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David W Roberts

Publications and source records attributed to David W Roberts.

At least 37 records · Page 2Linked to original sources
PubMed2005

From experiment to theory: molecular orbital parameters to interpret the skin sensitization potential of 5-chloro-2-methylisothiazol-3-one and 2-methylisothiazol-3-one.

5-Chloro-2-methylisothiazol-3-one (MCI) and 2-methylisothiazol-3-one (MI) are the major constituents of the commercial biocide Kathon CG. These two compounds have both been shown to exhibit skin sensitization potential: MCI is classified as an extreme sensitizer while MI is classified as a moderate sensitizer. The purpose of the present investigation was to provide further insights into the chemistry underlying their skin sensitizing properties. First, a molecular modeling (in silico) study was carried out of the initial reaction pathways of MI and MCI with nucleophiles representative of those involved in the skin sensitization process, and we compared the findings with the reported chemical and allergenic properties of these compounds. These reaction pathways were assessed using molecular orbital calculations. A novel parameter, the activation energy (AE) index, is proposed and is calculated from a knowledge of the energy changes in the frontier molecular orbitals as the electrophile is converted to an anionic intermediate. The AE indices correspond to the reactivity of MCI and MI with nucleophiles and also their skin sensitization potential. Second, the previously unexplained formation of final reaction products from MCI and butylamine is discussed and a reaction mechanism is proposed. A key finding of this analysis is that the reaction produces "positive chlorine" in the form of N-chloro- and/or N,N-dichloro-butylamine, which could contribute to the skin sensitizing properties of MCI.

Animals↗
PubMed2005

Structure-toxicity relationships for the effects to Tetrahymena pyriformis of aliphatic, carbonyl-containing, alpha,beta-unsaturated chemicals.

Toxicity data for 82 aliphatic chemicals with an alpha,beta-unsaturated substructure were compiled. Toxicity was assessed in the 2-day Tetrahymena pyriformis population growth impairment assay. Toxic potency [log(IGC50(-1))] for most of these chemicals was in excess of baseline narcosis as quantified by the 1-octanol/water partition coefficient (log K(ow)). The toxicity of the alpha,beta-unsaturated aldehydes was modeled well by log K(ow) in conjunction with the sum of partial charges on the vinylene carbon atoms (Q(C4) + Q(C3)) and the energy of the lowest unoccupied molecular orbital (E(lumo)). These electronic descriptors were also successful at modeling the toxicity of alpha,beta-unsaturated ketones. The toxicity of a range of acrylates was constant within about 0.2 of a log unit. Conversely, the toxicity of methacrylates and esters containing the vinylene group varied considerably and was explained by their hydrophobicity. The comparison of the quantitative structure-activity relationship (QSAR) for the methacrylates and esters with that for non-polar narcosis showed little significant difference and hence suggested that substitution on the carbon-carbon double bond in the methacrylates and vinylene unsaturated esters does not enhance toxicity over that of baseline. Substitution on the carbon-carbon double bond in the alpha,beta-unsaturated aldehydes resulted in toxicity that was similar to that for saturated derivatives. Although an excellent hydrophobicity-dependent QSAR was developed for the esters containing ethynylene group, these compounds are considered to act as Michael-type acceptors. Attempts to combine different groups of Michael-type acceptors into a single QSAR, based on mechanistically derived descriptors, were unsuccessful. Thus, the modeling of the toxicity of the alpha,beta-unsaturated carbonyl domain is currently limited to models for narrow subdomains.

Animals↗
PubMed2005

Skin sensitization: reaction mechanistic applicability domains for structure-activity relationships.

The prediction of skin sensitization potential with minimum animal testing is currently of great importance in light of forthcoming legislation. A number of structure-activity relationships for skin sensitization have been published over the years, but their applicability has often been limited to structural classes. The concept of an applicability domain for a quantitative structure-activity relationship [(Q)SAR] is increasingly being viewed as key for the predictive application of (Q)SARs. This is particularly the case for skin sensitization if more widely applicable SARs are to be developed. In this paper, we analyze a recently published chemical data set for skin sensitization, apply reaction mechanistic criteria to domain classification, and evaluate the structure-activity trends observed within each of these mechanistic domains.

Acylation↗
PubMed2005

Stereopsis-guided brain shift compensation.

Brain deformation models have proven to be a powerful tool in compensating for soft tissue deformation during image-guided neurosurgery. The accuracy of these models can be improved by incorporating intraoperative measurements of brain motion. We have designed and implemented a passive intraoperative stereo vision system capable of estimating the three-dimensional shape of the surgical scene in near real-time. This intraoperative shape is compared with the cortical surface in the co-registered preoperative magnetic resonance (MR) volume for the estimation of the cortical motion resulting from the open cranial surgery. The estimated cortical motion is then used to guide a full brain model, which updates a preoperative MR volume. We have found that the stereo vision system is accurate to within approximately 1 mm. Based on data from two representative clinical cases, we show that stereopsis guidance improves the accuracy of brain shift compensation both at and below the cortical surface.

Algorithms↗
PubMed2005

Cortical surface tracking using a stereoscopic operating microscope.

OBJECTIVE: To measure and compensate for soft tissue deformation during image-guided neurosurgery, we have developed a novel approach to estimate the three-dimensional (3-D) topology of the cortical surface and track its motion over time. METHODS: We use stereopsis to estimate the 3-D cortical topology during neurosurgical procedures. To facilitate this process, two charge-coupled device cameras have been attached to the binocular optics of a stereoscopic operating microscope. Before surgery, this stereo imaging system is calibrated to obtain the extrinsic and intrinsic camera parameters. During surgery, the 3-D shape of the cortical surface is automatically estimated from a stereo pair of images and registered to the preoperative image volume to provide navigational guidance. This estimation requires robust matching of features between the images, which, when combined with the camera calibration, yields the desired 3-D coordinates. After the 3-D cortical surface has been estimated from stereo pairs, its motion is tracked by comparing the current surface with its previous locations. RESULTS: We are able to estimate the 3-D topology of the cortical surface with an average error of less than 1.2 mm. Executing on a 1.1-GHz Pentium machine, the 3-D estimation from a stereo pair of 1024 x 768 resolution images requires approximately 60 seconds of computation. By applying stereopsis over time, we are able to track the motion of the cortical surface, including the pulsatile movement of the cortical surface, gravitational sag, tissue bulge as a result of increased intracranial pressure, and the parenchymal shape changes associated with tissue resection. The results from 10 surgical patients are reported. CONCLUSION: We have demonstrated that a stereo vision system coupled to the operating microscope can be used to efficiently estimate the dynamic topology of the cortical surface during surgery. The 3-D surface can be coregistered to the preoperative image volume. This unique intraoperative imaging technique expands the capability of the current navigational system in the operating room and increases the accuracy of anatomic correspondence with preoperative images through compensation for brain deformation.

Adult↗
PubMed2005

Abolition of spindle oscillations and 3-Hz absence seizurelike activity in the thalamus by using high-frequency stimulation: potential mechanism of action.

OBJECT: The mechanism of action whereby high-frequency stimulation (HFS) in the thalamus ameliorates tremor and epilepsy is unknown. The authors studied the effects of HFS on thalamocortical relay neurons in a ferret in vitro slice preparation to test the hypothesis that HFS abolishes synchronized oscillations by neurotransmitter release. METHODS: Intracellular and extracellular electrophysiological recordings were made in thalamic slices. The neurons in the thalamic slice spontaneously generated spindle oscillations, and treatment with picrotoxin, a gamma-aminobutyric acid A receptor antagonist, resulted in 3- to 4-Hz absence seizurelike activity. High-frequency stimulation (stimulation parameters: 10-1000-microA amplitude; l00-microsec pulse width; 100-Hz frequency; 1-60 seconds) was applied using a concentric bipolar stimulating electrode placed adjacent to the recording electrodes. High-frequency stimulation within the thalamus generated inhibitory and excitatory postsynaptic potentials, membrane depolarization, an increase in action potential firing during the stimulation period, and abolished the spindle oscillations in the thalamocortical relay neurons. High-frequency stimulation applied to 20-microM picrotoxin-treated slices eliminated the 3- to 4-Hz absence seizurelike activity. CONCLUSIONS: High-frequency stimulation eliminates spontaneous spindle oscillations and picrotoxin-induced absence seizurelike activity in thalamic slices by synaptic neurotransmitter release; thus, HFS may abolish synchronous oscillatory activities such as those that generate tremor and seizures. Paradoxically, HFS, which is excitatory, and surgical lesions of the ventrointermedius thalamus, which are presumably inhibitory, both suppress tremors. This paradox is resolved by recognizing that HFS-mediated neurotransmitter release and thalamic surgery both disrupt the circuit generating tremor or seizure, albeit by different mechanisms.

Action Potentials↗
PubMed2005

Ventriculoperitoneal shunt as treatment for perilymphatic fistula: a report of six cases.

We report six cases of perilymphatic fistula in patients who received ventriculoperitoneal shunts as part of their final mode of therapy. The last of our 6 patients actually received a ventriculoperitoneal shunt as her initial mode of therapy. All but one had benign intracranial hypertension. All six felt better (less disequilibrium, tinnitus, and pressure and occasional hearing improvement) after LP with removal of 15-20 ml of cerebrospinal fluid.

Adult↗
PubMed2004

Further evaluation of quantitative structure--activity relationship models for the prediction of the skin sensitization potency of selected fragrance allergens.

Fragrance substances represent a very diverse group of chemicals; a proportion of them are associated with the ability to cause allergic reactions in the skin. Efforts to find substitute materials are hindered by the need to undertake animal testing for determining both skin sensitization hazard and potency. One strategy to avoid such testing is through an understanding of the relationships between chemical structure and skin sensitization, so-called structure-activity relationships. In recent work, we evaluated 2 groups of fragrance chemicals -- saturated aldehydes and alpha,beta-unsaturated aldehydes. Simple quantitative structure-activity relationship (QSAR) models relating the EC3 values [derived from the local lymph node assay (LLNA)] to physicochemical properties were developed for both sets of aldehydes. In the current study, we evaluated an additional group of carbonyl-containing compounds to test the predictive power of the developed QSARs and to extend their scope. The QSAR models were used to predict EC3 values of 10 newly selected compounds. Local lymph node assay data generated for these compounds demonstrated that the original QSARs were fairly accurate, but still required improvement. Development of these QSAR models has provided us with a better understanding of the potential mechanisms of action for aldehydes, and hence how to avoid or limit allergy. Knowledge generated from this work is being incorporated into new/improved rules for sensitization in the expert toxicity prediction system, deductive estimation of risk from existing knowledge (DEREK).

Aldehydes↗
PubMed2004

Quantitative structure-activity relationship modeling of acute toxicity of quaternary alkylammonium sulfobetaines to Daphnia magna.

The logarithm of the octanol/water partition coefficient has been widely used as the sole physicochemical property to define various types of biological activity, such as aquatic toxicity. In the present study, we derive a quantitative structure-activity relationship (QSAR) equation for the prediction of acute aquatic toxicity (48-h median effective concentration) of quaternary alkylammonium sulfobetaines to the aquatic invertebrate Daphnia magna Straus. The single-parameter approach described is also based on the hydrophobicity parameter, log P. The 17 zwitterionic compounds were considered for QSAR development. They have the general formula RN+(CH3)2(CH2)nSO3-, where n = 2 to 4, and were synthesized by reacting the corresponding N,N-dimethylamines with either sodium-2-chloroethanesulfonate (n = 2), 1,3-propanesultone (n = 3), or 1,4-butanesultone (n = 4). The R group was either a C6 to C12 alkyl chain, a phenylalkyl unit bearing a C1 to C4 chain, or a phenylpropyl unit with a C4 to C6 para-substituted alkyl group. Octanol/water partition coefficients were experimentally determined via a conventional stir-flask procedure, which was quantified using a reverse-phase, high-performance liquid chromatographic technique coupled with either an ultraviolet or an electrospray ionization mass spectrometry detection system. Median effective concentration values were also determined experimentally via a standard acute immobilization test recommended by Organisation for Economic Cooperation and Development (Paris, France) Guideline 202. The established QSAR equation for such zwitterionic compounds is consistent with the standard equation that normally defines the polar narcosis mode of toxic action.

Animals↗
PubMed2004

Neurotransmitter release from high-frequency stimulation of the subthalamic nucleus.

OBJECT: High-frequency stimulation (HFS) delivered through implanted electrodes in the subthalamic nucleus (STN) has become an established treatment for Parkinson disease (PD). The precise mechanism of action of deep brain stimulation (DBS) in the STN is unknown, however. In the present study, the authors tested the hypothesis that HFS within the STN changes neuronal action potential firing rates during the stimulation period by modifying neurotransmitter release. METHODS: Intracellular electrophysiological recordings were obtained using sharp electrodes in rat STN neurons in an in vitro slice preparation. A concentric bipolar stimulating electrode was placed in the STN slice, and electrical stimulation (pulse width 50-100 microsec, duration 100-2000 msec, amplitude 10-500 microA, and frequency 10-200 Hz) was delivered while simultaneously obtaining intracellular recordings from an STN neuron. High-frequency stimulation of the STN either generated excitatory postsynaptic potentials (EPSPs) and increased the action potential frequency or it generated inhibitory postsynaptic potentials and decreased the action potential frequency of neurons within the STN. These effects were blocked after antagonists to glutamate and gamma-aminobutyric acid were applied to the tissue slice, indicating that HFS resulted in the release of neurotransmitters. Intracellular recordings from substantia nigra pars compacta (SNc) dopaminergic neurons during HFS of the STN revealed increased generation of EPSPs and increased frequency of action potentials in SNc neurons. CONCLUSIONS: During HFS of STN neurons the mechanism of DBS may involve the release of neurotransmitters rather than the primary electrogenic inhibition of neurons.

Animals↗
PubMed2003

Applications of immobilised artificial membrane chromatography to quaternary alkylammonium sulfobetaines and comparison of chromatographic methods for estimating the octanol-water partition coefficient.

The chromatographic behaviour of a series of quaternary alkylammonium sulfobetaines of general formula RN-(CH3)2(CH2)nSO3-, where n = 2-4, has been examined using an immobilised artificial membrane column. The k values have been correlated both with experimentally determined values for the octanol-water partition coefficient (P) and with aquatic toxicity measurements. Other indirect chromatographic methods for measuring log P for these compounds using reversed-phase columns and octanol-coated columns have also been investigated.

Betaine↗
PubMed2003

Determination of the platinum drug cis-amminedichloro(2-methylpyridine)platinum(II) in human urine by liquid chromatography-tandem mass spectrometry.

A validated stable isotope dilution liquid chromatography-tandem mass spectrometry assay for the novel platinum drug cis-amminedichloro(2-methylpyridine)platinum(II) (ZD0473) in human urine has been developed. This method uses selected reaction monitoring on the transition of m/z 393 [M+NH(4)](+) to m/z 304 [M+NH(4)-NH(3)-2 x H(35)Cl](+) for ZD0473, and m/z 400 [M+NH(4)](+) to m/z 310 [M+NH(4)-NH(3)-H(35)Cl-(2)H(35)Cl](+) for the internal standard [(2)H(7)]ZD0473. Standard curves were prepared over the range from 0.15 to 50 microg/ml. The lower limit of quantitation was 0.2 microg/ml for 100 microl of urine. This simple, rapid, reliable, and sensitive method of quantitation displayed acceptable accuracy and precision over the 3 days of assay validation. A novel platinum adduct was formed during the storage of ZD0473 in human urine. The adduct did not correspond to any of the typical sulfhydryl adducts that have been identified previously for platinum drugs. Formation of the adduct was prevented by the addition of 50% (w/v) sodium chloride to the urine. The assay can be used to quantify intact ZD0473 in the urine of subjects dosed with this new platinum drug.

Calibration↗
PubMed2003

Validation of ictal single photon emission computed tomography with depth encephalography and epilepsy surgery.

Many centers have reported that ictal single photon emission computed tomography (SPECT) localizes regions of seizure onset with greater sensitivity and specificity than interictal SPECT. Here we report interictal and ictal SPECT scan results in both lesional and nonlesional cases. Using technetium hexamethyl propylamenamine oxide (HMPAO) or ethyl cysteinate dimer (ECD), these scans were done in 52 patients with partial and secondarily generalized seizures. Twenty-five had normal MRI and 27 showed structural lesions. None had mesial temporal sclerosis clearly identified on MRI. All 52 subsequently had interictal and ictal intracranial EEG studies that appeared to localize the seizure focus. Thirty-nine patients had surgery and have been followed for 2 or more years. Interictal SPECT scans showed focal hypoperfusion consistent with intracranial EEG localization of the seizure focus in 29% of patients. In another 13%, there was correct lateralization but not localization. Ictal SPECT scans showed focal hyperperfusion consistent with intracranial EEG localization of the seizure focus in 52% of patients. In another 25%, there was correct lateralization but not localization. The presence or absence of structural lesions on MRI did not affect ictal hyperperfusion or its correlation with intracranial EEG. Thirty-nine patients had resective surgery, of whom 62% had class I outcomes. There was a trend towards better outcome when ictal SPECT data were concordant with intracranial EEG data. The presence or absence of structural lesions on MRI did not affect the likelihood of class I outcome. Ictal SPECT is superior to interictal SPECT in localizing and lateralizing seizure foci. Its results correlate well with intracranial EEG, but in more than one third of cases, the latter shows focal seizure onset in areas that do not show focal hyperperfusion. Surgical outcome tends to be better when the two modalities give concordant results.

Adolescent↗
PubMed2003

A comparison of the quantitative methods for the analysis of the platinum-containing anticancer drug [cis-[amminedichloro(2-methylpyridine)]platinum(II)] (ZD0473) by HPLC coupled to either a triple quadrupole mass spectrometer or an inductively coupled plasma mass spectrometer.

The use of high performance liquid chromatography coupled with inductively coupled plasma mass spectrometry (HPLC-ICPMS) as means for the quantitative determination of ZD0473, a platinum anticancer drug, and its related biologically active "aqua" compounds in biofluid samples is described. The performance of the resulting HPLC-ICPMS method was compared with that of a conventional HPLC-triple quadrupole mass spectrometer-based (HPLC-MS/MS) system for properties such as limit of detection, linearity, and reproducibility using spiked samples. The methods were then applied to the determination of plasma ultrafitrate concentrations of ZD0473 in dog plasma samples obtained following intravenous and oral administration at 0.5 and 6 mg/kg, respectively. These experiments showed that both methods were capable of providing accurate and precise results but that the HPLC-ICPMS method had advantages of extended linear range and superior sensitivity, providing a limit of quantification of 0.1 ng/mL for ZD0473, as compared to 5 ng/mL using the current HPLC-MS/MS method. In addition, by using a single combined HPLC-ICPMS/MS/MS system, it was possible to determine the relative MS/MS response of the aqua compounds for the first time.

Animals↗
PubMed2003

Coregistered intraoperative ultrasonography in resection of malignant glioma.

OBJECT: The authors present their experience with coregistration of preoperative imaging data to intraoperative ultrasonography in the resection of high-grade gliomas, focusing on methodology and clinical observation. METHODS: Images were obtained preoperatively and coregistered to intraoperative hand-held ultrasound images by merging the respective imaging coordinate systems. After patient registration and imaging calibration, the authors computed the location on the magnetic resonance (MR) space of each pixel on an ultrasound image acquired in the operating room. The data were retrospectively reviewed in 11 patients with high-grade gliomas who underwent ultrasonography-assisted resection at our institution between June 2000 and December 2002. Satisfactory coregistration of intraoperative ultrasound and preoperative MR images was accomplished in all cases. Ultrasound and MR image data were closely congruent. Preoperative setup and intraoperative use of the system were unencumbering. CONCLUSIONS: Based on these preliminary results, intraoperative ultrasonography is an attractive neuronavigational alternative, by which a less expensive and constraining imaging technique is used to acquire updated information. Optimal intraoperative guidance can be provided by the integration of this with other imaging studies.

Adult↗
PubMed2003

Statistical mapping of scalp-recorded ictal EEG records using wavelet analysis.

PURPOSE: The wavelet transform (WT) is well suited for the analysis of signals whose characteristics vary rapidly over time. We devised a computerized method for objective scoring of scalp-recorded seizures that takes advantage of the WT. METHODS: Using wavelet coefficients as a metric, we devised a statistical scoring method aimed at detecting significant and sustained rhythmic buildup. The approach was used to create spatiotemporal significance maps for each seizure. Each seizure was also independently analyzed by computer and an expert reader not involved in the clinical workup or computer analysis of these patients. Hierarchical decision rules for determining seizure lateralization and localization were established from a training set of seizures and subsequently tested on those from an independent test set of seizures. The test dataset included a total of 57 scalp-recorded seizures from 18 patients, each with a > or =12-month seizure-free surgical outcome. RESULTS: Validation was determined by the site of surgical resection. Of the 57 seizure records in the test dataset, the computerized approach resulted in 48 correctly lateralized seizures as compared to 34 for the expert reader. Further, the computer correctly localized 41 seizures to the expert's 31. CONCLUSIONS: The method presented appears to provide an objective basis for the intrachannel scoring of ictal EEGs with minimal interference from artifacts and intermittent discharges. Although the approach has so far shown a substantial improvement over expert scoring in estimating the lateralization and locus of seizure onset, further testing is required to fully evaluate fully its diagnostic accuracy.

Brain Mapping↗