Who are the watchdogs?
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Biomedical subjects
Publications and source records attributed to C Miller.
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Prescribing the combined oral contraceptive pill is a rewarding combination of hands-on clinical medicine, logical therapeutics, prevention, and patient education. Lowest dose with the least side-effects is the overriding principle of prescribing. It is important to spend time teaching patients and partners how to manage their pill-taking and to be responsible for their medication and prevention follow up.
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Single Ca2+-activated K+ channels from rat skeletal muscle plasma membranes were studied in neutral phospholipid bilayers. Channels were chemically modified by briefly exposing the external side to the carboxyl group modifying reagent trimethyloxonium (TMO). TMO modification, in a "multi-hit" fashion, reduces the single-channel conductance without affecting ion selectivity. Modification also shifts the voltage activation curve toward more depolarized voltages and reduces the affinity of the channel blocker charybdotoxin (CTX). CTX, bound to the channel during the TMO exposure, prevents the TMO-induced reduction of the single-channel conductance. These data suggest that the high-conductance Ca2+-activated K+ channel has carboxyl groups on its external surface. These groups influence ion conduction, gating, and the binding of CTX.
This paper demonstrates that local electric fields originating from negatively charged groups on a K+-specific ion channel modify its behavior. Single high-conductance, Ca2+-activated K+ channels were studied in neutral phospholipid bilayers. The channel protein surface charges were manipulated experimentally by carboxyl group esterification using trimethyloxonium (TMO) or by electrolyte screening. Three channel properties--ion conduction, ion blockade, and voltage-dependent gating--are affected by surface electrostatics. Negative charges increase the affinity of cationic pore blockers by establishing a local negative potential at the pore entrance; these charges modify channel gating by establishing a potential gradient across the ion channel; finally, both effects influence ion permeation through the pore.
The inhibition by charybdotoxin of A-type potassium channels expressed in Xenopus oocytes was studied for several splicing variants of the Drosophila Shaker gene and for several site-directed mutants of this channel. Charybdotoxin blocking affinity is lowered by a factor of 3.5 upon replacing glutamate-422 with glutamine, and by a factor of about 12 upon substituting lysine in this position. Replacement of glutamate-422 by aspartate had no effect on toxin affinity. Thus, the glutamate residue at position 422 of this potassium channel is near or in the externally facing mouth of the potassium conduction pathway, and the positively charged toxin is electrostatically focused toward its blocking site by the negative potential set up by glutamate-422.
We carried out a controlled clinical trial to examine the potential of baclofen to slow the functional decline of patients with early Huntington's disease (HD). The basis of the trial was: (1) the hypothesis that excitatory amino acid neurotransmission mediates the neuronal degeneration of HD, (2) preclinical evidence that baclofen retards corticostriatal release of glutamate and aspartate, and (3) reports that baclofen produces short-term clinical benefits in some HD patients. Sixty patients with early HD were randomized to chronic baclofen, 60 mg/day, or placebo treatments and followed systematically for up to 42 months. Total functional capacity was not favorably influenced by baclofen treatment. Factors that contributed, although nonsignificantly, to a more rapid rate of total functional capacity decline included younger age (less than 35 years), earlier stage (stage I) of illness, paternal inheritance of the HD gene, and baclofen treatment. Our patients declined at a pace slower than that observed in other prospective studies, a finding likely due to selection criteria, avoidance of neuroleptic therapy, and strong psychosocial support.
Clinical studies have indicated that dietary fish oil may have therapeutic value in the treatment of psoriasis, a hyperproliferative, inflammatory skin disorder characterized by elevated LTB4. To evolve a possible mechanism for these beneficial effects, we determined the metabolic fate of fish oil derived n-3 fatty acids in the skin. Specifically, we incubated guinea pig epidermal enzyme preparations with [3H]eicosapentaenoic acid (20:5 n-3) and [14C]docosahexaenoic acid (22:6 n-3). Analyses of the radiometabolites revealed the transformation of these n-3 fatty acids into n-6 lipoxygenase (arachidonate 15-lipoxygenase) products: 15-hydroxyeicosapentaenoic acid (15-HEPE) and 17-hydroxydocosahexaenoic acid (17-HDHE), respectively. Since 15-lipoxygenase products have been suggested as possible endogenous inhibitors of 5-lipoxygenase (an enzyme which catalyzes the formation of LTB4) we tested the ability of 15-HEPE and 17-HDHE in vitro to inhibit the activity of the 5-lipoxygenase. Incubations of these metabolites with enzyme preparations from rat basophilic leukemia (RBL-1) cells demonstrated that 15-HEPE (IC50 = 28 microM) and 17-HDHE (IC50 = 25 microM) are respectively potent inhibitors of RBL-I-5-lipoxygenase. The inhibitory potential of these fish oil metabolites provides a possible mechanism by which fish oil might act to decrease local cutaneous levels of LTB4, and thereby alleviate psoriatic symptoms.
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We assessed how children's self-concepts of ability for mathematics, English, social, and physical skills activities, ratings of the importance of these activities, and general self-esteem change across the transition to junior high school. Three types of change were assessed: change in mean levels, change in stability, and change in relationships. Twice each year during the sixth and seventh grades, 1,450 children completed questionnaires. Mean levels of children's self-esteem were lowest immediately after the transition, but recovered during seventh grade. Self-concept of ability and importance ratings for math and sports activities showed linear declines. Self-concept of ability for social activities showed a cubic trend, but importance ratings for social activities declined in a linear fashion. Children's self-concepts of ability for math and English became less stable across the junior high transition, whereas beliefs about other activities and general self-esteem were more stable in seventh grade.