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Biomedical subjects

A Campbell

Publications and source records attributed to A Campbell.

At least 37 records · Page 2Linked to original sources
PubMed2002

Aluminum as a toxicant.

Although aluminum is the most abundant metal in nature, it has no known biological function. However, it is known that there is a causal role for aluminum in dialysis encephalopathy, microcytic anemia, and osteomalacia. Aluminum has also been proposed to play a role in the pathogenesis of Alzheimer's disease (AD) even though this issue is controversial. The exact mechanism of aluminum toxicity is not known but accumulating evidence suggests that the metal can potentiate oxidative and inflammatory events, eventually leading to tissue damage. This review encompasses the general toxicology of aluminum with emphasis on the potential mechanisms by which it may accelerate the progression of chronic age-related neurodegenerative disorders.

Aluminum↗
PubMed2001

Modulation of oxidative events by multivalent manganese complexes in brain tissue.

Manganese toxicity can evoke neuropsychiatric and neuromotor symptoms, which have frequently been attributed to profound oxidative stress in the dopaminergic system. However, the characterization of manganese as a pro-oxidant remains controversial because antioxidant properties also have been associated with this metal. The current study was designed to address these disparate findings concerning the oxidative properties of manganese. The apparent ability of manganese in its divalent form to promote formation of reactive oxygen species (ROS) within a cortical mitochondrial-synaptosomal (P2) fraction was completely abolished by the addition of one five hundredth of its molarity of desferroxamine (DFO), a trivalent metal chelator. This large ratio and the high specificity of DFO for trivalent metal ions discounted the possibility of inhibition of ROS generation by direct sequestration of divalent manganese, and implied the trace presence of a trivalent metal. Further analysis suggested that this trace metal was manganic rather than ferric ion. Ferric ion was able to dampen the reactive oxygen species-generating capacity of manganous chloride, whereas manganic ion markedly promoted this property attributed to manganous ion. Such findings of the potent effects of trace amounts of trivalent cations upon Mn2+-related free radical generation offer resolution of earlier disparate findings concerning the oxidative character of manganese.

Animals↗
PubMed2001

Mechanisms by which metals promote events connected to neurodegenerative diseases.

Although the exact causative phenomenon responsible for the onset and progression of neurodegenerative disorders is at present unresolved, there are some clues as to the mechanisms underlying these chronic diseases. This review addresses mechanisms by which endogenous or environmental factors, through interaction with redox active metals, may initiate a common cascade of events terminating in neurodegeneration.

Aging↗
PubMed2001

The bacteriophage lambda attachment site in wild strains of Escherichia coli.

The attachment site (attlambda) of bacteriophage lambda was examined in wild strains of Escherichia coli. Although the att region is non-coding, the DNA sequence was invariant in the 13 strains examined. Two other non-coding regions showed nine changes, all associated with a single strain. In four of 33 strains, sequences were inserted in or near the attlambda site and in two of these the insert was related to lambda. Among strains that can be lysogenized by lambda, integration was via the attlambda site in all cases. Some resistant strains can be lysogenized, and these have been termed "lenient." Most of these fail to give normal phage yield after induction. In some cases rare lysogens have been formed in cells that belong to a mutant subpopulation.

Bacteriophage lambda↗
PubMed2001

Differential toxicity of aluminum salts in human cell lines of neural origin: implications for neurodegeneration.

Aluminum is highly oxophilic and its minerals are usually found surrounded by six oxygen atoms. A role for the metal has been established in dialysis encephalopathy and Al-induced osteomalacia. The metal has been implicated in Alzheimer's disease but the issue is at present controversial. Human cell lines of neural origin were utilized to study the effect of lipophilic aluminum acetylacetonate and non-lipophilic aluminum sulfate on cell proliferation and viability. Although analysis of Al species in the cell culture media demonstrated that there are positively charged Al species present in solutions prepared with both Al salts, only the aluminum acetylacetonate salt caused changes in cell proliferation and viability. Therefore, the lipophilic nature of the organic Al salt is a critical determinant of toxicity. The effect of aluminum acetylacetonate was dose-dependent and time-dependent. Neuroblastoma (SK-N-SH) cells were more susceptible to decreased cell proliferation although the lipophilic Al salt was more toxic to the glioblastoma (T98G) cells. While the toxicity of aluminum acetylacetonate was inhibited in the T98G cells by the addition of phosphate, the same treatment did not reverse cell death in the SK-N-SH cells. Thus, the mechanism of Al toxicity appears to be different in the two cell lines. It is possible that the principal neurotoxic target of the metal is glial and when these cells are in a compromised state, this may secondarily impact the neuronal population and thus eventually lead to neurodegeneration.

Aluminum Compounds↗
PubMed2001

Fatty acid derivatives of clozapine: prolonged antidopaminergic activity of docosahexaenoylclozapine in the rat.

Stable amides of clozapine derived from fatty acids prominent in cerebral tissue might enhance the central activity of clozapine and reduce its exposure to peripheral tissues. Such derivatives might enhance the safety of this unique drug, which is the only agent with securely established superior antipsychotic effectiveness, but with a risk of potentially lethal systemic toxicity. Amide derivatives of clozapine were prepared from structurally varied fatty acid chlorides and evaluated for ability to inhibit behavioral arousal in rat induced by dopamine agonist apomorphine and to induce catalepsy. Their duration-of-action and potency were compared to free clozapine, and concentrations of clozapine were assayed in brain and blood. Selected agents were also evaluated for affinity at dopamine receptors and other potential drug-target sites. Clozapine-N-amides of linoleic, myristic, oleic, and palmitic acids had moderate initial central depressant activity but by 6 h, failed to inhibit arousal induced by apomorphine. However, the docosahexaenoic acid (DHA) derivative was orally bioavailable, 10-times more potent (ED(50) 5.0 micromol/kg) than clozapine itself, and very long-acting (>/= 24 h) against apomorphine, and did not induce catalepsy. DHA itself was inactive behaviorally. Clozapine showed expected dopamine receptor affinities, but DHA-clozapine was inactive at these and other potential target sites. After systemic administration of DHA-clozapine, serum levels of free clozapine were very low, and brain concentrations somewhat lower than after administering clozapine. DHA-clozapine is a long-acting central depressant with powerful and prolonged antidopaminergic activity after oral administration or injection without inducing catalepsy, and it markedly reduced peripheral exposure to free clozapine. It lacked the receptor-affinities shown by clozapine, suggesting that DHA-clozapine may be a precursor of free, pharmacologically active clozapine. Such agents may represent potential antipsychotic drugs with improved central/peripheral distribution, and possibly enhanced safety.

Amides↗
PubMed2001

Use of recombinant FSH and recombinant LH in multiple follicular stimulation for IVF: a preliminary study.

Twelve patients (17 cycles) who needed >3000 IU of recombinant FSH (rFSH) on previous follicular stimulation attempts for IVF using rFSH (group A) underwent further attempts (a total of 12 cycles) using rFSH supplemented with rLH from day 7 of stimulation (group B). There was no significant difference in the total quantitative administration of rFSH (mean: 4759 versus 4800 IU rFSH), days of stimulation (14.0 versus 12.6), number of M2 oocytes per patient (3.76 versus 4.17) or embryo morphology between group A and group B respectively. However, there was a significant increase in the incidence of fertilization (60.9 versus 86.0%; P = 0.006) and clinical (ongoing) pregnancies (1 versus 6; P = 0.022). The higher incidence of fertilization increased the mean number of embryos transferred per patient, although in this small group the data was not significant (1.75 versus 2.71). This preliminary clinical trial suggests that in poor responders superimposing rLH upon a down-regulated cycle stimulated with rFSH improves relevant outcome data; and this preliminary trial has encouraged the need for a larger and more detailed study.

Journal Article↗
PubMed2001

Mathematical modeling of Clostridium difficile infection.

Clostridium difficile diarrhea is a major cause of morbidity and mortality in hospitals. However, the number of cases in an outbreak is usually relatively small. This precludes many traditional statistical methods of modeling epidemics. Stochastic models are designed to deal with small numbers and are promising methods of understanding C. difficile epidemiology. This is illustrated by a reversible jump Markov chain Monte Carlo model based on the herd immunity hypothesis of C. difficile outbreaks.

Clostridioides difficile↗
PubMed2001

beta-amyloid: friend or foe.

The function of the amyloid precursor protein (APP) and its product, beta-amyloid, (Abeta) is at present unknown. The deposition of Abeta in senile plaques as well as meningeal and cerebral vessels has led many researchers to discount the possibility of a beneficial protective function for the protein. Thus it is generally believed that the aberrant processing of APP leads to increased beta-amyloid secretion that in turn leads to subsequent plaque formation and Alzheimer's disease. Here, a hypothesis is presented that the protein may indeed be protective and that a potential role for beta amyloid in innate immunity may exist.

Aging↗
PubMed2001

Reduced basal levels and enhanced LPS response of IL-6 mRNA in aged mice.

Senescence is a complex and multifactorial process that may predispose organisms to altered responses to environmental stressors. The cytokine interleukin-6 (IL-6) is expressed by a variety of cells and is one of the earliest mediators of the acute inflammatory response. In this study, the level of IL-6 mRNA in younger (7 months) and old (23 months) mice was determined in the tissue of several organs with or without stimulation with lipopolysaccharide (LPS). Whereas younger animals had a basal expression of IL-6 mRNA in all organs, this was undetectable in the old animals. In contrast, when the mice were injected with LPS, in a majority of the organ tissues there was a robust stimulation of IL-6 mRNA in the old mice whereas the younger animals had a more variable response. These data indicate that the aging process may predispose animals to an exaggerated and potentially harmful inflammatory response.

Aging↗
PubMed2001

Characterizations of highly expressed genes of four fast-growing bacteria.

Predicted highly expressed (PHX) genes are characterized for the completely sequenced genomes of the four fast-growing bacteria Escherichia coli, Haemophilus influenzae, Vibrio cholerae, and Bacillus subtilis. Our approach to ascertaining gene expression levels relates to codon usage differences among certain gene classes: the collection of all genes (average gene), the ensemble of ribosomal protein genes, major translation/transcription processing factors, and genes for polypeptides of chaperone/degradation complexes. A gene is predicted highly expressed (PHX) if its codon frequencies are close to those of the ribosomal proteins, major translation/transcription processing factor, and chaperone/degradation standards but strongly deviant from the average gene codon frequencies. PHX genes identified by their codon usage frequencies among prokaryotic genomes commonly include those for ribosomal proteins, major transcription/translation processing factors (several occurring in multiple copies), and major chaperone/degradation proteins. Also PHX genes generally include those encoding enzymes of essential energy metabolism pathways of glycolysis, pyruvate oxidation, and respiration (aerobic and anaerobic), genes of fatty acid biosynthesis, and the principal genes of amino acid and nucleotide biosyntheses. Gene classes generally not PHX include most repair protein genes, virtually all vitamin biosynthesis genes, genes of two-component sensor systems, most regulatory genes, and most genes expressed in stationary phase or during starvation. Members of the set of PHX aminoacyl-tRNA synthetase genes contrast sharply between genomes. There are also subtle differences among the PHX energy metabolism genes between E. coli and B. subtilis, particularly with respect to genes of the tricarboxylic acid cycle. The good agreement of PHX genes of E. coli and B. subtilis with high protein abundances, as assessed by two-dimensional gel determination, is verified. Relationships of PHX genes with stoichiometry, multifunctionality, and operon structures are also examined. The spatial distribution of PHX genes within each genome reveals clusters and significantly long regions without PHX genes.

Amino Acyl-tRNA Synthetases↗
PubMed2001

Evaluation and survey of intravenous vitamin K1 for treatment of coagulopathy in critically ill patients.

STUDY OBJECTIVES: To determine patient factors associated with coagulopathy, to assess variables affecting response to vitamin K1, to describe vitamin K1-associated adverse reactions, and to survey Canadian tertiary care hospitals about vitamin K1 practice patterns in their intensive care units (ICUs). DESIGN: Retrospective chart audit and prospective survey. SETTING: Medical-surgical ICU with a 23-bed complement in a tertiary care, university-affiliated hospital, and 47 Canadian tertiary care hospitals. PATIENTS: Forty-eight critically ill patients with nonconsumptive coagulopathies. INTERVENTION: Intravenous vitamin K1 utilization over 4 months. MEASUREMENTS AND MAIN RESULTS: The only independent risk factor for elevated baseline international normalized ratios (INRs) was Acute Physiologic and Chronic Health Evaluation (APACHE) II score (r2 = 0.51, p<0.05). The INR values decreased after two doses of vitamin K1 10 mg for patients grouped as a whole (2.14 +/- 0.96 to 1.61 +/- 0.62, p<0.0001) and when patients were stratified according to APACHE II scores below 23 (1.83 +/- 0.44 to 1.34 +/- 0.18, p<0.05). The INRs were not significantly reduced for patients with APACHE II scores of 23 or greater (2.44 +/- 1.23 to 1.82 +/- 0.66). No variables were associated with response, and adverse events were not observed. Of 47 Canadian tertiary care hospitals surveyed, 27 (55%) responded. Twenty-four (89%) indicated that vitamin K1 was administered intravenously, and no adverse events resembling anaphylaxis were reported. CONCLUSION: Administration of two doses of intravenous vitamin K1 10 mg was associated with reversal of coagulopathies, but variable responses may be expected for patients with high APACHE II scores. Randomized, placebo-controlled studies are necessary to confirm the effectiveness of vitamin K1.

APACHE↗
PubMed2001

The chemistry of transition metals in relation to their potential role in neurodegenerative processes.

Cells rely on several transition metals to regulate a wide range of metabolic and signaling functions. The diversity and efficiency of their physiological functions are derived from atomic properties that are specific to transition metals, most notably an incomplete inner valence subshell. These properties impart upon these elements the ability to fluctuate among a variety of positively charged ionic forms, and a chemical flexibility that allows them to impose conformational changes upon the proteins to which they bind. By this means, transition metals can serve as the catalytic centers of enzymes for redox reactions including molecular oxygen and endogenous peroxides. This review addresses the consequences of the aberrant translocation of the redox-capable essential transition elements, iron, copper, and manganese, upon the brain with an emphasis on uncontrolled and deleterious oxidative events. The potential of metal-protein interactions in facilitating such events, and their association with the physiologically redox-inert metals zinc and aluminum, are related to their postulated contribution to the pathology of neurodegeneration.

Animals↗
PubMed2001

Informing river management policies and programs with science.

Conventional wisdom has it that we already have enough science to address the problems causing degradation of our environment, including rivers. This is not true. However it is the case that we could be using existing knowledge better, and that we could be doing more to learn the lessons from the huge sums being spent on river restoration and management. Informing good policy and practical on-ground management with R&D outputs has proven to be is difficult, but essential. This paper reviews some of the history of water and river management in Australia and how perceptions of rivers have evolved. It discusses the challenge of enhancing the linkages between science, policy and practice in river management. It outlines the knowledge exchange, R&D and capacity building strategies of the National Rivers Consortium--a new initiative whose founding partners are LWRRDC, the MDBC, CSIRO Land and Water and the Western Australian Waters and Rivers Commission. This strategic collaboration between policy makers, river managers and scientists brings together organisations with responsibility and expertise to improve the health and management of Australian rivers. The National Rivers Consortium is making a major investment in knowledge exchange and capacity building, based on direct personal contact and learning by doing. The Consortium is establishing a program of training activities targeting river managers and policy makers, based on the best available science and high quality information products. It will support river managers as they plan and implement river restoration and protection projects. The paper concludes with a discussion of the key knowledge gaps that remain impediments to the better management of Australia's unique and diverse river landscapes.

Australia↗
PubMed2001

The legal status of clinical and ethics policies, codes, and guidelines in medical practice and research.

This article examines the legal status of "soft law" in the fields of medicine and medical research. Many areas of clinical practice and research involve complex and rapidly changing issues for which the law provides no guidance. Instead, guidance for physicians and researchers comes from what has often been called "soft law"--non-legislative, non-regulatory sources, such as ethics policy statements, codes, and guidelines from professional or quasi-governmental bodies. This article traces the evolution of these "soft law" instruments: how they are created, how they are adopted within the professional community, and how they become accepted by the courts. It studies the relationship between soft law instruments and the courts. It includes an examination of the approaches to judicial analysis used by the courts in theory and in practice. The authors then examine the jurisprudence to see how courts will adopt professional norms as the legal standard of care in some circumstances and not others. They consider the legal concerns and ethical issues surrounding the weight attached to professional practices and norms in law. The authors demonstrate how practices and policies that guide professional conduct may ultimately bear weight as norms recognizable and enforceable within the legal sphere.

Bioethical Issues↗