Biomedical subjects

J F Ross

Publications and source records attributed to J F Ross.

At least 19 recordsLinked to original sources

PubMed2003

Acrylamide axonopathy revisited.

Distal swelling and eventual degeneration of axons in the CNS and PNS have been considered to be the characteristic neuropathological features of acrylamide (ACR) neuropathy. These axonopathic changes have been the basis for classifying ACR neuropathy as a central-peripheral distal axonopathy and, accordingly, research over the past 30 years has focused on the primacy of axon damage and on deciphering underlying mechanisms. However, based on accumulating evidence, we have hypothesized that nerve terminals, and not axons, are the primary site of ACR action and that compromise of corresponding function is responsible for the autonomic, sensory, and motor defects that accompany ACR intoxication (NeuroToxicology 23 (2002) 43). In this paper, we provide a review of data from a recently completed comprehensive, longitudinal silver stain study of brain and spinal cord from rats intoxicated with ACR at two different daily dosing rates, i.e., 50 mg/kg/day, ip or 21 mg/kg/day, po. Results show that, regardless of dose-rate, ACR intoxication was associated with early, progressive nerve terminal degeneration in all CNS regions and with Purkinje cell injury in cerebellum. At the lower dose-rate, initial nerve terminal argyrophilia was followed by abundant retrograde axon degeneration in white matter tracts of spinal cord, brain stem, and cerebellum. The results support and extend our nerve terminal hypothesis and suggest that Purkinje cell damage also plays a role in ACR neurotoxicity. Substantial evidence now indicates that axon degeneration is a secondary effect and is, therefore, not pathophysiologically significant. These findings have important implications for future mechanistic research, classification schemes, and assessment of neurotoxicity risk.

Acrylamide↗

PubMed2003

Acrylamide neuropathy. III. Spatiotemporal characteristics of nerve cell damage in forebrain.

Previous studies of acrylamide (ACR) neuropathy in rat PNS [Toxicol. Appl. Pharmacol. (1998) 151:211-221] and in spinal cord, brainstem and cerebellum [NeuroToxicology (2002a) 23:397-414; NeuroToxicology (2002b) 23:415-429] have suggested that axon degeneration was not a primary effect and was, therefore, of unclear neurotoxicological significance. To conclude our studies of neurodegeneration in rat CNS during ACR neurotoxicity, a cupric silver stain method was used to define spatiotemporal characteristics of nerve cell body, dendrite, axon and terminal argyrophilia in forebrain regions and nuclei. Rats were exposed to ACR at a dose-rate of either 50 mg/kg per day (i.p.) or 21 mg/kg per day (p.o.) and at selected times brains were removed and processed for silver staining. Results show that intoxication at either ACR dose-rate produced a terminalopathy, i.e. nerve terminal degeneration and swelling were present in the absence of significant argyrophilic changes in neuronal cell bodies, dendrites or axons. Exposure to the higher ACR dose-rate caused early onset (day 5), widespread nerve terminal degeneration in most of the major forebrain areas, e.g. cerebral cortex, thalamus, hypothalamus and basal ganglia. At the lower dose-rate, nerve terminal degeneration in the forebrain developed early (day 7) but exhibited a relatively limited spatial distribution, i.e. anteroventral thalamic nucleus and the pars reticulata of the substantia nigra. Several hippocampal regions were affected at a later time point (day 28), i.e. CA1 field and subicular complex. At both dose-rates, argyrophilic changes in forebrain nerve terminals developed prior to the onset of significant gait abnormalities. Thus, in forebrain, ACR intoxication produced a pure terminalopathy that developed prior to the onset of significant neurological changes and progressed as a function of exposure. Neither dose-rate used in this study was associated with axon degeneration in any forebrain region. Our findings indicate that nerve terminals were selectively affected in forebrain areas and, therefore, might be primary sites of ACR action.

Acrylamide↗

PubMed2003

Acrylamide neuropathy. II. Spatiotemporal characteristics of nerve cell damage in brainstem and spinal cord.

Previous studies of acrylamide (ACR) neuropathy in rat PNS [Toxicol. Appl. Pharmacol. 151 (1998) 211] and cerebellum [NeuroToxicology 23 (2002) 397] have suggested that axon degeneration was not a primary effect and was, therefore, of unclear neurotoxicological significance. To continue morphological examination of ACR neurotoxicity in CNS, a cupric silver stain method was used to define spatiotemporal characteristics of nerve cell body, dendrite, axon and terminal degeneration in brainstem and spinal cord. Rats were exposed to ACR at a dose-rate of either 50 mg/kg per day (i.p.) or 21 mg/kg per day (p.o.), and at selected times brains and spinal cord were removed and processed for silver staining. Results show that intoxication at the higher ACR dose-rate produced a nearly pure terminalopathy in brainstem and spinal cord regions, i.e. widespread nerve terminal degeneration and swelling were present in the absence of significant argyrophilic changes in neuronal cell bodies, dendrites or axons. Exposure to the lower ACR dose-rate caused initial nerve terminal argyrophilia in selected brainstem and spinal cord regions. As intoxication continued, axon degeneration developed in white matter of these CNS areas. At both dose-rates, argyrophilic changes in brainstem nerve terminals developed prior to the onset of significant gait abnormalities. In contrast, during exposure to the lower ACR dose-rate the appearance of axon degeneration in either brainstem or spinal cord was relatively delayed with respect to changes in gait. Thus, regardless of dose-rate, ACR intoxication produced early, progressive nerve terminal degeneration. Axon degeneration occurred primarily during exposure to the lower ACR dose-rate and developed after the appearance of terminal degeneration and neurotoxicity. Spatiotemporal analysis suggested that degeneration began at the nerve terminal and then moved as a function of time in a somal direction along the corresponding axon. These data suggest that nerve terminals are a primary site of ACR action and that expression of axonopathy is restricted to subchronic dosing-rates.

Acrylamide↗

PubMed2002

Nerve terminals as the primary site of acrylamide action: a hypothesis.

Acrylamide (ACR) is considered to be prototypical among chemicals that cause a central-peripheral distal axonopathy. Multifocal neurofilamentous swellings and eventual degeneration of distal axon regions in the CNS and PNS have been traditionally considered the hallmark morphological features of this axonopathy. However, ACR has also been shown to produce early nerve terminal degeneration of somatosensory, somatomotor and autonomic nerve fibers under a variety of dosing conditions. Recent research from our laboratory has demonstrated that terminal degeneration precedes axonopathy during low-dose subchronic induction of neurotoxicity and occurs in the absence of axonopathy during higher-dose subacute intoxication. This relationship suggests that nerve terminal degeneration, and not axonopathy, is the primary or most important pathophysiologic lesion produced by ACR. In this hypothesis paper, we review evidence suggesting that nerve terminal degeneration is the hallmark lesion of ACR neurotoxicity, and we propose that this effect is mediated by the direct actions of ACR at nerve terminal sites. ACR is an electrophile and, therefore, sulfhydryl groups on presynaptic proteins represent rational molecular targets. Several presynaptic thiol-containing proteins (e.g. SNAP-25, NSF) are critically involved in formation of SNARE (soluble N-ethylmaleimide (NEM)-sensitive fusion protein receptor) complexes that mediate membrane fusion processes such as exocytosis and turnover of plasmalemmal proteins and other constituents. We hypothesize that ACR adduction of SNARE proteins disrupts assembly of fusion core complexes and thereby interferes with neurotransmission and presynaptic membrane turnover. General retardation of membrane turnover and accumulation of unincorporated materials could result in nerve terminal swelling and degeneration. A similar mechanism involving the long-term consequences of defective SNARE-based turnover of Na+/K(+)-ATPase and other axolemmal constituents might explain subchronic induction of axon degeneration. The ACR literature occupies a prominent position in neurotoxicology and has significantly influenced development of mechanistic hypotheses and classification schemes for neurotoxicants. Our proposal suggests a reevaluation of current classification schemes and mechanistic hypotheses that regard ACR axonopathy as a primary lesion.

Acrylamide↗

PubMed2002

Neurological evaluation of toxic axonopathies in rats: acrylamide and 2,5-hexanedione.

This research was conducted to determine which neurological test or combination of tests can provide sufficient functional information to compliment biochemical or morphological endpoints in mechanistic studies of toxic axonopathies. Using several neurological indices, we evaluated the effects of two prototypical neurotoxicants that cause distal axonopathy: acrylamide monomer (ACR) and 2,5-hexanedione (HD). For each toxicant, rats were exposed to two daily dosing rates (ACR, 50 mg/kg per day i.p. or 21 mg/kg per day, p.o.; HD, 175 or 400 mg/kg per day, p.o.) and neurological endpoints were determined two to three times per week. Specific tests included observations of spontaneous locomotion in an open field, and measurements of hindlimb landingfoot splay, forelimb and hindlimb grip strength and the hindlimb extensor thrust response. For all neurological parameters, the magnitude of defect induced by either neurotoxicant was not related to daily dose-rate, e.g. both the lower and higher ACR dose-rates produced the same degree of neurological dysfunction. Instead, dose-rate determined onset and progression of neurotoxicity, e.g. the higher ACR dose-rate produced moderate neurotoxicity after approximately 8 days of intoxication, whereas the lower dose-rate caused moderate neurotoxicity after 26 days. Regardless of dose-rate, ACR-exposed rats exhibited gait abnormalities (ataxia, splayed hindlimbs), in conjunction with increased landing hindfoot spread and decreased hindlimb grip strength and extensor thrust HD intoxicated rats exhibited hindlimb muscle weakness as indicated by a gait abnormality (dropped hocks) and decreases in grip strength and the extensor thrust response. However, hindlimb landingfoot spread was not affected by HD exposure. For both neurotoxicants, gait changes preceded or coincided with alterations in other neurologic indices. These results suggest that observations of spontaneous behavior in an open field represent a practical approach to assessing temporal development and extent of neurological dysfunction induced by axonopathic toxicants such as ACR and HD.

Acrylamide↗

PubMed2002

Acrylamide neuropathy. II. Spatiotemporal characteristics of nerve cell damage in brainstem and spinal cord.

Previous studies of acrylamide (ACR) neuropathy in rat PNS [Toxicol. Appl. Pharmacol. 151 (1998) 211] and cerebellum [Neurotoxicology, 2002a] have suggested that axon degeneration was not a primary effect and was, therefore, of unclear neurotoxicological significance. To continue morphological examination of ACR neurotoxicity in CNS, a cupric silver stain method was used to define spatiotemporal characteristics of nerve cell body, dendrite, axon and terminal degeneration in brainstem and spinal cord. Rats were exposed to ACR at a dose-rate of either 50 mg/kg per day (i.p.) or 21 mg/kg per day (p.o.), and at selected times brains and spinal cord were removed and processed for silver staining. Results show that intoxication at the higher ACR dose-rate produced a nearly pure terminalopathy in brainstem and spinal cord regions, ie. widespread nerve terminal degeneration and swelling were present in the absence of significant argyrophilic changes in neuronal cell bodies, dendrites or axons. Exposure to the lower ACR dose-rate caused initial nerve terminal argyrophilia in selected brainstem and spinal cord regions. As intoxication continued, axon degeneration developed in white matter of these CNS areas. At both dose-rates, argyrophilic changes in brainstem nerve terminals developed prior to the onset of significant gait abnormalities. In contrast, during exposure to the lower ACR dose-rate the appearance of axon degeneration in either brainstem or spinal cord was relatively delayed with respect to changes in gait. Thus, regardless of dose-rate, ACR intoxication produced early, progressive nerve terminal degeneration. Axon degeneration occurred primarily during exposure to the lower ACR dose-rate and developed after the appearance of terminal degeneration and neurotoxicity. Spatiotemporal analysis suggested that degeneration began at the nerve terminal and then moved as a function of time in a somal direction along the corresponding axon. These data suggest that nerve terminals are a primary site of ACR action and that expression of axonopathy is restricted to subchronic dosing-rates.

Acrylamide↗

PubMed2002

Acrylamide neuropathy. I. Spatiotemporal characteristics of nerve cell damage in rat cerebellum.

Based on evidence from morphometric studies of PNS, we suggested that acrylamide (ACR)-induced distal axon degeneration was a secondary effect related to duration of exposure [Toxicol. Appl. Pharmacol. 151 (1998) 211]. To test this hypothesis in CNS, the cupric-silver stain method of de Olmos was used to define spatiotemporal characteristics of nerve somal, dendritic, axonal and terminal degeneration in rat cerebellum. Rats were exposed to ACR at either 50 mg/kg per day (i.p.) or 21 mg/kg per day (p.o.) and at selected times (i.p. = 5, 8 and 11 days; p.o. = 7, 14, 21, 28 and 38 days) brains were removed and processed for silver staining. Results demonstrate that intoxication at the higher ACR dose-rate produced early (day 5) and progressive degeneration of Purkinje cell dendrites in cerebellar cortex. Nerve terminal degeneration occurred concurrently with somatodendritic argyrophilia in cerebellar and brainstem nuclei that receive afferent input from Purkinje neurons. Relatively delayed (day 8), abundant axon degeneration was present in cerebellar white matter but not in cortical layers or in tracts carrying afferent fibers (cerebellar peduncles) from other brain nuclei. Axon argyrophilia coincided with the appearance of perikaryal degeneration, which was selective for Purkinje cells since silver impregnation of other cerebellar neurons was not evident in the different cortical layers or cerebellar nuclei. Intoxication at the lower ACR dose-rate produced simultaneous (day 14) dendrite, axon and nerve terminal argyrophilia and no somatic Purkinje cell degeneration. The spatiotemporal pattern of dendrite, axon and nerve terminal loss induced by both ACR dose-rates is consistent with Purkinje cell injury. Injured neurons are likely to be incapable of maintaining distal processes and, therefore, axon degeneration in the cerebellum is a component of a "dying-back" process of neuronal injury. Because cerebellar coordination of somatomotor activity is mediated solely through efferent projections of the Purkinje cell, injury to this neuron might contribute significantly to gait abnormalities that characterize ACR neurotoxicity.

Acrylamide↗

PubMed2001

Active repression and E2F inhibition by pRB are biochemically distinguishable.

To understand mechanistically how pRB represses transcription, we used a reconstituted transcription assay and compared pRB activity on naked versus chromatin templates. Surprisingly, when pRB was directly recruited to a naked template, no transcriptional repression was observed. However, we observed active repression when the same promoter was assembled into chromatin. Histone deacetylases do not appear to play a role in this observed repression. Further experiments showed repression could occur after preinitiation complex assembly, in contrast with pRB inhibition of E2F, suggesting discrete mechanisms by which pRB directly inhibits an activator such as E2F or actively represses proximally bound transcription factors.

Carrier Proteins↗

PubMed2001

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. I: behavioral effects.

Alterations in nervous system function after exposure to a developmental neurotoxicant may be identified and characterized using neurobehavioral methods. A number of methods can evaluate alterations in sensory, motor, and cognitive functions in laboratory animals exposed to toxicants during nervous system development. Fundamental issues underlying proper use and interpretation of these methods include a) consideration of the scientific goal in experimental design, b) selection of an appropriate animal model, c) expertise of the investigator, d) adequate statistical analysis, and e) proper data interpretation. Strengths and weaknesses of the assessment methods include sensitivity, selectivity, practicality, and variability. Research could improve current behavioral methods by providing a better understanding of the relationship between alterations in motor function and changes in the underlying structure of these systems. Research is also needed to develop simple and sensitive assays for use in screening assessments of sensory and cognitive function. Assessment methods are being developed to examine other nervous system functions, including social behavior, autonomic processes, and biologic rhythms. Social behaviors are modified by many classes of developmental neurotoxicants and hormonally active compounds that may act either through neuroendocrine mechanisms or by directly influencing brain morphology or neurochemistry. Autonomic and thermoregulatory functions have been the province of physiologists and neurobiologists rather than toxicologists, but this may change as developmental neurotoxicology progresses and toxicologists apply techniques developed by other disciplines to examine changes in function after toxicant exposure.

Animals↗

PubMed1999

Folate receptor type beta is a neutrophilic lineage marker and is differentially expressed in myeloid leukemia.

BACKGROUND: The membrane-associated folate receptor (FR) type beta is elevated in the spleen in patients with chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). In this study, the authors investigated possible cell type and differentiation stage specificity of expression of FR-beta in normal and leukemic hematopoietic cells. METHODS: An affinity-purified rabbit polyclonal antibody specific for FR-beta was employed for immunostaining representative bone marrow smears and peripheral blood smears from normal individuals and from a limited number of patients with various leukemias. Multiple samples of normal bone marrow and peripheral blood were analyzed for the expression of FR-beta and selected CD antigens by two- or three-color flow cytometry. RESULTS: Of the morphologically identifiable cells, only neutrophils were positive for FR-beta. The leukemic blasts in CML patients showed expression of FR-beta with no apparent relation to the occurrence of the Philadelphia chromosome. Among acute nonlymphocytic leukemias, FR-beta was expressed in promyelocytic leukemia, in the myeloblast populations of myelomonocytic and erythroleukemias, and variably in M1/M2 AML. Neither the blasts of acute lymphocytic leukemia nor the more mature cells of chronic lymphocytic and hairy cell leukemias expressed FR-beta. The less differentiated FR-beta positive AML samples also were positive for CD34 and HLA-DR. Flow cytometric analysis of normal bone marrow and peripheral blood revealed low or insignificant coexpression of FR-beta with CD34, CD19, and CD3, whereas significant coexpression was observed with high levels of CD33, CD13, and CD11b; coexpression of FR-beta with CD14 was high in the immature bone marrow cells, comparable to that in myeloid cells, but relatively low in peripheral blood. CONCLUSIONS: The results of this study suggest a narrow expression pattern of FR-beta marking the neutrophilic lineage and the possibility of defining a subtype or subtypes of myeloid leukemia based on FR-beta expression. The identification of FR-beta positive leukemias and the absence of the receptor in normal CD34 positive cells may enable selective receptor-mediated targeting of leukemic cells.

Animals↗

PubMed1999

Mechanism of transcriptional repression of E2F by the retinoblastoma tumor suppressor protein.

The retinoblastoma tumor suppressor protein (pRB) is a transcriptional repressor, critical for normal cell cycle progression. We have undertaken studies using a highly purified reconstituted in vitro transcription system to demonstrate how pRB can repress transcriptional activation mediated by the E2F transcription factor. Remarkably, E2F activation became resistant to pRB-mediated repression after the establishment of a partial (TFIIA/TFIID) preinitiation complex (PIC). DNase I footprinting studies suggest that E2F recruits TFIID to the promoter in a step that also requires TFIIA and confirm that recruitment of the PIC by E2F is blocked by pRB. These studies suggest a detailed mechanism by which E2F activates and pRB represses transcription without the requirement of histone-modifying enzymes.

Carrier Proteins↗

PubMed1998

Structure and regulation of a polymorphic gene encoding folate receptor type gamma/gamma'.

The human folate receptor (hFR) type gamma and gamma' are constitutively secreted proteins that are expressed primarily in hematopoietic tissues and are potential serum markers for certain hematopoietic malignancies. hFR-gamma' is a variant of hFR-gamma with a two base deletion in its cDNA resulting in a truncated polypeptide. The gene encoding hFR-gamma' was isolated from a placental genomic library. The gene has five exons, four introns and a 5' flanking sequence which contains multiple putative regulatory elements. From RNase protection assay and RACE analysis, the major site of transcriptional initiation was identified at -56 nt. Systematically deleted fragments in the 5' region of the genomic DNA of FR-gamma' were ligated into the PGL3Basic plasmid and the reporter luciferase activity was assayed in cell lysates from transiently transfected NIH3T3 cells. From those results, putative positive and negative regulatory regions in the 5' flanking sequences were noted, and a TATA-less proximal promoter was located between -206 and -22 nt. Gel mobility shift and supershift analyses as well as mutagenesis experiments revealed that Sp1 and ets binding elements in the proximal promoter region confer transcriptional activity. From partial sequencing of genomic DNA, genomic Southern blots, RACE analysis and RNase protection assays, it appears that hFR-gamma shares the gene organization of hFR-gamma'. The results of the analysis of genomic DNA in spleen tissues from several individuals, were consistent with the interpretation that hFR-gamma and hFR-gamma' are encoded by a polymorphic gene.

Amino Acid Sequence↗

PubMed1998

Expanded clinical observations in toxicity studies: historical perspectives and contemporary issues.

Recent or proposed changes in major testing guidelines require expanded clinical observations (ECOs) for a wide variety of toxicity studies in animals. ECOs supplement the simple cageside and hand-held observations traditionally employed during such studies. The new guidelines specify out-of-cage observations [e.g., posture, gait, and reactivity to various stimuli (e.g., auditory, tactile, noxious)] using defined scales and are intended as a Tier 1 screen for neurotoxicity. These new guidelines imply an elevation in the status of clinical observations to equivalency with other major categories of toxicity end points, such as anatomic and clinical pathology. The increased importance of neurological end points in routine studies indicates that there will be a need for many trained professionals to generate and interpret the results of ECOs. However, currently there is wide variation in the training and experience of individuals who conduct and interpret ECOs. The value of ECO data will be increased when industry standards for conducting and interpreting ECOs are systematized and elevated to the level of those for anatomic and clinical pathology.

Animals↗

PubMed1998

A force plate system for measuring low-magnitude reaction forces in small laboratory animals.

We present a force plate system which measures low-magnitude vertical reaction forces generated by small laboratory animals. The force plate mechanical design minimizes radiated transverse waves, acoustic reverberation, and standing waves caused by impacts on the force plate surface. A secondary force plate and PC-based software algorithm minimize floor vibrational artifact. The force plate was used to measure function of rats during two tests: forelimb/hindlimb hopping reaction and surface righting reaction. In control rats, forelimb hopping rate exceeded hindlimb hopping rate during 16 weeks of repeated testing. Subchronic intraperitoneal (i.p.) dosing of 10 mg/kg/day acrylamide produced a selective impairment of hindlimb hopping. In contrast, single doses of haloperidol (1-5 mg/kg, i.p.) slowed the righting reaction and produced a relatively selective impairment of forelimb hopping. The force plate system presents new opportunities for performing quantitative neurological assessments of small laboratory animals when previously such tests had been performed subjectively and qualitatively.

Acrylamides↗

PubMed1996

Variant GPI structure in relation to membrane-associated functions of a murine folate receptor.

Two variant sublines of murine L1210 leukemia cells (L1210A and L1210JF) overexpress the cell surface folate receptor (FR). The membrane bound FR in L1210A cells exhibited significantly (up to 17-fold) greater relative affinities for (6S)-N5-methyltetrahydrofolate, (6S)-N5-formyltetrahydrofolate and methotrexate compared to the FR in L1210JF cells. Furthermore, receptor-mediated transport of [3H]-(6S)-N5-methyltetrahydrofolate was much more efficient in L1210A cells compared to L1210JF cells. When solubilized with Triton X-100, the ligand binding characteristics of FR from both sublines resembled those of the receptor associated with L1210 JF cell membranes. N-terminal amino acid sequence analysis as well as RT-PCR analysis of the entire coding region revealed a single species of FR in both cells, identical to murine FR-alpha. The FR in L1210JF cells was sensitive to phosphatidylinositol specific phospholipase C (PI-PLC) indicating the presence of a glycosyl-phosphatidylinositol (GPI) membrane anchor while the FR in L1210A cells was resistant to PI-PLC; however, the FR in L1210A cells was released from plasma membranes by nitrous acid, as expected for GPI and its PI-PLC resistant structural variants. Treatment of L1210A cell membranes with mild base rendered the protein PI-PLC sensitive as expected for GPI anchors acylated in the inositol ring and also decreased the affinities of the membrane associated FR for reduced folates. When the cDNA for murine FR-alpha was expressed in parental L1210 cells the protein was PI-PLC resistant but was sensitive to PI-PLC when the cDNA was expressed in human 293 fibroblasts. In L1210JF, L1210A, and parental L1210 cells, several cell surface proteins, including FR, incorporated [3H]ethanolamine, a component of the GPI membrane anchor; however, the labeled proteins were released by PI-PLC only in L1210JF cells. The above results preclude any peculiarity of the FR polypeptide in either L1210 subline as the basis for the observed differences in PI-PLC sensitivity and membrane-associated functions of FR. Partial deglycosylation of membrane associated FR from either cell with N-glycanase did not influence its ligand binding characteristics. The results of this study lead to the hypothesis that variant GPI structures may modulate the function of a protein by influencing its conformation/topography in the membrane. Such effects may be identified by their disappearance/reduction upon detergent solubilization or mild base treatment of the membrane.

Amino Acid Sequence↗

PubMed1996

Distribution of bismuth in the brain after intraperitoneal dosing of bismuth subnitrate in mice: implications for routes of entry of xenobiotic metals into the brain.

Bismuth (Bi) can produce neurotoxic effects in both humans and animals under certain dosing conditions, but little else is known about the effects of Bi in the brain. In the present study we determined the distribution of Bi in the brains of adult female Swiss-Webster mice 4, 7, 14, 21 and 28 days after a single 2500 mg/kg i.p. injection of Bi subnitrate (BSN), which establishes a depot of absorbable Bi and produces morphological signs of neurotoxicity. Sections of brains were processed by autometallographic (AMG) procedures that produced silver grains at the site of Bi localization (AMGBi). Ventricular dilation was observed in all BSN-dosed mice. Among treated mice there were marked interanimal differences in the absolute amount of AMGBi, but consistent regional and cellular patterns of AMGBi were observed. AMGBi was observed in many cell types in brain regions adjacent to fenestrated blood vessels of the circumventricular organs (CVOs) and olfactory epithelium. Prominent intrasomal AMGBi was observed in nuclei containing large cell bodies, including cranial motor neurons innervating somatic muscle, lateral vestibular and red nucleus and pontine/medullary reticular nuclei. In the hypothalamus, the supraoptic and paraventricular nuclei demonstrated the densest AMGBi. In the cerebellum, Purkinje and granule cell layers with the densest AMGBi were in folia adjacent to the fourth ventricle. In the hippocampus, AMGBi was densest in the fasciola cinerum, polymorph cells of the dentate gyrus, and pyramidal cell layer of the CA3 regions. Neuropil of subcortical auditory nuclei (cochlear nucleus, trapezoid body, lateral lemniscus and nucleus of lateral lemniscus, medial geniculate nucleus and inferior colliculus) had a high density of AMGBi. Among nonneuronal cells, ependyma and meninges lining the ventricular and subarachnoid spaces were labeled extensively. Glial labeling was prominent adjacent to CVOs, in subependymal regions, and in fiber tracts. Presumptive perivascular cells lining large blood vessels had extremely dense AMGBi as early as 4 days after dosing. Smaller blood vessels had moderate AMGBi. However, in regions (e.g. cerebral cortex, striatum) known to have low brain Bi levels after i.p. dosing, vascular deposits accounted for most of the AMGBi. Several animals had foci of AMGBi which suggested that vascular or perivascular aberrations may have contributed to the unusually dense accumulations. The results of the present studies indicate that Bi accumulates predictably in certain regions and cell types. The pattern of regions and cells with the highest AMGBi accumulations is very similar to pattern reported for other xenobiotic metals (i.e. mercury, silver, gold), and supports the hypothesis that these metals may share some mechanisms for entry, distribution and storage in the brain.

Animals↗

PubMed1996

A history of the American Board of Nuclear Medicine.

The American Board of Nuclear Medicine gave its first certifying examination in 1972 to 1,096 candidates. It was established with the support of the Society of Nuclear Medicine amid considerable conflict involving the American Board of Radiology, the American Board of Internal Medicine, and the American Board of Pathology. As a result of the numerous parties involved, the initial formation of the Board was as a conjoint Board that required the approval of one of its sponsoring Boards for the acceptance of candidates for certification. Conflicting certifications were subsequently established, including the subspecialty certification in Nuclear Radiology by the American Board of Radiology and subspecialty certification in Radioisotopic Pathology by the American Board of Pathology. In 1985, the American Board of Nuclear Medicine was finally relieved of the burden of conjoint Board status and became one of the primary Boards of the American Board of Medical Specialties. There are presently 12 active members of the American Board of Nuclear Medicine, 40 living life members who serve the Board, and 3 deceased life members. As of this date, the Board has certified 4,236 specialists in nuclear medicine and continues to grow and thrive.

History, 20th Century↗

PubMed1995

Folate receptor type gamma is primarily a secretory protein due to lack of an efficient signal for glycosylphosphatidylinositol modification: protein characterization and cell type specificity.

A novel isoform of the human folate receptor (FR, type gamma) was recently identified in hematopoietic tissues [Shen et al. (1994) Biochemistry 33, 1209-1215]. In that report, Cos-1 cells, transiently transfected with the cDNA for FR-gamma, produced relatively poor expression of the receptor on the cell surface. In this study, several recombinant Chinese hamster ovary (CHO) cell lines were produced by stable transfection with the cDNA for FR-gamma followed by amplification. Similar recombinant CHO cell lines were produced that expressed the glycosylphosphatidylinositol-(GPI-) anchored FR type beta and a truncated form of FR type beta (FR-beta delta), in which the normal carboxyl-terminal signal for GPI anchor attachment was deleted. Both FR-gamma-and FR-beta delta-expressing CHO cells produced a [3H]folic acid binding protein in the medium with a similar time course over a 24-h period; in contrast to intact FR-beta, relatively insignificant amounts of either FR-gamma or FR-beta delta were associated with the CHO cell surface and this was unaltered by the absence of serum in the medium. The FR-gamma- and FR-beta delta-producing CHO cells did not differ significantly in intracellular FR levels. Furthermore, the mRNA level for FR-gamma did not exceed that for FR-beta delta. When deglycosylated with hydrogen fluoride, both FR-gamma and FR-beta delta showed similar apparent molecular weights on Western blots as predicted for the intact polypeptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗