Biomedical subjects
A L Russell
Publications and source records attributed to A L Russell.
Above and beyond the call of duty.
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Testing methods for developmental neurotoxicity of environmental chemicals.
Human brain development is slow and delicate, involving many unique, though interrelated, cellular events. The fetus and child are often more susceptible to chemical toxins that alter the structure and/or function of the brain, although susceptibility varies for individual neurotoxicants. Early exposure to neurotoxins has been implicated in neurological diseases and mental retardation. Pesticide exposures pose a particular concern since many are designed to be neurotoxic to pests and can also affect humans. Acknowledging the potential for vulnerability of the developing brain, EPA recently began to "call in" data on developmental neurotoxicity (DNT) from manufacturers of pesticides already registered and considered to be neurotoxic-around 140 pesticides. Chemicals are to be tested following the DNT testing guideline (OPPTS 870.6300). This paper assesses whether tests performed according to this guideline can effectively identify developmental neurotoxicants. We found the testing guideline deficient in several respects, including: It is not always triggered appropriately within the current tiered system for testing; It does not expose developing animals during all critical periods of vulnerability; It does not assess effects that may become evident later in life; It does not include methodology for consideration of pharmacokinetic variables; Methodology for assessment of neurobehavioral, neuropathological, and morphometry is highly variable; Testing of neurochemical changes is limited and not always required. We propose modifications to the EPA testing guideline that would improve its adequacy for assessing and predicting risks to infants and children. This paper emphasizes that deficiencies in the testing methodology for developmental neurotoxicants represent a significant gap and increase the uncertainty in the establishment of safe levels of exposure to developing individuals.
Sulfated glycosaminoglycans and glucosamine may synergize in promoting synovial hyaluronic acid synthesis.
High-molecular-weight hyaluronic acid (HA) produced by the synovium may function physiologically to aid preservation of cartilage structure and prevent arthritic pain; both the size and concentration of HA in synovial fluid are diminished in osteoarthritis (OA). Glucosamine therapy for OA can be expected to increase synovial HA production by providing rate-limiting substrate. In addition, certain sulfated glycosaminoglycans and polysaccharides - including chondroitin sulfate (CS), dermatan sulfate, and pentosan polysulfate - stimulate synovial HA production, apparently owing to a hormone-like effect triggered by the binding of these polymers to membrane proteins of synovial cells. Surprisingly, a significant proportion of orally administered CS is absorbed as intact polymers - apparently by pinocytosis. These considerations may rationalize clinical studies concluding that oral CS provides slow-onset but durable pain relief and functional improvement in OA. The possibility that oral glucosamine and CS may interact in a complementary or synergistic fashion to improve synovial fluid HA content in OA should be assessed in clinical studies, and the potential of adjunctive CS administration to improve the clinical response achievable with optimal intakes of glucosamine should likewise be evaluated. In light of the fact that the synovium virtually functions as a 'placenta' for cartilage, focusing on synovium as the target for therapeutic intervention in OA may be a rational strategy.
Glucosamine for migraine prophylaxis?
Following a fortuitous observation that migraine headaches ceased in a patient receiving glucosamine therapy for osteoarthritis, a further ten patients with migraine or migraine-like vascular headaches, refractory to established preventive or abortive therapies, have been treated with daily oral glucosamine. After a lag of 4-6 weeks, a substantial reduction in headache frequency and/or intensity has been noted; in some cases, the benefit appears to be dose-dependent. Since glucosamine can be a rate-limiting precursor for mucopolysaccharide synthesis, it is germane to note previous reports that heparin and pentosan polysulfate may have migraine-preventive activity. There is reason to suspect that mast cells are central mediators of the neurogenic inflammation associated with migraine and cluster headaches. The heparin produced by mast cells may function to provide feedback down-regulation of mast cell activation, and exerts a range of other anti-inflammatory effects. We postulate that supplemental glucosamine can boost mast cell heparin synthesis - perhaps correcting a functional heparin deficiency - thereby preventing or ameliorating the neurogenic inflammation that mediates pain in vascular headache. Whether or not this idea has validity, a controlled study of glucosamine for migraine prophylaxis appears to be warranted.
DL-phenylalanine markedly potentiates opiate analgesia - an example of nutrient/pharmaceutical up-regulation of the endogenous analgesia system.
In the author's clinical experience, concurrent treatment with DL-phenylalanine (DLPA) often appears to potentiate pain relief and also ease depression in patients receiving opiates for chronic non-malignant pain. An analysis of this phenomenon suggests that it may be mediated, at least in part, by up-regulation of the 'endogenous analgesia system' (EAS), a neural pathway that projects caudally from medullary nuclei to the dorsal horn of the spinal column; when stimulated by chronic pain or therapeutic measures such as opiates or acupuncture, the EAS suppresses activation of second-order pain-receptive neurons in the dorsal horn, and thereby alleviates pain. Since serotonin and enkephalins are key neurotransmitters in the EAS, it is reasonable to predict that measures which promote serotonin activity (such as 5-hydroxytryptophan and serotonin-reuptake inhibitors) as well as enkephalin activity (such as D-phenylalanine, an enkephalinase inhibitor) should potentiate EAS-mediated analgesia - a view consistent with much previous medical research. Comprehensive support of the EAS with well-tolerated nutrients and pharmaceuticals may amplify the analgesic efficacy of chronic opiate therapy, while enabling dosage reductions that minimize opiate side-effects. Analogously, this approach may complement the efficacy of acupuncture and other analgesic measures that activate the EAS.
The genetics and evolution of the mariner transposable element in Drosophila simulans: worldwide distribution and experimental population dynamics.
We have studied both the frequency and biogeographical distribution of the transposable DNA element mariner in natural populations of Drosophila simulans and the short-term evolutionary characteristics of mariner in experimental populations. The mariner element has been identified in natural populations of D. simulans from Africa, Europe, the Middle East, Japan, Australia, several Pacific islands, North America, and South America. Only four lines out of 296 were devoid of active mariner elements, as measured by the presence of functional mariner transposase. A slight correlation was found between the latitudinal coordinate of the collection sites and the level of mariner activity in the populations; this correlation became highly significant in Australia where a cline in mariner activity was observed along the eastern coast of the continent. We also observed that wild-type laboratory strains kept for several years as small populations might lose mariner activity over time. Using experimental populations, we modeled what might happen when naturally occurring populations exhibiting high and low levels of mariner activity encounter one another. We found that active mariner elements either will tend to lose their activity over time and gradually become inactive or possibly will be lost from the population; in either case, this will lead to the pattern seen in this experiment of a significant loss of mariner activity over time.
Glycoaminoglycan (GAG) deficiency in protective barrier as an underlying, primary cause of ulcerative colitis, Crohn's disease interstitial cystitis and possibly Reiter's syndrome.
Ulcerative colitis, Crohn's disease and interstitial cystitis share many common features, the most important of which is a defect in the glycoaminoglycan (GAG) defensive barrier. This defect allows penetration of toxins causing localized inflammatory response, followed by fibrosis and distant pathological changes, together with a myriad of biochemical and immunological changes. The latter has caused confusion as to etiology of the aforementioned disorders. This hypothesis is somewhat supported by the fact that agents such as glucosamine and pentosan polysulphate (Elmiron) that replace the GAG layer, improve the conditions. The potential for extrapolation of this hypothesis to atherosclerosis and arthropathies exists. There is a great danger in modern medical research that if one misses the wood for the trees, one becomes hopelessly lost in the minutiae of research. At present, it is embarrassing that ulcerative colitis (UC), Crohn's (CR) and interstitial cystitis (IC) are the cause of a great deal of morbidity and occasionally mortality, yet after intensive research, the etiology and effective treatment eludes us. The research in the past has focused extensively on inflammatory response in the mucosal lining, and biochemical, infective and immunological changes in the serum. This has led to a vast array of research pathways that seem at the present time to be totally lost and, might I say, aimless in direction, as a cause for these conditions, that remain amongst the most imperically treated in modern medicine. Another possible syndrome in this class would be Reiter's, which has many features in common with the above. The basic tenet of a GAG deficiency hypothesis is that, as shown in Figure 1A, an intact GAG layer provides, firstly, a mechanical and electrostatic defence against penetration of infective agents, toxins, antigenic protein moieties, etc. and, secondly, the prevention of extravasation of body fluid components. A degraded GAG layer is the start of the disease cascade of the above group of illnesses.
Niacinamide therapy for osteoarthritis--does it inhibit nitric oxide synthase induction by interleukin 1 in chondrocytes?
Fifty years ago, Kaufman reported that high-dose niacinamide was beneficial in osteoarthritis (OA) and rheumatoid arthritis. A recent double-blind study confirms the efficacy of niacinamide in OA. It may be feasible to interpret this finding in the context of evidence that synovium-generated interleukin-1 (IL-1), by inducing nitric oxide (NO) synthase and thereby inhibiting chondrocyte synthesis of aggrecan and type II collagen, is crucial to the pathogenesis of OA. Niacinamide and other inhibitors of ADP-ribosylation have been shown to suppress cytokine-mediated induction of NO synthase in a number of types of cells; it is therefore reasonable to speculate that niacinamide will have a comparable effect in IL-1-exposed chondrocytes, blunting the anti-anabolic impact of IL-1. The chondroprotective antibiotic doxycycline may have a similar mechanism of action. Other nutrients reported to be useful in OA may likewise intervene in the activity or synthesis of IL-1. Supplemental glucosamine can be expected to stimulate synovial synthesis of hyaluronic acid; hyaluronic acid suppresses the anti-catabolic effect of IL-1 in chondrocyte cell cultures, and has documented therapeutic efficacy when injected intra-articularly. S-adenosylmethionine (SAM), another proven therapy for OA, upregulates the proteoglycan synthesis of chondrocytes, perhaps because it functions physiologically as a signal of sulfur availability. IL-1 is likely to decrease SAM levels in chondrocytes; supplemental SAM may compensate for this deficit. Adequate selenium nutrition may down-regulate cytokine signaling, and ample intakes of fish oil can be expected to decrease synovial IL-1 production; these nutrients should receive further evaluation in OA. These considerations suggest that non-toxic nutritional regimens, by intervening at multiple points in the signal transduction pathways that promote the synthesis and mediate the activity of IL-1, may provide a substantially superior alternative to NSAIDs (merely palliative and often dangerously toxic) in the treatment and perhaps prevention of OA.
Alternative therapies and alternative medicine.
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Comment on Egan and Krieger, PAIN, 69 (1997) 213-218.
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Glucosamine in osteoarthritis and gastrointestinal disorders: an exemplar of the need for a paradigm shift.
Glucosamine, after a latent period, is rapidly developing a position in the treatment of osteoarthritis, as well as a potential therapeutic place in wound healing and gastrointestinal disorders. Although recognized for a great many years, the association of gastrointestinal disorders and arthritis has been looked on as an unexplained oddity. Could this be indicative of a common etiology in the rate-limiting production of glucosamine? Could diverse presentations and pathology be due to a common-stem biochemical defect?
Comment on Stein and Yassouridis, PAIN, 71 (1997) 119-121.
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Sustained relief of oral aphthous ulcer pain from topical diclofenac in hyaluronan: a randomized, double-blind clinical trial.
OBJECTIVES: The purpose of this study was to test the hypothesis that topically applied 3% diclofenac in 2.5% hyaluronan reduces aphthous ulcer pain. STUDY DESIGN: A randomized, double-blind, single dose study of 60 healthy adults with aphthous ulcers in three treatment groups--3% diclofenac in 2.5% hyaluronan, 2.5% hyaluronan, 3% viscous lidocaine--was undertaken. Visual analogue scale pain scores were obtained before and after gel application and hourly, for up to 8 hours after gel application. Statistical analysis was performed with repeated measures ANOVA with square root transformation and Bonferroni correction. RESULTS: A 48% overall reduction in pain (p < 0.01) was observed 10 minutes after gel application; however, no significant difference was found between the three topical agents. A 35% to 52% pain reduction (p < 0.01) was reported 2 to 6 hours after the application of diclofenac in hyaluronan, whereas hyaluronan gel alone and viscous lidocaine failed to produce significant VAS reductions. CONCLUSIONS: A dose of 3% diclofenac in 2.5% hyaluronan is an effective and novel treatment for this common, painful disorder.
1H- and 13C-NMR characterization of the digalactosylmannopentaose liberated from legume seed galactomannan by beta-mannanase action.
Incubation of Locust bean gum with an Aspergillus niger beta-D-mannanase released a wide variety of galactomannan oligomers. A single heptasaccharide, digalactosylmannopentaose, was obtained from fractionation of the mixture by size exclusion chromatography. The purity and chemical composition of the sample was demonstrated using mass spectrometry, high performance anion-exchange chromatography and monosaccharide composition analysis. The primary structure of this heptasaccharide was unambiguously identified using 2D 1H and 13C homonuclear and heteronuclear NMR. A complete assignment of the 1H and 13C signals of this oligomer was achieved, producing an NMR dataset that will be of importance in the primary structure elucidation of larger and more complex galactomannan oligomers.
Prescribing NSAIDs for elderly people.
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Suppression of multi-drug resistance gene expression in the mouse liver by 1,4-bis[2,(3,5-dichloropyridyloxy)]benzene.
P-glycoproteins encoded by the (multi-drug resistance) mdr genes play a central role in the resistance of tumor cells to a wide range of anti-cancer drugs. Modulation of P-glycoprotein function could therefore provide a means of sensitising tumor cells to chemotherapy. Studies in this context have centred around the use of compounds which antagonise the P-glycoprotein membrane transport system. To investigate the possibility of modulating P-glycoprotein expression at a transcriptional level, we investigated the effects of hormonal factors and cytochrome P450-inducing agents on hepatic expression of murine mdr 1, mdr 2 and mdr 3. Hepatic mdr 2 and mdr 3 expressions were significantly suppressed in hypophysectomised animals, indicating that pituitary hormones activate the hepatic expression of these genes. Many of the foreign compounds and anti-cancer drugs tested did not significantly induce mdr 1, 2 or 3 expression. However, it was of particular interest that a potent cytochrome P450 inducer, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, almost completely suppressed hepatic mdr 2 and 3 expressions.
Mitochondrial RNA editing of cytochrome c oxidase subunit II (coxII) in the primitive vascular plant Psilotum nudum.
A 634-nucleotide tract, including primers, was amplified via the polymerase chain reaction within a mitochondrial coxII gene of the primitive vascular plant Psilotum nudum and sequenced. Alignment with homologous coxII gene sequences from diverse plant species having known RNA editing sites which restore amino acid sequence consensus was used to infer eight sites of C-to-U transitions in Psilotum. In every case, the predicted editing event would confer the selective advantage of conserving the amino acid residue at a site where amino acid sequence divergence has not been observed in other plant species. The plant mitochondrial editing machinery is shown for the first time to extend to one of the deepest branches of vascular plant phylogeny.