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Biomedical subjects

S M Ferguson

Publications and source records attributed to S M Ferguson.

At least 19 recordsLinked to original sources
PubMed2001

K-shell photodetachment of Li(-): experiment and theory.

An experimental K-shell photodetachment study of Li(-) giving rise to doubly photoionized Li(+) ions has been carried out at the Advanced Light Source, using a collinear photon-ion beam apparatus. The experiment reveals dramatic structure, differing substantially both qualitatively and quantitatively from the corresponding processes above the 1s ionization threshold in Li and Li(+), as predicted by our enhanced R-matrix calculation. The experimental/theoretical comparison shows good agreement over some of the photon energy range, and also reveals some puzzling discrepancies.

Journal Article↗
PubMed2001

Molecular cloning and characterization of a murine hemicholinium-3-sensitive choline transporter.

In cholinergic neurons, a specific requirement for precursor choline in the biosynthesis of acetylcholine (ACh) is thought to be sustained by a presynaptic, hemicholinium-3 (HC-3)-sensitive choline transporter (CHT). This transporter exhibits micromolar affinity for choline and transport activity is Na(+)- and Cl(-)-dependent. Based on the sequence information available with the recent cloning of rat and human CHTs [Okuda, Haga, Kanai, Endou, Ishihara and Katsura (2000) Nat. Neurosci. 3, 120-125; Apparsundaram, Ferguson, George Jr and Blakely (2000) Biochem. Biophys. Res. Commun. 276, 862-867; Okuda and Haga (2000) FEBS Lett. 484, 92-97], we have identified a murine CHT orthologue (mCHT) by reverse transcriptase-PCR of spinal cord mRNA and confirmed this sequence using assembled mouse genomic DNA. Inferred splice junctions for mCHT exons are conserved with those of hCHT. The mCHT cDNA encodes a protein of 580 amino acids with 93% and 98% amino acid identity to human CHT and rat CHT1, respectively. Hydropathy analysis of the predicted amino acid sequence of mCHT indicates a protein containing 13 transmembrane domains (TMDs), with the N-terminus oriented extracellularly and the C-terminus oriented intracellularly. Northern blot analysis of mouse tissues reveals the expression of mCHT as a single transcript of approximately 5 kb with highest expression in regions that are rich in cholinergic cell bodies, e.g. the spinal cord, brainstem, mid-brain and striatum, whereas hybridization signals are absent in regions lacking cholinergic soma, e.g. the cerebellum and kidney. Expression of mCHT in COS-7 cells results in high-affinity [(3)H]HC-3-binding sites (K(d)=5 nM), and Na(+)- and Cl(-)-dependent HC-3-sensitive choline uptake (K(m)=2 microM), assessed in resealed membrane vesicles. The availability of cloned, functional mCHT and its cognate genomic DNA should prove useful for studies of mCHT regulation and should open possibilities for evaluation of CHT dysfunction in murine models.

Animals↗
PubMed2000

Molecular cloning of a human, hemicholinium-3-sensitive choline transporter.

Under many physiological circumstances, Na(+)- and Cl(-)-dependent, hemicholinium-3 (HC-3)-sensitive, high-affinity choline uptake (HACU) in cholinergic neurons is thought to be rate-limiting in the biosynthesis of acetylcholine (ACh). Based on sequence information provided by the Human Genome Project and the recently reported rat CHT1 (rCHT1), we cloned a human CHT cDNA from spinal cord. The hCHT cDNA encodes a protein of 580 amino acids having 93% identity to rCHT1 and 51% identity to the Caenorhabditis elegans homolog CHO-1, and is distantly related to members of the Na(+)-coupled glucose transporter (SGLT) gene family of Na(+)-coupled glucose (SGLT), nucleoside and iodide transporters. Northern blot analysis reveals the expression of a approximately 5 kb transcript in human brain regions rich in cholinergic neurons including the putamen, spinal cord, and medulla. Expression of hCHT cDNA in COS-7 cells results in saturable, Na(+)/Cl(-)-dependent choline uptake (K(m) = 1.2 microM) in membrane vesicles and [(3)H] HC-3 binding (K(d) = 4 nM) in membrane fractions, consistent with characteristics reported in mammalian cholinergic neurons. Using radiation hybrid mapping techniques, we localized the hCHT gene to human chromosome 2q12. These studies elucidate the primary structure and chromosomal localization of hCHT and provide a basis for mechanistic analysis of HACU regulation and an investigation of the role of hCHT in disease states.

Amino Acid Sequence↗
PubMed2000

Antidepressant-like effects of the subtype-selective nicotinic acetylcholine receptor agonist, SIB-1508Y, in the learned helplessness rat model of depression.

RATIONALE: Epidemiological studies of smokers suggest that there is a link between nicotine and depression. Nonetheless, few studies have examined the potential use of nicotinic ligands in the treatment of depression. OBJECTIVES: The goal of this study was to evaluate the effects of SIB-1508Y, a novel subtype-selective ligand for high affinity nicotinic acetylcholine receptors (nAChRs), in the learned helplessness model of depression in rats. METHODS: In this model, exposure to inescapable foot-shock produces a lasting deficit in escape responses emitted in a subsequent conditioned avoidance procedure (learned helplessness). The effect of SIB-1508Y on learned helplessness was compared to the clinically used antidepressants, imipramine and fluoxetine, and the non-selective nAChR ligand, nicotine. RESULTS: Similarly to imipramine and fluoxetine, subchronic treatment (5 days) with SIB-1508Y reversed the escape deficit in the learned helplessness model in a dose dependent manner. The effect of SIB-1508Y on learned helplessness was still apparent 1 week following drug administration and was also maintained after 4 weeks of daily administration. In contrast, while nicotine was able to attenuate the learned helplessness deficit, this trend only reached statistical significance after chronic administration. The non-competitive ion channel blocker mecamylamine increased escape failures when administered alone and blocked the effects of SIB-1508Y but not imipramine. SIB- 1508Y also produced an increase in avoidance responding, which suggests an enhancement of learning. CONCLUSION: These results not only suggest a role for nAChRs in the development of a depressive-like syndrome, but also that subtype-selective nAChR agonists, such as SIB-1508Y, may offer a novel therapeutic approach to the treatment of depression.

Animals↗
PubMed2000

Knowledge, attitudes, and behaviors of Alabama's primary care physicians regarding cancer genetics.

PURPOSE: To determine Alabama's primary care physicians' knowledge, attitudes, and behaviors regarding cancer genetics. METHOD: A questionnaire was mailed to a random sample of 1,148 physicians: family and general practitioners, internists, and obstetrician-gynecologists. RESULTS: Of the surveyed physicians, 22.1% responded. Of the respondents, 63% to 85% obtained family histories of cancer from 76% to 100% of their patients. Obstetrician-gynecologists referred more patients for cancer genetic testing (p = .008) and were more confident in their abilities to tailor preventive recommendations based on the results (p = .05) than were the other physicians. Primary care physicians were more likely than were obstetrician-gynecologists to identify lack of time during the patient visit as hindering efforts to do genetic counseling (p = .01). Physicians in practice for ten years or less were more confident in explaining genetic test results than were those in practice for more than 20 years (p = .01). CONCLUSION: These data validate gaps in primary care practices in obtaining family history of cancer, as well as lack of confidence in explaining genetic test results and in tailoring recommendations based on the tests.

Adult↗
PubMed1999

Purification and reconstitution of an osmosensor: transporter ProP of Escherichia coli senses and responds to osmotic shifts.

The ProP protein of Escherichia coli is an osmoregulatory H+-compatible solute cotransporter. ProP is activated by an osmotic upshift in both whole cells and membrane vesicles. We are using biochemical and biophysical techniques to explore the osmosensory and catalytic mechanisms of ProP. We now report the purification and reconstitution of the active transporter. Protein purification was facilitated by the addition of six histidine (His) codons to the 3' end of proP. The recombinant gene was overexpressed from the E. coli galP promoter, and ProP-(His)6 was shown to be functionally equivalent to wild-type ProP by enzymatic assay of whole cells. ProP-(His)6, purified by Ni2+ (NTA) affinity chromatography, cross-reacted with antibodies raised against the ProP protein. ProP-(His)6 was reconstituted into Triton X-100 destabilized liposomes prepared with E. coli phospholipid. The reconstituted transporter mediated proline accumulation only if (1) a membrane potential was generated by valinomycin-mediated K+ efflux and (2) the proteoliposomes were subjected to an osmotic upshift (0.6 M sucrose). Activity was also stimulated by DeltapH. Pure ProP acts, in the proteoliposome environment, as sensor, transducer, and respondent to a hyperosmotic shift. It is the first such osmosensor to be isolated.

Bacterial Proteins↗
PubMed1995

Mast cell cholangiopathy: another cause of sclerosing cholangitis.

A 75-year-old woman with known systemic mastocytosis presented with abdominal pain, ascites, and bile duct thickening on computed tomography and ultrasonography. A liver biopsy specimen showed infiltration with mast cells. Endoscopic retrograde cholangiography showed ductal changes compatible with those found in primary sclerosing cholangitis. Brush cytology of the intrahepatic bile ducts confirmed mast cell infiltration. Systemic mastocytosis can infiltrate the biliary system, producing a cholangiopathy radiographically similar to primary sclerosing cholangitis.

Aged↗
PubMed1984

Use of hexadeuterated valproic acid and gas chromatography-mass spectrometry to determine the pharmacokinetics of valproic acid.

Di-[( 3,3,3-2H3]propyl)acetic acid, a hexadeuterated analogue of valproic acid, was synthesized and its pharmacokinetic properties compared with valproic acid. Concentrations of valproic acid and [2H]valproic acid in serum and saliva were determined by GC-MS using selected-ion monitoring. Saliva drug levels were measured with good precision down to 0.1 microgram/mL. Kinetic equivalence of valproic acid and [2H]valproic acid was demonstrated in a single-dose study in a human volunteer. An isotope effect was observed for omega-oxidation, but the difference in metabolism was not sufficient to make [2H]valproic acid biologically nonequivalent. The application of [2H]valproic acid to determine the kinetics of valproic acid under steady-state concentrations was evaluated in the same volunteer. The kinetic data obtained with [2H]valproic acid was consistent with previously reported values for valproic acid including kinetic differences observed between single-dose and steady-state experiments. Saliva levels of valproic acid were found to give a good correlation (r = 0.953) with total serum valproic acid under multiple-dose conditions. A concentration dependence was found for the ratio of saliva valproic acid to free valproic acid in serum, low ratios being observed at high serum concentrations of valproic acid.

Adult↗
PubMed1983

Outcomes and indications of corpus callosum section for intractable seizure control.

Callosotomy (CCS) was performed in 9 cases of rigorously classified drug-refractory epilepsy not eligible for focal cortical resection. Complete CCS was carried out in two stages in 8 patients. 1 case had an anterior CCS only. None of the 9 patients has become seizure free. In 7, seizure frequency has diminished by a factor of 3-60 for at least one seizure type. Drop attacks in 2 cases have ceased. Clinical seizure patterns appeared more helpful in predicting outcome than preoperative EEG and stereoelectroencephalographic studies. Complete CCS may result in prolonged behavioral disturbances in the areas of language, hemisphere competition and attention-memory sequencing with impact on the sphere of daily living.

Adolescent↗