In vivo upregulation of endogenous NGF in the rat brain by the alpha2-adrenoreceptor antagonist dexefaroxan: potential role in the protection of the basalocortical cholinergic system during neurodegeneration.

We have previously reported that the alpha2-adrenoceptor antagonist dexefaroxan protects against the degeneration of nucleus basalis magnocellularis (NbM) cholinergic neurons following cortical devascularization in the adult rat. Since nerve growth factor (NGF) is critical to the survival of NbM cholinergic neurons in the adult brain and its synthesis is known to be regulated by noradrenergic mechanisms, we examined whether the protective effect of dexefaroxan in the devascularization model was associated with regional induction of NGF biosynthesis. Dexefaroxan or vehicle was administered to rats via subcutaneous minipumps for 28 days following devascularization or sham operation procedures. In vehicle-treated devascularized rats, NGF protein levels in the cortex were increased at 5 days but had normalized by 2 weeks postoperation; NGF levels in NbM remained unchanged during this time. In dexefaroxan-treated devascularized rats, increases in NGF protein levels (2-fold) and immunoreactivity were maintained in both the cortex and NbM over the entire 28-day postoperation period; these increases were coincident with changes in functional markers characteristic of NGF's actions, including increases in choline acetyltransferase (ChAT), p75 and TrkA immunoreactivities, and a preservation of NbM cholinergic cell numbers. Dexefaroxan also increased NGF protein levels in sham-operated rats, but without any significant consequence to the otherwise normal NbM cholinergic phenotype in these animals. Results indicate that activation of endogenous NGF systems could contribute to the cholinergic protective effect of dexefaroxan in the cortical devascularization model, and provide further support for a potential therapeutic utility of dexefaroxan in neurodegenerative diseases where central cholinergic function is progressively compromised.

Behavioral sensitization to different dopamine agonists in a parkinsonian rodent model of drug-induced dyskinesias.

Repeated treatment with dopamine (DA) receptor agonists strongly potentiates contralateral turning behavior due to selective stimulation of D1 or D2-class receptors in 6-hydroxydopamine (6-OHDA)-lesioned rats. This phenomenon, referred to as sensitization, is believed to be related to the motor response complications (dyskinesias, on-off states) that occur during chronic administration of levodopa in Parkinson's disease patients. In recent years a new method for the evaluation of abnormal involuntary movements (AIMs) secondary to dopaminergic stimulation in 6-OHDA-lesioned rats was described. These AIMs resemble dyskinesias as seen in parkinsonian patients under levodopa therapy. Our objective was to evaluate the effects of repeated treatment with different regimes of DA agonists on turning behavior and on an AIMs scale in 6-OHDA lesioned rats, with the aim of discriminating between drugs with different dyskinesia-inducing potential. In addition, we explored the effects of a previous exposure to a DA agonist (priming) on the behavioral response to the subsequent administration of a DA agonist with the same or different pharmacologic profile. Our results show that in apomorphine-treated rats, rotational behavior and AIMs run a parallel course of enhancement, while in those receiving quinpirole there is a dissociation, suggesting that they could be mediated by different mechanisms. The finding of a significant priming effect on subsequent testing of 6-OHDA lesioned rats should be borne in mind as the use of these pharmacological tests in the screening of well lesioned animals could lead to an erroneous interpretation of further results on dyskinesias and rotational behavior.

The concentration and distribution of 2,3,7,8-dibenzo-p-dioxins/-furans in chickens.

The concentrations of the 2,3,7,8-Cl substituted dibenzo-p-dioxins/-furans (PCDDs/PCDFs) were determined in the edible tissues of whole chicken fryers and compared with the values found in their abdominal fat. The values are presented both on a whole weight basis and on a lipid adjusted basis for each tissue. While there is a marked difference in the concentration of the 2,3,7,8-dibenzo-p-dioxins in the edible tissues expressed on a whole weight basis, the lipid-adjusted concentrations of the individual dioxins were not statistically different in the various tissues. This validates the use of lipid adjusted concentrations of 2,3,7,8-PCDDs/PCDFs in abdominal fat for the determination of the presence of these compounds in different tissues.

Increased [125I]sulpiride binding in the subthalamic nucleus of rats with nigrostriatal lesions.

Subthalamic nucleus (STN) hyperactivity follows lesions of mesencephalic dopaminergic neurons in animal models of Parkinson's disease. The mechanism leading to sustained STN hyperactivity in parkinsonism is not well understood, but it seems not to depend on the integrity of striato-pallido-subthalamic connections (the so called indirect pathway). Sustained STN hyperactivity could result from the loss of the direct dopaminergic innervation of the STN. Here we report increased [125I]sulpiride binding in the STN of rats with 6-hydroxydopamine (6-OHDA) lesions of mesencephalic dopaminergic neurons. Furthermore, we found that chronic oral treatment with levodopa reverted the lesion-induced increase in [125I]sulpiride binding. Our results demonstrate that most STN D2-class dopamine receptors are postsynaptic to afferent dopaminergic fibers. Furthermore, they suggest that alterations of local STN dopaminergic mechanisms could play a role in the pathophysiology of parkinsonism and mediate the therapeutic/adverse effects of chronic levodopa administration.

Dose-response relationships for disposition and hepatic sequestration of polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls following subchronic treatment in mice.

Humans are exposed to mixtures of polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls mainly through the diet. Many of these chemicals are dioxin-like and their relative toxicity is related to their ability to bind and activate the Ah receptor. The present study examines the structure-activity relationship for disposition of these chemicals in female B6C3F1 mice following subchronic exposures. Mice were treated 5 days/week for 13 weeks by oral gavage with different doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD),2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzofuran (1-PeCDF), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), octachlorodibenzofuran (OCDF), 3,3',4,4',5-pentachlorobiphenyl (126), 3,3',4,4',5,5'-hexachlorobiphenyl (169), 2,3,3',4,4'-pentachlorobiphenyl (105), 2,3',4,4',5-pentachlorobiphenyl (118), and 2,3,3',4,4',5-hexachlorobiphenyl (156). All of the chemicals examined exhibited dose-dependent increases in the liver/fat concentrations except PCBs 105, 118, and 156. While TCDD is the most potent toxicant in this class of chemicals, 4-PeCDF, PeCDD, OCDF, TCDF, and PCB126 were sequestered in hepatic tissue to a greater extent than was TCDD. The high affinity for hepatic tissue supports the presence of an inducible hepatic binding protein for some dixin-like chemicals. The differences in disposition between these chemicals suggests that pharmacokinetic differences between congeners is important in the relative potency of these chemicals.

Background contamination by coplanar polychlorinated biphenyls (PCBs) in trace level high resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS) analytical procedures.

The addition of the "dioxin-like" polychlorinated biphenyl (PCB) congeners to the assessment of risk associated with the 2,3,7,8-chlorine substituted dioxins and furans has dramatically increased the number of laboratories worldwide that are developing analytical procedures for their detection and quantitation. Most of these procedures are based on established sample preparation and analytical techniques employing high resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS), which are used for the analyses of dioxin/furans at low parts-per-trillion (ppt) levels. A significant and widespread problem that arises when using these sample preparation procedures for the analysis of coplanar PCBs is the presence of background levels of these congeners. Industrial processes, urban incineration, leaking electrical transformers, hazardous waste accidents, and improper waste disposal practices have released appreciable quantities of PCBs into the environment. This contamination has resulted in the global distribution of these compounds via the atmosphere and their ubiquitous presence in ambient air. The background presence of these compounds in method blanks must be addressed when determining the exact concentrations of these and other congeners in environmental samples. In this study reliable procedures were developed to accurately define these background levels and assess their variability over the course of the study. The background subtraction procedures developed and employed increase the probability that the values reported accurately represent the concentrations found in the samples and were not biased due to this background contamination.

Extensive amplification and self-renewal of human primitive hematopoietic stem cells from cord blood.

The use of umbilical cord blood as a source of marrow repopulating cells for the treatment of pediatric malignancies has been established. Given the general availability, the ease of procurement, and progenitor content, cord blood is an attractive alternative to bone marrow or growth factor mobilized peripheral blood cells as a source of transplantable hematopoietic tissue. However, there is a major potential limitation to the widespread use of cord blood as a source of hematopoietic stem cells for marrow replacement and gene therapy. There may be enough hematopoietic stem cells to reconstitute children, but the ability to engraft an adult might require ex vivo manipulations. We describe an in vitro system in which the growth of cord blood CD34+ cells is sustained and greatly expanded for more than 6 months by the simple combination of two hematopoietic growth factors. Progenitors and cells belonging to all hematopoietic lineages are continuously and increasingly generated (the number of colony-forming unit-granulocyte-macrophage [CFU-GM] present at the end of 6 months of culture are well over 2,000,000-fold the CFU-GM present at the beginning of the culture). Very primitive hematopoietic progenitors, including long-term culture-initiating cells (LTC-ICs) and blast cell colony-forming units, are also greatly expanded (after 20 weeks of liquid culture, LTC-IC number is over 200,000-fold the initial number). The extremely prolonged maintenance and the massive expansion of these progenitors, which share many similarities with murine long-term repopulating cells, suggest that extensive renewal and little differentiation take place. This system might prove useful in diverse clinical settings involving treatment of grown-up children and adults with transplantation of normal or genetically manipulated hematopoietic stem cells.

A statistical survey of dioxin-like compounds in United States beef: a progress report.

The USEPA and the USDA have completed the first statistically designed survey of the occurrence and concentration of CDDs and CDFs in the fat of beef animals raised for human consumption in the United States. Back fat was sampled from 63 carcasses at federally inspected slaughter establishments nationwide. The sample design called for sampling beef animal classes in proportion to national annual slaughter statistics. All samples were analyzed using a modification of EPA method 1613, using isotope dilution, High Resolution GC/MS to determine the rate of occurrence of 2,3,7,8-substituted CDDs/CDFS. The whole weight method detection limits ranged from 0.05 ng kg-1 for TCDD to 3 ng kg-1 for OCDD. The results of this survey showed a mean concentration (reported as I-TEQ, lipid adjusted) in U.S. beef animals of 0.35 ng kg-1 and 0.89 ng kg-1 when either non-detects are treated as 0 value or assigned a value of 1/2 the detection limit, respectively.

Determination of 2,3,7,8-chlorine-substituted dibenzo-p-dioxins and -furans at the part per trillion level in United States beef fat using high-resolution gas chromatography/high-resolution mass spectrometry.

As part of the U.S. EPA Dioxin Reassessment Program, the 2,3,7,8-chlorine-substituted dibenzo-p-dioxins and furans were measured at part per trillion (ppt) levels in beef fat collected from slaughter facilities in the United States. This is the first statistically designed national survey of these compounds in the U.S. beef supply. Analyte concentrations were determined by high-resolution gas chromatography/high-resolution mass spectrometry, using isotope dilution methodology. Method limits of detection on a whole weight basis were 0.05 ppt for TCDD and 0.10 ppt for TCDF, 0.50 ppt for the pentas (PeCDDs/PeCDFs)/hexas (HxCDDs/HxCDFs)/heptas (HpCDDs/HpCDFs), and 3.00 ppt for the octas (OCDD/OCDF). Method detection and quantitation limits were established on the basis of demonstrated performance criteria utilizing fortified samples rather than by conventional signal-to-noise or variability of response methods. The background subtraction procedures developed for this study minimized the likelihood of false positives and increased the confidence associated with reported values near the detection limits. Mean and median values for each of the 2,3,7,8-Cl-substituted dioxins and furans are reported, along with the supporting information required for their interpretation. The mean toxic equivalence values for the samples are 0.35 ppt (nondetects = 0) and 0.89 ppt (nondetects = 1/2 LOD).

Calming aggressive reactions--a preventive program.

1. Aggressive behavior of nursing home residents towards caregivers, specifically nurse aides, is increasingly a problem in nursing homes. 2. The C.A.R.E. Program was developed to educate nursing personnel about prevention of aggressive incidents through early identification of residents most likely to become abusive. 3. The C.A.R.E. Program utilizes didactic presentation, role playing, sharing experiences, and group support as teaching strategies. 4. A major implication for professional nurses is to assume responsibility for identifying elders at risk for aggression and to provide the nursing team with the training to best care for these residents.

Revision of the Wayne State University Medical Library subject catalog using the 1966 Medical Subject Heading system.

Wayne State University Medical Library (WSUML) revised its monograph subject catalog in 1961 utilizing the 1960 edition of MeSH as an authority list. With the introduction of MEDLARS in 1963 by NLM, all topical subheadings were omitted from MeSH. Inasmuch as this omission could not accommodate the needs of WSUML, the 1960 edition of MeSH was retained as a guideline. In January 1966, when MeSH resumed the incorporation of topical subheadings, WSUML was faced with a decision whether to continue the current policy or to adopt the form as presented in the latest edition of MeSH. This report describes the methodology employed in adopting a new policy, the findings which resulted from the change, and an evaluation of this reorganization.