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L Simmons

Publications and source records attributed to L Simmons.

At least 19 recordsLinked to original sources
PubMed2003

A Phase I clinical and pharmacological study of cis-diamminedichloro(2-methylpyridine) platinum II (AMD473).

AMD473 is a novel sterically hindered platinum cytotoxic with demonstrated ability to overcome acquired resistance to cisplatin in vitro and in human tumour xenografts. A single-agent dose escalating Phase I study was performed. AMD473 was initially administered intravenously as a 1 h infusion every 21 days to patients with advanced solid tumours. In total, 42 patients received a total of 147 cycles (median 3, range 1-8) of treatment at doses of 12, 24, 48, 96, 110, 120, 130, and 150 mg m(-2). Dosing intervals of 21 and 28 days were explored at the recommended dose. Neutropenia and thrombocytopenia proved dose limiting. Other toxicities included moderate nausea, vomiting, anorexia, and a transient metallic taste. There was no significant alopecia. The maximum tolerated dose was 150 mg m(-2). Plasma pharmacokinetics were linear. Two patients with heavily pretreated ovarian cancer showed partial response. Five patients (mesothelioma, ovary, nonsmall cell lung, and melanoma) showed prolonged stable disease. AMD473 demonstrates encouraging activity in patients, including those with prior platinum exposure. Toxicity is predictable with linear pharmacokinetics, as was predicted by preclinical studies. A dose of 120 mg m(-2) every 21 days is recommended for Phase II evaluation although there is evidence that chemo-naive patients and those of good performance status may tolerate a higher dose.

Adult↗
PubMed2003

The distraction effects of phone use during a crucial driving maneuver.

Forty-two licensed drivers were tested in an experiment that required them to respond to an in-vehicle phone at the same time that they were faced with making a crucial stopping decision. Using test track facilities, we also examined the influence of driver gender and driver age on these dual-task response capacities. Each driver was given task practice and then performed a first block of 24 trials, where one trial represented one circuit of the test track. Half of the trials were control conditions in which neither the stop-light was activated nor was the in-vehicle phone triggered. Four trials required only stop-light response and a further four, phone response only. The remaining four trials required the driver to complete each task simultaneously. The order of presentation of specific trials was randomized and the whole sequence was repeated in a second block giving 48 trials per driver. In-vehicle phone response also contained an embedded memory task that was evaluated at the end of each trial circuit. Results confirmed our previous observation that in the dual-task condition there was a slower response to the light change. To compensate for this slowed response, drivers subsequently brake more intensely. Most importantly, we recorded a critical 15% increase in non-response to the stop-light in the presence of the phone distraction task which equates with increased stop-light violations on the open road. These response patterns varied by driver age and driver gender. In particular, age had a large effect on task components that required speed of response to multiple, simultaneous demands. Since driving represents a highly complex and interactive environment, it is not possible to specify a simplistic relationship between these distraction effects and outcome crash patterns. However, we can conclude that such in-vehicle technologies erode performance safety margin and distract drivers from their critical primary task of vehicle control. As such it can be anticipated that a causal relation exists to collision events. This is a crucial concern for all in-vehicle device designers and for the many safety researchers and professionals seeking to reduce the adverse impacts of vehicle collisions.

Adult↗
PubMed2003

The feasibility of ultrasonic regional strain and strain rate imaging in quantifying dobutamine stress echocardiography.

BACKGROUND: Ultrasonic strain rate and strain can characterize regional one-dimensional myocardial deformation at rest. In theory, these deformation indices could be used to quantify normal or abnormal regional function during a dobutamine stress echo test. AIMS: The aims of our pilot study were threefold: (1) to determine the percentage of segments in which interpretable strain rate/strain data could be obtained during routine dobutamine stress echo, (2) to establish whether either the increase in heart rate or artefacts induced by respiration during dobutamine stress echo would influence analysis by degrading the data and (3) to determine the optimal frame rate vs image sector angle settings for data acquisition. Furthermore, although the detection of ischaemia was not to be addressed specifically in this study, we would describe the findings on the potential clinical role of regional deformation vs velocity imaging in detecting ischaemia-induced changes. METHODS: A standard dobutamine stress echo protocol was performed in 20 consecutive patients with a history of chest pain (16 with angiographic coronary artery disease and four with normal coronary angiograms). DMI velocities were acquired at baseline, low dose, peak dose, and recovery. To evaluate radial function (basal segment of the left ventricle posterior wall segment), parasternal LAX, SAX views were used. For long axis function data were acquired (4-CH, 2-CH views) from the septum; lateral, inferior and anterior left ventricle walls. Data was acquired using both 15 degrees (>150 frames per second (fps) and 45 degrees (115fps) sector angles. During post-processing each wall was divided into three segments: basal, mid and apical. Strain rate/strain values were averaged over three consecutive heart cycles. RESULTS: Data was obtained from 1936 segments, of which only 54 had to be excluded from subsequent analysis (2.8%) because of suboptimal quality. An increase in heart rates (up to 150/min) was not associated with a significant reduction in the number of interpretable segments. There was a significant correlation between maximal systolic strain rate/strain values obtained at narrow and at wide sector angles (e.g. a correlation for the septal segments: r=0.73,P <0.001 for strain rate, and r=0.71; P<0.001 for strain). The correlation for the timing of events obtained from narrow and wide sector angles was weaker. This would indicate that there was the insufficient temporal resolution for the latter acquisition method. Normal and abnormal regional strain rate/strain responses to an incremental dobutamine infusion were defined. In normal segments, maximal systolic strain rate values increased continuously from baseline, reaching the highest values at the peak dose of dobutamine. The segmental strain response was different. For strain, there was an initial slight increase at low dose of dobutamine (5, 10 microg/kg/min), but no further increase with increasing dose. A pattern representing an ischaemic response was identified and described. CONCLUSIONS: The feasibility study would suggest that with appropriate data collection and post-processing methodologies, strain rate/strain imaging can be applied to the quantification of dobutamine stress echo. However, appropriate post-processing algorithms must be introduced to reduce data analysis time in order to make this a practical clinical technique.

Adult↗
PubMed2001

Three mutations in v-Rel render it resistant to cleavage by cell-death protease caspase-3.

The retroviral oncoprotein v-Rel is a transcriptional activator in the Rel/NF-kappa B family. v-Rel causes rapidly fatal lymphomas in young chickens, and transforms and immortalizes chicken lymphoid cells in vitro. Several mutations that have enhanced the oncogenicity of v-Rel have been selected during in vitro and in vivo passage of v-Rel-containing retroviruses. In this report, we show that the C-terminal deletion and two point mutations (Asp-->Gly at residue 91 and Asp-->Asn at residue 437) in v-Rel make it resistant to cleavage by the cell-death protease caspase-3. In contrast, c-Rel, which has Asp residues at these sites, can be cleaved by caspase-3 in vitro as well as in vivo in cells induced to undergo apoptosis. We have characterized activities of v-Rel mutants with recreated single caspase-3 cleavage sites, two cleavage sites, or an introduced artificial cleavage site. All of these mutant v-Rel proteins are sensitive to caspase-3 cleavage in vitro, and show wild-type activity in terms of nuclear localization in chicken fibroblasts and DNA binding in vitro. Moreover, all caspase-3-sensitive v-Rel mutants transform chicken spleen cells in vitro and induce fatal lymphoid tumors in vivo to approximately the same extent as wild-type v-Rel. As with v-Rel mutants, caspase-3-resistant c-Rel mutants behave similarly to caspase-3-sensitive wild-type c-Rel in terms of DNA binding, transcriptional activation, in vitro transformation, and tumorigenicity. Mammalian c-Rel proteins can also be cleaved by caspase-3 in vitro, and a c-Rel mutant from a human pre-T lymphoma cell line is less sensitive than wild-type human c-Rel to cleavage by caspase-3. Taken together, these results demonstrate that specific mutations render oncogenic forms of Rel proteins resistant to cleavage by a cell-death caspase; however, the biological relevance of this resistance remains unclear. Nevertheless, to our knowledge, this is the first demonstration of mutations in caspase-3 recognition sites occurring during the evolution of an oncogenic protein.

Animals↗
PubMed1998

Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons.

Glial cell line-derived neurotrophic factor (GDNF) exhibits potent effects on survival and function of midbrain dopaminergic (DA) neurons in a variety of models. Although other growth factors expressed in the vicinity of developing DA neurons have been reported to support survival of DA neurons in vitro, to date none of these factors duplicate the potent and selective actions of GDNF in vivo. We report here that neurturin (NTN), a homolog of GDNF, is expressed in the nigrostriatal system, and that NTN exerts potent effects on survival and function of midbrain DA neurons. Our findings indicate that NTN mRNA is sequentially expressed in the ventral midbrain and striatum during development and that NTN exhibits survival-promoting actions on both developing and mature DA neurons. In vitro, NTN supports survival of embryonic DA neurons, and in vivo, direct injection of NTN into the substantia nigra protects mature DA neurons from cell death induced by 6-OHDA. Furthermore, administration of NTN into the striatum of intact adult animals induces behavioral and biochemical changes associated with functional upregulation of nigral DA neurons. The similarity in potency and efficacy of NTN and GDNF on DA neurons in several paradigms stands in contrast to the differential distribution of the receptor components GDNF Family Receptor alpha1 (GFRalpha1) and GFRalpha2 within the ventral mesencephalon. These results suggest that NTN is an endogenous trophic factor for midbrain DA neurons and point to the possibility that GDNF and NTN may exert redundant trophic influences on nigral DA neurons acting via a receptor complex that includes GFRalpha1.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor.

Glial-cell-line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent survival factors for sympathetic, sensory and central nervous system neurons. GDNF mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) and the transmembrane protein tyrosine kinase Ret. In contrast, the mechanism by which the NTN signal is transmitted is not well understood. Here we describe the identification and tissue distribution of a GPI-linked protein (designated NTNR-alpha) that is structurally related to GDNFR-alpha. We further demonstrate that NTNR-alpha binds NTN (K[d] approximately 10 pM) but not GDNF with high affinity; that GDNFR-alpha binds to GDNF but not NTN with high affinity; and that cellular responses to NTN require the presence of NTNR-alpha. Finally, we show that NTN, in the presence of NTNR-alpha, induces tyrosine-phosphorylation of Ret, and that NTN, NTNR-alpha and Ret form a physical complex on the cell surface. These findings identify Ret and NTNR-alpha as signalling and ligand-binding components, respectively, of a receptor for NTN and define a novel family of receptors for neurotrophic and differentiation factors composed of a shared transmembrane protein tyrosine kinase and a ligand-specific GPI-linked protein.

Amino Acid Sequence↗
PubMed1996

Substitution and caloric regulation in a closed economy.

Three experiments were conducted to study the effect of an imperfect substitute for food on demand for food in a closed economy. In Experiments 1 and 2, rats pressed a lever for their entire daily food ration, and a fixed ratio of presses was required for each food pellet. In both experiments, the fixed ratio was held constant during a daily session but was increased between sessions. The fixed ratio was increased over a series of daily sessions once in the absence of concurrently available sucrose and again when sucrose pellets were freely available. For both series, increases in the fixed ratio reduced food intake, but body weight was reduced only in the no-sucrose condition. In the sucrose condition, body weight and total caloric intake (sucrose plus food) were relatively unaffected by increases in the fixed ratio. At all fixed ratios, food intake was proportionally reduced by the intake of sucrose. In Experiment 3, monkeys obtained food or saccharin by pressing keys; the fixed ratio of presses per food pellet was increased once when tap water was each monkey's only source of fluid, again when each monkey's water was sweetened with saccharin, and a third time when each monkey had concurrent access to the saccharin solution and plain water. Increases in the fixed ratio, but not the intake of the saccharin solution, reduced each monkey's food intake. Because neither rats' sucrose nor monkeys' saccharin intakes affected the slope of the respective demand curves for food, monkeys and rats increased their daily output of presses and thereby defended their daily intake of those complementary elements of food. However, sucrose reduced rats' food intake. The relative constancy of body weight and total caloric intake in the sucrose condition is consistent with the possibility that rats tended to regulate caloric intake.

Animals↗
PubMed1996

The abnormalities of nailfold capillaries in scleroderma as assessed by video image analysis and photomicroscopy.

Scleroderma is a systemic connective tissue disease in which the diagnosis in supported by morphological changes in nailfold capillary size and density. These changes are open to observer bias. In this paper we describe 2 objective methods that allow quantitative definition of capillary changes, video image analysis (VIA) and photomicroscopy. VIA was used to assess 15 healthy control subjects and 22 patients with scleroderma. Scleroderma patients had a significantly larger capillary diameter (43 microns versus 20 microns, p = 0.0001) and capillary density was reduced by a mean factor of 0.5. Image stored on computer will facilitate serial assessments of nailfold capillary changes and possibly provide information on disease progression.

Adult↗
PubMed1994

GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle.

For survival, embryonic motoneurons in vertebrates depend on as yet undefined neurotrophic factors present in the limb bud. Members of the neurotrophin family are currently the best candidates for such neurotrophic factors, but inactivation of their receptor genes leads to only partial loss of motoneurons, which suggests that other factors are involved. Glial cell line-derived neurotrophic factor (GDNF), originally identified as a trophic factor specific for dopaminergic neurons, was found to be 75-fold more potent than the neurotrophins in supporting the survival of purified embryonic rat motoneurons in culture. GDNF messenger RNA was found in the immediate vicinity of motoneurons during the period of cell death in development. In vivo, GDNF rescues and prevents the atrophy of facial motoneurons that have been deprived of target-derived survival factors by axotomy. GDNF may therefore be a physiological trophic factor for spinal motoneurons. Its potency and specificity in vitro and in vivo also make it a good candidate for treatment of motoneuron disease.

Animals↗
PubMed1992

Perceptual bisection in rats: the effects of physostigmine, scopolamine and pirenzepine.

The effects of cholinergic drugs on three different perceptual bisection tasks were studied in rats. Physostigmine (0.056-0.56 mg/kg), a reversible anticholinesterase, produced dose-dependent decrements in discriminability (A'), but did not affect the bisection point (BP) in visual duration, auditory duration, and auditory intensity bisection tasks. This finding is consistent with results previously obtained in an auditory duration bisection task with an irreversible anticholinesterase, diisopropyl phosphofluoridate. Scopolamine (0.075-0.422 mg/kg), a muscarinic cholinergic-receptor antagonist, produced dose-dependent decrements in both A' and BP in visual and auditory duration bisection tasks. The behavioral antagonism between physostigmine (0.56 mg/kg) and scopolamine (0.075-0.237 mg/kg) was studied in the visual and auditory duration bisection tasks. The BP was not affected by physostigmine alone or in combination with scopolamine, except at the largest dose of scopolamine, which produced a reliable decrement in the BP. A', however, was equally decreased by physostigmine alone and all combinations of physostigmine and scopolamine. Pirenzepine (1, 3 and 10 mg/kg), a selective high-affinity M1 muscarinic antagonist, had no effect on A' or the BP in the duration bisection tasks, suggesting changes in perception produced by muscarinic antagonists do not involve the M1 receptor subtype. The similar drug effects in different sensory modalities (visual and auditory) and perceptual systems (subjective duration and loudness) suggest that cholinergic drugs may affect perceptual mechanisms responsible for sensory coding, such as the output of a neural generator.

Animals↗
PubMed1992

Loudness bisection and masking in the rat (Rattus norvegicus).

The bisection method of animal psychophysical scaling was examined as a measurement procedure. The critical assumptions of bisection scaling, as described by Pfanzagl (1968), were tested to determine if a valid equal-interval scale could be derived. A valid scale was derived in which loudness for the rat (Rattus norvegicus; n = 13) was a power function of sound pressure for 4-kHz tones. Masking noise reduced the discriminability of tonal stimuli but did not affect the bisection point. This result is consistent with an interval scale representation of loudness and demonstrates scale meaningfulness. Loudness bisection data that have been reported in the literature for 3 species (humans, rats, and pigeons) are in substantial agreement with our results.

Animals↗
PubMed1992

Intertrial-interval effects on sensitivity (A') and response bias (B") in a temporal discrimination by rats.

Killeen and Fetterman's (1988) behavioral theory of animal timing predicts that decreases in the rate of reinforcement should produce decreases in the sensitivity (A') of temporal discriminations and a decrease in miss and correct rejection rates (decrease in bias toward "long" responses). Eight rats were trained on a 10- versus 0.1-s temporal discrimination with an intertrial interval of 5 s and were subsequently tested on probe days on the same discrimination with intertrial intervals of 1, 2.5, 5, 10, or 20 s. The rate of reinforcement declined for all animals as intertrial interval increased. Although sensitivity (A') decreased with increasing intertrial interval, all rats showed an increase in bias to make long responses.

Animals↗
PubMed1990

Circadian variations in time perception in rats.

The hypothesis that time perception is determined by an internal clock's rate, which is sensitive to physiological circadian changes was examined. This hypothesis suggests that when body temperature and activity increase, clock rate increases causing overestimations of time and a decrease in time interval production. The following experiments examine this hypothesis with rats. Since rats are nocturnal, and body temperature is highest at night, time estimation should be longer and time production shorter than during the day. All experiments were run 24 hr a day under a 12:12 light:dark cycle. In the first experiment, rats discriminated among stimulus durations. Consistent with the hypothesis, both rats reliably judged standard durations as "longer" during the night than during the day. In Experiment 2, fixed-interval (FI) schedules of 60, 120 and 180 sec were used to examine circadian variations in time production. All seven rats produced longer postreinforcement pause (PRP) durations as FI length increased, and shorter PRP durations at night than during the day. However, absolute differences in PRP durations between day and night did not increase as FI duration increased, suggesting the PRP durations alone do not directly characterize proportional changes in internal clock rate. To more directly examine circadian variation in clock rate and the production of shorter intervals (i.e., between 1 and 16 sec) Experiment 3 used a lever holding procedure. Since this procedure requires the measured lever hold duration to meet or exceed the required hold duration, it more accurately characterizes the timing process.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

The effects of diisopropyl phosphorofluoridate (DFP) on time perception in rats.

The hypothesis that DFP alters circadian rhythms by altering the output of an "internal clock" which is also used to time events in behavioral tasks was tested. Since any clock has a mean rate (ticks/unit time) and an associated variance (changes in the rate across time), measures of time perception which depend upon both the mean clock rate and its variance (discriminability, A'), or only the mean clock rate (Bisection Point) were examined. In Experiment 1, two groups of rats were trained to discriminate between a standard duration and six comparison durations of a light. Six weeks following three injections of DFP (1.0 mg/kg/week) or vehicle (saline and 5% alcohol), the discriminability (A') between the standard and comparison durations was reliably reduced for the DFP-treated animals. In Experiment 2, rats were trained to perform on a temporal bisection task. Relative to performance during the weeks following vehicle (peanut oil) treatments, discriminability (A') during the weeks following treatment with DFP (1.0 mg/kg/week) was reliably degraded but measures of the Bisection Point were unaffected. Since Experiments 1 and 2 both used a light duration as a discriminative stimulus, Experiment 3 examined the possibility that DFP treatments produced a change in visual function rather than clock function. Two groups of rats were trained to discriminate between light-on and light-off periods in a standard free-operant successive discrimination paradigm. No changes in discriminability or response rates were evident following two injections of DFP (1.0 mg/kg/week) or vehicle (peanut oil).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

A cost-benefit analysis of demand for food.

Laboratory studies of consumer demand theory require assumptions regarding the definition of price in the absence of a medium of exchange (money). In this study we test the proposition that the fundamental dimension of price is a cost-benefit ratio expressed as the effort expended per unit of food value consumed. Using rats as subjects, we tested the generality of this "unit price" concept by varying four dimensions of price: fixed-ratio schedule, number of food pellets per fixed-ratio completion, probability of reinforcement, and response lever weight or effort. Two levels of the last three factors were combined in a 2 x 2 x 2 design giving eight groups. Each group was studied under a series of six FR schedules. Using the nominal values of all factors to determine unit price, we found that grams of food consumed plotted as a function of unit price followed a single demand curve. Similarly, total work output (responses x effort) conformed to a single function when plotted in terms of unit price. These observations provided a template for interpreting the effects of biological factors, such as brain lesions or drugs, that might alter the cost-benefit ratio.

Animals↗