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Biomedical subjects

D Johnston

Publications and source records attributed to D Johnston.

At least 37 records · Page 2Linked to original sources
PubMed2001

Structural, magnetic and catalytic properties of a self-recognized mu-oxo-bridged diiron(III) bis(benzimidazole) complex.

The inherent nonplanarity and C(2) symmetry of the dimethyl-substituted bis(benzimidazole) ligand (Me(2)BBZ) results in two distinct atropisomers that, when separated, have been suggested to have potential for chiral recognition and catalysis. Here is reported the synthesis and characterization of a diiron mu-oxo-bridged bis(benzimidazole) complex, 1, that provides indirect support for this hypothesis. Dimerization of a racemic solution of iron-Me(2)BBZ monomers via the mu-oxo bridge yields (+,+) and (-,-) diastereomers whose complementary association can be attributed to the inherent sidedness of the metal-Me(2)BBZ interaction surface, and to the differences in the torsional angles of the phenyl(benzimidazole) units (34 degrees) and the Schiff base linkages (54 degrees). These results highlight the steric differences between the phenyl(benzimidazole) and Schiff-base portions of the ligand, features that could be important in the chiral recognition of ligands and in differentiating substrate trajectories as required for asymmetric catalysis. For completeness, studies of 1 in the catalytic epoxidation of styrene are also reported.

Journal Article↗
PubMed2001

Samarium(II)-mediated 4-exo-trig cyclization. A stereocontrolled approach to the core of pestalotiopsin A.

[reaction: see text] Pestalotiopsin A is a structurally unique caryophyllene-type sesquiterpene which has shown immunosuppressive activity and cytotoxicity in preliminary assays. A stereocontrolled approach to the functionalized 2-oxabicyclo[3.2.0]heptane core of pestalotiopsin A is described. The approach includes a samarium(II)-mediated 4-exo-trig cyclization and a trans-lactonization process triggered by the addition of alkylytterbium reagents to a cyclobutanone intermediate.

Cyclization↗
PubMed2001

Forest fires and environmental haze in Southeast Asia: using the 'stakeholder' approach to assign costs and responsibilities.

The 'seasonal haze' problem is one which afflicts large parts of Southeast Asia in years of drought. The major cause is forest, bush and field fires in the states of Kalimantan and Sumatra in Indonesia, and to a lesser extent in Sabah, Sarawak, and other parts of Malaysia. Almost all of these fires now seem preventable, since they are intentionally set to clear land for cultivation. Theoretically, the government authorities at central, provincial and local levels in these countries should be responsible for controlling activities in their territory. In practice, however, air pollution control through regulatory policies and practices is extraordinarily difficult to implement and maintain in a situation of this kind in developing countries, especially at a time of crippling economic setbacks. Moreover, the establishment of legal liability, through an international tribunal or otherwise, hardly seems a politically feasible course of action for the government of an affluent 'victim state' such as Singapore. Faith in the usual solutions--science, regulation, law and diplomacy--is weakened by one's sense of current realities. The purpose of this paper is to review the issues and suggested responses, the cost implications of each, the responsibilities as well as entitlements that might apply to the various stakeholders, and the special role of Singapore as an affluent 'victim state'. We also discuss the incentive mechanisms that would be needed to manage forest fires.

Air Pollution↗
PubMed2001

Signal source separation in the analysis of neural activity in brain.

This research examines the spatial and temporal characteristics of the responses to stimulation of the barrel cortex in anesthetized rats using optical imaging with particular emphasis on methods of analysis which reduce the effects of low-frequency oscillations on localization of the activated cortical region. Image sequences were captured using a light source with a narrow bandwidth of wavelength (590 +/- 2 nm). On each trial image data were collected at 15 Hz and stored over a 12-s period starting 8 s before stimulation onset. Stimulation was for 1 s using an oscillating whisker vibrator (approximately 1-mm deflection at 5 Hz). For each subject a total of 30 experimental trials were collected and averaged. There was an interstimulus interval of 26 s. The trial-averaged data were analyzed using two related signal source separation algorithms. Both algorithms use a weak model of the expected temporal response as a filter to exclude contributions from low-frequency baseline oscillations which we call the V-signal. We found that both algorithms successfully separated most of the effects of the V-signal from the response to the stimulation. The performance of the algorithms compared favorably with the performance of related algorithms without weak constraints and the "ratio of means" strategy used by C. H. Chen-Bee et al. (1996b, J. Neurosci. Methods 68:28-37; C. H. Chen-Bee et al., 2000, J. Neurosci. Methods 97:157-173).

Algorithms↗
PubMed2001

Increased oxygen consumption following activation of brain: theoretical footnotes using spectroscopic data from barrel cortex.

Optical imaging spectroscopy (OIS) and laser Doppler flowmetry (LDF) data sequences from anesthetized rats were used to determine the relationship between changes in oxy-and deoxygenated hemoglobin concentration and changes in blood volume and flow in the presence and absence of stimulation. The data from Jones et al. (accompanying paper) were used to explore the differences between two theoretical models of flow activation coupling. The essential difference between the two models is the extension of the model of Buxton and Frank by Hyder et al. (1998, J. Appl. Physiol. 85: 554--564) to incorporate change in capillary diffusivity coupled to flow. In both models activation-increased flow changes increase oxygen transport from the capillary; however, in Hyder et al.'s model the diffusivity of the capillary itself is increased. Hyder et al. proposed a parameter (Omega), a scaling "constant" linking increased blood flow and oxygen "diffusivity" in the capillary bed. Thus, in Buxton and Frank's theory, Omega = 0; i.e., there are no changes in diffusivity. In Hyder et al.'s theory, 0 < Omega < 1, and changes in diffusivity are assumed to be linearly related to flow changes. We elaborate the theoretical position of both models to show that, in principle, the different predictions from the two theories can be evaluated using optical imaging spectroscopy data. We find that both theoretical positions have limitations when applied to data from brief stimulation and when applied to data from mild hypercapnia. In summary, the analysis showed that although Hyder et al.'s proposal that diffusivity increased during activation did occur; it was shown to arise from an implementation of Buxton and Frank's theory under episodes of brief stimulation. The results also showed that the scaling parameter Omega is not a constant as the Hyder et al. model entails but in fact varies over the time course of the flow changes. Data from experiments in which mild hypercapnia was administered also indicated changes in the diffusivity of the capillary bed, but in this case the changes were negative; i.e., oxygen transport from the capillary decreased relative to baseline under hypercapnia. Neither of the models could account for the differences between the hypercapnia and activation data when matched for equivalent flow changes. A modification to the models to allow non-null tissue oxygen concentrations that can be moderated by changes due to increased metabolic demand following increased neural activity is proposed. This modification would allow modulation of oxygen transport from the capillary bed (e.g., changes in diffusivity) by tissue oxygen tension and would allow a degree of decoupling of flow and oxygen delivery, which can encompass both the data from stimulation and from hypercapnia.

Animals↗
PubMed2001

Concurrent optical imaging spectroscopy and laser-Doppler flowmetry: the relationship between blood flow, oxygenation, and volume in rodent barrel cortex.

Functional magnetic resonance imaging (fMRI) is based on the coupling between neural activity and changes in the concentration of the endogenous paramagnetic contrast agent deoxygenated hemoglobin. Changes in the blood oxygen level-dependent (BOLD) signal result from a complex interplay of blood volume, flow, and oxygen consumption. Optical imaging spectroscopy (OIS) has been used to measure changes in blood volume and saturation in response to increased neural activity, while laser Doppler Flowmetry (LDF) can be used to measure flow changes and is now commonplace in neurovascular research. Here, we use concurrent OIS and LDF to examine the hemodynamic response in rodent barrel cortex using electrical stimulation of the whisker pad at varying intensities. Spectroscopic analysis showed that stimulation produced a biphasic early increase in deoxygenated hemoglobin (Hbr), followed by a decrease below baseline, reaching minima at approximately 3.7 s. There was no evidence for a corresponding early decrease in oxygenated hemoglobin (HbO(2)), which simply increased after stimulation, reaching maximum at approximately 3.2 s. The time courses of changes in blood volume (CBV) and blood flow (CBF) were similar. Both increased within a second of stimulation onset and peaked at approximately 2.7 s, after which CBV returned to baseline at a slower rate than CBF. The changes in Hbr, Hbt, and CBF were used to estimate changes in oxygen consumption (CMRO(2)), which increased within a second of stimulation and peaked approximately 2.2 s after stimulus onset. Analysis of the relative magnitudes of CBV and CBF indicates that the fractional changes of CBV could be simply scaled to match those of CBF. We found the relationship to be well approximated by CBV = CBF(0.29). A similar relationship was found using the response to elevated fraction of inspired carbon dioxide (FICO(2)).

Animals↗
PubMed2001

Gastric emptying after a new, more physiological anti-obesity operation: the Magenstrasse and Mill procedure.

The Magenstrasse and Mill (M&M) procedure for obesity is designed to preserve normal gastric emptying mechanisms. The hypothesis investigated in this study was that gastric emptying would be normal after the M&M gastroplasty. Gastric emptying studies were performed using both liquid and solid test meals, in ten morbidly obese patients (MO group) and in 13 patients after the M&M procedure (MM group). Seven people of normal weight served as controls and were matched for age, sex and height to the M&M and MO groups. Three years after the M&M procedure, mean (SD) weight loss was 42 (19) kg, with a mean loss of excess weight of 58% (20%). Gastric emptying half-times (t 1/2) are expressed in minutes, as median values (25th and 75th percentiles). The t 1/2 for solids was 97 (85-110) min in the control group, 140 (86-220) min in the MO group and 79 (46-150) min in the MM group. Median gastric emptying for solids was 0.7% (0.6%-0.8%) per minute in the control group, 0.5% (0.3%-0.8%) in the MO group and 0.9% (0.4%-1.4%) in the M&M group. There were no statistically significant differences in the emptying times of the three groups. It is concluded that the M&M procedure achieves acceptable weight loss, while preserving gastric emptying mechanisms and thus minimising possible side-effects such as vomiting, dumping and diarrhoea, which are common complications of gastric bypass procedures.

Administration, Oral↗
PubMed2001

Hippocampal mossy fiber activity evokes Ca2+ release in CA3 pyramidal neurons via a metabotropic glutamate receptor pathway.

Mossy fiber activity can evoke Ca2+ release from internal stores in CA3 neurons, but the physiological conditions under which this occurs and the mechanisms underlying the release are not understood. Using rat hippocampal slices we report here that short trains of mossy fiber stimulation activate group I metabotropic glutamate receptors (mGluRs) on CA3 pyramidal neurons and elicit waves of Ca2+ release from inositol 1,4,5-trisphosphate (IP3) sensitive internal stores that propagate from stratum lucidum to the soma and in some cases distally out the dendrites. Activation of mGluR1,5 receptors by an agonist trans-azetidine-2,4-dicarboxylic acid (tADA) applied to stratum lucidum was also sufficient to induce waves of Ca2+ release. This release was blocked by internal heparin, but not by dantrolene, suggesting the involvement of IP3 rather than ryanodine receptors in not only the initial release but also in the maintenance of the propagating waves. Release could be facilitated by Ca2+ influx through voltage-gated Ca2+ channels, which is consistent with the known Ca2+ sensitivity of IP3 receptors.These results provide insight into the mechanisms and conditions of Ca2+ release in CA3 neurons and demonstrate the powerful influence mossy fiber input can have on these neurons.

Action Potentials↗
PubMed2001

Mapping and genome sequence analysis of chromosome 5 regions involved in bladder cancer progression.

We studied the evolution of allelic losses on chromosome 5 by whole-organ histologic and genetic mapping in 234 mucosal DNA samples of 5 cystectomy specimens with invasive bladder cancer and preneoplastic changes in adjacent urothelium. The frequency of alterations in individual loci was verified on 32 tumors and 29 voided urine samples from patients with bladder cancer. Finally, deleted regions on chromosome 5 were integrated with the human genome contigs and sequence-based databases. Deleted regions on chromosome 5 involved in intraurothelial phases of bladder neoplasia defined by their nearest flanking markers and predicted size were identified as follows: q13.3-q22 (D5S424-D5S656; 38.8 centimorgan [cM]); q22-q31.1 (D5S656-D5S808; 19.2 cM), q31.1-q32 (D5S816-SPARC; 11.5 cM), and q34 (GABRA1-D5S415; 6.4 cM). The two most frequently deleted neighbor markers (D5S2055 and D5S818) mapping to q22-q31.1 defined a 9 cM region, which may contain genes that play an important role in early phases of urinary bladder carcinogenesis. Human genome database analysis provided an accurate map of deleted regions with positions of 138 known genes and revealed several smaller gene-rich areas representing putative targets for further mapping. The strategic approach presented here, which combines whole-organ histologic and genetic mapping with analysis of the rapidly emerging human genome sequence database, facilitates identification of genes potentially involved in early phases of bladder carcinogenesis.

Aged↗
PubMed2001

The human oesophageal squamous epithelium exhibits a novel type of heat shock protein response.

The human oesophageal epithelium is subject to damage from thermal stresses and low extracellular pH that can play a role in the cancer progression sequence, thus identifying a physiological model system that can be used to determine how stress responses control carcinogenesis. The classic heat shock protein HSP70 is not induced but rather is down-regulated after thermal injury to squamous epithelium ex vivo; this prompted a longer-term study to address the nature of the heat shock response in this cell type. An ex vivo epithelial culture system was subsequently used to identify three major proteins of 78, 70, and 58 kDa, whose steady-state levels are elevated after heat shock. Two of the three heat shock proteins were identified by mass spectrometric sequencing to be the calcium-calmodulin homologue transglutaminase-3 (78 kDa) and a recently cloned oesophageal-specific gene called C1orf10, which encodes a 53-kDa putative calcium binding protein we have named squamous epithelial heat shock protein 53 (SEP53). The 70-kDa heat shock protein (we have named SEP70) was not identifiable by mass spectrometry, but it was purified and studied immunochemically to demonstrate that it is distinct from HSP70 protein. Monoclonal antibodies to SEP70 protein were developed to indicate that: (a) SEP70 is induced by exposure of cultured cells to low pH or glucose starvation, under conditions where HSP70 protein was strikingly down-regulated; and (b) SEP70 protein exhibits variable expression in preneoplastic Barrett's epithelium under conditions where HSP70 protein is not expressed. These results indicate that human oesophageal squamous epithelium exhibits an atypical heat shock protein response, presumably due to the evolutionary adaptation of cells within this organ to survive in an unusual microenvironment exposed to chemical, thermal and acid reflux stresses.

Amino Acid Sequence↗
PubMed2001

Effects of the Magenstrasse and Mill operation for obesity on plasma leptin and insulin resistance.

BACKGROUND: We evaluated the effect of the Magenstrasse and Mill (M & M) operation--a new form of non-banded vertical gastroplasty-on weight loss, plasma leptin levels and insulin resistance. METHODS: Fasting plasma glucose, leptin and insulin levels were measured in 12 normal controls, 39 morbidly obese patients and 39 patients a median 3 years after the M & M procedure. Insulin resistance was calculated by the homeostasis model insulin resistance index. RESULTS: Body mass index mean (s.d.) decreased significantly (p < 0.0001), from 48(7) to 33(5) kg/m2, after the M & M procedure. Fasting plasma leptin concentration in the morbidly obese group was 37.9(15.4) ng/ml, significantly (p < 0.0001) higher than the control group (12.2(8.4)) and the M & M group (19.1(12.7)) ng/ml. Fasting plasma insulin concentrations were also significantly (p < 0.0001) higher in the morbidly obese group compared with than in the M & M group or in the control group: 35.5(22.3) mU/l, 15.5(7.1) mU/l and 13.6(3.4) mU/l, respectively. Insulin resistance was 9.6(7.2) in the morbidly obese group and 3.5(1.9) in the M & M group (p < 0.0001). CONCLUSION: This is one of the first studies to show that the decrease in insulin resistance after weight loss achieved by anti-obesity surgery is associated with significantly lower levels of plasma leptin.

Adult↗
PubMed2001

Reliability of telepsychiatry assessments: subjective versus observational ratings.

Geriatric patients in underserved areas could benefit from the use of telecommunications to expand access to mental health services. It is important to determine the clinical limitations of using videoconferencing for psychiatric assessments, particularly in the elderly. The goal of this study was to test the hypothesis that videoconferencing ratings based on visual observations of behavior would be less reliable than ratings based on patients' verbal reports of symptoms. Videoconferencing assessments of 30 geriatric patients using low-bandwidth (ISDN) equipment were compared to gold standard face-to-face assessments. The Brief Psychiatric Rating Scale (BPRS) was dichotomized into subjective items based on patients' verbal reports and observational items based on visual ratings of behavior. Reliability of the BPRS subjective items was consistently higher than for the observational items. Future studies should emphasize the accuracy of telemedicine ratings that require visual observation of behavior, which is crucial to clinical assessment of psychogeriatric conditions.

Aged↗
PubMed2001

Telepsychiatry consultations to a rural nursing facility: a 2-year experience.

This report describes the operation of a telepsychiatry consultation service provided from an academic medical center to a skilled nursing facility in a rural setting. Seventy-one consultations via low-cost ISDN videoconferencing equipment were provided over the 2-year period to 40 patients. The average duration of the consultation period was about 3 months. A wide variety of diagnostic conditions were encountered, with the majority being either depression or dementia-related behavior problems. Advantages of the program included the ability to respond promptly to rural patients' clinical needs, the flexibility to consult more frequently if clinically indicated, and more efficient use of the consultant's time, as travel time was eliminated. The program is an example of how telepsychiatry can successfully expand access to mental health services to residents of long-term care facilities.

Aged↗
PubMed2001

Spontaneous, elicited and cued causal attributions in the year following a first myocardial infarction.

OBJECTIVES: To assess myocardial infarction (MI) patients' causal beliefs, how they change over time and the effects of different assessment methods. METHOD: The study used a longitudinal design with a follow-up to 1 year. The participants were 100 MI patients who were recruited within 72 hours of admission. Each participant was interviewed and their causal attributions (spontaneous, elicited and cued) were assessed using four different methods. RESULTS: 'Stress', 'smoking', 'it is in the family', 'eating fatty foods' and 'work' items were the most commonly mentioned causes for the MI at all times of measurement and across all measures. On each occasion 'stress' and 'smoking' were selected as the most important causes and patients made fewer attributions over time. Finally, the attributional assessment method used did not affect type of attributions but fewer attributions were reported using the spontaneous method. CONCLUSION: Patients do provide causal attributions following an MI. While many are similar to causal factors identified by medicine, patients appear to place more emphasis on 'stress'. As predicted by attribution theory, attributions changed over time. The method of obtaining the attributions does not appear to affect the attributions made but greatly affects their number. While all the methods used have their place, the cued method with a list of possible attributions offers a rich return for effort expended.

Journal Article↗
PubMed2001

Quality of life after the Magenstrasse and Mill procedure for morbid obesity.

BACKGROUND: The authors assessed the quality of life (QOL) of patients after the Magenstrasse and Mill (M-M) procedure for morbid obesity (MO) and compared this with the QOL of MO patients and non-obese controls. METHODS: Personal, postal and telephone questionnaire survey was completed by 82 patients after the M-M procedure, 35 MO patients and 20 normal controls. QOL was assessed by Short Form 36 (SF-36), Hospital Anxiety and Depression (HAD) scale, and obesity surgery related questionnaire. RESULTS: Physical, social and psychological well-being of patients was substantially better after the M-M compared with their MO counterparts. After the M-M procedure, patients were significantly less depressed but remained anxious when compared with morbidly obese patients. The majority of patients (88%) were pleased with the result of surgery. CONCLUSION: This study provides empirical evidence that the M-M procedure for MO leads to a substantially better QOL.

Adult↗
PubMed2000

Identification of HLA-A*03, A*11 and B*07-restricted melanoma-associated peptides that are immunogenic in vivo by vaccine-induced immune response (VIIR) analysis.

With the discovery of increasing numbers of tumor antigens, there is a need to rapidly determine whether these antigens and the individual peptides they express are able to stimulate immune responses in vivo and thus, can be used to construct cancer vaccines. In this study we used the method of vaccine-induced immune response (VIIR) analysis to identify multiple immunogenic peptide epitopes derived from several melanoma associated antigens and presented by HLA-A*03, A*11 and B*07. Thirty-one patients with melanoma were immunized to a polyvalent vaccine containing multiple antigens, including MAGE-3, Melan A/MART-1, gp100 and tyrosinase. Their peripheral blood was tested for peptide-specific, vaccine-induced CD8+ T cell responses before and after immunization using an enzyme-linked immune spot (ELISPOT) assay with panels of peptides restricted by these three alleles. The peptides were selected for immunogenic potential based on their strong binding affinity in vitro to HLA-A*03, A*11 or B*07. Overall, 60% of the 20 peptides studied were recognized by at least one patient and 50% of the patients showed a vaccine-induced CD8+ T cell response to at least one peptide that matched their HLA specificity. We conclude that VIIR analysis is an effective strategy to directly identify immunogenic peptides that are good candidates for vaccine construction.

Alleles↗
PubMed2000

Pseudo-random procedures for rapid presentation rates using optical imaging and spectroscopy.

Optical imaging of rat barrel cortex has provided detailed spatio-temporal maps of functional cortical architecture. We describe an event-related procedure (ERP) for optical imaging based on selective signal averaging as reported by Burock et al., using an anti-correlative pseudo-random event sequence. The sequence used 1 s vibrissal stimulation at 5 Hz, with an interevent interval of 2 s. This rapid presentation rate allows for greater statistical power per unit time, and allows for direct comparison of event-related studies with other imaging modalities. The spatio-temporal characteristics of single wavelength and spectrographic results were found to be comparable with those obtained by standard techniques, although a general lessening of haemodynamic response function (HRF) was noted. We also describe a method of locating barrel activity by spectral analysis of summed event data. Using this technique, the power spectrum of remitted light from the barrel region was found to peak within +/- 0.12 Hz of the inter-event interval frequency.

Algorithms↗