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Biomedical subjects

L Bush

Publications and source records attributed to L Bush.

At least 19 recordsLinked to original sources
PubMed1998

Apolipoprotein A-1 is a negative target of v-Jun overexpression.

The product of the Jun oncogene influences a variety of processes including cell proliferation and differentiation. Jun exerts its influence by binding to the promoter and enhancer regions of a number of different target genes resulting in their activation or repression. We describe here the isolation and characterization of a gene differentially downregulated upon overexpression of v-Jun but not c-Jun. DNA and amino acid homology search analysis revealed this gene to be identical to chicken apolipoprotein A-1, the major component of high density lipoprotein (HDL). The half life of apolipoprotein A-1 RNA remains constant in the presence or absence of v-Jun overexpression suggesting downregulation by v-Jun is at the level of promoter activity. Consistent with this hypothesis, apolipoprotein A-1 upstream promoter fragments active in normal and c-Jun expressing CEF are inactive in v-Jun transformed CEF. Analysis of expression of apolipoprotein A-1 in CEF overexpressing other oncogenes revealed a similar downregulation by Myc and v-Src but not c-Fos, v-Ha-Ras, c-Src or c-Ski. Our findings point to a potential regulatory affect on cholesterol metabolism by v-Jun, as a result of altered levels of apolipoprotein A-1 message expression.

Animals↗
PubMed1998

The formulation of recombinant factor IX: stability, robustness, and convenience.

A lyophilized recombinant factor IX (rFIX) formulation has been developed that is stable and contains no preservatives. No blood or plasma products are used in the production or formulation of rFIX. The formulation contains 10 mmol/L histidine, 0.26 mol/L glycine, 1% sucrose, and 0.005% polysorbate-80 (pH 6.8). Polysorbate-80 acts as a protectant for the protein from freezing-induced damage (eg, aggregation). Sucrose provides protection to the protein in the freeze-dried state. Glycine provides for a high-quality cake morphology. Histidine provides optimal buffering stability at the desired pH and minimizes aggregate formation upon storage in the lyophilized state. This optimized combination of excipients provides a high degree of long-term stability, as demonstrated by a variety of analytical methods, including clotting assays, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing (IEF), size-exclusion chromatography (SEC), peptide mapping, oligosaccharide fingerprinting, and reverse-phase high-performance liquid chromatography (HPLC). The rFIX product is easy to reconstitute and demonstrates excellent stability in solution after reconstitution.

Chemistry, Pharmaceutical↗
PubMed1997

Exacerbation of methamphetamine-induced neurochemical deficits by melatonin.

Methamphetamine (METH), administered in large, repeated doses, compromises the dopaminergic and serotonergic systems as indicated by prolonged suppression of tyrosine hydroxylase and tryptophan hydroxylase activity and concurrent decreases in the content of dopamine and 5-hydroxytryptamine. Because dopamine is necessary for these dopaminergic and serotonergic deficits we postulated that dopamine and/or its reactive metabolites are responsible for these degenerative alterations. Because we previously demonstrated that in vitro reducing conditions reverse the decrease in tryptophan hydroxylase activity, we reasoned that melatonin, a purported endogenous antioxidant, may alter this response. Rats were treated with METH and/or melatonin and trytophan hydroxylase activity and 5-hydroxytryptamine content were assessed; tyrosine hydroxylase activity and dopamine content were also measured. Not only did melatonin not prevent METH-induced deficits in serotonergic and dopaminergic parameters, but coadministration of melatonin with METH actually enhanced most of the monoaminergic effects of METH. This enhancing effect could not be attributed to alteration of body temperature. Because METH abuse causes insomnia and melatonin is promoted in some countries for insomnia, the implications of the interaction between these two drugs could be clinically important.

Animals↗
PubMed1995

Evaluation of recombinant human factor IX: pharmacokinetic studies in the rat and the dog.

The pharmacokinetics of intravenously administered recombinant human factor IX (rhFIX) were studied in Sprague-Dawley rats and Beagle dogs. Rats received rhFIX (50 IU/kg once daily) for 28 days, and the plasma half-life was 5 h. Anti-Human Factor IX serum antibody levels were found in only 1 of 12 rats. The pharmacokinetic profiles of rhFIX or Mononine, a purified human plasma-derived factor IX, after single 100 IU/kg i.v. doses in dogs, were similar. Peak plasma concentrations of rhFIX and Mononine were 4-5 micrograms/ml. The mean plasma half-lives were 13.2 +/- 1.6 h for rhFIX and 13.3 +/- 1.6 h for Mononine. Dogs also received rhFIX (40 IU/kg i.v., daily) for 28 days or Mononine (40 IU/kg i.v. daily) for 14 days. Anti-human Factor IX serum antibody levels were determined for each compound. Pharmacokinetic half-lives decreased in these treated dogs which developed antihuman Factor IX antibodies. The antibody responses in 28 day rhFIX (40 IU/kg) dogs were similar to 14 day Mononine (40 IU/kg) dogs.

Animals↗
PubMed1992

Response of monoaminergic and neuropeptide systems to 4-methylaminorex: a new stimulant of abuse.

4-Methylaminorex is an amphetamine analog which has recently gained attention due to its potential as a stimulant of abuse and the ease with which it is synthesized. Administration of acute and multiple doses of 4-methylaminorex caused rapid (3-h) and long-term (7-day) declines in striatal tryptophan hydroxylase activity with few changes in other serotonergic parameters. The acute response by tryptophan hydroxylase to this drug was reversed by incubating the tissues in a reducing environment suggesting that 4-methylaminorex alters this enzyme through oxidative mechanisms. The 4-methylaminorex-induced long-term reduction in tryptophan hydroxylase activity might be due to neurotoxic action on serotonergic systems. In contrast, although a decline in striatal tyrosine hydroxylase occurred 3 h following a single dose of 4-methylaminorex, no changes in this enzyme were observed at 7 days after acute or multiple dosing with this drug. This result suggests that 4-methylaminorex is not neurotoxic to the dopaminergic neurons. Even though this amphetamine analog apparently does not have long-term effects on dopaminergic systems, it does appear to enhance substantially dopaminergic activity. Evidence for increased dopamine activity resulting from 4-methylaminorex administration included dramatic but temporary rises in the levels of nigral neurotensin, dynorphin A and substance P following multiple drug administration. Similar peptide changes have been observed with other amphetamine-related stimulants and are mediated by increases in dopaminergic activity. In summary, 4-methylaminorex has significant impact on monoaminergic pathways. In general, its spectrum of effects on these systems is like that of the ring-substituted amphetamines, such as methylenedioxymethamphetamine.

Animals↗
PubMed1992

Responses of limbic and extrapyramidal neurotensin systems to stimulants of abuse. Involvement of dopaminergic mechanisms.

In summary, we have observed that drugs of abuse, which can cause schizophrenia-like paranoia, alter striatal and accumbens NT systems in a similar, dramatic fashion. The NT responses to these drugs, in particular METH, are mediated by activation of DA D1 receptors. We have observed that NMDA-type glutamate receptors are essential for the D1-NT interaction. NMDA receptors are selective, since they do not contribute to the antagonistic effects of DA D2 receptors on NT activity. This observation suggests that NT responses to D1 and D2 regulation are mediated through separate and distinct mechanisms. Finally, we found that the presence of METH dramatically reduces striatal NT release, which most likely leads to NT accumulation in nerve terminals and the observed increase in NT tissue level. The blockade of NT release by a psychotogenic drug, such as METH, is consistent with the hypothesis that NT has antipsychotic activity and a decrease in its release may contribute to some forms of schizophrenia similar to that caused by intense use of the stimulants of abuse.

Animals↗
PubMed1991

Response of extrapyramidal and limbic neuropeptides to fenfluramine administration: comparison with methamphetamine.

The responses of extrapyramidal and limbic neuropeptide and striatal dopamine and serotonin systems were evaluated after treatment with fenfluramine in rats. After multiple administrations of fenfluramine, its active metabolite, norfenfluramine, and methamphetamine (METH), striatal neurotensin (NT) content was similarly increased to approximately 200% of control. In contrast, nigral NT levels were unaltered by fenfluramine, intermediately increased by norfenfluramine (148% of control) and maximally increased by METH (267% of control). Striatal and nigral substance P (SP) and dynorphin A (Dyn) systems were unaltered by fenfluramine, whereas norfenfluramine caused an intermediate increase in striatal Dyn content but did not significantly alter striatal SP or nigral SP and Dyn levels. However, METH significantly elevated striatal and nigral Dyn and SP concentrations to 280 to 425% (Dyn) and 140% (SP) of control. For the most part, the response of the limbic peptides was similar to that seen in the striatum with a couple of notable differences. Further investigation of the striatal NT system showed that the increases induced by fenfluramine were completely blocked by the D1 antagonist, SCH 23390, and the noncompetitive N-methyl-D-aspartate antagonist, MK801. Depletion of 5-hydroxytryptamine with pretreatment by parachloroamphetamine did not alter the response of the striatal NT system to fenfluramine. The present results demonstrate common and unique features in the response of peptide systems to fenfluramine and methamphetamine, which might explain some of the similarities and differences between these two drugs.

Animals↗
PubMed1991

Effects of the fungal endophyte Acremonium coenophialum in fescue on pregnant mares and foal viability.

Effects of the endophyte Acremonium coenophialum in tall fescue on pregnant mares and foal viability were evaluated. Twenty-two mature pregnant mares were randomly chosen to graze either Kentucky-31 tall fescue that was free from A coenophialum (endophyte-free, EF) or tall fescue infected with A coenophialum (endophyte-present, EP) after the first 90 days of pregnancy through parturition. Concentrations of pyrrolizidine and ergopeptine alkaloids were significantly greater in EP grass, compared with EF pasture. Ten of 11 mares grazing EP pasture had obvious dystocia. Mean duration of gestation was significantly greater for the EP group, compared with the EF group. Foal survivability was severely reduced among mares grazing EP fescue with only 1 foal surviving the natal period. Udder development and lactation were low in mares grazing EP grass. The absence of clinical problems in mares grazing EF grass implicated the endophyte as the causative agent of reproductive problems and perinatal foal mortality in pregnant mares grazing endophyte-infected fescue grass. Caution should be exercised in allowing pregnant mares to graze pastures infected with the endophyte A coenophialum.

Acremonium↗
PubMed1990

Importance of neutralizers in the stripping fluid in a simulated healthcare personnel handwash.

The Food and Drug Administration (FDA) healthcare personnel handwash procedure allows for the use of a non-neutralizing stripping fluid after washing with an antimicrobial handwash product. The antimicrobial in the handwash product can remain active up until the time of neutralization or plating. A modified healthcare personnel handwash procedure using a pigskin substrate and a 4% chlorhexidine gluconate handwash product was used to demonstrate the need for a neutralizer in the stripping fluid. When tests were run with and without neutralizers in the dilution blanks, but with adequate neutralizers in the stripping fluid, there were no significant differences (p greater than .05) between results obtained after five washes or after each wash. When tests were run with a non-neutralizing stripping fluid, significant differences were noticed in the first and the fifth wash (p less than .05), and in the presence or absence of neutralizers in the dilution blanks (p less than .05). The data generated indicate that in order to determine the true activity of an antimicrobial handwash product, an adequate neutralizer should be incorporated into the stripping fluid and not just the dilution media. They also suggest that neutralizer carry-over from the stripping fluid is not a valid concern.

Chlorhexidine↗
PubMed1990

The effects of surfactant systems and moisturizing products on the residual activity of a chlorhexidine gluconate handwash using a pigskin substrate.

A series of handwashing experiments using a pigskin substrate and Serratia marcescens as the contaminant compared the residual activity of a chlorhexidine detergent handwash product alone and in combination with anionic and nonionic-based moisturizing products and surfactant systems. The anionic based moisturizing products and the anionic surfactant system almost completely destroyed the residual antibacterial activity of the chlorhexidine, while the nonionic-based products had minimal effect.

Administration, Topical↗
PubMed1990

Employment problems and diabetes.

A survey of employment problems in a random sample of diabetic patients and a group of control subjects aged 17-65 years was carried out in eight centres in the UK. Data were linked to information collected from patients' diabetic clinic notes relating to the presence and treatment of any diabetic complications and quality of diabetic control. Difficulties in obtaining employment because of diabetes were reported by 13% of diabetic patients, and because of illness by 2% of control subjects (p less than 0.001). Nine percent of diabetic patients and 2% of control subjects reported having to change their job because of their illness (p less than 0.001), and 7% of people with diabetes and 2% of people without diabetes reported losing a job because of their illness (p less than 0.001). Diabetic shift workers were twice as likely as control subjects working shifts to experience problems with their job (18 vs 8%, p = 0.045). Reports of any sickness absence in the last 12 months were not significantly different for people with and without diabetes (49 vs 45%). Sickness absence in excess of 20 days in the last 12 months was more common among diabetic patients than control subjects (29 vs 16%, p less than 0.001). People with diabetes are more likely to experience problems in obtaining employment and staying employed than people without diabetes.

Adolescent↗
PubMed1990

Effects of cocaine on extrapyramidal and limbic dynorphin systems.

The principal central nervous system effects of cocaine are a consequence of its ability to inhibit monoaminergic uptake systems. This agent influences dopamine-related behavior in a manner similar to other sympathomimetics, such as methamphetamine; however, the effect of these two agents on neurochemical dopaminergic parameters are distinct. Several peptidergic neurotransmitter systems, such as the dynorphin pathways, have been shown to be distal to and regulated by the postsynaptic activity of dopaminergic pathways; therefore, we evaluated the response of extrapyramidal and limbic dynorphin A1-17 (Dyn) systems to cocaine by measuring Dyn content in associated structures. Extrapyramidal and limbic dynorphin-like immunoreactivity (DLI) content markedly increased after cocaine treatment. This change appeared to be due primarily to the ability of cocaine to block dopamine re-uptake; consequently, the increase in DLI levels was either totally or partially blocked by coadministration of selective D1 (SCH 23390) and D2 (sulpiride) receptor blockers and multiple doses of the selective dopamine uptake blockers, amfonelic acid and GBR 12909, caused cocaine-like enhancement of extrapyramidal DLI content. Serotonin did not appear to play a major role in mediating the cocaine effects on Dyn systems as multiple doses of the selective serotonin uptake blocker, fluoxetine, did not alter extrapyramidal DLI levels, and depletion of serotonin by pretreatment with parachloroamphetamine did not significantly alter the increases in extrapyramidal Dyn content caused by cocaine administration. Because the behavioral effects of cocaine and methamphetamine are similar, the neurochemical response of Dyn systems to both of these agents is compared and discussed.

Animals↗
PubMed1989

Conversion of domains into subunits in the processing of egg yolk biotin-binding protein I.

Biotin-binding protein I (BBP-I), a protein that differs in its heat stability at low concentrations from that of BBP-II, has been purified from the yolk of hen oocytes and compared to BBP-II. Rabbit antiserum to BBP-II cross-reacts with identity to BBP-I. The molecular mass of BBP-I under denaturing conditions is about 68 kDa, a value four times that of BBP-II. Limited trypsin proteolysis of BBP-I generates subunits of 18 kDa with intermediate forms of approximately 51 and 34 kDa. The NH2-terminal sequence of BBP-I is very similar to that of BBP-II but has little of the polymorphism that is presumed to be generated at several positions by the slightly different subunits of BBP-II. These results indicate an unusual processing pathway in which four tandemly repeated biotin-binding domains of BBP-I become the subunits of BBP-II after limited proteolysis.

Amino Acid Sequence↗