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Biomedical subjects

J Dunbar

Publications and source records attributed to J Dunbar.

At least 37 records · Page 2Linked to original sources

Skin and soft tissue infections: development of a collaborative management plan between community and hospital care.

The commonest indication in the US for referral to an outpatient/home i.v. antibiotic therapy programme is the management of skin and soft tissue infections. In the UK, however, these infections account for 10% or more of admissions to infection units. The main indication for hospitalisation is to receive parenteral antibiotics. A retrospective audit of one year of admissions to a regional infection unit revealed that, although most of these patients do not progress to complications ('low risk'), they occupy a mean time of five days in hospital and for nearly half of that time they receive parenteral antibiotics. This period in hospital reflected 11.4% of the unit's bed occupancy. Even if 75% of these patients were treated in the community with parenteral therapy, this would result in bed savings of 8.55%, nearly one-tenth of the unit's occupied capacity. This type of audit should help key decision makers thinking of developing similar services in their region. Outpatient or home parenteral antimicrobial therapy (OHPAT) should be delivered as part of a complete disease management programme in collaboration with primary care.

Algorithms↗

The structure of L-aspartate ammonia-lyase from Escherichia coli.

The X-ray crystal structure of l-aspartate ammonia-lyase has been determined to 2.8 A resolution. The enzyme contains three domains, and each domain is composed almost completely of alpha helices. The central domain is composed of five long helices. In the tetramer, these five helices form a 20-helix cluster. Such clusters have also been seen in delta-crystallin and in fumarase. The active site of aspartase has been located in a region that contains side chains from three different subunits. The structure of the apoenzyme has made it possible to identify some of the residues that are involved in binding the substrate. These residues have been examined by site-directed mutagenesis, and their putative roles have been assigned [Jayasekera, M. M. K., Shi, W., Farber, G. K., & Viola, R. E. (1997) Biochemistry 36, 9145-9150].

Aspartate Ammonia-Lyase↗

The effect of denaturants on protein structure.

Virtually all studies of the protein-folding reaction add either heat, acid, or a chemical denaturant to an aqueous protein solution in order to perturb the protein structure. When chemical denaturants are used, very high concentrations are usually necessary to observe any change in protein structure. In a solution with such high denaturant concentrations, both the structure of the protein and the structure of the solvent around the protein can be altered. X-ray crystallography is the obvious experimental technique to probe both types of changes. In this paper, we report the crystal structures of dihydrofolate reductase with urea and of ribonuclease A with guanidinium chloride. These two classic denaturants have similar effects on the native structure of the protein. The most important change that occurs is a reduction in the overall thermal factor. These structures offer a molecular explanation for the reduction in mobility. Although the reduction is observed only with the native enzyme in the crystal, a similar decrease in mobility has also been observed in the unfolded state in solution (Makhatadze G, Privalov PL. 1992. Protein interactions with urea and guanidinium chloride: A calorimetric study.

Crystallography, X-Ray↗

Strengthening partnerships between state programs for children with special health care needs and managed care organizations.

The roles and responsibilities of state Title V Programs for Children with Special Health Care Needs (CSHCN) are changing with the rapid expansion of managed care. The authors surveyed Title V CSHCN programs to learn about critical issues and examples of collaboration with managed care organizations in the following areas: (1) defining and identifying children with special health care needs, (2) enrollment assistance and family participation, (3) pediatric provider and service requirements, (4) education and training, (5) quality of care, and (6) pediatric risk-adjusted capitation mechanisms. This article also includes recommendations developed by the federal Maternal and Child Health Bureau's Work Group on Managed Care.

Capitation Fee↗

Genetic Diversity through the Looking Glass: Effect of Enrichment Bias.

The effect of enrichment bias on the diversity of 2,4-dichlorophenoxyacetate (2,4-D)-degrading (2,4-D(sup+)) bacteria recovered from soil was evaluated by comparing the diversity of isolates obtained by direct plating to the diversity of isolates obtained from 85 liquid batch cultures. By the two methods, a total of 159 isolates were purified from 1 g of soil and divided into populations based on repeated extragenic palindromic sequence PCR (rep-PCR) genomic fingerprints. Approximately 42% of the direct-plating isolates hybridized with the tfdA and tfdB genes from Alcaligenes eutrophus JMP134(pJP4), 27% hybridized with the tfdA and tfdB genes from Burkholderia sp. strain RASC, and 30% hybridized with none of the probes. In contrast, the enrichment isolates not only represented fewer populations than the isolates obtained by direct plating but also exhibited, almost exclusively, a single hybridization pattern with 2,4-D catabolic gene probes. Approximately 98% of the enrichment isolates possessed pJP4-type tfdA and tfdB genes, whereas isolates containing RASC-type tfdA and tfdB genes were obtained from only 2 of the 85 enrichment cultures. The skewed occurrence of the pJP4-type genes among the isolates obtained by enrichment suggests that the competitive fitness of 2,4-D(sup+) populations during growth with 2,4-D may be influenced either by specific tfd alleles or by genetic factors linked to these alleles. Moreover, the results indicate that evaluation of the diversity and distribution of catabolic pathways in nature can be highly distorted by the use of enrichment culture techniques.

Journal Article↗

Use of ankle brachial pressure index to predict cardiovascular events and death: a cohort study.

OBJECTIVE: To determine whether a low ankle brachial pressure index is associated with an increased risk of cardiovascular events and death, and whether the prediction of such events could be improved by including this index. DESIGN: Cohort study. SETTING: 11 practices in Edinburgh, Scotland. SUBJECTS: 1592 men and women aged 55-74 years selected at random from the age-sex registers of 11 general practices and followed up for 5 years. MAIN OUTCOME MEASURES: Incidence of fatal and non-fatal cardiovascular events and all cause mortality. RESULTS: At baseline 90 (5.7%) of subjects had an ankle brachial pressure index < or = 0.7, 288 (18.2%) had an index < or = 0.9, and 566 (35.6%) < or = 1.0. After five years subjects with an index < or = 0.9 at baseline had an increased risk of non-fatal myocardial infarction (relative risk 1.38, 95% confidence interval 0.88 to 2.16), stroke (1.98, 1.05 to 3.77), cardiovascular death (1.85, 1.15 to 2.97), and all cause mortality (1.58, 1.14 to 2.18) after adjustment for age, sex, coronary disease, and diabetes at baseline. The ability to predict subsequent events was greatly increased by combining the index with other risk factors--for example, hypertensive smokers with normal cholesterol concentrations had a positive predictive value of 25.0%, increasing to 43.8% in subjects with a low index and decreasing to 15.6% in those with a normal index. CONCLUSION: The ankle brachial pressure index is a good predictor of subsequent cardiovascular events, and improves on predictions by conventional risk factors alone. It is simple and accurate and could be included in routine screening of cardiovascular status.

Aged↗

Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population.

BACKGROUND: Intermittent claudication is associated with a poor prognosis, but less is known of the risks associated with asymptomatic peripheral arterial disease. The aims of this study were to determine the incidence and natural history of claudication, and the incidence of cardiovascular events in symptomatic and asymptomatic peripheral arterial disease. METHODS: In 1988, 1592 subjects aged 55-74 years were selected randomly from the age-sex register of 10 general practices in Edinburgh, Scotland. The presence of peripheral arterial disease was determined by the World Health Organization questionnaire on intermittent claudication, the ankle brachial pressure index and a reactive hyperaemia test. This cohort was followed prospectively over 5 years for subsequent cardiovascular events and death. RESULTS: One hundred and sixteen new cases of claudication were identified (incidence density 15.5 per 1000 person-years). Of those with claudication at baseline, 28.8% and still had pain after 5 years, 8.2% underwent vascular surgery or amputation, and 1.4% developed leg ulceration. Claudicants had a significantly increased risk of developing angina compared with normals (RR: 2.31, 95% CI: 1.04-5.10), and asymptomatic subjects had a slightly increased risk of myocardial infarction and stroke. Deaths from cardiovascular disease were more likely in both claudicants (RR: 2.67, 95% CI: 1.34-5.29) and subjects with major (RR: 2.08, 95% CI: 1.13-3.83) or minor asymptomatic disease (RR: 1.74, 95% CI: 1.09-2.76). Subjects with major asymptomatic disease also had an increased risk of non-cardiovascular death (RR: 2.19, 95% CI: 1.33-3.59), and therefore had the highest overall risk of death (RR: 2.44, 95% CI: 1.59-3.74). CONCLUSIONS: Subjects with asymptomatic peripheral arterial disease appear to have the same increased risk of cardiovascular events and death found in claudicants.

Aged↗

Autoradiographic method for isolation of diverse microbial species with unique catabolic traits.

A novel autoradiographic method for isolation of bacteria with unique catabolic traits was developed to overcome many of the limitations of traditional selective enrichment techniques. The method consists of five steps. (i) An environmental sample is directly plated (without enrichment) on a microporous filter atop a solid medium that allows cultivation of diverse kinds of microorganisms. (ii) Once colonies form, two replicas of the filter are prepared and the colonies are regrown. (iii) The replica filters are starved 24 to 72 h to deplete intracellular carbon reserves and then (iv) placed on Na(inf2)(sup35)SO(inf4)-containing solid media with and without a test compound. (v) Following an incubation period, the replica filters are exposed to film in order to identify colonies that incorporate more (sup35)S into cell biomass in the presence of the test compound than in its absence, providing presumptive evidence for metabolism of the compound. The colonies identified in this manner can be recovered from the master filter. To demonstrate this technique, bacteria capable of degrading benzoate were isolated from a single soil slurry by traditional enrichment as well as by autoradiography. From the enrichment culture, a single isolate able to degrade benzoate was obtained. In contrast, 18 distinct strains were obtained by purifying 19 putative benzoate-degrading colonies identified by autoradiography. Each of the 18 strains was able to completely transform the substrate, as determined by high-performance liquid chromatography analyses. The doubling times of a subset of the isolates grown in benzoate medium ranged from 1.4 to 17.1 h, whereas the doubling time of the isolate obtained by enrichment was 2.0 h. These data demonstrate that the method described here can be used to obtain a collection of diverse organisms able to metabolize a specific compound.

Journal Article↗

Magnetic resonance imaging-monitored acute blood-brain barrier changes in experimental traumatic brain injury.

The authors posit that cellular edema is the major contributor to brain swelling in diffuse head injury and that the contribution of vasogenic edema may be overemphasized. The objective of this study was to determine the early time course of blood-brain barrier (BBB) changes in diffuse closed head injury and to what extent barrier permeability is affected by the secondary insults of hypoxia and hypotension. The BBB disruption was quantified and visualized using T1-weighted magnetic resonance (MR) imaging following intravenous administration of the MR contrast agent gadolinium-diethylenetriamine pentaacetic acid. To avoid the effect of blood volume changes, the maximum signal intensity (SI) enhancement was used to calculate the difference in BBB disruption. A new impact-acceleration model was used to induce closed head injury. Forty-five adult Sprague-Dawley rats were separated into four groups: Group I, sham operated (four animals), Group II, hypoxia and hypotension (four animals), Group III, trauma only (23 animals), and Group IV, trauma coupled with hypoxia and hypotension (14 animals). After trauma was induced, a 30-minute insult of hypoxia (PaO2 40 mm Hg) and hypotension (mean arterial blood pressure 30 mm Hg) was imposed, after which the animals were resuscitated. In the trauma-induced animals, the SI increased dramatically immediately after impact. By 15 minutes permeability decreased exponentially and by 30 minutes it was equal to that of control animals. When trauma was coupled with secondary insult, the SI enhancement was lower after the trauma, consistent with reduced blood pressure and blood flow. However, the SI increased dramatically on reperfusion and was equal to that of control by 60 minutes after the combined insult. In conclusion, the authors suggest that closed head injury is associated with a rapid and transient BBB opening that begins at the time of the trauma and lasts no more than 30 minutes. It has also been shown that addition of posttraumatic secondary insult-hypoxia and hypotension-prolongs the time of BBB breakdown after closed head injury. The authors further conclude that MR imaging is an excellent technique to follow (time resolution 1-1.5 minutes) the evolution of trauma-induced BBB damage noninvasively from as early as a few minutes up to hours or even longer after the trauma occurs.

Animals↗

Old problem, different approach: alternatives to physical restraints.

Individualized care, resident assessment by a multidisciplinary team, and rehabilitation enhance functional independence in nursing home residents. Creativity in choosing alternatives to restraints was important in successful restraint reduction. Residents free of restraints had higher ADL levels, were more continent, and sustained fewer serious injuries, all of which are important quality of life indicators.

Aged↗

Brain edema resolution by CSF pathways and brain vasculature in cats.

Brain edema is a major contributor to the brain swelling process and raised intracranial pressure, yet the specific pathways involved in clearance of brain edema (fluid and proteins) and their relative contribution to the resolution process remain unknown. The objective of this study was to document the temporal course of edema resolution from brain to cerebrospinal fluid (CSF) and by the brain vasculature. Radioiodinated (125I) cat serum albumin (RICSA) was infused continuously into the white matter of anesthetized adult cats for 8 h, and ventriculocisternal perfusion was used to monitor the RICSA activity in CSF at 15-min intervals and to compare with the blood taken at 15-min intervals. The RICSA that cleared from the brain in 8 h measured 29.8% of the amount infused. Of the amount of RICSA leaving the brain, we found that the CSF compartment accounted for 87.14% of the cleared RICSA volume, while only 10.96% of RICSA was found in the blood during the 8-h experiment. The amount of RICSA remaining in the brain when the animal was killed equaled 71.2 +/- 15.9% (mean +/- SD) of the RICSA infused. We conclude that vascular clearance during the acute stage of resolution is minimal and that clearance of RICSA occurs predominantly via the CSF pathways.

Animals↗

Circulatory assist techniques in cardiogenic shock: metabolic aspects.

Assisted circulation in severe cardiogenic shock was evaluated using a reservoir and a single pump without an oxygenator in 88 dogs. Study groups included: no treatment, substrates only (cysteine, ribose), nitroprusside, left ventricular (LV) + right atrial (RA) bypass + substrates, LV + RA bypass, left atrial (LA) + RA bypass, LA bypass, LV bypass, LV + RA + fluosol. Metabolic studies of O2 consumption, acid and alkaline phosphatase, lactate, creatine phosphokinase (CPK), myocardial depressant factor (MDF), and tissue adenosine triphosphate (ATP) were done in the course of 4-hour treatment periods followed by 2-hour observation periods. Best survival at 4-hour and 6-hour levels were achieved in LV + RA bypass. Cysteine and ribose reduced survival when added to the pump supported (LV + RA bypass) group. Cysteine/ribose improved survival over the no treatment group. O2 consumption increased significantly in the groups with best survival but remained unchanged from control or shock levels when cysteine/ribose were added. Unusually high levels of CPK, acid and alkaline phosphatase, and MDF occurred in both groups receiving cysteine/ribose, indicating significant organ damage correlating with poor survival. Lactate levels were less predictive. Heart tissue ATP levels were higher in groups with good survival. Liver ATP levels were lower in high survival groups. Lung ATP did not differ between groups.

Acid Phosphatase↗

Streptozotocin-induced renal hemodynamic changes in isogenic Lewis rats: a kidney transplant study.

Streptozotocin (STZ)-induced diabetes mellitus is associated with decreased renal clearances of inulin and p-aminohippurate (PAH). The present experiments were designed to determine whether STZ-induced renal hemodynamic changes are due to the drug per se, rather than to the diabetic state that it induces. Isogenic Lewis rats with native right and transplanted left kidneys were studied. In one group, kidney donors received 50 mg STZ/kg body wt on day 1 and transplantation was performed on day 4 (untreated recipients). On day 29, the inulin and PAH clearances of these nondiabetic recipients were, respectively, 0.94 +/- 0.04 and 2.58 +/- 0.11 ml.min-1 x g-1 for the transplanted left kidney (previously exposed to STZ) and 0.95 +/- 0.07 and 2.54 +/- 0.14 ml.min-1 x g-1 for the native right kidney (never exposed to STZ). In another group, recipients received STZ on day 1 and transplantation was performed on day 4 (untreated donors). On day 29, the inulin and PAH clearances of these diabetic recipients were, respectively, 0.62 +/- 0.04 and 1.46 +/- 0.11 ml.min-1 x g-1 for the transplanted left kidney (never exposed to STZ) and 0.61 +/- 0.05 and 1.42 +/- 0.08 ml.min-1 x g-1 for the native right kidney (previously exposed to STZ). We conclude that the diabetic state, rather than STZ, is responsible for the decreased renal clearances of inulin and PAH in this experimental model.

Animals↗

2-(aminoalkyl)-5-nitropyrazolo[3,4,5-kl]acridines, a new class of anticancer agents.

2-(Aminoalkyl)-5-nitropyrazolo[3,4,5-kl]acridines were prepared from substituted anilines via the 1-chloro-4-nitroacridones followed by condensation with [(alkylamino)alkyl]hydrazines. Impressive activity was demonstrated for the 9-hydroxy, 9-alkoxy, and 9-acyloxy analogs in vitro on a L1210 leukemia line and in vivo against the P388 leukemia. Advanced studies led to the selection of 3bbb for clinical trial.

Acridines↗

Simple alternatives using a single centrifugal pump for biventricular assistance in cardiogenic shock.

The application of pumps and other mechanical and physiologic aids for improving circulation and heart recovery must be based on physiologic requirements. The needs of circulation and cardiac recovery are different and depend on competence of the right ventricle as well as the left ventricle and the pattern of cannulation and decompression. Our studies of various bypass techniques and drugs in a standardized severe cardiogenic shock model lead us to believe that biventricular decompression can be accomplished with a single centrifugal pump without an oxygenator. Cardiogenic shock and severe biventricular failure was best treated by LV + RA bypass, based on survival, hemodynamics and metabolism. LA + RA bypass was the next best. LA bypass, LV bypass, substrates (cysteine and ribose) and nitroprusside were intermediate. Circulatory support is not enough unless appropriate cardiac decompression ensures myocardial recovery.

Equipment Design↗

Contribution of brainstem edema to neurophysiologic deterioration in the cat infusion edema model.

These results show that infusion edema produces a significant increase in brainstem tissue water similar to the distribution seen after traumatic injury. The increased brainstem water of 0.24 cc is equivalent to a brainstem volume rise of 7.26% and was sufficient to cause a marked reduction in the PVI and sustained elevation of the ICP. Despite the ICP rise, somatosensory and brainstem potentials are only mildly affected and return to normal within 8 hr. The fact that severe fluid percussion injury results in obliteration of BAER immediately after impact would suggest that the neurologic deterioration seen in the fluid percussion model of injury is due to direct structural damage of the tissue, which was received at the moment of impact, and not to the compressive effect of the developing brainstem edema at levels achieved in these experiments (7.62% swelling). As in other mechanical models, edema results in secondary compression of the tissue and contributes to the general brain swelling, which if unabated could lead to tentorial herniation and death. In these infusion studies, we must conclude that in some cases, mild secondary compression was sufficient to affect other control centers and produce systemic failure at levels of edema that do not result in alteration of evoked potentials. This might explain the deaths of those animals that occurred during the infusion period in which brainstem potentials remained intact.

Animals↗