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Biomedical subjects

F D Miller

Publications and source records attributed to F D Miller.

At least 91 records · Page 5Linked to original sources
PubMed1991

Response of facial and rubrospinal neurons to axotomy: changes in mRNA expression for cytoskeletal proteins and GAP-43.

Neurons confined within the mammalian CNS usually do not regenerate after axonal injury, while axonal regeneration is the rule in the PNS. It has been hypothesized that this may be related to differences in the microenvironment of the PNS versus CNS and to differences in the neuronal response to injury. In order to test the latter hypothesis, we compared changes in gene expression after axotomy in two populations of neurons: rat facial motoneurons and rat rubrospinal neurons. In situ hybridization with cDNA probes for the medium and light neurofilament protein revealed a reduced mRNA content in both facial and rubrospinal neurons at all times investigated (i.e., 1, 2, and 3 weeks after axotomy). On the other hand, mRNAs for actin and tubulin were increased in both neuronal populations during the first week after axotomy. While this increase was sustained in facial motoneurons for several weeks, total tubulin mRNA and actin mRNA were decreased in rubrospinal neurons at 2 and 3 weeks after axotomy, coincident with their atrophy. The developmentally regulated T alpha 1 tubulin mRNA, which was previously shown to be reexpressed in facial motoneurons after axotomy, was elevated severalfold in axotomized rubrospinal neurons, and increased levels persisted in some rubrospinal neurons as late as 7 weeks after axotomy. Similarly, the developmentally regulated GAP-43 mRNA increased in both axotomized facial and rubrospinal neurons, and increased levels were sustained in some axotomized rubrospinal neurons for at least 7 weeks. The response of rubrospinal neurons to axotomy in the cervical spinal cord is, in the first week, qualitatively similar to the response of facial motoneurons. However, by 2 weeks after axotomy there is a generalized reduction in mRNA levels for all three cytoskeletal proteins that is associated with neuronal atrophy. During this period, mRNA levels for the two specific markers of the growth state, T alpha 1 tubulin and GAP-43, remain elevated. Thus, axotomy of rubrospinal neurons appears to set in motion two independent events. First, an axotomy signal initiates a cell-body reaction similar to that of PNS neurons, including increased mRNA levels for T alpha 1 tubulin and GAP-43. Later, a generalized cellular atrophy and decrease in mRNA levels occur without reversing the specific responses of T alpha 1 and GAP-43 to axotomy. We conclude that the failure of rubrospinal neurons to regenerate is not due to a failure to initiate gene-expression changes characteristic of regenerating peripheral neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Actins↗
PubMed1990

Increased expression of the embryonic form of a developmentally regulated mRNA in Alzheimer's disease.

There is increasing evidence that an aberrant sprouting response may contribute to some of the neuronal alterations observed in Alzheimer's disease (AD). In this study, we demonstrate that in the rat CNS, sprouting results in the reinduction of the embryonic form of the mRNA for alpha-tubulin. The fetal form of alpha-tubulin mRNA was also elevated in the hippocampus obtained from five AD patients, as compared to five elderly controls. These results suggest that the reexpression of embryonic forms of cytoskeletal proteins, in association with an aberrant sprouting response, may contribute to the neuropathological alterations in AD.

Adult↗
PubMed1990

Molecular markers of reactive plasticity.

Sprouting has been studied extensively using morphological markers, but relatively little is known regarding the molecular and biochemical events which underlie the sprouting response. Moreover, due to the lack of suitable markers, it has been difficult to examine changes in the major hippocampal pathways in animal lesion models and in neurological disorders. We utilized two markers, obtained through molecular genetic analysis, to examine alterations in hippocampal circuits following partial deafferentation. SNAP-25, a neuronal specific protein, is located presynaptically in the perforant path, Schaffer collaterals, mossy fibers, and commissural/associational pathways. Selective destruction of CA3 pyramidal neurons, dentate gyrus granule cells, and entorhinal cortical neurons resulted in a loss of SNAP-25 immunoreactivity at the site of the axonal projections of the lesioned neurons. SNAP-25 immunoreactivity was maintained in projections to the lesioned region, and enhanced in areas adjacent to those deafferented by the lesions. Expression of SNAP 25 mRNA was increased in denervated regions, and in neurons which would be expected to participate in the sprouting response. Tubulin-alpha 1 is an mRNA which is expressed at high levels in the fetal brain during periods of neurite outgrowth, but at low levels in the adult brain. The expression of T alpha 1 mRNA was increased in the rat hippocampal neurons following entorhinal lesions, and in the human hippocampus in patients with Alzheimer's disease. These results demonstrate that sprouting in the CNS may result in the replay of developmental patterns of gene expression. Examination of SNAP-25 and T alpha 1 mRNA expression and of SNAP-25 immunoreactivity may be useful in investigating alterations in major hippocampal circuits in a variety of conditions such as learning, hypoxia, hypoglycemia, and also in neurological disorders such as temporal lobe epilepsy and Alzheimer's disease.

Animals↗
PubMed1990

Increased expression of T alpha 1 alpha-tubulin mRNA during collateral and NGF-induced sprouting of sympathetic neurons.

We have examined expression of T alpha 1 alpha-tubulin mRNA in the rat superior cervical ganglion (SCG) to determine whether changes in gene expression accompany neuronal sprouting and to investigate factors that regulate growth-associated genes in intact neurons. Northern blot analysis demonstrates that levels of T alpha 1 alpha-tubulin mRNA increase in the uninjured SCG following transection of contralateral neurons that project to bilaterally innervated, but not unilaterally innervated target organs. The observed increase in uninjured neurons is associated with collateral sprouting, as measured by increased tyrosine hydroxylase immunoreactivity within the pineal gland. These data suggest that target-derived factors may regulate T alpha 1 mRNA in sprouting neurons. Consistent with this hypothesis, systemic NGF treatment of neonatal animals over a developmental interval when T alpha 1 alpha-tubulin mRNA normally decreases led to a 5- to 10-fold increase in T alpha 1 mRNA levels in developing sympathetic neurons. In addition, deafferentation of the SCG, which promotes neuronal sprouting in the ganglion, increases T alpha 1 mRNA in ganglia on the ipsilateral and contralateral sides. Together, these data demonstrate that T alpha 1 alpha-tubulin mRNA elevates as a function of neuronal sprouting, and that T alpha 1 mRNA expression in intact neurons can be regulated by extrinsic cues, including NGF and changes in connectivity.

Animals↗
PubMed1990

Health status and life style in elderly Japanese men with a long life expectancy.

The Japanese population in Hawaii has one of the longest life expectancies of any large population subgroup in the U.S. and the world. Cross-sectional data on 1,379 elderly, noninstitutionalized, male Japanese American survivors of a population-based cohort study indicated the most common health problems were hypertension (43%), arthritis (33%), diabetes (13%), and gout (9%). For cancer and hypertension there is a trend toward higher prevalence in older age groups. For coronary heart disease, stroke, and angina the oldest age group (75-81 years) has a higher prevalence than that seen in younger age groups. Other relatively common diseases such as diabetes, gout, peptic ulcer, and arthritis do not have higher prevalence in older age groups. Drugs reported to be used frequently by study participants were for hypertension, gout, CHD, and diabetes. The prevalence rates of major limitations of mobility and of living alone appear to be relatively low in this population. Less than one percent of the current population rate their health status as poor. The prevalence of normal serum cholesterol and smoking are similar to those seen in U.S. White males, while the rates of hypertension appear lower. Prevalence rates for stroke and heart attack also appear to be somewhat lower in these long-lived individuals than those seen in U.S. Whites.

Activities of Daily Living↗
PubMed1990

Water contact and Schistosoma haematobium infection: a case study from an upper Egyptian village.

The quantitative relationship between water contact and Schistosoma haematobium infection was studied in a cohort of male school children aged 6-17 in El Ayaisha village, Upper Egypt, during a two-year study. An exposure index (total body minutes, TBM) was used to identify the activities responsible for exposure to cercariae-infested water and to examine the relationship between water contact and infection. Results show that 65% of all contacts and 86% of all TBM were due to swimming in the Nile and canals and that swimming was the most important exposure and contamination activity. Using multivariate analysis, several sites, study periods, residence groups and mostly canal contacts were significantly correlated with egg-counts. Positive relationships could also be identified using egg-counts with water contact data from preceding study periods, indicating the influence of pre-existing infections, prepatency and seasonality of water contact and transmission. TBM were usually more significantly correlated with egg-counts than frequency and duration of contact. The relevance of the findings for control programmes and the use of school children and the exposure index for water contact studies are discussed.

Adolescent↗
PubMed1990

Branched-chain fatty acids produced by mutants of Streptomyces fradiae, putative precursors of the lactone ring of tylosin.

Three branched-chain fatty acids (7-hydroxy-4,6-dimethylnona-2,4-dienoic acid [compound 1], its 7-epimer [compound 2], and 7-keto-4,6-dimethylnona-2,4-dienoic acid [compound 3]) and a ketone (9-hydroxy-6,8-dimethylundeca-4,6-dien-3-one [compound 4]) were isolated from the culture broth of mutants of Streptomyces fradiae which were blocked in the biosynthesis of the macrolide antibiotic tylosin. Two phenotypic classes of mutants of this organism which were blocked in the addition of mycaminose to tylactone (compound 6) accumulated these compounds. These compounds were not produced by mutants which were blocked in lactone synthesis, in steps beyond mycaminose addition, or by the wild-type strain. Synthesis of these compounds, like synthesis of tylosin, was inhibited by the addition of cerulenin. Compounds 1, 2, and 3 were partially interconvertible by these mutants; but they were not produced from the degradation of tylactone and they were not directly incorporated into tylosin by intact cells. The structures of compounds 1 and 2 were equivalent to that of a predicted intermediate (S. Yue, J. S. Duncan, Y. Yamamoto, and C. R. Hutchinson, J. Am. Chem. Soc. 109:1253-1255, 1987) in the biosynthesis of tylactone. The ketone (compound 4) reported previously (N. D. Jones, M. O. Chaney, H. A. Kirst, G. M. Wild, R. H. Baltz, R. L. Hamill, and J. W. Paschal, J. Antibiot. 35:420-425, 1982) appears to be the decarboxylation product of the intermediate following that represented by compound 1. This represents the first report of the isolation of putative precursors of tylactone from tylosin-producing organisms.

Alcohols↗
PubMed1990

Regulation of neural oxytocin gene expression by gonadal steroids in pubertal rats.

We have previously demonstrated that neuronal oxytocin mRNA increases during the pubertal development of female rats. In this paper we have examined the factors that regulate this developmental increase in both male and female rats. Northern blot analysis demonstrated that neural oxytocin mRNA increased 5- to 10-fold from postnatal day 20 (P20) to P60 in animals of both sexes, coincident with puberty. Mature male rats and females at all stages of the estrous cycle expressed similar levels of neural oxytocin mRNA. Pubertal up-regulation of oxytocin mRNA was largely, but not completely, inhibited by prepubescent gonadectomy, indicating a requirement for intact gonads as well as some other as yet undefined factor(s). Pubertal treatment of gonadectomized animals with estradiol or testosterone abolished the effects of gonadectomy; treated animals expressed levels of neural oxytocin mRNA similar to those in controls. However, treatment of prepubertal animals with estradiol or testosterone from P10 to P20 had no effect on oxytocin mRNA levels, suggesting that neural maturation or other factors are necessary requisites for steroid sensitivity. To determine whether neural activin played any role in regulating oxytocin mRNA during puberty, we examined levels of inhibin/activin beta A-chain mRNA. This mRNA was expressed at similar levels in all brain regions and did not vary as a function of gonadectomy or steroid treatment, making it unlikely that activin mediates the observed changes. Together, these data indicate that neural oxytocin mRNA is induced by gonadal steroids during puberty, and suggest a mechanism for coordinating development of reproductive functions with other pubertal changes.

Activins↗
PubMed1989

Regulation of neuronal oxytocin mRNA by ovarian steroids in the mature and developing hypothalamus.

We have examined the changes in neuronal expression of oxytocin mRNA in the perinatal and mature female rat as a function of endogenous gonadal steroids. Northern blot analysis demonstrated a significant developmental increase in the abundance of oxytocin mRNA in the female brain concomitant with puberty. Ovariectomy of adult females decreased total brain oxytocin mRNA to significantly lower levels. In contrast, lactating mothers had increased levels of neuronal oxytocin mRNA. In situ hybridization analysis of neuronal oxytocin mRNA in adolescent, mature virgin, and ovariectomized virgin female brains demonstrated that the location and number of neurons expressing oxytocin mRNA was unchanged and that total brain oxytocin mRNA differences were attributable to amounts expressed per neuron. Differences in mRNA abundance were noted in oxytocin neurons throughout the hypothalamus, including those known to project as magnocellular neurons to the neurohypophysis and those of parvocellular origin thought to make wholly intracerebral connections. This developmental and dynamic regulation of oxytocin mRNA levels during gonadal maturation may coordinate the peripheral and central effects of this peptide on the reproductive biology of the female rat.

Aging↗
PubMed1989

Environmental health education in Micronesia.

Water supply and sanitation programmes in Micronesia require substantial capital investments. In the past, many of these projects have failed to achieve their maximum impact on preventing water-related diseases. Cases of cholera and the continuation of frequently occurring gastro-intestinal diseases undermine the expectations that new and planned water and sanitation systems will result in disease prevention. This report indicates that knowledge of water-related diseases and the understanding of the benefits of safe water supply and sanitation are limited as programmes in Micronesia that would educate the different sectors of the community have never been institutionalised. We have developed the first comprehensive system for teaching about water supply, sanitation and health in a Micronesian environment. The educational materials will be used as curricula in public education and as information resources for appropriate individuals in these remote and scattered communities of the Pacific.

Environmental Health↗
PubMed1989

Rapid induction of the major embryonic alpha-tubulin mRNA, T alpha 1, during nerve regeneration in adult rats.

The mRNAs for 2 isotypes of alpha-tubulin, termed T alpha 1 and T26, are differentially regulated in the developing rat nervous system. T alpha 1 alpha-tubulin mRNA is expressed at high levels when neurons extend processes whereas T26 mRNA is expressed constitutively (Miller et al., 1987b). We have examined the expression of these 2 alpha-tubulin mRNAs in regenerating facial and sciatic motor neurons of the rat using Northern blot and in situ hybridization analyses. T alpha 1 alpha-tubulin mRNA is rapidly induced in axotomized motor neurons of the facial nerve: increased levels of mRNA are detectable 4 hr after a lesion is made 1.5 cm distal to the neuronal cell bodies. T alpha 1 mRNA levels are highest from 3-7 d postcrush and decline slowly to control levels following functional reinnervation of facial muscles. In contrast, T26 mRNA levels remain constant throughout the regeneration process. Total alpha-tubulin mRNA levels do not change until 1 d postaxotomy; otherwise the changes in expression are similar to T alpha 1 mRNA, although the relative increase is not as great. Enhanced T alpha 1 alpha-tubulin mRNA expression also occurs in motor neurons of crushed or tied sciatic nerve. Ligature or crush of the sciatic nerve leads to approximately the same peak in the expression of T alpha 1 mRNA at 7-15 d postaxotomy. Following the facial nerve transection, under conditions in which reinnervation is prevented, T alpha 1 alpha-tubulin mRNA levels remain elevated significantly longer than when the nerve is crushed. Taken together, the data indicate that T alpha 1 alpha-tubulin mRNA is rapidly induced following neuronal axotomy, remains elevated during the period of axonal regrowth, and is subsequently down-regulated at the approximate time of target contact. These results are reminiscent of changes in T alpha 1 mRNA that occur during neuronal development. This growth-associated pattern of T alpha 1 gene expression can be modified by inhibiting appropriate regeneration of the damaged nerve.

Animals↗
PubMed1988

Immunohistochemical and in situ hybridization analysis of the development of the rat somatostatin-containing neocortical neuronal system.

The chemical differentiation of somatostatin (SS) neurons in rat neocortex was characterized by molecular biochemical and morphological methods. Northern (RNA) blotting indicates that regional distribution of SS mRNA correlates with the known distribution patterns of SS-containing neurons in the adult, while similar analysis of poly (A)+ RNA isolated from telencephalon at various times postnatally shows an increase between P9 and P15, with a slight decrease in the adult. In situ hybridization with a probe specific to SS mRNA, and immunohistochemistry using antisera specific for the N-terminally extended form of SS, SS28, and SS28(1-12), were used to detect neocortical neurons containing this mRNA or its translation product. The appearance of SS mRNA is coincident with detectable immunoreactivity for SS peptides. The expression of the SS gene by cortical neurons occurs in two waves. From P1 to P11, hybridizing neurons are predominant below the cortical plate in the developing infragranular layers. Immunohistochemical analysis of immunoreactivity to SS28 reveals a significant development of this neocortical system by late gestation (E20). At this point SS28(1-12), the predominant SS form detected, is mainly in neurons of the subplate, with less detectable immunoreactivity in the intermediate zone and cortical plate. By P2, neurons in the subplate exhibit detectable SS28 and SS28(1-12). Although immunoreactive perikarya are no longer detectable at P2 in the cortical plate or marginal zone, a very dense plexus of SS28(1-12) fibers is seen in the subplate, marginal zone, and intermediate zone; relatively few immunoreactive fibers are found in the cortical plate. By P12, a dramatic shift occurs; a large supragranular population of these SS neurons is observed by both mRNA and antibody methods, as is a subsequent decrease in number in the adult. The shift in immunoreactivity occurs with supragranular SS28-containing neurons now prominent, and SS28(1-12)-containing neurons and fibers greatly diminished. The number of neurons containing SS mRNA or SS28 immunoreactivity decreases from P12 to adult, when these neurons exhibit a bilaminar distribution. Neurons immunoreactive for SS28(1-12) are now sparsely distributed throughout the cortex, while SS28(1-12) fibers densely innervate layers I and V/VI.

Age Factors↗
PubMed1988

A prospective study of mortality and morbidity among carpenters in the Honolulu Heart Program Cohort.

The relationship of occupation as a carpenter to the development of definite coronary heart disease, stroke, cancer and total mortality was examined in men of Japanese ancestry participating in the Honolulu Heart Program. After 18 years of follow-up those men who indicated that their present and usual occupation was carpentry had a significantly lower age-adjusted rate of definite coronary heart disease and a significantly lower mortality rate compared to participants who were never occupied as carpenters. There were no significant differences for age-adjusted rates for stroke and cancer nor any differences for those whose usual occupation was carpentry but present occupation was not carpentry. These results were unchanged when controlling for several cardiovascular risk factors and potentially confounding variables. Unlike earlier observations, these findings are not affected by the "healthy worker bias" and support the relationship that carpentry is associated with lower rates of cardiovascular disease.

Cerebrovascular Disorders↗
PubMed1987

Isotypes of alpha-tubulin are differentially regulated during neuronal maturation.

The mRNAs for two isotypes of alpha-tubulin, termed T alpha 1 and T26, are known to be expressed in the rat nervous system. We have compared the expression of these two alpha-tubulin mRNAs during neural development, using RNA blotting and in situ hybridization techniques with probes directed against unique sequences of each mRNA. T alpha 1 mRNA is highly enriched in the embryonic nervous system but is markedly less abundant in the adult brain; T26 mRNA is expressed in many embryonic tissues with little change in abundance during development. Within the nervous system, T alpha 1 mRNA is enriched in regions with neurons actively undergoing neurite extension, such as the cortical plate, whereas T26 mRNA is relatively homogeneous in distribution, with some enrichment in proliferative zones. Expression of T alpha 1 mRNA is also increased in PC12 cells induced to differentiate and extend neurite processes by nerve growth factor. Taken together, the data indicate that T alpha 1-tubulin mRNA is expressed at high levels during the extension of neuronal processes. The abundant expression of T alpha 1-tubulin mRNA may therefore reflect either a means to increase the available pool of alpha-tubulin or a specific requirement for the T alpha 1 isotype for neurite extension.

Cell Differentiation↗
PubMed1987

Developmentally regulated rat brain mRNAs: molecular and anatomical characterization.

In order to identify markers for developing neural cell populations and gain molecular insights into the processes of neural development and differentiation, we have selected cDNA clones of rat brain mRNAs that are expressed in brain at embryonic day 16 (E16) with at least 10-fold greater abundance than they are in adult brain. Eleven such clones were obtained from a cDNA library of E16 brain poly(A)+ RNA using a combination of differential and subtractive hybridization screens. The temporal and spatial patterns of expression of the mRNAs corresponding to these clones were characterized by Northern (RNA) blotting and by in situ hybridization. Although all the mRNAs were enriched in embryonic brain, different mRNAs demonstrated maximum abundance at different times in late embryogenesis. The mRNAs can be grouped into 3 classes on the basis of their patterns of spatial expression in the embryo: one cDNA clone from each class and its corresponding mRNAs have been characterized in more detail. Class C represents mRNAs that are highly enriched in the nervous system and may be expressed in newly differentiating neurons; the example chosen was shown by nucleotide sequence analysis to encode the brain alpha 1 isotype of tubulin. Class B mRNAs have a broader distribution in the developing embryo but are expressed predominantly in the ventricular germinal zones of the developing nervous system and may represent molecules involved with neurogenesis. A third class (Class A) includes mRNAs with a more homogeneous distribution within the embryo and developing nervous system, which may encode "housekeeping" molecules. These clones and their encoded products will provide markers for cell populations at particular stages of neural development.

Animals↗
PubMed1986

Assembly of DNA onto the histone octamer facilitates the B-to-Z transition.

Nucleosomal core particles containing the right- and left-handed conformations of DNA were examined for their ability to support the B----Z or Z----B transition. Nucleosomes were assembled onto the B-and Z-conformations of poly[d(Gm5C)] and the B-conformation of poly[d(GC)] as previously described. Absorbance and circular dichroic spectroscopy indicated that the DNA on all three core particle populations could undergo the conformational B----Z transition. Further, the right- to left-handed transition for both poly[d(Gm5C)] and poly[d(GC)] appeared to be facilitated by the DNAs association with the histone octamer. The DNA remained associated with the protein core subsequent to the transition, and electron microscopy and sedimentation velocity analysis indicated that there were no gross changes in nucleosomal structure. However, a change in the sedimentation value of the poly[d(Gm5C)] core particles was detected when the conformation of the DNA was altered from B to Z, resulting in a lower S20,w value for the Z-form particles than for the corresponding B-form particles.

DNA↗