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Biomedical subjects

M Keenan

Publications and source records attributed to M Keenan.

At least 19 recordsLinked to original sources
PubMed2002

Recent progress in the development of subtype selective nicotinic acetylcholine receptor ligands.

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand gated ion channels, which are found at the neuromuscular junction and in the central and peripheral nervous systems. The channels can be assembled from fourteen known subunits. The exact combination and function of all the channels are still not determined but in the CNS certain combinations have been identified which appear to modulate the release of specific neurotransmitters. Non-specific nAChR agonists like nicotine and epibatidine, have been shown to have interesting pharmacology but their clinical value is limited by their undesirable side effects. Selective ligands for different receptor subtypes have been reported and these compounds are probably the best tools for determining the function of the subtypes. The expectation is that some receptor subtype selective nAChR ligands will be clinically useful for the treatment of a broad range of CNS disorders. The development of stable cell lines functionally expressing specific combinations of subunits has greatly improved our understanding of ligand specificity. There have also been advances in the modelling of the ligand binding site, thanks to the discovery of a homologous snail ACh binding protein the X-ray structure of which was determined in 2001. These techniques should lead to rapid advances in the development of truly subtype selective ligands. In this review we describe recent progress in the area and describe the first 1000 fold selective low molecular weight ligands from the AstraZeneca group. We also comment on the first subtype specific channel modulators.

Alkaloids↗
PubMed2001

The regioselective aminohydroxylation of allylic carbamates.

The synthesis and aminohydroxylation of a series of acyclic allylic carbamates is described: the formation of a putative O=Os=NR linkage between the transition metal and substrate is proposed to account for the high levels of regioselectivity that were observed; proof of the structure of one of the aminohydroxylation products was obtained through X-ray crystallography.

Journal Article↗
PubMed2001

Developing fluency and endurance in a child diagnosed with attention deficit hyperactivity disorder.

We examined the effect of a teaching method on skill fluency and on-task endurance of a 9-year-old boy who had been diagnosed with attention deficit hyperactivity disorder. An academic task that occurred at low fluency during 10-min baseline sessions was taught to fluency. When responding was not yet fluent, brief reversals to baseline showed that the learner's rate of responding decreased and that he did not spend entire sessions on task. However, once a fluency goal had been reached, responding remained fluent and he remained on task in the third reversal condition.

Achievement↗
PubMed2000

Independent use of activity materials by the elderly in a residential setting.

A lottery was implemented to encourage the elderly clients of a residential home to use activity materials any time they wished, independently of staff intervention and the institutional routine of the home. During baseline, there were minimal levels of independent use of activity materials by residents. Various conditions were implemented but only the introduction of a ł20 lottery prize brought about a significant increase in the frequency of independent use of activity materials. A follow-up suggested that the reinforcing properties of the activity materials themselves eventually maintained the target behavior.

Aged↗
PubMed2000

Treatment of allergic asthma by targeting janus kinase 3-dependent leukotriene synthesis in mast cells with 4-(3', 5'-dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97).

4-(3',5'-Dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97) is a rationally designed potent inhibitor of Janus kinase (JAK)-3. Treatment of mast cells with WHI-P97 inhibited the translocation of 5-lipoxygenase (5-LO) from the nucleoplasm to the nuclear membrane and consequently 5-LO-dependent leukotriene (LT) synthesis after IgE receptor/FcepsilonRI crosslinking by >90% at low micromolar concentrations. WHI-P97 did not directly inhibit the enzymatic activity of 5-LO, but prevented its translocation to the nuclear membrane without affecting the requisite calcium signal. WHI-P97 was very well tolerated in mice, with no signs of toxicity at dose levels ranging from 5 microg/kg to 50 mg/kg, and LD(10) was not reached at a 50 mg/kg dose level when administered as a single i. p. or i.v. bolus dose. Therapeutic WHI-P97 concentrations, which inhibit mast cell leukotriene synthesis in vitro, could easily be achieved in vivo after the i.v. or i.p. administration of a single nontoxic 40 mg/kg bolus dose of WHI-P97. Notably, WHI-P97 showed promising biological activity in a mouse model of allergic asthma at nontoxic dose levels. Treatment of ovalbumin-sensitized mice with WHI-P97 prevented the development of airway hyper-responsiveness to methacholine in a dose-dependent fashion. Furthermore, WHI-P97 inhibited the eosinophil recruitment to the airway lumen after the ovalbumin challenge in a dose-dependent fashion. Further development of WHI-P97 may therefore provide the basis for new and effective treatment as well as prevention programs for allergic asthma in clinical settings.

Animals↗
PubMed1999

Glowing jellyfish, luminescence and a molecule called coelenterazine.

Luminescence has assumed an important role in analytical biochemistry and molecular biology as an extremely sensitive method for determining the concentration of specific ions and molecules. The luminescent system of the jellyfish Aequorea victoria consists of the photoprotein aequorin, which contains the molecule coelenterazine as a prosthetic group and shows considerable potential in this area.

Aequorin↗
PubMed1996

An inhibitor of the sodium pump obtained from human placenta.

BACKGROUND: Much effort has been expended in the search for an endogenous inhibitor of the cellular sodium/potassium pump, a compound of major physiological importance, which has been implicated in the mechanism of essential hypertension. Others have suggested that ouabain or an isomer of ouabain may be the endogenous pump inhibitor. Neonatal cord serum contains an inhibitor of the sodium pump; we attempted to isolate and characterise this substance from human placentas. METHODS: Homogenised placentas were dialysed and the resulting solutes were trapped on octadecylsilyl silica and then separated by high-performance liquid chromatography. Measurement of the activity of the sodium pump of human leucocytes was used to test each fraction for the presence of the inhibitor. FINDINGS: An inhibitor of the sodium pump was obtained by this technique in a mass spectrometrically pure form with a mass of 370 Da, an empirical formula of C24H34O3 and only one hydroxyl group. The characteristic fragmentation pattern observed in negative-ion mass spectrometry was compared with those of various model compounds; this comparison suggested that the active material was a dihydropyrone-substituted steroid. INTERPRETATION: These results suggest that a dihydropyrone-substituted steroid is an endogenous regulator of the sodium pump in humans and, presumably, other mammals. Proof of the endogenous origin will require the demonstration of a previously unrecognised biosynthetic pathway.

Bufanolides↗
PubMed1996

The psychoeducational profile of boys with Klinefelter syndrome.

Klinefelter syndrome (KS) affects about 1 in 900 males due to an extra X chromosome. Although there are no obvious physical features associated with childhood KS, many boys demonstrate a cognitive deficit in verbal processing. The first section of this article integrates the extant literature on intelligence and achievement outcomes in boys with KS. The second section presents our findings from a 20-year study involving one of the largest unselected cohorts of boys with KS. We followed 36 boys with KS and 33 sibling controls from 6 until 20 years of age. Boys with KS are shown to demonstrate a verbal cognitive deficit and significant underachievement in reading and spelling, as well as in arithmetic. These problems, which are evident from early school years, increase with age such that by late adolescence, boys with KS are four to five grade levels behind. In addition, we also found that they were most likely to have a generalized type of learning disability, with very few boys indicating a pure reading or pure arithmetic problem. They also showed deficits in written language skills and acquisition of knowledge-based subject material were also problematic. Despite significant underachievement and frequent grade failure, many boys with KS had completed high school, and a few were also pursuing postsecondary educations. The discussion section examines how their language-based disability affects comprehension and learning, leading to underachievement.

Achievement↗
PubMed1995

Intelligence and achievement in children with extra X aneuploidy: a longitudinal perspective.

Forty-seven children (35 male, 12 female) identified as having a supernumerary X chromosome by neonatal screening were studied psychologically from childhood to late adolescence. This paper compares their findings relative to sibling controls on tests of intelligence and achievement collected over a 14-year period. Children with a supernumerary X chromosome were found to score consistently below controls on Verbal IQ and subtests comprising the Verbal Comprehension factor but they did not differ on Performance IQ, which was in the normal range. At all ages, they showed poorer reading and arithmetic achievement; relative risk for reading and arithmetic impairment was 2.6 and 2.6 in males and 1.1 and 1.7 in females. Males with an extra X chromosome were more likely to receive special education than females, who more often failed a grade. Academic achievement was not affected in aneuploid children with higher levels of intelligence. Overall, these results suggest milder impairment than previously reported, particularly among trisomy X females.

Achievement↗
PubMed1993

Concurrent activities and instructed human fixed-interval performance.

Two experiments explored the effects of two types of concurrent activity on human fixed-interval performance. Eight adult subjects were given access to either reading material or a working television set across three fixed-interval values (60 s, 300 s, and 600 s). During Experiment 1, 2 subjects produced "scalloped" patterns and reported no verbal regulation (e.g., counting) in the presence of the reading material, but shifted to low-rate patterns and reported verbal regulation when the reading material was withdrawn. The 2 other subjects in Experiment 1 produced consistent low-rate performances and reported verbal regulation during access to reading material. However, when these subjects were given access to a working television set, they produced scalloped patterns and reported no verbal regulation. During Experiment 2, 4 experimentally naive subjects showed consistent scalloped patterning and no verbal regulation across fixed-interval values when they were allowed to watch television. When access to the television was denied, subjects reliably reported verbal regulation, and low-rate patterns emerged. These behavioral effects focus our attention on the contingencies that control human performance on fixed-interval schedules.

Adult↗
PubMed1993

A transfer of functions through derived arbitrary and nonarbitrary stimulus relations.

During Experiments 1 and 2, subjects were trained in a series of related conditional discriminations in a matching-to-sample format (A1-B1, A1-C1 and A2-B2, A2-C2). A low-rate performance was then explicitly trained in the presence of B1, and a high-rate performance was explicitly trained in the presence of B2. The two types of schedule performance transferred to the C stimuli for all subjects in both experiments, in the absence of explicit reinforcement through equivalence (i.e., C1 = low rate and C2 = high rate). In Experiment 2, it was also shown that these discriminative functions transferred from the C1-C2 stimuli to two novel stimuli that were physically similar to the C stimuli (SC1 and SC2, respectively). For both these experiments, subjects demonstrated the predicted equivalence responding during matching-to-sample equivalence tests. In Experiments 3 and 4, the conditional discrimination training from the first two experiments was modified in that two further conditional discrimination tasks were trained (C1-D1 and C2-D2). However, for these tasks the D stimuli served only as positive comparisons, and ND1 and ND2 stimuli served as negative comparisons (i.e., C1 x ND1 and C2 x ND2). Subsequent to training, the negatively related stimuli (ND1 and ND2) did not become discriminative for the schedule performances explicitly trained in the presence of B1 and B2, respectively. Instead, the ND1 stimulus became discriminative for the schedule performance trained in the presence of B2, and ND2 became discriminative for the schedule performance trained in the presence of B1. All subjects from Experiment 4 showed that the novel stimulus SND1, which was physically similar to ND1, became discriminative for the same response pattern as that controlled by ND1. Similarly, SND2, which was physically similar to ND2, became discriminative for the same response pattern as that controlled by ND2. Subjects from both Experiments 3 and 4 also produced equivalence responding on matching-to-sample equivalence tests that corresponded perfectly to the derived performances shown on the transfer of discriminative control tests.

Journal Article↗
PubMed1993

Total quality management: a matter of quality polarity analysis and management.

Alvin Zander claims that group members are often more concerned with personal needs and rights than those of the organization. People tend to have their attention on only half (the upside of their preferred pole and the downside of the other) of the whole "picture" of a polarity. By making a complete, accurate diagram of the entire polarity and continually updating and using it, people can promote collaboration and effectiveness despite the automatic tendency for people to be both blind to the entire situation and individualistically undermining successful management of the polarity over time. In other words, most efforts to produce noteworthy and lasting results in successful implementation of total quality management most likely will be limited--or result in failure--due to the fact that nursing managers, staff, and administrators view autocratic management and employee empowerment as separate choices to be made and are unclear that their day-to-day action impacts both direction and empowerment continually. Polarity analysis and management tend to integrate what appear to be personal and individual needs with those of others in a collaborative partnership. When addressing any polarity, it is important to acknowledge that people at all levels of the organization potentially are paradoxically the greatest resources and the biggest barriers to unprecedented breakthrough results. Overzealous action to reduce autocratic leadership will subsequently affect empowerment negatively and thus ultimately erode direction. Likewise overzealous action to increase empowerment will promote a lack of focus and finally erode organization and compliance. As any group of people begins to experience the recurrence of the ups and downs of both poles, there is increased frustration, resignation, and sense of ineffectiveness.

Choice Behavior↗