PubMed Health⌕ Search

Biomedical subjects

M L Sutherland

Publications and source records attributed to M L Sutherland.

9 recordsLinked to original sources
PubMed1999

Overexpression of a Shaker-type potassium channel in mammalian central nervous system dysregulates native potassium channel gene expression.

The nervous system maintains a delicate balance between excitation and inhibition, partly through the complex interplay between voltage-gated sodium and potassium ion channels. Because K+ channel blockade or gene deletion causes hyperexcitability, it is generally assumed that increases in K+ channel gene expression should reduce neuronal network excitability. We have tested this hypothesis by creating a transgenic mouse that expresses a Shaker-type K+ channel gene. Paradoxically, we find that addition of the extra K+ channel gene results in a hyperexcitable rather than a hypoexcitable phenotype. The presence of the transgene leads to a complex deregulation of endogenous Shaker genes in the adult central nervous system as well as an increase in network excitability that includes spontaneous cortical spike and wave discharges and a lower threshold for epileptiform bursting in isolated hippocampal slices. These data suggest that an increase in K+ channel gene dosage leads to dysregulation of normal K+ channel gene expression, and it may underlie a mechanism contributing to the pathogenesis of human aneuploidies such as Down syndrome.

Animals↗
PubMed1997

A breast cancer care report card. An assessment of performance and a pursuit of value.

The transition to managed care raises concerns about the resulting quality of care. The report card, a publicly released, standardized report on quality, has received widespread acceptance as a method to evaluate physician performance. Current report cards provide insufficient information to allow purchasers of health care to assess accurately the performance of professionals who provide breast care. To overcome these limitations, we propose an expanded report card on breast cancer care. Mammographers and general surgeons would assess an independent series of at least 100 consecutive cases of newly diagnosed breast cancer. Mammographers would determine the percentage of invasive cancers < 15 mm detected on screening mammograms in asymptomatic women aged 50 to 74 years. Surgeons would determine the percentage of combined stages 0 and 1 breast cancers detected and the percentage of patients receiving breast-conserving surgical therapy. Performance targets are set at 60% for invasive cancers < 15 mm detected on screening mammography, 60% for combined stage 0 and 1 breast cancers, and 50% for patients receiving breast-conserving therapy.

Aged↗
PubMed1996

Glutamate transporter mRNA expression in proliferative zones of the developing and adult murine CNS.

Neuronal migration, differentiation, and synapse formation are developmental processes within the CNS significantly influenced by ionotropic and metabotropic glutamate receptor activity. Extracellular glutamate concentrations mediating this activity are regulated by transport proteins localized in neuronal and glial cell membranes. We have used in situ hybridization analysis with subtype-specific antisense-oligonucleotides to study the distribution of glia-specific excitatory amino acid transporter (mEAAT1 and mEAAT2) mRNAs during the later stages of embryogenesis and postnatal CNS development. Distinct but overlapping embryonic and postnatal patterns of localization were observed for the two transporter transcripts. Both mEAAT1 and mEAAT2 mRNAs were found during the peak period of gliogenesis (E15-E19) in the telencephalic and mesencephalic CNS proliferative zones. The overall expression of mEAAT1 mRNA diminished after the completion of cell migration, whereas mEAAT2 mRNA expression increased significantly during postnatal development. Interestingly, mEAAT2 transcript expression continued in the subventricular zone postnatally and persisted in this proliferative zone in the adult brain. From PO onward, mEAAT1 mRNA was present predominantly in the cerebellar Purkinje cell layer and at a much lower abundance in the cortex, hippocampus, basal nuclei, and septum, whereas from P7 onward, mEAAT2 mRNA expression increased throughout most of the neuraxis. Postnatally, transcripts for mEAAT1 and mEAAT2 were found in cell bodies, processes, and commissural white matter tracts of the CNS. The divergent temporal and spatial expression of EAAT subtypes and their persistence in mature fiber tracts and radial glia layers reveal that specific EAATs are likely to play multiple distinct roles in the developing and adult CNS, including the regulation of cell proliferation, axon-glia interactions, and neuronal survival.

ATP-Binding Cassette Transporters↗
PubMed1996

Molecular and cellular plasticity in developing epileptic brain.

Defined transgenic models of epilepsy in the mouse represent unique opportunities to examine interactions between synchronous synaptic activity and cellular programs of brain development. We are beginning to acquire a list of the kinds of genes favoring sudden, intermittent aberrant discharges in central neurons, and we have found that, rather than arising from a few gene superfamilies regulating membrane excitability, they are involved in many diverse functions of the cell. Whereas some primary gene defects impinge directly on membrane electrogenesis and neurotransmitter signaling at synapses, others are too far removed from these processes to clearly visualize the steps by which they promote epileptogenesis. We have tantalizing evidence that several, and probably all, epilepsy genes entrain some degree of secondary molecular and cellular plasticity, and we can guess that these downstream rearrangements may account for the delayed onset of epileptic phenotypes in some syndromes. It is too early to tell whether these, or other induced changes, provide the basis for the reversibility of some epilepsies. The diversity of epilepsy genes and their intervening cellular phenotypes promise to provide a rich source of novel molecular targets for therapeutic discovery and will have a lot to teach us in the future about the developmental potential of neural circuits in the mammalian brain.

Animals↗
PubMed1995

Molecular characterization of a high-affinity mouse glutamate transporter.

The complete coding sequence of a mouse glutamate transporter (mEAAT2) has been cloned by polymerase chain reaction (PCR) from adult whole-brain total RNA. Southern hybridization analysis of PCR products amplified from templates derived from various murine adult tissues demonstrated that the transcript for mEAAT2 was specific to the central nervous system. High-affinity transport of D-aspartate, Km value (17 +/- 5 microM), was determined in a vaccinia/T7 RNA polymerase expression system. The deduced amino-acid sequence of mEAAT2 shares 96 and 93% identity with the rat and human EAAT2 homologues, respectively.

ATP-Binding Cassette Transporters↗
PubMed1991

Effects of subunit types of the cloned GABAA receptor on the response to a neurosteroid.

Combinations of cloned GABAA receptor subtypes, having the subunit combinations alpha i + beta 1 or alpha i + beta 1 + gamma 2 (i = 1, 2, 3), were expressed in Xenopus oocytes. The endogenous steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one potentiates GABA currents induced therein by GABA. This potentiation was greater in the alpha 1 + beta and alpha 3 + beta 1 than in the alpha 2 + beta 1 combinations. The presence of the gamma 2-subunit increased the steroid potency in alpha 1 + beta 1 and alpha 2 + beta 1, but the combination alpha 3 + beta 1 + gamma 2 became much less steroid-sensitive. It is concluded that the steroid modification of the GABAA receptor is strongly influenced by the alpha- and the gamma 2-subunit types.

Animals↗
PubMed1990

Inter- and intra-observer variability of Doppler peak velocity measurements: an in-vitro study.

To determine the variability of pulsed Doppler peak velocity measurements, four radiologists with differing experience were tested using a calibrated flow phantom. Two ultrasound units, three probes and eight velocity rates varying between 40.5 and 78 cm/sec were studied, with a total of 303 measurements. The results were normalized against a set of 106 separate measurements made under highly-controlled conditions. The residual error standard deviation (not attributable to any systematically varied factor, including the velocity rate) was 6.8 cm/sec, with most of the remaining variation due to changing transducer or machine. Observer/equipment interactions accounted for 15.8% of the observed variability. The duration of the radiologist's Doppler experience had no significant effect.

Blood Flow Velocity↗
PubMed1989

Transabdominal versus endovaginal pelvic sonography: prospective study.

Transabdominal and endovaginal pelvic sonograms were obtained in 108 nonpregnant patients referred for pelvic sonography. The studies were independently obtained by two radiologists and interpreted on the basis of identical clinical information. The sonograms were then compared for anatomic detail and abnormalities. A determination was made about which examination, if either, was superior. Follow-up was performed through a review of the medical records and follow-up studies. Overall, the endovaginal study was judged superior in 65 cases (60.2%), equal in 39 (36.1%), and inferior in four (3.7%). The authors conclude that the endovaginal examination can effectively replace the transabdominal examination as the initial approach for routine pelvic sonography.

Abdomen↗