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Biomedical subjects

C R Clark

Publications and source records attributed to C R Clark.

At least 37 records · Page 2Linked to original sources
PubMed2000

Kinetic origin of the chelate effect. Base hydrolysis, H-exchange reactivity, and structures of syn,anti-[Co(cyclen)(NH3)2]3+ and syn,anti-[Co(cyclen)(diamine)]3+ ions (diamine = H2N(CH2)2NH2, H2N(CH2)3NH2).

The synthesis of syn,anti-[Co(cyclen)en](ClO4)3 (1(ClO4)3) and syn,anti-[Co(cyclen)tn](ClO4)3 (2(ClO4)3) is reported, as are single-crystal X-ray structures for syn,anti-[Co(cyclen)(NH3)2](ClO4)3 (3(ClO4)3). 3(ClO4)3: orthorhombic, Pnma, a = 17.805(4) A, b = 12.123(3) A, c = 9.493(2) A, alpha = beta = gamma = 90 degrees, Z = 4, R1 = 0.030. 1(ClO4)3: monoclinic, P2(1)/n, a = 8.892(2) A, b = 15.285(3) A, c = 15.466(3) A, alpha = 90 degrees, beta = 91.05(3) degrees, gamma = 90 degrees, Z = 4, R1 = 0.0657. 2Br3: orthorhombic, Pca2(1) a = 14.170(4) A, b = 10.623(3) A, c = 12.362(4) A, alpha = beta = gamma = 90 degrees, Z = 4, R1 = 0.0289. Rate constants for H/D exchange (D2O, I = 1.0 M, NaClO4, 25 degrees C) of the syn and anti NH protons (rate law: kobs = ko + kH[OD-]) and the apical NH, and the NH3 and NH2 protons (rate law: kobs = kH[OD-]) in the 1, 2, and 3 cations are reported. Deprotonation constants (K = [Co(cyclen-H)(diamine)2+]/[Co(cyclen)(diamine)3+][OH-]) were determined for 1 (5.5 +/- 0.5 M-1) and 2 (28 +/- 3 M-1). In alkaline solution 1, 2, and 3 hydrolyze to [Co(cyclen)(OH)2]+ via [Co(cyclen)(amine)OH)]2+ monodentates. Hydrolysis of 3 is two step: kobs(1) = kOH(1)[OH-], kobs(2) = ko + kOH(2)[OH-] (kOH(1) = (2.2 +/- 0.4) x 10(4) M-1 s-1, ko = (5.1 +/- 1.2) x 10(-4) s-1, kOH(2) = 1.0 +/- 0.1 M-1 s-1). Hydrolysis of 2 is biphasic: kobs(1) = k1K[OH-]/(1 + K[OH-] (k1 = 5.0 +/- 0.2 s-1, K = 28 M-1), kobs(2) = k2K2[OH-]/(1 + K2[OH-]) (k2 = 3.5 +/- 1.2 s-1, K2 = 1.2 +/- 0.8 M-1). Hydrolysis of 1 is monophasic: kobs = k1k2KK2[OH-]2/(1 + K[OH-1])(k-1 + k2K2[OH-]) (k1 = 0.035 +/- 0.004 s-1, k-1 = 2.9 +/- 0.6 s-1, K = 5.5 M-1, k2K2 = 4.0 M-1 s-1). The much slower rate of chelate ring-opening in 1, compared to loss of NH3 from 3, is rationalized in terms of a reduced ability of the former system to allow the bond angle expansion required to produce the SN1CB trigonal bipyramidal intermediate.

Journal Article↗
PubMed2000

Biomechanical rationale for the pathology of rheumatoid arthritis in the craniovertebral junction.

STUDY DESIGN: A finite-element model of the craniovertebral junction was developed and used to determine whether a biomechanical mechanism, in addition to inflammatory synovitis, is involved in the progression of rheumatoid arthritis in this region of the spine. OBJECTIVES: To determine specific structure involvement during the progression of rheumatoid arthritis and to evaluate these structures in terms of their effect on clinically observed erosive changes associated with the disease by assessing changes in loading patterns and degree of anterior atlantoaxial subluxation. SUMMARY OF BACKGROUND DATA: Rheumatoid arthritis involvement of the occipito-atlantoaxial (C0-C1-C2) complex is commonly seen. However, the biomechanical contribution to the development and progression of the disease is neither well understood nor quantified. Although previous cadaver studies have elucidated information on kinematic motion and fusion techniques, the modeling of progressive disease states is not easily accomplished using these methods. The finite-element method is well suited for studying progressive disease states caused by the gradual changes in material properties that can be modeled. METHODS: A ligamentous, nonlinear, sliding-contact, three-dimensional finite-element model of the C0-C1-C2 complex was generated from 0.5 mm thick serial computed tomography scans. Validation of the model was accomplished by comparing baseline kinematic predictions with experimental data. Transverse, alar, and capsular ligament stiffness were reduced sequentially by 50%, 75%, and 100% (removal) of their intact values. All models were subjected to flexion moments replicating the clinical diagnosis of rheumatoid arthritis using full flexion lateral plane radiographs. Stress profiles at the transverse ligament-odontoid process junction were monitored. Changes in loading profiles through the C0-C1 and C1-C2 lateral articulations and their associated capsular ligaments were calculated. Anterior and posterior atlantodental interval values were calculated to correlate ligamentous destruction with advancement of atlantoaxial subluxation. RESULTS: Model predictions (at 0.3 Nm) fell within one standard deviation of experimental means, and range of motion data agreed with published in vitro and in vivo values. The model predicted that stresses at the posterior base of the odontoid process were greatly reduced with transverse ligament compromise beyond 75%. Decreases through the lateral C0-C1 and C1-C2 articulations were compensated by their capsular ligaments. Anterior and posterior atlantodental interval values indicate that the transverse ligament stiffness decreases beyond 75% had the greatest effect on atlantoaxial subluxation during the early stages of the disease (no alar and capsular ligament damage). Subsequent involvement of the alar and capsular ligaments produced advanced atlantoaxial subluxation, for which surgical intervention may be warranted. CONCLUSIONS: To the best of the authors' knowledge, this is the first report of a validated, three-dimensional model of the C0-C1-C2 complex with application to rheumatoid arthritis. The data indicate that there may be a mechanical component (in addition to enzymatic degradation) associated with the osseous resorption observed during rheumatoid arthritis. Specifically, erosion of the odontoid base may involve Wolff's law of unloading considerations. Changes through the lateral aspects of the atlas suggest that this same mechanism may be partially responsible for the erosive changes seen during progressive rheumatoid arthritis. Anterior and posterior atlantodental interval values indicate that complete destruction of the transverse ligament coupled with alar and/or capsular ligament compromise is requisite if advanced levels of atlantoaxial subluxation are present.

Arthritis, Rheumatoid↗
PubMed2000

Updating working memory for words: a PET activation study.

A PET study of 10 normal individuals was carried out to investigate the cerebral regions involved in the controlled updating of verbal working memory. Subjects viewed single concrete words on a computer monitor and detected occasional target words in an attended color. In the activating condition, a target was defined as a word that was identical to the previous word presented in the attended color. In the control condition, the target was a predesignated word. The same word lists, target probabilities, and target response demands were used for both conditions, with interword intervals constrained to ensure equivalence in the demand for target rehearsal. A comparison of the conditions found bilateral activation of dorsolateral prefrontal (middle frontal gyrus; MFG) and inferior parietal (supramarginal gyrus; SMG) cortical regions. Activation of the MFG is taken to reflect executive control by prefrontal regions over the working memory updating process linking posterior representations of the anticipated target stimulus to anterior representations of the planned response. It is proposed that the updating of the stimulus link is mediated via connections between the MFG and SMG. The role of the SMG as an amodal region binding the various modal representations in posterior association cortex of the word being retained in working memory is considered and reviewed. It is suggested that the combined activation of these regions is related to the executive control of goal-setting in planned behavior.

Blood Flow Velocity↗
PubMed2000

MALDI-ToF/MS as a diagnostic tool for the confirmation of sulfur mustard exposure.

The continual threat of chemical and biological warfare has prompted the need for unambiguous analytical methods for the confirmation of agent exposure. In this paper, we have investigated the use of matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-ToF/MS) as a diagnostic tool for this purpose. Mass spectral studies of the interaction of sulfur mustard (bis-(2-chloroethyl) sulfide, HD) with hemoglobin and metallothioneine were conducted. In vitro experiments with purified proteins were performed, using both HD and chloroethylethyl sulfide (CEES), in an effort to determine the extent of alkylation and occurrence of HD cross-linking using the MALDI-ToF/MS technique. In a typical experiment, 50 ml of 5 mM HD in acetonitrile was added to an equal volume of 0.5 mM hemoglobin in deionized water followed by vortexing and incubation at room temperature. After 24 h, the samples were analyzed by MALDI-ToF/MS. Mass spectral results indicated the presence of at least two distinct alkylation adducts for both HD and CEES experiments. These results demonstrate that MALDI-ToF/MS is a useful analytical technique to investigate the interaction of HD with biomolecules and may be employed potentially as a diagnostic tool for the confirmation of exposure to chemical warfare agents.

Acetonitriles↗
PubMed2000

The effect of clozapine on the speed and accuracy of information processing in schizophrenia.

1. The study aimed to investigate the effects of clozapine on the speed and accuracy of information processing in patients with schizophrenia. Data are reported from 13 subjects with schizophrenia, treated with clozapine for 6.8 (+/- 1.8) months. 2. Reaction time and accuracy of target detection on a tone detection task were measured before and during clozapine treatment, and these results were compared with a matched control group. 3. Symptom severity and performance on three timed tests of cognitive function were also measured prior to clozapine treatment in the schizophrenia group, and these measures were repeated during treatment with clozapine. 4. Treatment with clozapine was found to significantly improve reaction time and the accuracy of target detection in patients with schizophrenia. Despite this improvement their performance remained significantly inferior to that of a matched control group. Both positive and negative symptoms improved with clozapine treatment, as did performance on the WAIS-R digit symbol substitution test. 5. Improved performance on the WAIS-R digit symbol substitution test correlated with reduction in negative symptoms, and faster reaction time showed some correlation with reduction in positive symptoms. 6. The results of this pilot study indicate that treatment with clozapine can produce limited improvement in cognitive function in schizophrenia.

Acoustic Stimulation↗
PubMed2000

Chromatographic and mass spectral methods of identification for the side-chain and ring regioisomers of methylenedioxymethamphetamine.

The popular drug of abuse 3,4-methylenedioxymethamphetamine (MDMA) is one of a total of 10 regioisomeric 2,3- and 3,4-methylenedioxyphenethylamines of MW 193 that yields regioisomeric fragment ions with equivalent mass (m/z 58 and 135/136) in the electron-impact (EI) mass spectrum. Thus, these 10 methylenedioxyphenethylamines are uniquely isomeric; they have the same molecular weight and equivalent major fragments in their mass spectra. The specific identification of one of these compounds (i.e., Ecstasy or 3,4-MDMA) in a forensic drug sample depends upon the analyst's ability to eliminate the other regioisomers as possible interfering or coeluting substances. This study reports the synthesis, chemical properties, spectral characterization, and chromatographic analysis of these 10 unique regioisomers. The ten 2,3- and 3,4-regioisomers of MDMA are synthesized from commercially available precursor chemicals. In the EI mass spectra, the side-chain regioisomers show some variation in the relative intensity of the major ions, with the exception of only one or two minor ions that might be considered side-chain specific fragments. The position of substitution for the methylenedioxy ring is not easily determined by mass spectral techniques, and the ultimate identification of any one of these amines with the elimination of the other nine must depend heavily upon chromatographic methods. The chromatographic separation of these 10 uniquely regioisomeric amines are studied using reversed-phase liquid chromatographic methods with gradient elution and gas chromatographic techniques with temperature program optimization.

Chromatography↗
PubMed2000

In-vitro hydrolysis, permeability, and ocular uptake of prodrugs of N-[4-(benzoylamino)phenylsulfonyl]glycine, a novel aldose reductase inhibitor.

To enhance the ocular uptake of N-[4-(benzoylamino)phenylsulfonyl]glycine (BAPSG), two ester (methyl and isopropyl) prodrugs were synthesized and evaluated for their stability in various buffers (pH 1-9), hydrolysis in rabbit ocular tissues (cornea, conjunctiva, iris-ciliary body, lens, aqueous humor, and vitreous humor), transport across cornea and conjunctiva, and in-vivo uptake following topical administration. Over the pH range of 1-9, the rate constants for degradation ranged from 5.67 to 218.9 x 10(-3) h(-1) for the methyl ester and from 3.14 to 4.45 x 10(-3) h(-1) for the isopropyl ester. At all pH conditions, the isopropyl ester was more stable when compared with the methyl ester. A change in buffer concentration at pH 7.4 did not influence the stability of the prodrugs. The prodrugs were rapidly hydrolysed in the tissue homogenates, with the rate constants for hydrolysis ranging from 1.98 to 7.2x 10(-3) min(-1) for the methyl ester and 3.32 to 6.53 x 10(-3) min(-1) for the isopropyl ester. The in-vitro permeability of the methyl ester was less than the parent drug across cornea and conjunctiva. Isopropyl ester levels were not detectable in the receiver chamber even at the end of the 4-h transport study. Following topical administration of BAPSG and the two prodrugs at a dose of 60 microg/eye, the lowest levels were seen in vitreous humor for parent compound and its methyl ester. In general, the tissue uptake of methyl ester was less than BAPSG. Isopropyl ester levels were below detection limits in all the ocular tissues. Lipophilic ester prodrugs of BAPSG showed good aqueous solution stability in tissue homogenates. However, these prodrugs lacking the free carboxylate anion exhibited reduced in-vitro permeability and in-vivo uptake, suggesting the importance of free carboxylate anion in the delivery of BAPSG.

Aldehyde Reductase↗
PubMed2000

Treating cognitive dysfunction in patients with schizophrenia.

Cognitive dysfunction is a common, chronically disabling component of schizophrenia. It has been proposed that many of the symptoms of schizophrenia can be understood as a result of disruption of fundamental cognitive processes. This paper reviews treatment strategies aimed at improving cognitive function in patients with schizophrenia. Nonpharmacologic interventions include instruction in the performance of tasks such as the Wisconsin Card Sorting Test. Mixed results have been achieved, but it appears that instruction methods involving reinforcement of information held in working memory are more successful. Computer-aided remediation has also been used with variable success. Novel antipsychotic drugs appear to have an advantage over conventional antipsychotic drugs in terms of their effect on cognitive function. The development of more precisely tailored methods of remedial teaching, along with optimal pharmacologic treatment, may lead to more effective treatment of cognitive dysfunction in patients with schizophrenia.

Cognition Disorders↗
PubMed1999

Development of an in vitro screening method for evaluating decontamination of sulfur mustard by reactive dermal formulations.

New barrier creams known as topical skin protectants (TSPs) recently have been formulated and demonstrated to be effective in delaying skin penetration of the blistering warfare agent sulfur mustard (HD). To further inactivate or neutralize HD, compounds that react with the toxic agent must be incorporated in the formulations, which then become reactive topical skin protectants (rTSPs). Specific and fast screening methods are necessary to assess the decontaminating activity of rTSPs. A headspace sampling technique in conjunction with thermal desorption and gas chromatography-mass spectrometry was evaluated as a potential screening method. A lower detection limit of 1 ng and a coefficient of variation of <20% were observed for the repetitive measurements of residual HD. Using this method, we evaluated a candidate rTSP. The percentage recovery of HD applied to the rTSP decreased by 35% over a 20-min time period compared with a non-rTSP. The candidate formulation showed an instant decontamination of the HD simulant dibutyl sulfide (decontamination was achieved in 2 s). The instrument set-up has the potential to accommodate multiple samples and can be automated. The method can be extended also to test reactive dermal formulations with toxic organophosphorus compounds.

Administration, Topical↗
PubMed1999

Cervical electromyographic activity during low-speed rear impact.

Whiplash motion of the neck is characterized by having an extension-flexion motion of the neck. It has been previously assumed that muscles do not play a role in the injury. Eight healthy males were seated in a car seat mounted on a sled. The sled was accelerated by a spring mechanism. Muscle electromyographic (EMG) activity was measured by wire electrodes in semi-spinalis capitis, splenius capitis, and levator scapulae. Surface EMG activity was measured over trapezius and sternocleidomastoideus. Wavelet analysis was used to establish the onset of muscle activity with respect to sled movement. Shorter reaction times were found to be as low as 13.2 ms from head acceleration and 65.6 ms from sled acceleration. Thus the muscles could influence the injury pattern. It is of interest that clinical symptoms are often attributed to muscle tendon injuries.

Acceleration↗
PubMed1999

Ultrasonographic examination of the distal limb of cattle.

Ultrasonography has proven its worth in both small animal and equine musculoskeletal work. It allows visualization of soft tissue that is not possible with anything barring magnetic resonance imaging. In bovine practice, ultrasound has been used to great effect in reproductive work and has also shown itself to be of value in the evaluation of the thorax, abdomen, and the udder. Ultrasound examination of the bovine limb is certainly feasible because of the availability of small portable and affordable equipment. The restraint necessary is dependent on the animal. Cattle, because of their size and inherent dislike of restraint, pose a challenge for ultrasonographic examination. However, if proper restraint is used, it seems possible that ultrasonography may become a helpful tool in the evaluation of soft tissue injuries. It should prove to provide valuable information that may be used to offer better advice with regard to treatment and prognosis.

Animals↗
PubMed1999

Effects of clozapine for non-treatment-resistant patients with schizophrenia.

Clozapine is generally used for patients meeting criteria for treatment resistance. In this study clozapine was given to 19 patients with schizophrenia who did not meet these criteria and whose symptoms were mild to moderate in severity. Clozapine was associated with significant improvement in positive and negative symptoms and quality of life. A more modest improvement on a range of tests of cognitive functioning was also noted. These results suggest that consideration should be given to broadening the usual criteria for patients' eligibility for clozapine treatment.

Adult↗
PubMed1999

Rabbit corneal and conjunctival permeability of the novel aldose reductase inhibitors: N-[[4-(benzoylamino)phenyl] sulphonyl]glycines and N-benzoyl-N-phenylglycines.

Corneal and conjunctival permeability has been investigated for novel aldose reductase inhibitors (ARIs) of the N{[4-(benzoylamino)phenyl]sulphonyl}glycine (benzoylaminophenylsulphonylglycine) and N-benzoyl-N-phenylglycine (benzoylphenylglycine) series, compounds developed for prevention of cataract formation in diabetic subjects. Six benzoylaminophenylsulphonylglycines were synthesized with modifications either of the phenyl group or of the glycine structure and three benzoylphenylglycines were synthesized with modification in the phenyl group of the benzoyl moiety. Transport of ARIs in the mucosal to serosal direction was evaluated across rabbit cornea and conjunctiva bathed in glutathione-bicarbonate Ringer's solution maintained at pH 7.4 and 37 degrees C. The permeability coefficients of the novel ARIs across cornea and conjunctiva ranged from 1.87 to 8.95 x 10(-6) cm s(-1) and from 4.6 to 19.15 x 10(-6) cm s(-1), respectively. The ratio of corneal to conjunctival permeability ranged from 0.12 to 0.79. The calculated log partition coefficient (log P) values for the ARIs were in the range 0.84 to 2.78. The log distribution coefficients (log D) were in the range -2.87 to -0.89. There was no apparent relationship between log P or log D and the permeability coefficients of the ARIs for either tissue. Cornea was more resistant to ARI transport than was conjunctiva. Substitution of a phenyl group for hydrogen in the glycine methylene group reduced the permeability coefficient. Permeability coefficients were different for different stereoisomers. Compared with the permeability coefficient of benzoylaminophenylsulphonylglycine, that of 4-fluorobenzoylaminophenylsulphonylglycine was lower in the cornea but similar in the conjunctiva. In both tissues, the permeability coefficient of 2-nitrobenzoylaminophenylsulphonylglycine was less than that of 4-nitrobenzoylaminophenylsulphonylglycine. There was no significant difference between the permeability coefficients of 3-nitro- and 4-nitrobenzoylphenylglycines through either tissue and the permeability coefficients of these compounds were greater than that of the more lipophilic 4-methylbenzoylphenylglycine. The lack of dependence of the permeability coefficients on log P or log D and the different permeabilities of stereoisomers imply the existence of specialized transport processes for the ARIs tested in this study.

Animals↗
PubMed1998

A subacute inhalation exposure evaluation of a scrubbing solution used in petroleum refineries.

The potential for subacute toxicity and neurotoxicity of a potassium carbonate-based scrubbing solution used in petroleum refineries was evaluated in Sprague-Dawley Crl:CD BR rats. Exposures were to aerosols of a "used" scrubbing solution by wholebody inhalation, 6 h/d, for 21 consecutive days at target concentrations of 0 (filtered air-control), 0.1, 0.2, or 0.4 mg/L (30 animals/sex/group). A functional observation battery (FOB) and locomotor activities tests were conducted and monitored. No apparent adverse effects were noted at any exposure level as determined by clinical observations, food consumption, hematology, serum chemistry, ophthalmologic observations, and gross pathology. Statistically significant increases in lung weights were noted at all treatment levels but returned to control values upon cessation of exposure except for the 0.4 mg/L female group. There were no significant changes in other organ weights. Histopathologic findings were restricted to the respiratory tract and characterized by minimal to moderate epithelial hyperplasia, epithelial necrosis, and cytoplasmic vacuolation at levels I and II of the nasal cavities. Lung bronchiolization and alveolar macrophage infiltration were also observed. The respiratory-tract findings were considered a local response to the high alkalinity of the test material as substantiated by the return to normal upon cessation of exposure. Exposure to scrubbing solution had no adverse effect on FOB endpoints and locomotor activity evaluations, brain weight and size, and neuropathologic examinations. In conclusion, inhalation exposure to a used scrubbing solution aerosol for 21 d did not result in any persistent systemic toxicity or neurotoxicity in either male or female rats.

Animals↗
PubMed1998

Developmental toxicity evaluation of a scrubbing solution used in petroleum refineries.

The developmental toxicity potential of a scrubbing solution used extensively in petroleum refineries to remove CO2 from hydrogen gas streams was evaluated via inhalation. Pregnant female CD (Sprague-Dawley) rats were exposed to aerosols of a "used" scrubbing solution at 0.05, 0.1, 0.2, or 0.3 mg/l for 6 h/d on d 6-19 of pregnancy. Control animals were exposed to filtered air under the same exposure conditions. Dams were sacrificed on d 20 of pregnancy and a laparohysterectomy was performed. The mass median aerodynamic diameter of the aerosol revealed that all particles ranged from 1.6 to 2.8 microm, with geometric standard deviations between 2.0 and 2.3 microm. The overall pregnancy rate was high (>95%) and equivalent across all groups. All pregnant dams had live litters, and 22-24 litters were examined in each group. Treatment-related clinical signs consisted of rales, observed at all exposure levels, and gasping noted only at the 0.3 mg/l exposure level. The occurrence of rales was presumably a localized effect on the respiratory tract and likely due to the irritating properties of the scrubbing solution. Maternal toxicity was exhibited in the 0.3 mg/l group, including reduced body weight, weight gain, and food consumption and one possible treatment-related death on gestation d 17. At scheduled necropsy, there were no treatment-related gross pathological observations and no statistically significant reproductive and developmental effects. The incidences of fetuses with skeletal variations involving the sternum were clustered in two litters at the highest exposure level with atypically low term fetal body weights. Under the conditions of this investigation, potassium carbonate scrubbing solution is not a selective developmental toxicant.

Accidents, Occupational↗
PubMed1997

Relationships between changes in symptom ratings, neurophysiological test performance and quality of life in schizophrenic patients treated with clozapine.

This study examined the correlations between reduction in symptoms, changes in neuropsychological test performance and improved quality of life in 19 schizophrenic outpatients treated with clozapine. Reduction in both negative symptoms and general psychopathology was associated with a better quality of life. Some improvement in neuropsychological test performance was found, with a variable pattern of association with change in psychopathology. Improved verbal fluency was associated with reduction in negative symptoms, while improved verbal concept formation was associated with reduction in positive symptoms.

Adult↗