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Biomedical subjects

D A Hall

Publications and source records attributed to D A Hall.

At least 19 recordsLinked to original sources
PubMed2006

Prevalence of FMR1 repeat expansions in movement disorders. A systematic review.

We reviewed prevalence rates of fragile X mental retardation gene (FMR1) repeat expansions in movement disorder populations. Inclusion criteria included published epidemiological studies from systematic searches of Medline, Pubmed, Cochrane Databases and Web Science. Thirteen cross-sectional studies were carried out between 2003 and 2005. Subjects with ataxia showed higher than expected rates while those with essential tremor and parkinsonism showed lower rates. The heterogeneous design of the studies, inclusion criteria and mean age of subjects may have led to underestimation of FMR1 repeat expansion prevalence rates.

Cross-Sectional Studies↗
PubMed2006

Reliable identification of the auditory thalamus using multi-modal structural analyses.

The medial geniculate body (MGB) of the thalamus is a key component of the auditory system. It is involved in relaying and transforming auditory information to the cortex and in top-down modulation of processing in the midbrain, brainstem, and ear. Functional imaging investigations of this region in humans, however, have been limited by the difficulty of distinguishing MGB from other thalamic nuclei. Here, we introduce two methods for reliably delineating MGB anatomically in individuals based on conventional and diffusion MRI data. The first uses high-resolution proton density weighted scanning optimized for subcortical grey-white contrast. The second uses diffusion-weighted imaging and probabilistic tractography to automatically segment the medial and lateral geniculate nuclei from surrounding structures based on their distinctive patterns of connectivity to the rest of the brain. Both methods produce highly replicable results that are consistent with published atlases. Importantly, both methods rely on commonly available imaging sequences and standard hardware, a significant advantage over previously described approaches. In addition to providing useful approaches for identifying the MGB and LGN in vivo, our study offers further validation of diffusion tractography for the parcellation of grey matter regions on the basis of their connectivity patterns.

Adult↗
PubMed2006

Safe magnetic resonance scanning of patients with metallic middle ear implants.

OBJECTIVE: To determine the MR scanning risk to patients with otologic implants. DESIGN: We used a repeated-measures study with an additional control measure to assess two aspects of risk; (i) movement of the device in the magnetic field, and (ii) absorption of energy leading to local heating. We used an ex vivo test method that met with international standards. We measured the effects in a Philips Intera Achieva 3 Tesla (T) MR scanner using a Sense Head 8 channel RF coil. SETTING: University-based magnetic resonance research facility. MAIN OUTCOME MEASURES: Heating or displacement of the stapedectomy pistons. RESULTS: No evidence of displacement or heating was found. CONCLUSION: Complying with the ex vivo standard testing protocols, the Schuknecht and McGee wire pistons (device product numbers 140106 and 140108, respectively) were found to be safe in a 3 T MR scanner. These conclusions can be extrapolated to the in vivo case.

Ear Diseases↗
PubMed2005

Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a newly described disorder that occurs in premutation carriers of the fragile X mental retardation 1 (FMR1) gene. Fifty-six patients with FXTAS were given 98 prior diagnoses: most were in the categories of parkinsonism, tremor, ataxia, dementia, or stroke. Data from this study and others were used to develop guidelines for FMR1 diagnostic testing for FXTAS.

Age Factors↗
PubMed2005

PRNP H187R mutation associated with neuropsychiatric disorders in childhood and dementia.

Described is a large family with an autosomal dominant dementia associated with an H187R mutation in the prion protein gene (PRNP). Clinical features include neuropsychiatric disturbances in childhood and adolescence, dementia in young adulthood with frontotemporal manifestations, and long disease duration. Neuropathology revealed atrophy and mild gliosis, whereas prion protein analysis revealed an abnormal conformer with unusual sensitivity to protease digestion. Mutations in PRNP may cause neuropsychiatric disorders that predate dementia by many years.

Adolescent↗
PubMed2001

Mapping the interactions between flavodoxin and its physiological partners flavodoxin reductase and cobalamin-dependent methionine synthase.

Flavodoxins are electron-transfer proteins that contain the prosthetic group flavin mononucleotide. In Escherichia coli, flavodoxin is reduced by the FAD-containing protein NADPH:ferredoxin (flavodoxin) oxidoreductase; flavodoxins serve as electron donors in the reductive activation of anaerobic ribonucleotide reductase, biotin synthase, pyruvate formate lyase, and cobalamin-dependent methionine synthase. In addition, domains homologous to flavodoxin are components of the multidomain flavoproteins cytochrome P450 reductase, nitric oxide synthase, and methionine synthase reductase. Although three-dimensional structures are known for many of these proteins and domains, very little is known about the structural aspects of their interactions. We address this issue by using NMR chemical shift mapping to identify the surfaces on flavodoxin that bind flavodoxin reductase and methionine synthase. We find that these physiological partners bind to unique overlapping sites on flavodoxin, precluding the formation of ternary complexes. We infer that the flavodoxin-like domains of the cytochrome P450 reductase family form mutually exclusive complexes with their electron-donating and -accepting partners, complexes that require conformational changes for interconversion.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2001

Can meaningful effective connectivities be obtained between auditory cortical regions?

Structural equation modeling (SEM) of neuroimaging data can be evaluated both for the goodness of fit of the model and for the strength of path coefficients (as an index of effective connectivity). SEM of auditory fMRI data is made difficult by the necessary sparse temporal sampling of the time series (to avoid contamination of auditory activation by the response to scanner noise) and by the paucity of well-defined anatomical information to constrain the functional model. We used SEM (i.e., a model incorporating latent variables) to investigate how well fMRI data in four adjacent cortical fields can be described as an auditory network. Seven of the 14 models (2 hemispheres x (6 subjects and 1 group)) produced a plausible description of the measured data. Since the auditory model to be tested is not fully validated by anatomical data, our approach requires that goodness of fit be confirmed to ensure generalizability of connectivity patterns. For good-fitting models, connectivity patterns varied significantly across subjects and were not replicable across stimulus conditions. SEM of central auditory function therefore appears to be highly sensitive to the voxel-selection procedure and/or the sampling of the time series.

Adult↗
PubMed2001

Neuropsychological evidence for case-specific reading: multi-letter units in visual word recognition.

We describe a patient (GK) who shows symptoms associated with Balint's syndrome and attentional dyslexia. GK was able to read words, but not nonwords. He also made many misidentification and mislocation errors when reporting letters in words, suggesting that his word-naming ability did not depend upon preserved position-coded, letter identification. We show that GK was able to read lower-case words better than upper-case words, but upper-case abbreviations better than lower-case abbreviations. Spacing the letters in abbreviations disrupted identification, as did mixing the case of letters within words. These data cannot be explained in terms of letter-based reading or preserved holistic word recognition. We propose that GK was sensitive to the visual familiarity of adjacent letter forms.

Adult↗
PubMed2001

Functional magnetic resonance imaging measurements of sound-level encoding in the absence of background scanner noise.

Effects of sound level on auditory cortical activation are seen in neuroimaging data. However, factors such as the cortical response to the intense ambient scanner noise and to the bandwidth of the acoustic stimuli will both confound precise quantification and interpretation of such sound-level effects. The present study used temporally "sparse" imaging to reduce effects of scanner noise. To achieve control for stimulus bandwidth, three schemes were compared for sound-level matching across bandwidth: component level, root-mean-square power and loudness. The calculation of the loudness match was based on the model reported by Moore and Glasberg [Acta Acust. 82, 335-345 (1996)]. Ten normally hearing volunteers were scanned using functional magnetic resonance imaging (tMRI) while listening to a 300-Hz tone presented at six different sound levels between 66 and 91 dB SPL and a harmonic-complex tone (F0= 186 Hz) presented at 65 and 85 dB SPL. This range of sound levels encompassed all three bases of sound-level matching. Activation in the superior temporal gyrus, induced by each of the eight tone conditions relative to a quiet baseline condition, was quantified as to extent and magnitude. Sound level had a small, but significant, effect on the extent of activation for the pure tone, but not for the harmonic-complex tone, while it had a significant effect on the response magnitude for both types of stimulus. Response magnitude increased linearly as a function of sound level for the full range of levels for the pure tone. The harmonic-complex tone produced greater activation than the pure tone, irrespective of the matching scheme for sound level, indicating that bandwidth had a greater effect on the pattern of auditory activation than sound level. Nevertheless, when the data were collapsed across stimulus class, extent and magnitude were significantly correlated with the loudness scale (measured in phons), but not with the intensity scale (measured in SPL). We therefore recommend the loudness formula as the most appropriate basis of matching sound level to control for loudness effects when cortical responses to other stimulus attributes, such as stimulus class, are the principal concern.

Adult↗
PubMed2000

Interaction of flavodoxin with cobalamin-dependent methionine synthase.

Cobalamin-dependent methionine synthase catalyzes the transfer of a methyl group from methyltetrahydrofolate to homocysteine, forming tetrahydrofolate and methionine. The Escherichia coli enzyme, like its mammalian homologue, is occasionally inactivated by oxidation of the cofactor to cob(II)alamin. To return to the catalytic cycle, the cob(II)alamin forms of both the bacterial and mammalian enzymes must be reductively remethylated. Reduced flavodoxin donates an electron for this reaction in E. coli, and S-adenosylmethionine serves as the methyl donor. In humans, the electron is thought to be provided by methionine synthase reductase, a protein containing a domain with a significant degree of homology to flavodoxin. Because of this homology, studies of the interactions between E. coli flavodoxin and methionine synthase provide a model for the mammalian system. To characterize the binding interface between E. coli flavodoxin and methionine synthase, we have employed site-directed mutagenesis and chemical cross-linking using carbodiimide and N-hydroxysuccinimide. Glutamate 61 of flavodoxin is identified as a cross-linked residue, and lysine 959 of the C-terminal activation domain of methionine synthase is assigned as its partner. The mutation of lysine 959 to threonine results in a diminished level of cross-linking, but has only a small effect on the affinity of methionine synthase for flavodoxin. Identification of these cross-linked residues provides evidence in support of a docking model that will be useful in predicting the effects of mutations observed in mammalian homologues of E. coli flavodoxin and methionine synthase.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2000

Time-course of the auditory BOLD response to scanner noise.

It is a concern for auditory fMRI studies that acoustic noise generated by the scanner produces an auditory response that can confound stimulus-induced activation. To establish how to minimize this problem, the present study mapped the time-course of the auditory response to a burst of acoustic scanner noise by employing a single-event method. Recorded bursts of scanner noise were interspersed with clustered-volume acquisitions at a range of stimulus-to-imaging delays to map the response with a temporal resolution of 1 sec. There were strong responses (1.5% signal change) to scanner noise in primary and secondary auditory cortex. In both cortical areas, the mean response rose to a peak by 4-5 sec after stimulus onset and decayed after a further 5-8 sec. The time course indicates that noise contamination in auditory fMRI can be substantially reduced by using a 9-12-sec repetition time, thus maximizing the dynamic range available for displaying the response to acoustical stimuli of interest.

Adult↗
PubMed2000

Sound-level measurements and calculations of safe noise dosage during EPI at 3 T.

This paper describes systematic methods for measuring and controlling sound levels within a magnetic resonance scanner. The methods are illustrated by application to the acoustic noise generated by a 3 T scanner during echoplanar imaging (EPI). Across five measurement sessions, sound pressure levels at the center of the head gradient coil ranged from 122 to 131 dB SPL [123 to 132 dB(A)]. For protection against damaging noise exposure, UK and US industrial guidelines stipulate that the maximum permitted daily noise dosage is equivalent to 90 dB(A) for 8 hours, where noise dosage is a function of the level of an acoustic signal and the length of exposure to it. Without hearing protection, this equivalent level would be exceeded by less than 5 seconds of exposure to the measured levels of scanner acoustic noise. These findings highlight the importance of noise reduction and hearing protection for those exposed to the acoustic noise generated during EPI.

Auditory Threshold↗
PubMed2000

High-frequency dynamic nuclear polarization in the nuclear rotating frame.

A proton dynamic nuclear polarization (DNP) NMR signal enhancement (epsilon) close to thermal equilibrium, epsilon = 0.89, has been obtained at high field (B(0) = 5 T, nu(epr) = 139.5 GHz) using 15 mM trityl radical in a 40:60 water/glycerol frozen solution at 11 K. The electron-nuclear polarization transfer is performed in the nuclear rotating frame with microwave irradiation during a nuclear spin-lock pulse. The growth of the signal enhancement is governed by the rotating frame nuclear spin-lattice relaxation time (T(1rho)), which is four orders of magnitude shorter than the nuclear spin-lattice relaxation time (T(1n)). Due to the rapid polarization transfer in the nuclear rotating frame the experiment can be recycled at a rate of 1/T(1rho) and is not limited by the much slower lab frame nuclear spin-lattice relaxation rate (1/T(1n)). The increased repetition rate allowed in the nuclear rotating frame provides an effective enhancement per unit time(1/2) of epsilon(t) = 197. The nuclear rotating frame-DNP experiment does not require high microwave power; significant signal enhancements were obtained with a low-power (20 mW) Gunn diode microwave source and no microwave resonant structure. The symmetric trityl radical used as the polarization source is water-soluble and has a narrow EPR linewidth of 10 G at 139.5 GHz making it an ideal polarization source for high-field DNP/NMR studies of biological systems.

Chemical Phenomena↗
PubMed2000

Modeling the functional effects of allosteric modulators at pharmacological receptors: an extension of the two-state model of receptor activation.

Allosteric modulation is a mechanism for modifying pharmacological receptor activity that has largely been ignored in terms of therapeutic drug design, although benzodiazepine receptor ligands are an example of the serendipitous discovery of this class of compound. The current mathematical models of allosteric interactions at (particularly G-protein-coupled) receptors concentrate on the effects of the allosteric ligand on orthosteric ligand binding and ignore potential effects of these compounds on the ability of orthosteric ligands to cause receptor activation. In this report a mathematical model of allosteric interactions at pharmacological receptors has been investigated that explicitly includes effects of the allosteric ligand on receptor activation. This model uses the two-state model of receptor activation as its basis and is qualitatively consistent with currently reported behavior of allosteric modulators. The predictions of this model suggest a series of criteria that should be tested before the effects of an allosteric modulator can be quantified in a nonsystem-dependent manner. It has also been used to provide a potential mechanistic explanation for the functional effects of the A(1) adenosine receptor allosteric enhancer PD 81,723 and a recently reported allosteric modulator of type 1 metabotropic glutamate receptors.

Allosteric Regulation↗
PubMed2000

Dihydropyridine-sensitive Ca(2+) channels in human glomerular mesangial cells.

In mesangial cells (MC), the response of intracellular Ca(2+) concentration ([Ca(2+)](i)) to a contractile agonist is biphasic with a large, transient increase in [Ca(2+)](i) followed by a smaller but sustained elevation as Ca(2+) flows into the cell from the extracellular fluid. It has been postulated that membrane depolarization precedes opening of Ca(2+) channels in the plasmalemmal membrane. However, a role for voltage-gated Ca(2+) channels (VGCC) in human MC has been controversial, and their existence has not been verified with single-channel analysis. We used fura 2 fluorescence and patch-clamp techniques to determine the properties of the Ca(2+) entry pathway responsible for the sustained response of [Ca(2+)](i) in human MC. We found that ANG II at 10 nM, 100 nM, and 1 microM increased [Ca(2+)](i) to sustained levels of 22%, 35%, and 49%, respectively, above baseline. The sustained response to 1 microM ANG II was attenuated by diltiazem and was reduced to a value less than baseline in the absence of external Ca(2+). None of the peak responses (due to release of intracellular stores of Ca(2+)) were affected by removal of external Ca(2+) or addition of diltiazem. Upon elevating the extracellular [K(+)] from 5 mM to 75 mM, [Ca(2+)](i) reached a sustained level of 48% greater than baseline. This effect of high K(+) was attenuated by either Ca(2+) removal or addition of diltiazem. In the presence of 75 or 140 mM K(+), the dihydropyridine agonist BAY K 8644 (1 microM and 10 microM) initiated sustained [Ca(2+)](i) responses averaging 18% and 25%, respectively, greater than baseline. With <10 nM Ca(2+) in the external solution, BAY K 8644 did not significantly affect [Ca(2+)](i). In separate patch-clamp experiments, barium-selective channels were found in cell-attached patches with 90 mM BaCl(2) and 10 microM BAY K 8644 in the pipette solution. The single-channel conductance was 11.2 pS, and the open probability increased steeply at membrane potentials between -30 mV and 0 mV. It is concluded that human glomerular MC contain dihydropyridine-sensitive Ca(2+) channels responsible for the voltage-regulated entry of Ca(2+) into the cell during an agonist-induced contraction.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2000

Regulation of Ca(2+)-activated K(+) channels by multifunctional Ca(2+)/calmodulin-dependent protein kinase.

Activation of mesangial cells by ANG II provokes release of intracellular Ca(2+) stores and subsequent Ca(2+) influx through voltage-gated channels, events that are reflected by a large transient increase in intracellular concentration [Ca(2+)](i) followed by a modest sustained elevation in [Ca(2+)](i). These ANG II-induced alterations in [Ca(2+)](i) elicit activation of large Ca(2+)-activated K(+) channels (BK(Ca)) in a negative-feedback manner. The mechanism of this BK(Ca) feedback response may involve the direct effect of intracellular Ca(2+) on the channel and/or channel activation by regulatory enzymes. The present study utilized patch-clamp and fura 2 fluorescence techniques to assess the involvement of multifunctional calcium calmodulin kinase II (CAMKII) in the BK(Ca) feedback response. In cell-attached patches, KN62 (specific inhibitor of CAMKII) either abolished or reduced to near zero the ANG II-induced BK(Ca) feedback response. This phenomenon did not reflect direct effects of KN62 on the BK(Ca) channel, because this agent alone did not significantly alter BK(Ca) channel activity in inside-out patches. KN62 also failed to alter either the transient peak or sustained plateau phases of the [Ca(2+)](i) response to ANG II. In inside-out patches (1 microM Ca(2+) in bath), calmodulin plus ATP activated BK(Ca) channels in the presence but not the absence of CAMKII. These observations are consistent with the postulate that CAMKII is involved in the BK(Ca) feedback response of mesangial cells, acting to potentiate the influence of increased [Ca(2+)](i) on the BK(Ca) channel or a closely associated regulator of the channel. An additional effect of CAMKII to activate a voltage-gated Ca(2+) channel cannot be ruled out by these experiments.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗