray micro- analysis and wavelength dispersive spectrometry. Calcium and aluminum were distributed in cell bodies and axonal processes of NFT-bearing neurons. The elemental images show that both calcium and aluminum deposits occur within the same NFT- bearing hippocampal neuron in this dementing disease, sug- gesting that these elements are involved in NFT formation. No prominent concentrations of calcium and aluminum were im- aged in non-NFT-containing regions within the pyramidal cell layer of the parkinsonism-dementia cases or in the control cas- es. These findings support the hypothesis that secondary hyperparathyroidisnm resulting from low environmental calci- um and magnesium in the high-incidence focus of amyotrophic lateral sclerosis and parkinsonism-dementia on Guam had led to abnormal deposition of calcium and aluminum in the cen- tral nervous system.
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Papers by Ralph Garruto