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Administrative Personnel↗
Biomedical subjects
G R Fink
Publications and source records attributed to G R Fink.
Regional cerebral glucose metabolism and postmortem pathology in Alzheimer's disease.
In four patients with an antemortem diagnosis of probable Alzheimer's disease (AD) regional cerebral glucose metabolism (rCMRGl) was studied prospectively by positron emission tomography (PET) and compared with postmortem semiquantitative neuropathology. The interval between the last PET study and autopsy was 1.3 +/- 0.8 years. In comparison with age-matched controls, the AD patients showed predominant temporoparietal hypometabolism spreading to other cortical and subcortical regions during serial PET scans. All patients had neuropathological findings typical for AD. There was a significant relationship between rCMRGl and density of senile plaques (SP) in one patient (tau b = -0.86, P < 0.05). SP were distributed quite homogeneously in all regions examined. Neurofibrillary tangles (NFT) were concentrated focally in the hippocampus-amygdala-entorhinal complex. In the context of widespread developing cortical hypometabolism, the predilection of NFT for involvement in limbic areas suggests a disruption of projection neurons as the pathogenetic process of cortical dysfunction.
Aged↗
Temporal lobe epilepsy: evidence for interictal uncoupling of blood flow and glucose metabolism in temporomesial structures.
Measurements of regional cerebral glucose metabolism (rCMRGlc) and blood flow (rCBF) are widely considered exchangeable for the detection of dysfunctional zones in temporal lobe epilepsy (TLE). However, the underlying assumption of preserved coupling of rCBF and rcMRGlc is questionable and requires verification. Thirteen patients with unilateral mesiolimbic TLE underwent interictal positron emission tomography (PET) measurements of rCBF using [15(O)]butanol and of rcMRGlc using (18)FDG. rcMRGlc, rCBF and glucose extraction fraction (rGEF) were obtained from temporomesial and temporolateral structures. When compared to the respective homotopic contralateral reference region, in temporomesial structures ipsilateral to the EEG-defined focus ('dysfunctional zone'), average rCMRGlc and rGEF were decreased while rCBF was unaffected. Analysis of (18)FDG kinetics revealed that (18)FDG transport was unaltered but the hexokinase reaction was specifically decreased. In the temporolateral structures, no such mismatch between metabolism and blood flow was observed. In mesiolimbic TLE, interictal rCMRGlc-PET is superior to rCBF-PET with respect to the sensitivity to detect regional functional abnormalities. This seems to be due to focal uncoupling of glucose metabolism and blood-brain barrier transport or blood flow. We hypothesize that the observed uncoupling of transport and metabolism may be characteristic of epileptogenic zones in TLE of typical etiology.
Adult↗
DLH1 is a functional Candida albicans homologue of the meiosis-specific gene DMC1.
DMC1/LIM15 homologue 1 (DLH1), a gene related to meiosis-specific genes, has been isolated from Candida albicans, a fungus thought not to undergo meiosis. The deduced protein sequence of DLH1 contains 74% amino acid identity with Dmc1p from Saccharomyces cerevisiae and 63% with Lim15p from the plant Lilium longiflorum, meiosis-specific homologues of Escherichia coli RecA. Candida DLH1 complements a dmc1/dmc1 null mutant in S. cerevisiae. High copy expression of DLH1 restores both sporulation and meiotic recombination to a Saccharomyces dmc1 delta/dmc1 delta strain. Unlike the DMC1 gene, which is transcribed only in meiotic cells, the heterologous Candida DLH1 gene is transcribed in both vegetative and meiotic cells of S. cerevisiae. Transcription of DLH1 is not detected or induced in C. albicans under conditions that induce DMC1 and meiosis in S. cerevisiae. The presence of an intact homologue of a meiosis-specific gene in C. albicans raises the possibility that this organism has a cryptic meiotic pathway.
Amino Acid Sequence↗
Saccharomyces cerevisiae S288C has a mutation in FLO8, a gene required for filamentous growth.
Diploid strains of baker's yeast Saccharomyces cerevisiae can grow in a cellular yeast form or in filaments called pseudohyphae. This dimorphic transition from yeast to pseudohyphae is induced by starvation for nitrogen. Not all laboratory strains are capable of this dimorphic switch; many grow only in the yeast form and fail to form pseudohyphae when starved for nitrogen. Analysis of the standard laboratory strain S288C shows that this defect in dimorphism results from a nonsense mutation in the FLO8 gene. This defect in FLO8 blocks pseudohyphal growth in diploids, haploid invasive growth, and flocculation. Since feral strains of S. cerevisiae are dimorphic and have a functional FLO8 gene, we suggest that the flo8 mutation was selected during laboratory cultivation.
Alleles↗
Calcineurin inhibits VCX1-dependent H+/Ca2+ exchange and induces Ca2+ ATPases in Saccharomyces cerevisiae.
The PMC1 gene in Saccharomyces cerevisiae encodes a vacuolar Ca2+ ATPase required for growth in high-Ca2+ conditions. Previous work showed that Ca2+ tolerance can be restored to pmc1 mutants by inactivation of calcineurin, a Ca2+/calmodulin-dependent protein phosphatase sensitive to the immunosuppressive drug FK506. We now report that calcineurin decreases Ca2+ tolerance of pmc1 mutants by inhibiting the function of VCX1, which encodes a vacuolar H+/Ca2+ exchanger related to vertebrate Na+/Ca2+ exchangers. The contribution of VCX1 in Ca2+ tolerance is low in strains with a functional calcineurin and is high in strains which lack calcineurin activity. In contrast, the contribution of PMC1 to Ca2+ tolerance is augmented by calcineurin activation. Consistent with these positive and negative roles of calcineurin, expression of a vcx1::lacZ reporter was slightly diminished and a pmc1::lacZ reporter was induced up to 500-fold by processes dependent on calcineurin, calmodulin, and Ca2+. It is likely that calcineurin inhibits VCX1 function mainly by posttranslational mechanisms. Activities of VCX1 and PMC1 help to control cytosolic free Ca2+ concentrations because their function can decrease pmc1::lacZ induction by calcineurin. Additional studies with reporter genes and mutants indicate that PMR1 and PMR2A, encoding P-type ion pumps required for Mn2+ and Na+ tolerance, may also be induced physiologically in response to high-Mn2+ and -Na+ conditions through calcineurin-dependent mechanisms. In these situations, inhibition of VCX1 function may be important for the production of Ca2+ signals. We propose that elevated cytosolic free Ca2+ concentrations, calmodulin, and calcineurin regulate at least four ion transporters in S. cerevisiae in response to several environmental conditions.
Amino Acid Sequence↗
Human cerebral activity with increasing inspiratory force: a study using positron emission tomography.
Human cerebral activity with increasing inspiratory force: a study using positron emission tomography. J. Appl. Physiol. 81(3): 1295-1305, 1996.--The major aim of this study was to use positron emission tomography (PET) to assess dose-dependent effects of inspiratory loads on relative regional cerebral blood flow as an indication of neuronal activation and recruitment. Six normal men underwent H2 15O-PET scanning during unloaded breathing and with external inspiratory loads (generating mouth pressures of -5, -10, and -15 cmH2O); positive-pressure ventilation against relaxed respiratory muscles acted as control. During unloaded breathing, the supplementary motor area was significantly activated. With the addition of the smallest load, activations also occurred in the right premotor area and bilaterally in the superolateral motor cortex (MI) in areas previously shown to be activated with deeper breathing. There was little further change in these areas with greater loads. Additional force-related activations occurred in the inferolateral sensorimotor cortex, parietal cortex, and midbrain/hypothalamus. The results suggest that volitionally induced increases in inspiratory muscle force are achieved via a complex integration of neuronal activations in cortical and subcortical regions associated with motor control.
Adult↗
Heterogeneity of cerebral hemodynamics and metabolism in carotid artery disease.
METHODS: Eight patients with severe unilateral carotid stenosis (> 70%) were evaluated using PET to assess parametric changes in cerebral blood flow, blood volume, metabolic rate for oxygen, metabolic rate for glucose, oxygen extraction fraction and glucose extraction fraction. We performed these examinations because clinical history and physical exam results suggested possible cerebral vascular disease. Four patients were neurologically asymptomatic with other signs of peripheral vascular disease (e.g., episodic vertigo, TIA and claudication). All patients had normal neurologic examinations and normal CT or MRI studies. PET images were analyzed by two methods. First, regions of interest were used for the entire hemisphere, vascular territories and borderzones. Regions ipsilateral to the carotid stenosis were compared to respective regions in the contralateral hemisphere using Student's t-test. Second, visual inspection of each image was performed. RESULTS: Statistical analysis demonstrated no significant differences between hemodynamic and metabolic parameters for regions ipsilateral to the carotid stenosis and contralateral homotopic reference regions. Upon visual examination, however, all patients had focal changes in either cerebral blood flow, blood volume, glucose extraction fraction and/or oxygen extraction fraction. CONCLUSION: Visual inspection is important in the evaluation of pathophysiological changes caused by unilateral carotid stenosis. Clinical decisions in patients with carotid artery disease should be based on careful visual examinations and statistical analyses of appropriately selected regions.
Brain↗
The Whitehead Institute for Biomedical Research.
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Genetic Diseases, Inborn↗
Hyperpnoea during and immediately after exercise in man: evidence of motor cortical involvement.
1. The neurophysiological basis for the increase in breathing associated with exercise remains obscure. The present study uses positron emission tomography (PET) to measure relative regional cerebral blood flow (rCBF) in order to identify sites of increased neuronal activation during and immediately following exercise. 2. Male volunteers underwent H2(15)O PET scanning during two complementary studies. Firstly, six subjects performed right leg exercise, adequate to increase oxygen uptake 2.5-fold. Secondly, five different subjects were scanned immediately following bicycle exercise (adequate to increase oxygen uptake 5-fold) while breathing was still increased. In each study, as a control, scanning was also performed during matched passive isocapnic positive pressure ventilation; additionally, in the first study, passive right leg movement was performed. 3. Increases in relative rCBF were obtained in each individual and co-registered with their magnetic resonance image of the brain defining individual gyral morphology. 4. During exercise, individual and group analysis revealed significant relative rCBF increases in the left and right superomedial primary motor cortex (the motor cortical 'leg' areas) and also in the left and right superolateral primary motor cortex in areas previously shown to be associated with volitional breathing. After exercise, there was no significant increase in relative rCBF in the superomedial areas but such increases were still present bilaterally in the superolateral areas which had been activated during the exercise. Other relative rCBF increases were also found, both during and after exercise, in cortical and subcortical areas known to be involved in motor control. 5. The results from PET scans during and after exercise, taken together, provide evidence for motor cortical involvement in the exercise-related hyperpnoea in man.
Adult↗
Epigenetic control of an endogenous gene family is revealed by a novel blue fluorescent mutant of Arabidopsis.
The Wassilewskija strain of Arabidopsis has four genes encoding the tryptophan enzyme phosphoribosylanthranilate isomerase (PAI) located at three unlinked sites. These four PAI genes are methylated over their regions of DNA homology. When PAI copy number is reduced by deletion of two tandemly arrayed genes (MePAI1-PAI4), a mutant with fluorescent, tryptophan-deficient phenotypes results, because the two remaining methylated PAI genes (MePAI2 and MePAI3) supply insufficient PAI activity. These two methylated genes can be inherited through meiosis, even when they are segregated away from each other in crosses to a strain with unmethylated PAI genes. However, the mutant phenotypes conferred by the methylated PAI genes are unstable, and mutant plants yield occasional revertant somatic sectors and progeny. Revertant lines display coordinately reduced methylation of both PAI2 and PAI3, implying that this hypomethylation acts in a concerted manner across the genome rather than at individual sites.
Aldose-Ketose Isomerases↗
Evidence for limbic system activation during CO2-stimulated breathing in man.
1. The role of supra-brainstem structures in the ventilatory response to inhaled CO2 is unknown. The present study uses positron emission tomography (PET), with infusion of H2(15)O, to measure changes in relative regional cerebral blood flow (rCBF) in order to identify sites of increased neuronal activation during CO2-stimulated breathing (CO2-SB) in awake man. 2. Five male volunteers were scanned during CO2-SB (mean +/- S.E.M.; end-tidal PCO2, 50.3 +/- 1.7 mmHg; respiratory frequency, 16.4 +/- 2.7 min-1; tidal volume, 1.8 +/- 0.2 l). As control, scans were performed during 'passive' isocapnic (elevated fraction of inspired CO2) positive pressure ventilation (end-tidal PCO2, 38.4 +/- 1.0 mmHg; respiratory frequency, 15.5 +/- 2.2 min-1; tidal volume, 1.6 +/- 0.2 l). With CO2-SB, all subjects reported dyspnoea. 3. The anatomical locations of the increases in relative rCBF (CO2-SB versus control) were obtained using magnetic resonance imaging. 4. Group analysis identified neuronal activation within the upper brainstem, midbrain and hypothalamus, thalamus, hippocampus and parahippocampus, fusiform gyrus, cingulate area, insula, frontal cortex, temporo-occipital cortex and parietal cortex. No neuronal activation was seen within the primary motor cortex (at sites previously shown to be associated with volitional breathing). 5. These results suggest neuronal activation within the limbic system; this activation may be important in the sensory and/or motor respiratory responses to hypercapnia in awake man.
Adult↗
A pathway for lateral root formation in Arabidopsis thaliana.
In plants, the hormone indole-3-acetic acid (IAA) can initiate the developmental program for lateral root formation. We have isolated mutants that have permitted the dissection of this program into initiation and maturation of lateral roots. The alf1-1 mutation causes hyperproliferation of lateral roots, alf4-1 prevents initiation of lateral roots, and alf3-1 is defective in the maturation of lateral roots. The alf3-1 mutant can be rescued by IAA, whereas the alf4-1 mutant is not rescued. Our data suggest a model in which IAA is required for at least two steps in lateral root development: (1) to initiate cell division in the pericycle, and (2) to promote cell division and maintain cell viability in the developing lateral root.
Arabidopsis↗
The yeast nuclear import receptor is required for mitosis.
The nuclear import system is highly conserved among eukaryotes. Here we report the effects of a conditional mutation in SRP1, which encodes a Saccharomyces cerevisiae homolog of the vertebrate nuclear import receptor importin. Importin was isolated as a factor required for the initial targeting step of a nuclear import substrate to the nuclear envelope in a mammalian in vitro assay. We show that yeast Srp1 is similarly required for protein import. In addition, Srp1 is also required for the execution of mitosis: we demonstrate that cells containing a conditional mutation of SRP1 arrest with a G2/M phenotype in a manner analogous to classic cdc mutants. This defect may be due to the failure of the mutant to degrade the mitotic cyclin Clb2 and other proteins required for mitosis. The requirement of a nuclear import receptor for cell cycle-regulated proteolysis implies that import of cell cycle regulators into the nucleus is critical for cell cycle progression.
Animals↗
[Neuralgic amyotrophy (Parsonage-Turner syndrome) following streptokinase thrombolytic therapy].
HISTORY AND CLINICAL FINDINGS: A 61-year-old man was given short-term thrombolytic treatment with streptokinase (1.5 million IU) 6 hours after the onset of anginal symptoms. Ten days later he complained of severe pain in the right upper arm and right shoulder, and also on the left 3 days later. Simultaneously there occurred severe atrophic pareses of the supra- and infraspinatus, deltoid and rhomboid muscles bilaterally, without sensory component. TESTS: When admitted to the neurological department 3 weeks later laboratory tests, immunological parameters, electrophoresis and cerebrospinal fluid were unremarkable. Radiological examinations of the cervical and thoracic vertebrae demonstrated moderate degenerative changes. Computed tomography and magnetic resonance imaging of the cervical vertebrae showed small disc protrusion and narrowing of the intervertebral foramina, but they could not explain the clinical picture. Electromyography demonstrated a bilateral peripheral neurogenic lesion without evidence of radicular distribution or any lesion of individual peripheral nerves. These findings led to the diagnosis of neuralgic amyotrophy (Parsonage-Turner syndrome). TREATMENT AND COURSE: With analgesics and physiotherapy the pareses slowly regressed over the following months. CONCLUSIONS: The infusion of streptokinase was the only probable cause found to explain the neuralgic amyotrophy, a connection that has never been reported until now.
Brachial Plexus Neuritis↗
ILR1, an amidohydrolase that releases active indole-3-acetic acid from conjugates.
In plants, the growth regulator indole-3-acetic acid (IAA) is found both free and conjugated to a variety of amino acids, peptides, and carbohydrates. IAA conjugated to leucine has effects in Arabidopsis thaliana similar to those of free IAA. The ilr1 mutant is insensitive to exogenous IAA-Leu and was used to positionally clone the Arabidopsis ILR1 gene. ILR1 encodes a 48-kilodalton protein that cleaves IAA-amino acid conjugates in vitro and is homologous to bacterial amidohydrolase enzymes. DNA sequences similar to that of ILR1 are found in other plant species.
Amidohydrolases↗
Long-term prognosis of poststroke aphasia studied with positron emission tomography.
OBJECTIVE: To evaluate positron emission tomography with the use of fludeoxyglucose F 18 as a predictor of the long-term outcome of poststroke aphasia. BACKGROUND: Positron emission tomography shows functional deficits after stroke even in morphologically intact brain regions. The regional metabolic impairment can be related to the clinical deficit. Little is known about whether regional hypometabolism early after stroke predicts the long-term prognosis of stroke sequelae. PATIENTS AND METHODS: Twenty-two patients with language disturbance caused by a single lesion in the territory of the left middle cerebral artery were studied with fludeoxyglucose positron emission tomography and with a neuropsychological test battery that included a test of receptive language (Token Test) and a test of word fluency (/f/, /a/, /s/ test). The neuropsychological test was readministered about 2 years after the initial test. RESULTS: Regional cerebral metabolic rates of glucose measured early after stroke showed a highly significant correlation with the results of the 2-year follow-up test. The receptive language disorder best correlated with cerebral metabolic rates of glucose in the left superior temporal cortex, and word fluency correlated with cerebral metabolic rates of glucose in the left prefrontal cortex. CONCLUSION: Cerebral metabolic rates of glucose in speech-relevant brain regions measured early after stroke are a predictor of the eventual outcome of aphasia.
Aged↗
Activation of limbic structures during CO2-stimulated breathing in awake man.
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Adult↗