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PubMed2003

Favourable influence of low molecular weight heparin in mitigating the peroxidative membrane damage induced by a cytotoxic agent and an atherogenic diet.

The present study is aimed to demonstrate the protective effect of a heparin derivative, low molecular weight heparin (LMWH) against erythrocyte membrane injury. Two models serve to induce membrane lipid peroxidative damage, namely a potent cytotoxic agent, adriamycin and a hypercholesterolemic atherogenic diet. Two groups of male Wistar rats (140 +/- 10 g) received a single intravenous injection of adriamycin (ADR, 7.5 mg/kg), while two other groups were fed an atherogenic diet comprising a supplementation of 4% cholesterol, 1% cholic acid and 0.5% thiouracil (CCT diet) for 2 weeks. For each of the above two groups, LMWH (Troparin; 300 microg/day per rat subcutaneously) treatment commenced on day 8 and continued for a week. One group was maintained as the normal control group, and another group that received only LMWH treatment was designated as the LMWH drug control group. Erythrocyte membrane was isolated and assayed for its cholesterol levels, lipid peroxidation and ATPases activity. The activities of antioxidant enzymes were assessed in the haemolysate. The findings of the study were that both adriamycin and the atherogenic diet produced elevated membrane cholesterol levels and lipid peroxidation. The membrane ATPases suffered loss in activity. Accentuated oxidative stress was marked by rise in the activities of antioxidant enzymes (SOD, catalase and GPx). LMWH intervention reverted these changes thereby normalizing the membrane composition and function. The membrane protective effect of LMWH is illuminated by this work.

Animals↗
PubMed2003

Radiation-induced versus endogenous DNA damage: possible effect of inducible protective responses in mitigating endogenous damage.

Ionizing radiation (IR) causes damage to DNA that is apparently proportional to absorbed dose. The incidence of radiation-induced cancer in humans unequivocally rises with the value of absorbed doses above about 300 mGy, in a seemingly linear fashion. Extrapolation of this linear correlation down to zero-dose constitutes the linear-no-threshold (LNT) hypothesis of radiation-induced cancer incidence. The corresponding dose-risk correlation, however, is questionable at doses lower than 300 mGy. Non-radiation induced DNA damage and, in consequence, oncogenic transformation in non-irradiated cells arises from a variety of sources, mainly from weak endogenous carcinogens such as reactive oxygen species (ROS) as well as from micronutrient deficiencies and environmental toxins. In order to relate the low probability of radiation-induced cancer to the relatively high incidence of non-radiation carcinogenesis, especially at low-dose irradiation, the quantitative and qualitative differences between the DNA damages from non-radiation and radiation sources need to be addressed and put into context of physiological mechanisms of cellular protection. This paper summarizes a co-operative approach by the authors to answer the questions on the quantitative and qualitative DNA damages from non-radiation sources, largely endogenous ROS, and following exposure to low doses of IR. The analysis relies on published data and justified assumptions and considers the physiological capacity of mammalian cells to protect themselves constantly by preventing and repairing DNA damage. Furthermore, damaged cells are susceptible to removal by apoptosis or the immune system. The results suggest that the various forms of non-radiation DNA damage in tissues far outweigh corresponding DNA damage from low-dose radiation exposure at the level of, and well above, background radiation. These data are examined within the context of low-dose radiation induction of cellular signaling that may stimulate cellular protection systems over hours to weeks against accumulation of DNA damage. The particular focus is the hypothesis that these enhanced and persisting protective responses reduce the steady state level of non-radiation DNA damage, thereby reducing deleterious outcomes such as cancer and aging. The emerging model urgently needs rigorous experimental testing, since it suggests, importantly, that the LNT hypothesis is invalid for complex adaptive systems such as mammalian organisms.

Adaptation, Physiological↗
PubMed2004

Animal health organizations: roles to mitigate the impact of ecologic change on animal health in the tropics.

Production of livestock across North and South America is extensive. The opportunities for production, commerce, and thriving economies related to animal agriculture are balanced against the devastating threats of disease. Commitment by livestock and poultry producers in exporting countries to production methods, herd health management, and biosecurity in their operations must be coupled with an animal health and marketing infrastructure that allows the industries to thrive and offers assurances to trading partners that their livestock industries will not be jeopardized. National and international animal health organizations play a key role in providing this infrastructure to the industries that they serve. The incentive for the successful World agricultural production economies to provide direction and support for improving animal health and conveying principles for competitive and safe production to lesser developed nations is the assurance that the expanding economies of these nations offer an eager and hungry market for the products of the other industries of an export-dependent economy. The World Trade Organization (WTO) was established after the Uruguay Round of the General Agreement on Tariffs and Trade (GATT). The WTO provides the permanent international multilateral institutional framework for implementing dispute resolution agreements and the agreement on the application of sanitary and phytosanitary (SPS) measures. The SPS agreements allow for the protection of animal and plant health.

Animal Diseases↗
PubMed1991

Granulocyte-macrophage colony-stimulating factor mitigates the neutropenia of combined interferon alfa and zidovudine treatment of acquired immune deficiency syndrome-associated Kaposi's sarcoma.

The combined use of zidovudine (ZDV) and interferon (IFN) alfa-2a has been shown to have antiretroviral and antitumor potential benefit in the treatment of acquired immune deficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS). However, the clinical use of this combination is frequently complicated by the overlapping myelotoxicity of these agents. We report here the results of a phase I/II study in which granulocyte-macrophage colony-stimulating factor (GM-CSF) was used for those KS patients who became neutropenic while receiving ZDV (1,200 mg/d) and IFN (9 x 10(6) U/d). Nineteen of 29 patients (66%) developed an absolute neutrophil count (ANC) of less than 1,000 cells per cubic millimeter and were begun on GM-CSF. All experienced a prompt increase in the ANC. Those patients receiving GM-CSF/ZDV/IFN alfa-2a had an improved end of study ANC when compared with the ZDV/IFN alfa-2a group, but did not have an increased rate of tumor response, end of study CD4 cell count, or improvement in any other hematologic variable. The use of GM-CSF was not associated with increased toxicity and, in particular, was not associated with a change in serum human immunodeficiency virus (HIV) p24 antigen. Tumor response was noted in 50% of the assessable patients (33% overall) despite "high-risk" characteristics in 80%. Of the responding patients, seven were on GM-CSF and might have otherwise required an alteration in ZDV/IFN alfa-2a dose level. Further study of GM-CSF as an alternate to dose modification of this (ZDV/IFN alfa-2a) and other combination therapies for AIDS patients is warranted.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Prior exposure to high glucose augments depolarization-induced insulin release by mitigating the decline of ATP level in rat islets.

A brief exposure to elevated glucose augments the insulin secretory response of islets to subsequent stimulation. The site of this priming effect of glucose in the mechanism of the regulation of insulin secretion is not completely known, however. Insulin release triggered by a depolarizing concentration of K+ in the presence of basal glucose is markedly enhanced in primed rat islets. To clarify the role of priming on Ca(2+) and ATP efficacy in the exocytotic apparatus, islets were electrically permeabilized to vary the intracellular Ca(2+) and ATP concentrations according to the extracellular medium, and insulin release was evaluated. Ca(2+) and ATP efficacy in Ca(2+)- and ATP-dependent insulin secretion was not affected by priming, and alteration of the intracellular Ca(2+) concentration after depolarization cannot account for the phenomenon. There was no difference in ATP content before depolarization between nonprimed and primed islets. Moreover, the decline in ATP level after depolarization with basal glucose was observed in both primed and nonprimed islets. However, a reduced decline in ATP level in the early phase was observed in primed islets. In addition, oligomycin, a mitochondrial metabolism inhibitor, abolished the difference in ATP level between primed and nonprimed islets, suggesting that mitochondrial ATP production may be linked to the phenomenon.

Adenosine Triphosphate↗
PubMed2002

Megalencephaly in NF1: predominantly white matter contribution and mitigation by ADHD.

BACKGROUND: Megalencephaly is a frequent CNS manifestation in neurofibromatosis type 1 (NF1); however, its tissue composition, modification by attention deficit hyperactivity disorder (ADHD), and relationship with unidentified bright objects (UBO) remain controversial. METHODS: Eighteen male patients with NF1, seven of whom had ADHD (NF1+ADHD), were compared with 18 age- and sex-matched controls in terms of MRI-, Talairach-based brain, cerebral, lobar, and sublobar gray and white matter volumes. Twelve subjects with NF1 had UBO in the centrencephalic region, whereas six had no UBO or exclusively infratentorial lesions. RESULTS: Patients with NF1 without ADHD (NF1-pure) had the largest total cerebral, gray, and white matter volumes with larger parietal/somatosensory white matter volumes than controls, particularly if UBO were present in the basal ganglia. All subjects with NF1 (including NF1+ADHD) had larger total and frontal white matter volumes than controls. Smaller frontal/right prefrontal gray matter volumes were found in NF1+ADHD when compared with NF1-pure patients. CONCLUSIONS: The increase in frontal and parietal white matter volumes in male patients with NF1, including the preferential centrencephalic distribution, supports the hypothesis that NF1's white matter pathology encompasses but is not limited to visible UBO. Male patients with NF1+ADHD, as compared with NF1-pure patients, showed frontal reductions that are largely consistent with those found in idiopathic ADHD.

Adolescent↗
PubMed2001

Mechanical forces imposed on echinoid eggs during spawning: mitigation of forces by fibrous networks within egg extracellular layers.

Many echinoderms spawn large numbers of eggs in rapid spawning bouts directly into the water column. During spawning, the eggs pass from the gonad along a narrow oviduct and through a rigid gonopore before reaching the water. As the eggs traverse this pathway, they are exposed to shear stress induced by the development of a velocity gradient within the fluid formed by the eggs. In some species, the diameter of the eggs is larger than the diameter of the gonopore. In these cases, the eggs also experience strain resulting from compression of the egg as it passes through the relatively small gonopore. The magnitude of shear stress experienced by eggs differs among species depending upon the viscosity of the eggs. The degree of strain experienced by eggs differs among species depending upon the relative sizes of the egg and gonopore and also changes within species as they grow. Recent evidence suggests that these forces have the propensity to damage eggs, thereby reducing their fertilizability, or to destroy them. Experimental evidence shows that the jelly coat around the eggs can protect them from shear stresses and reduce the strain imposed on them under a compressive force. Echinoderm eggs are surrounded by a jelly coat that has a composite structure of irregularly arranged fibrous networks embedded in a jelly matrix. These fibrous networks have characteristics that are similar to those of engineered and biological materials that are known to reduce the transmission of mechanical forces to other structures. Given this similarity to other materials, three possible mechanisms for the action of the jelly coat may be identified. First, the apparent viscosity of the eggs of echinoids declines as the rate at which they are sheared during spawning increases. This reduction in viscosity with increasing shear rate (shear-thinning) may, in part, be due to the structure of the jelly coat and its resultant non-Newtonian nature. Second, experimental evidence indicates that the jelly coat preferentially deforms under a compressive load, reducing the transmission of that load to the egg. Third, the jelly (but not the fibers in the coating) may deform in a nearly viscous manner. In this case, the fibers may serve to provide an elastic 'backbone' to the layer and remain in place to stiffen the outer layer of the egg. The composite structure of the jelly coat and the morphology of the fibrous network are likely to be critical to all these mechanisms.

Animals↗
PubMed1976

Mitigation of caffeine-induced fetopathy in mice by pretreatment with beta-adrenergic blocking agents.

In a previous experiment, fetopathic effects of caffeine were significantly reduced by pretreatment with propranolol at dosage levels of 2.5 to 10 mg/kg. The present experiments were undertaeken to investigate the relation between time intervals of propranolol pretreatment and its effect on reducing fetopathy. Furthermore, the effect of timolol, another beta-adrenergic blocking agent, on reducing fetopathy was compared with that of propranolol. Propranolol (5 mg/kg) administered 15, 30 or 60 minutes before caffeine treatment significantly reduced the caffeine-induced fetopathy. The optimal effect was found when propranolol was given 30 minutes before caffine. The reduction in fetopathy by timolol pretreatment was comparable to that of propranolol. The results lend support to the hypothesis that the fetopathic effect of caffeine is linked with released catecholamines in material or fetal issues of mice.

Abnormalities, Drug-Induced↗
PubMed2005

Clamoring for quiet: new ways to mitigate noise.

New technologies are providing innovative ways to reduce sound levels in many areas. Aircraft engineers are finding ways to reduce the noise produced by jet engines, while road builders are using rubber-enhanced pavement to quiet highway noise. Indoor acoustics are benefiting from materials that transform sound waves to heat, and so-called active noise control reduces harmful sounds through production of a mirror-image sound field. And new lawn equipment makes weekends at home quieter for yard lovers and their neighbors.

Ear Protective Devices↗
PubMed2004

Weight gain mitigation with topiramate in mood disorders.

OBJECTIVE: To review the evidence of weight loss with use of topiramate in patients with mood disorders. DATA SOURCES: Literature search included MEDLINE (1966-December 2003), International Pharmaceutical Abstracts (1970-December 2003), and EMBASE (1980-December 2003). Search terms included topiramate, weight loss, adverse effect, mood disorders, bipolar disorder. DATA SYNTHESIS: Weight gain is a common adverse effect of many agents used to treat mood disorders. Topiramate has been evaluated in the management of some mood disorders, and weight loss may be a beneficial side effect in these patients. Case reports, letters to the editor, prospective investigations, and retrospective observational studies were reviewed to identify evidence of weight loss with topiramate use in patients with mood disorders. CONCLUSIONS: Current evidence suggests an association between topiramate and weight loss. Based on the limited data, controlled studies need to be conducted to define the role of topiramate in patients with mood disorders who would also benefit from weight reduction.

Anticonvulsants↗
PubMed1996

Cardiopulmonary support mitigates the effects of experimental myocardial ischemia.

The effectiveness of cardiopulmonary support (CPS) as a rescue method following failed angioplasty is unknown. The proximal left anterior descending (LAD) was occluded for 20 min in 21 dogs. Group 1 animals (n=15) were given CPS and group 2 animals (n=6) served as controls. During coronary occlusion, animals receiving CPS had increased mean arterial pressure (71+/- 12 vs 58+/-7 mm Hg), decreased left atrial pressure (3+/-3 vs 12+/-3 mm Hg), increased ischemic area blood flow (0.20+/-0.16 vs 0.02+/-0.04 mL/min/g) and myocardial oxygen consumption (0.014+/- 0.008 vs 0.003+/-0.006 mL O2/min/g), decreased remote area myocardial oxygen consumption (0.026+/-0.010 vs 0.091+/-0.047 mL O2/min/g), and an improved myocardial oxygen consumption index (0.60+/-0.33 vs 0.02+/-0.03) when compared with controls (p<0.05). During reperfusion (no CPS), group 1 animals had increased cardiac index (210+/-95 vs 117+/-46 mL/min/kg), renal blood flow (110+/-38% vs 53+/-45%), ischemic area blood flow (1.13+/-0.40 vs 0.58+/-0.27), and myocardial oxygen consumption (0.066+/-0.015 vs 0.032+/-0.018) when compared with controls (p<0.05). CPS improves oxidative metabolism in selective myocardial segments during coronary occlusion, promotes recovery of the postischemic myocardium, and results in improved peripheral circulation.

Angioplasty, Balloon, Coronary↗
PubMed2006

The life-saving properties of blood: mitigating cerebral insult after traumatic brain injury.

Transfusion of packed red blood cells in critically injured patients has been a lifesaving (although not completely benign) intervention for decades. The traumatically injured brain has been thought to be particularly susceptible to injury from anemia, due to the well-documented association of worsening mortality and functional outcome in the presence of hypotension and hypoxia, as well as the known vulnerability of many neuronal populations to ischemia. Red blood cell transfusion has been used in traumatic brain injury (TBI) to prevent cerebral ischemia by maximizing the oxygencarrying capacity of blood that is otherwise decreased by blood loss and dilution with crystalloid fluid replacement during resuscitation. Although many practitioners have commonly utilized hemoglobin (Hgb) or hematocrit thresholds for transfusion in these patients, the rationale for this practice has largely been centered on older studies in general critical care populations and animal evidence. Furthermore, in addition to an ideal " target " Hgb, many other questions remain about this clinical practice, such as the optimal duration of maintaining a specific Hgb level, and the ultimate effects of transfusion on neurological and functional outcome.

Anemia↗
PubMed2005

Ablation of the inflammatory enzyme myeloperoxidase mitigates features of Parkinson's disease in mice.

Parkinson's disease (PD) is characterized by a loss of ventral midbrain dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Inflammatory oxidants have emerged as key contributors to PD- and MPTP-related neurodegeneration. Here, we show that myeloperoxidase (MPO), a key oxidant-producing enzyme during inflammation, is upregulated in the ventral midbrain of human PD and MPTP mice. We also show that ventral midbrain dopaminergic neurons of mutant mice deficient in MPO are more resistant to MPTP-induced cytotoxicity than their wild-type littermates. Supporting the oxidative damaging role of MPO in this PD model are the demonstrations that MPO-specific biomarkers 3-chlorotyrosine and hypochlorous acid-modified proteins increase in the brains of MPTP-injected mice. This study demonstrates that MPO participates in the MPTP neurotoxic process and suggests that inhibitors of MPO may provide a protective benefit in PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2005

Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease.

Epidemiological studies suggest that individuals with greater education or more cognitively demanding occupations have diminished risk of developing dementia. We wanted to test whether this effect could be recapitulated in rodents using environmental enrichment, a paradigm well documented to attenuate behavioral deficits induced by various pathological insults. Here, we demonstrate that learning and memory deficits observed in a transgenic mouse model of Alzheimer's disease can be ameliorated by enrichment. Female transgenic mice overexpressing amyloid precursor protein and/or presenilin-1 and nontransgenic controls were placed into enriched or standard cages at 2 months of age and tested for cognitive behavior after 6 months of differential housing. Enrichment significantly improved performance of all genotypes in the radial water maze and in the classic and repeated-reversal versions of the Morris water maze. However, enrichment did not benefit all genotypes equally. Mice overproducing amyloid-beta (Abeta), particularly those with amyloid deposits, showed weaker memory for the platform location in the classic Morris water maze and learned new platform positions in the repeated-reversals task less quickly than their nontransgenic cagemates. Nonetheless, enrichment normalized the performance of Abeta-overproducing mice to the level of standard-housed nontransgenic mice. Moreover, this functional preservation occurred despite increased neuritic plaque burden in the hippocampus of double-transgenic animals and elevated steady-state Abeta levels, because both endogenous and transgene-derived Abeta are increased in enriched animals. These results demonstrate that the generation of Abeta in vivo and its impact on the function of the nervous system can be strongly modulated by environmental factors.

Age Factors↗
PubMed2005

Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease.

Hyperphosphatemia, calcitriol deficiency, and secondary hyperparathyroidism (SHPT) are common complications of chronic kidney disease (CKD). Fibroblast growth factor-23 (FGF-23) is a novel phosphaturic hormone that also inhibits renal 1alpha-hydroxylase activity and thus may be involved in the pathogenesis of SHPT. Several hypotheses were tested: that FGF-23 increases as renal function declines; is linearly associated with serum phosphate levels; is associated with increased phosphaturia independent of parathyroid hormone (PTH); and is associated with decreased calcitriol levels independent of renal function, hyperphosphatemia, and vitamin D stores. FGF-23, PTH, 25(OH)D3, calcitriol, calcium, phosphate, and urinary fractional excretion of phosphate (Fe(PO4)) were measured in 80 CKD patients. Multiple linear regression was used to test the hypotheses. FGF-23 and PTH were inversely associated with estimated GFR (eGFR), whereas calcitriol levels were linearly associated with eGFR. Hyperphosphatemia and hypocalcemia were present in only 12 and 6% of patients, respectively, all of whose eGFR was <30. Increased Fe(PO4) was associated with decreased eGFR, and both increased FGF-23 and PTH were independently associated with increased Fe(PO4). Increased FGF-23 and decreased 25(OH)D3 were independent predictors of decreased calcitriol, but the effects on calcitriol levels of renal function itself and hyperphosphatemia were completely extinguished by adjusting for FGF-23. It is concluded that FGF-23 levels increase early in CKD before the development of serum mineral abnormalities and are independently associated with serum phosphate, Fe(PO4), and calcitriol deficiency. Increased FGF-23 may contribute to maintaining normal serum phosphate levels in the face of advancing CKD but may worsen calcitriol deficiency and thus may be a central factor in the early pathogenesis of SHPT.

Adult↗