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At least 595 records · Page 33Linked to original sources
PubMed2006

Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-alpha.

Activated microglia are implicated in the pathogenesis of disease-, trauma- and toxicant-induced damage to the CNS, and strategies to modulate microglial activation are gaining impetus. A novel action of the tetracycline derivative minocycline is the ability to inhibit inflammation and free radical formation, factors that influence microglial activation. Minocycline is therefore being tested as a neuroprotective agent to alleviate CNS damage, although findings so far have yielded mixed results. Here, we showed that administration of a single low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine (METH), a paradigm that causes selective degeneration of striatal dopaminergic nerve terminals without affecting the cell body in substantia nigra, increased the expression of mRNAs encoding microglia-associated factors F4/80, interleukin (IL)-1alpha, IL-6, monocyte chemoattractant protein-1 (MCP-1, CCL2) and tumor necrosis factor (TNF)-alpha. Minocycline treatment attenuated MPTP- or METH-mediated microglial activation, but failed to afford neuroprotection. Lack of neuroprotection was shown to be due to the inability of minocycline to abolish the induction of TNF-alpha and its receptors, thereby failing to modulate TNF signaling. Thus, TNF-alpha appeared to be an obligatory component of dopaminergic neurotoxicity. To address this possibility, we examined the effects of MPTP or METH in mice lacking genes encoding IL-6, CCL2 or TNF receptor (TNFR)1/2. Deficiency of either IL-6 or CCL2 did not alter MPTP neurotoxicity. However, deficiency of both TNFRs protected against the dopaminergic neurotoxicity of MPTP. Taken together, our findings suggest that attenuation of microglial activation is insufficient to modulate neurotoxicity as transient activation of microglia may suffice to initiate neurodegeneration. These findings support the hypothesis that TNF-alpha may play a role in the selective vulnerability of the nigrostriatal pathway associated with dopaminergic neurotoxicity and perhaps Parkinson's disease.

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

Melatonin mitigates mitochondrial malfunction.

Melatonin, or N-acetyl-5-methoxytryptamine, is a compound derived from tryptophan that is found in all organisms from unicells to vertebrates. This indoleamine may act as a protective agent in disease conditions such as Parkinson's, Alzheimer's, aging, sepsis and other disorders including ischemia/reperfusion. In addition, melatonin has been proposed as a drug for the treatment of cancer. These disorders have in common a dysfunction of the apoptotic program. Thus, while defects which reduce apoptotic processes can exaggerate cancer, neurodegenerative disorders and ischemic conditions are made worse by enhanced apoptosis. The mechanism by which melatonin controls cell death is not entirely known. Recently, mitochondria, which are implicated in the intrinsic pathway of apoptosis, have been identified as a target for melatonin actions. It is known that melatonin scavenges oxygen and nitrogen-based reactants generated in mitochondria. This limits the loss of the intramitochondrial glutathione and lowers mitochondrial protein damage, improving electron transport chain (ETC) activity and reducing mtDNA damage. Melatonin also increases the activity of the complex I and complex IV of the ETC, thereby improving mitochondrial respiration and increasing ATP synthesis under normal and stressful conditions. These effects reflect the ability of melatonin to reduce the harmful reduction in the mitochondrial membrane potential that may trigger mitochondrial transition pore (MTP) opening and the apoptotic cascade. In addition, a reported direct action of melatonin in the control of currents through the MTP opens a new perspective in the understanding of the regulation of apoptotic cell death by the indoleamine.

Animals↗
PubMed2006

Preservation of bile ductules mitigates bile duct loss.

The finer branches of the biliary tree (FBBT) contain a regenerative compartment. We hypothesized that preservation of the FBBT together with its microvasculature will lead to recovery of biliary damage and prolonged preservation of bile ductules during the development of chronic liver allograft rejection. The interlobular bile ducts, portal bile ductules and extraportal biliary cells with and without microvessels were studied in sequential biopsies in five patients who fulfilled the Banff criteria of early chronic rejection (CR) (imminence group). Biopsies of CR patients (n = 12) served as controls. Biopsies were double immunostained with CD34 (microvessels) and cytokeratin 7 (biliary structures). Proliferation and proangiogenic activity were assessed with Ki67 and VEGF-A immunostaining. Severe damage of bile ducts in the imminence group did not progress to significant bile duct loss. This was associated with a high proliferative activity in all biliary structures and preservation of the microvascular compartment. VEGF-A expression was increased in all but the reperfusion biopsies. In conclusion, both regenerative activity of the FBBT and an intact microvascular compartment are associated with less damage of the biliary tree and could therefore be prerequisites for biliary regeneration.

Adolescent↗
PubMed1979

Breast milk thyroxine and not cow's milk may mitigate and delay the clinical picture of neonatal hypothyroidism.

Thyroxine concentration was measured in human milk and Cow's milk products by a specific radioimmunoassay. The mean (+/- S.E.M.) milk T4 concentration during the first 5 days postpartum was 0.7 +/- 0.3 microgram/dl (n = 11). The mean T4 concentration between 6-49 days postpartum rose to 3.1 +/- 0.2 microgram/dl (n = 108), falling after 50 days to a mean of 1.4 +/- 0.2 microgram/dl (n = 39). The mean (+/- S.E.M.) T3 concentration in breast milk in the first 50 days postpartum was 386 +/- 17 ng/dl (n = 56). T4 concentration in cow's milk products was less than 0.3 microgram/dl. Thyroxine concentration in 24 hours breast milk collection ranged from 0.7 to 7.7 microgram/dl and the total T4 in this milk ranged from 0.7 to 28 microgram/day. These data suggest that milk of human but not bovine origin may provide a significant exogenous source of T4 to the premature infant. This amount of exogenous T4 which is insufficient in preventing the proceeding of neonatal hypothyroidism, may delay the clinical recognition of this disorder. This once again emphasized the importance of early screening for neonatal hypothyroidism.

Animals↗
PubMed2006

The L-type calcium channel blocker nimodipine mitigates cytoskeletal proteins phosphorylation in dichlorvos-induced delayed neurotoxicity in rats.

The present investigation was carried out to assess the protective efficacy of nimodipine against dichlorvos-induced organophosphate induced delayed neurotoxicity (OPIDN). Single subcutaneous dose of dichlorvos (200 mg/kg body weight) led to a consistent increase in the activity of both microtubule associated protein kinases viz. Ca2+/Calmodulin-dependent and cAMP dependent protein kinases, at all post exposure intervals (day 7, 15 and 21) as compared to that of controls. Autoradiography followed by microdensitometric studies demonstrated enhanced phosphorylation of 55 kDa and 280 kDa proteins in dichlorvos-exposed animals. These two proteins were confirmed to be tubulin and microtubule associated protein-2 (MAP-2) by western blotting. The hyperphosphorylation of these two proteins was shown to interfere with the assembly of neuronal microtubules as shown by electron microscopic studies that may eventually lead to possible disruption of neuronal cytoarchtecture resulting in axonal degeneration. Administration of nimodipine along with dichlorvos brought about a significant reduction in the activities of both the kinases as well as the extent of microtubule associated protein phosphorylation. This indicates that nimodipine, a centrally acting calcium channel blocker, may contribute to the amelioration of dichlorvos induced neurotoxicity by attenuation of calcium mediated disruption of cytoskeletal proteins and hence, calcium channel blockers like nimodipine have great future as new therapeutic agents for OPIDN.

Animals↗
PubMed2000

The role of critical access hospital status in mitigating the effects of new prospective payment systems under Medicare.

This article examines rural hospitals that potentially qualify as critical access hospitals (CAH) and identifies facilities at substantial financial risk as a result of Medicare's expansion of prospective payment systems (PPS) to nonacute settings. Using Health Care Financing Administration (HCFA) cost reports from the federal year ending Sept. 30, 1996, combined with county-level sociodemographic data from the Area Resource File (ARF), characteristics of potential CAHs were identified and their finances analyzed to determine whether they could benefit from the cost-based reimbursement rules applicable to CAH status. Rural hospitals were identified as potential CAHs if they met a combination of federal and state criteria for necessary providers. Rural facilities were classified as "at risk" if they had poor financial ratios in conjunction with high levels of dependence on outpatient, home-care or skilled nursing services. Almost 30 percent of all rural hospitals were identified as potential CAHs. Ninety percent of potential CAH facilities were identified as "at risk" by at least one of five possible risk criteria, and one-third were identified by at least three. Of those classified "at risk," 48 percent might not benefit from conversion to CAH because their inpatient Medicare reimbursement would likely be less under CAH payment rules than under their current PPS payment rules. Many potential CAHs were doing well under inpatient PPS because they were sole community hospitals (SCH) and were therefore eligible for special adjustments to the PPS rates. The Rural Hospital Flexibility Act would be more beneficial to the population of isolated rural hospitals if those eligible for both CAH and SCH status were given the option of retaining their SCH inpatient payment arrangements while still qualifying for outpatient cost-based reimbursement.

Costs and Cost Analysis↗
PubMed2000

Mitigation of bioterrorist threats in the 21st century.

There is a raising level of awareness and concern that agriculture and food supplies might serve as targets for bioterrorists. To minimize such threats a number of new initiates are urgently needed: 1. Greater levels of financial commitment from federal, state, and international organizations for research on highly infectious diseases and for emergency response infrastructure; 2. Wellorchestrated emergency response plans based on inter-agency, inter-departmental and stakeholder working groups; 3. Teams prepared for risk assessment and risk communication; 4. Modern systems of animal identification and accurate trace-back for animal movement; 5. Increased biosecurity in intensive production operations; 6. Accurate intelligence as to what pathogens pose the highest risks for economic and social impact; 7. Establishment of new international animal and plant disease research networks and partnerships; 8. Strengthen international disease surveillance networks for early detection and intervention; 9. New generations of rapid diagnostic tests for pathogen detection that are practical for field and diagnostic laboratories; 10. Increased level of commitment to pathogen genomics research for molecular epidemiology and vaccine development; 11. New chemical and immunological intervention strategies to prevent or control disease outbreaks; 12. Increased level of training on exotic and emerging animal diseases in basic veterinary education and through continuing education for veterinarians, state and federal field personnel and laboratory diagnosticians.

Agriculture↗
PubMed1992

The mitigating effects of phosphatidylcholines on bile salt- and lysophosphatidylcholine-induced membrane damage.

The effects, at pH 7.0, of a series of 0.2 mM phosphatidylcholines (PC), namely dicaproyl-PC (DCPC), didecanoyl-PC (DDPC), dilauroyl-PC (DLaPC), dimyristoyl-PC (DMPC), dipalmitoyl-PC (DPPC), dioleoyl-PC (DOPC) and dilinoleoyl-PC (DLPC) and a series of 0.2 mM fatty acid salts (namely sodium myristate, palmitate, stearate, oleate and linoleate) upon the erythrocyte haemolysis induced by 2 mM sodium taurodeoxycholate (STDC) were determined. The influence of egg PC and dihexadecyl phosphate (DHDP) concentration upon the haemolysis induced by 1.4 mM sodium deoxycholate (SDC), 2 mM STDC and 0.1 mM lysophosphatidylcholine (LPC) were also established. A bile salt:egg PC mole ratio of 0.5 virtually abolished the haemolysis induced by SDC and STDC, whereas the same ratio of LPC:egg PC only reduced haemolysis from 65 to 40% (maximum haemolysis). DHDP had no effect on the haemolytic action of SDC or STDC. The salts of the fatty acids were non-haemolytic, and when mixed with STDC did not affect the level of haemolysis induced by the bile salt. In contrast, DDPC and DLaPC enhanced the haemolysis of STDC and DCPC had no effect, whereas DMPC, DPPC, DSPC, DOPC, DLPC and egg PC all reduced haemolysis. Maximum reduction was determined for DMPC and egg PC. The mixed micelle preparation temperature (either room or 60 degrees C) and temperature of incubation (either 20 degrees C for 30 min or 37 degrees C for 5 min) had only minor effects on the net haemolysis induced by STDC. These findings may be of significance in understanding the aetiology of certain gastrointestinal diseases and in determining whether mixed bile salt micelles have a role as drug penetration enhancers.

Bile Acids and Salts↗
PubMed2002

Mitigating the tithonus error: genetic analysis of mortality phenotypes.

Summarizing an organism's age at death in terms of the mean or maximum life-span is the most popular way to describe genetic effects on aging. In this Perspective, the author describes a new study with the fly Drosophila melanogaster, in which another type of measure is also used: the age-dependent risk of death, or age-specific mortality. Changes in age-specific mortality reflect the underlying physiological deterioration of an organism as it ages. Thus, the author argues that these changes provide a phenotype that is ideal for the genetic analysis of aging.

Aging↗