Drug treatments for schizophrenia.
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Antipsychotic Agents↗
Biomedical subjects
R Lewis
Publications and source records attributed to R Lewis.
Regular exercise enhances insulin activation of IRS-1-associated PI3-kinase in human skeletal muscle.
Insulin action in skeletal muscle is enhanced by regular exercise. Whether insulin signaling in human skeletal muscle is affected by habitual exercise is not well understood. Phosphatidylinositol 3-kinase (PI3-kinase) activation is an important step in the insulin-signaling pathway and appears to regulate glucose metabolism via GLUT-4 translocation in skeletal muscle. To examine the effects of regular exercise on PI3-kinase activation, 2-h hyperinsulinemic (40 mU. m(-2). min(-1))-euglycemic (5.0 mM) clamps were performed on eight healthy exercise-trained [24 +/- 1 yr, 71.8 +/- 2.0 kg, maximal O(2) uptake (VO(2 max)) of 56.1 +/- 2.5 ml. kg(-1). min(-1)] and eight healthy sedentary men and women (24 +/- 1 yr, 64.7 +/- 4.4 kg, VO(2 max) of 44.4 +/- 2.7 ml. kg(-1). min(-1)). A [6, 6-(2)H]glucose tracer was used to measure hepatic glucose output. A muscle biopsy was obtained from the vastus lateralis muscle at basal and at 2 h of hyperinsulinemia to measure insulin receptor substrate-1(IRS-1)-associated PI3-kinase activation. Insulin concentrations during hyperinsulinemia were similar for both groups (293 +/- 22 and 311 +/- 22 pM for trained and sedentary, respectively). Insulin-mediated glucose disposal rates (GDR) were greater (P < 0.05) in the exercise-trained compared with the sedentary control group (9.22 +/- 0.95 vs. 6.36 +/- 0.57 mg. kg fat-free mass(-1). min(-1)). Insulin-stimulated PI3-kinase activation was also greater (P < 0.004) in the trained compared with the sedentary group (3.8 +/- 0.5- vs. 1.8 +/- 0.2-fold increase from basal). Endurance capacity (VO(2 max)) was positively correlated with PI3-kinase activation (r = 0.53, P < 0.04). There was no correlation between PI3-kinase and muscle morphology. However, increases in GDR were positively related to PI3-kinase activation (r = 0.60, P < 0.02). We conclude that regular exercise leads to greater insulin-stimulated IRS-1-associated PI3-kinase activation in human skeletal muscle, thus facilitating enhanced insulin-mediated glucose uptake.
Adult↗
The design of a practical and reliable fall detector for community and institutional telecare.
Falls are one of the greatest obstacles to independent living for frail and elderly people. Their early detection is an important step in providing people with the reassurance and confidence necessary to maintain an active lifestyle. We have investigated a worn fall detector linked to a community alarm system. A worn device is the only one which is satisfactory, provided that it generates few false alarms. The fall detector we have developed is the size of a small radio pager. It uses a two-stage detection process which senses shock and the orientation of the wearer. A fall is detected within 20 s and triggers a radio signal to a community alarm system. Tests were devised using a jointed mannequin to simulate five modes of falling to understand the effects of impact at different parts of the body. This allowed us to select the appropriate trigger threshold and wearing positions for the sensor. Prototypes were evaluated with 20 people to observe false alarms. The final design allowed reliable detection in 180 different falling scenarios.
Accidental Falls↗
The determinants of screening uptake and interventions for increasing uptake: a systematic review.
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Adult↗
Primary care. Communal living.
From this month, 80 per cent of health authorities will have at least one personal medical services pilot scheme in their area. The extension of the schemes raises concerns about equity and management issues for HAs. An HA where schemes will cover almost a third of the population has had to adopt an off-the-peg approach to development.
Family Practice↗
Peripheral neuropathy caused by proteolipid protein gene mutations.
Pelizaeus-Merzbacher disease (PMD) is a dysmyelinating disorder of the central nervous system typically caused by duplications or missense mutations of the proteolipid protein (PLP) gene. Most investigators have found that peripheral nerve function and structure is normal in PMD patients. We have found that null mutations of the PLP gene cause demyelinating peripheral neuropathy, whereas duplications and a proline 14 to leucine mutation do not affect nerve function. A family with a nonsense mutation at position 144, which affects only PLP but not the alternatively spliced gene product DM20, has a very mild syndrome, including normal peripheral nerve function. Our findings suggest that DM20 alone is sufficient to maintain normal nerve function and that there may be domains of PLP/DM20 that have a relatively more active role in the peripheral nervous system compared with that in the central nervous system.
Amino Acid Sequence↗
Correlation between weakness and axonal loss in patients with CMT1A.
We have developed a protocol to measure the progression of disability in patients with Charcot Marie Tooth (CMT) disease, particularly CMT1 over a several year period. Because CMT1 is a chronic disease, the natural history of changes occurring in such a brief period are not well understood, making clinical trials for CMT1 patients difficult to evaluate. We hypothesize that weakness in CMT1 correlates with axonal loss secondary to the abnormalities in Schwann cell myelin gene expression, which cause the disease. To test this hypothesis, we elected to carefully evaluate CMT patients by various modalities to measure strength, sensory loss, and axonal loss and demyelination and to compare these modalities to determine whether they correlated with findings on clinical examination. As suspected, patient weakness correlates more with secondary axonal loss than with demyelination, even though the primary abnormality in CMT1 is demyelination.
Adolescent↗
Famine in southern Sudan.
We provide baseline information and objective testimony on severe malnutrition and high mortality in the general population of southern Sudan that is affected by chronic civil war and severe famine.
Child, Preschool↗
Positionally selective growth of embryonic spinal cord neurites on muscle membranes.
Motor neurons from distinct positions along the rostrocaudal axis generally innervate muscles or muscle fibers from corresponding axial levels. These topographic maps of connectivity are partially restored after denervation or transplantation under conditions in which factors of timing and proximity are eliminated. It is therefore likely that motor neurons and some intramuscular structures bear cues that bias synapse formation in favor of positionally matched partners. To localize these cues, we studied outgrowth of neurites from embryonic spinal cord explants on carpets of membranes isolated from perinatal rat muscles. Neurites from rostral (cervical) and caudal (lumbar) spinal cord slices exhibit distinct growth preferences. In many instances, rostrally derived neurites grew selectively on membranes from forelimb muscles or from a single thoracic muscle (the serratus anterior) when given a choice between these membranes and membranes from hindlimb muscles or laminin. Caudally derived neurites almost never exhibited such rostral preferences, but instead preferred membranes from hindlimb muscles or a single hindlimb muscle (the gluteus) to rostral muscles or laminin. Likewise, spinal neurites exhibited distinct position-related preferences for outgrowth on membranes of clonal myogenic cell lines derived from specific rostral and caudal muscles. Taken together these results suggest that the membranes of motor axons and myotubes bear complementary labels that vary with rostrocaudal position and regulate neuromuscular connectivity.
Animals↗
Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors.
As part of our ongoing research program aimed at the identification of highly potent, selective, and systemically active agonists for group II metabotropic glutamate (mGlu) receptors, we have prepared novel heterobicyclic amino acids (-)-2-oxa-4-aminobicyclo[3.1. 0]hexane-4,6-dicarboxylate (LY379268, (-)-9) and (-)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-10). Compounds (-)-9 and (-)-10 are structurally related to our previously described nanomolar potency group II mGlu receptor agonist, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740 monohydrate, 5), with the C4-methylene unit of 5 being replaced with either an oxygen atom (as in (-)-9) or a sulfur atom (as in (-)-10). Compounds (-)-9 and (-)-10 potently and stereospecifically displaced specific binding of the mGlu2/3 receptor antagonist ([3H]LY341495) in rat cerebral cortical homogenates, displaying IC50 values of 15 +/- 4 and 8.4 +/- 0.8 nM, respectively, while having no effect up to 100 000 nM on radioligand binding to the glutamate recognition site on NMDA, AMPA, or kainate receptors. Compounds (-)-9 and (-)-10 also potently displaced [3H]LY341495 binding from membranes expressing recombinant human group II mGlu receptor subtypes: (-)-9, Ki = 14.1 +/- 1.4 nM at mGlu2 and 5.8 +/- 0.64 nM at mGlu3; (-)-10, Ki = 40.6 +/- 3.7 nM at mGlu2 and 4.7 +/- 1.2 nM at mGlu3. Evaluation of the functional effects of (-)-9 and (-)-10 on second-messenger responses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated each to be a highly potent agonist for group II mGlu receptors: (-)-9, EC50 = 2.69 +/- 0.26 nM at mGlu2 and 4.58 +/- 0.04 nM at mGlu3; (-)-10, EC50 = 3.91 +/- 0.81 nM at mGlu2 and 7.63 +/- 2. 08 nM at mGlu3. In contrast, neither compound (up to 10 000 nM) displayed either agonist or antagonist activity in cells expressing recombinant human mGlu1a, mGlu5a, mGlu4a, or mGlu7a receptors. The agonist effects of (-)-9 and (-)-10 at group II mGlu receptors were not totally specific, however, as mGlu6 agonist activity was observed at high nanomolar concentrations for (-)-9 (EC50 = 401 +/- 46 nM) and at micromolar concentrations (EC50 = 2 430 +/- 600 nM) for (-)-10; furthermore, each activated mGlu8 receptors at micromolar concentrations (EC50 = 1 690 +/- 130 and 7 340 +/- 2 720 nM, respectively). Intraperitoneal administration of either (-)-9 or (-)-10 in the mouse resulted in a dose-related blockade of limbic seizure activity produced by the nonselective group I/group II mGluR agonist (1S,3R)-ACPD ((-)-9 ED50 = 19 mg/kg, (-)-10 ED50 = 14 mg/kg), indicating that these molecules effectively cross the blood-brain barrier following systemic administration and suppress group I mGluR-mediated limbic excitation. Thus, heterobicyclic amino acids (-)-9 and (-)-10 are novel pharmacological tools useful for exploring the functions of mGlu receptors in vitro and in vivo.
Amino Acids↗
Non-ginsenoside nicotinic activity in ginseng species.
Amongst the many different therapeutic applications of ginseng are beneficial effects on age-related cognitive impairments. Ageing in the brain is associated with a loss of nicotinic receptor binding and receptor stimulation increases binding. Stimulation of the CNS (central nervous system) nicotinic receptor is considered to be beneficial in relation to symptomatic treatment and neuroprotection in age-associated cognitive disorders which involve a further receptor loss. We assessed Panax ginseng, Panax quinquefolium and several chemical constituents of these plants for nicotinic activity based on displacement of 3H-(-)nicotine from human brain cerebral cortex membranes in vitro. Dose-dependent displacement was evident in crude ethanol extracts of Panax ginseng and Panax quinquefolium. Assay of an extract of Panax ginseng showed the plant to have affinity for both the nicotinic receptor, and to a lesser extent the muscarinic receptor (IC50 2.12 mg/mL and 5.25 mg/mL respectively). Activity was largely conserved after the extraction of choline and other water soluble quaternary ammonium compounds (QAC), indicating that the activity of the plant extracts was not due to choline. Displacement binding assay of some purified chemical constituents, including a number of ginsenosides, showed that these were not primarily responsible for Panax activity. The active chemical constituent has yet to be identified, but the demonstrated nicotinic activity of ginseng warrants further investigation with reference to therapeutic activity in age-related conditions such as dementia.
Adult↗
The Effect of Gibberellins on Flowering in Roses.
The gibberellins A(1), A(3), A(5), A(8), A(19), A(20), and A(29) were identified in vegetative shoot tips of Rosa canina by comparing their mass spectra and Kovats retention indices with those of standards. Most wild roses have a short flowering season of 2-4 weeks in spring, whereas most modern cultivars flower recurrently. 'Félicité et Perpétue' is a short-season hybrid from a cross between a wild rose and a recurrent-flowering rose, whereas its sport, 'Little White Pet,' flowers recurrently. The concentrations of gibberellins (GAs) were measured in shoot apices of both cultivars. In March (before floral initiation in spring) the concentrations of GA(1) and GA(3) were respectively threefold and twofold higher in 'Félicité et Perpétue' than in 'Little White Pet.' In April (after floral initiation) the concentrations of both gibberellins were substantially greater than in March, and concentrations of GA(1) and GA(3) were, respectively, 17-fold and 12-fold greater in 'Félicité et Perpétue' than in 'Little White Pet.' It is postulated that, in 'Félicité et Perpétue,' floral initiation occurs when concentrations of GAs are low and is inhibited when concentrations of GAs are high, whereas in 'Little White Pet' concentrations of GAs remain at permissive levels throughout the growing season. Applications of GA(1) and GA(3) to axillary shoots in March inhibited floral development in 'Félicité et Perpétue' but not in 'Little White Pet.' This suggests that the combined concentration of exogenous and endogenous gibberellins might have been raised to inhibitory levels in the former but not in the latter cultivar.
Journal Article↗
Orbscan pachymetry: implications of a repeated measures and diurnal variation analysis.
INTRODUCTION: Corneal thickness changes reflect alterations in hydration and metabolism. Ultrasound pachymetry determinations may be adversely influenced by fluctuations in tissue hydration, whereas optical systems are apparently unaffected by these fluxes. A recently marketed, optical-based, topographic mapping system (Orbscan; Orbtek, Inc.) uses anterior and posterior corneal surface data to calculate corneal thickness. OBJECTIVE: This new instrumentation presents as a potentially useful pachymetry tool for evaluation of corneas under hydration flux or challenge (e.g., postphotorefractive keratectomy [PRK] healing studies) and was therefore evaluated for accuracy and variability. MEASUREMENTS: Three calibrated standards were measured in repeated fashion. Additionally, 1 test subject was measured 30 times in 1 day (5 measurements each at 8:00, 9:30, and 11:00 AM and at 1:00, 2:30, and 4:00 PM). Corresponding measurements were made at 8:00 and 11:00 AM and at 4:00 PM on 3 separate days to assess repeatability. Grouped data from 18 volunteer subjects were compared to the data of the test subject as well. RESULTS: Pachymetry accuracy on a calibrated standard was determined to be +/-2 microm (standard deviation, n = 12). Repeated measures on the subject demonstrated a mean standard deviation of 9.08 microm for 750 thickness data points across the central 7 mm of the cornea; peripheral measurement points exhibited progressively greater variability than at the apex (analysis of variance; P<0.0001). A plot of thickness by corneal location and time of day exhibited a diurnal pattern, with the peripheral cornea exhibiting progressively greater thickness changes than the central cornea (two-way analysis of variance; P<0.00001). The data significantly correlated across days when all times of day were considered (r = 0.999). However, thickness values obtained at 8:00 AM were significantly different across days (t test; P<0.0002). The subject's data correlated very well (r = 0.9996) with the grouped volunteer data. CONCLUSIONS: These data show this system to be useful in corneal research and in clinical settings. The data confirm early morning pachymetry to be highly variable. Additionally, the data not only indicate a diurnal variation of corneal hydration over time, but also imply the presence of a diurnal-based hydration gradient across the peripheral cornea, both of which can have significance for PRK, since excimer tissue ablation effectiveness is influenced by tissue hydration.
Circadian Rhythm↗
Convalescent excretion of Salmonella enteritidis in infants.
OBJECTIVES: To review the excretion of Salmonella enteritidis PT4 in the faeces of infants involved in a point-source outbreak in a nursery, and to relate these findings to advice given by the Outbreak Control Team (OCT). METHODS: Retrospective laboratory-based survey. RESULTS: Infection with S. enteritidis PT4 was microbiologically confirmed in 33 primary cases and one secondary case. Of the faeces submitted 4 weeks from exposure, 96% remained positive. None of the infants was symptomatic by this time, and none received antimicrobial treatment. Two infants aged less than 1 year were still excreting 22 weeks after the onset of the outbreak. CONCLUSIONS: As for other serotypes, S. enteritidis PT4 causes prolonged symptomless excretion after infection, particularly in infants aged less than 1 year. Infection control measures, including exclusion criteria, may need to be modified as an outbreak progresses.
Child, Preschool↗
Diabetic emergencies: Part 1. Hypoglycaemia.
Diabetes mellitus is a chronic, lifelong condition which can affect people of all ages, and is increasing in prevalence. Hypoglycaemia is probably the most common acute problem suffered by patients with diabetes. It is also a serious medical emergency with potentially fatal outcomes, and is the most common reason for patients with diabetes attending an accident and emergency (A&E) department. It is also a major source of anxiety for diabetics, particularly those controlled on insulin, and unfortunately, in the move towards ever tighter glycaemic control, it is inevitable that diabetics will continue to suffer from hypoglycaemia. This article examines the pathophysiology of hypoglycaemia and some of its main causes, and will look at the clinical management of the patient with hypoglycaemia, both in the community and in the A&E department. The importance of the recognition and prompt treatment of hypoglycaemia, and of the investigation of hypoglycaemia with no obvious cause are also discussed. Part 2 of the series will explore the pathophysiology and clinical management of diabetic emergencies involving hyperglycaemia, including both diabetic ketoacidosis and the rarer hypernatremic, non-ketotic coma.
Diabetes Mellitus, Type 1↗
Comparison of two regimens of beta-adrenergics in acute asthma.
BACKGROUND AND METHODS: Inhaled adrenergics and steroids are the main agents used in acute asthma. Dosing recommendations for adrenergics, while generally becoming more aggressive, lack prospective validation. A double blind, randomized trial of two regimens of nebulized metaproterenol was conducted in patients presenting to an Emergency Department with an acute asthma exacerbation. Asthmatics age 16-55, with no other cardio-pulmonary disease, presenting with peak expiratory flow rate (PEFR) < 30% of predicted and greater than 80 L/m were enrolled. All patients received 125 mg of methylprednisolone and theophylline, if needed, to reach therapeutic levels. The experimental group received 0.3 cc metaproterenol in 2.5 cc of saline at times 0, 20", 40", 1', 2', 3', 4', 5', 6', and 7'. The control group received metaproterenol at times 0, 1 hr, and hours 3, 5, and 7. Placebo was given to control group patients at 20", 40", 2', 4', and 6'. PEFR and vital signs were measured 10 min after each treatment. Study end points included discharge upon reaching set criteria or admission if patients were not discharged following the hour 7 treatment. RESULTS: Seventy one patients were enrolled, 40 in experimental group and 31 in the control group. The group characteristics did not differ at entry in any significant way, and the groups began with mean expected PEFR of 23.4% and 24.5%, respectively. There were no significant differences at any point in PEFR outcomes, time to discharge, or admission rate. The experimental group showed a greater increase in pulse rate and a reduced diastolic blood pressure at 20, 40 and 60 min. The experimental group had a 12- and 8-fold increase in the risk of a pulse rate > 140 at 40 and 60 min, respectively. This group also had two moderate complications, both near the 60-minute mark. These were an induction of atrial fibrillation in one patient and ischemic electrocardiographic changes in another. CONCLUSION: Three treatments in the first hour, and hourly thereafter showed no benefit over treatments initially, at one hour, and every other hour in acute, moderate, or severe exacerbation of asthma. Side effects were markedly increased in the control group. Such dosing should not be recommended as routine therapy.
Acute Disease↗
Use of a clinical Escherichia coli isolate expressing lux genes to study the antimicrobial pharmacodynamics of moxifloxacin.
Escherichia coli isolate 16,906 expressing lux genes was used for real-time monitoring of moxifloxacin effects on bacterial metabolism compared with effects on cell replication. Viable counts showed concentration-dependent killing by moxifloxacin; real-time measurement of bioluminescence on the same cultures showed metabolic activity over 54 h, but with greater inhibition at 1 x MIC than with higher MIC multiples. Post-antibiotic effect was longer when determined using bioluminescence than by viable counts. The control-related effective regrowth time was consistent with both methods. Bioluminescent bacteria provide a rapid and sensitive means for measuring antimicrobial effects on bacterial metabolism.
Anti-Bacterial Agents↗