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Biomedical subjects

M Davies

Publications and source records attributed to M Davies.

At least 73 records · Page 4Linked to original sources
PubMed2001

Mutagenesis of the GABA(A) receptor alpha1 subunit reveals a domain that affects sensitivity to GABA and benzodiazepine-site ligands.

We have mutated several amino acids in the region of the GABA(A) receptor alpha1 subunit predicted to form a small extracellular loop between transmembrane domains two and three to investigate its possible role in ligand sensitivity. The mutations were S275T, L276A, P277A, V279A, A280S and Y281F. Mutant alpha1 subunits were co-expressed with beta2 and gamma2 subunits in tsA201 cells or Xenopus oocytes. Binding studies revealed that the only mutation that significantly affected [3H]Ro15-4513 binding was the V279A substitution which reduced the affinity for this ligand. Electrophysiological examination of mutant receptors revealed that L276A, P277A and V279A displayed rightward shifts of their GABA concentration-response curves, the largest occurring with the L276A mutant. The impact of these mutations on allosteric modulation by benzodiazepine-site ligands was examined. V279A reduced the potency of both flunitrazepam and Ro15-4513 but, in each case, their efficacy was enhanced. A280S resulted in a decrease in flunitrazepam efficacy without affecting its potency. Additionally, P277A and A280S resulted in Ro15-4513 losing its inverse agonist effect at these receptors. These results suggest that a domain within this small extracellular loop between TMII-TMIII plays a role in determining the sensitivity of GABA(A) receptors to both GABA and benzodiazepine-site ligands.

Allosteric Regulation↗
PubMed2001

Cell surface heparan sulfate proteoglycans control the response of renal interstitial fibroblasts to fibroblast growth factor-2.

BACKGROUND: While the progression of renal disease to end stage is strongly correlated with tubulointerstitial changes, the control of the fibrotic process within the interstitium is poorly understood. Basic fibroblast growth factor (FGF-2) has been implicated as a major growth factor involved in fibroblast activation and extracellular matrix synthesis. Furthermore, in many cells, the activity of FGF-2 is controlled by a low-affinity but high-capacity interaction with heparan sulfate (HS) proteoglycans (PGs), such as members of the syndecan family. These molecules are likely to be central to the control of interstitial fibrosis, but as yet, there has been no characterization of their synthesis by interstitial cells. METHODS: The expression of HSPG on the surface of NRK 49F fibroblasts was demonstrated by immunohistochemistry and by metabolic labeling with [(35)S]-sulfate. HSs were characterized by specific enzymatic digestion, size exclusion chromatography, and anion exchange chromatography. The mRNA for syndecan 1 through syndecan 4 in the fibroblasts was detected by semiquantitative reverse transcription-polymerase chain reaction. Fibroblast proliferation was measured by the MTT assay. RESULTS: Immunohistochemistry and [(35)S]-sulfate-labeling demonstrated that renal fibroblasts expressed HSPGs on their surface. Furthermore, enzymatic removal of these HS (but not chondroitin sulfate) glycosaminoglycan (GAG) chains, or inhibition of GAG sulfation, abolished the proliferative response of both NRK cells and primary human cortical fibroblasts to FGF-2 but not to platelet-derived growth factor. The addition of conditioned medium, containing HS-GAG fragments, restored the proliferative response to FGF-2, confirming the specificity of the interaction. Finally, the mRNA for all four syndecans was detected in the fibroblasts, and that for syndecan 1 in particular was up-regulated by FGF-2. CONCLUSIONS: The present study demonstrates that the expression of cell surface HSPG was essential for the proliferation of renal fibroblasts in response to FGF-2, and therefore may play a major role in the development and persistence of a proliferating phenotype during interstitial nephritis.

Animals↗
PubMed2001

Methodological issues in designing a multisite trial of risperidone in children and adolescents with autism.

OBJECTIVE: To describe the methodological challenges and decisions made in developing a multisite, controlled study of risperidone in children and adolescents with autism. METHODS: Review the design considerations for clinical trials in children with autistic disorder accompanied by severe tantrums, aggressive and/or self-injurious behaviors. These design considerations include the definition of inclusion criteria that are relevant to clinical practice and matching study design to the goal of evaluating short- and long-term effects. Additional ethical and scientific issues concern the length of trial and sample size. RESULTS: We undertook a short-term, placebo-controlled study to evaluate the efficacy and safety of risperidone in children and adolescents with autistic disorder. This trial design was followed by an extended open-label maintenance on risperidone to confirm durability of treatment effects and to monitor safety. Finally, a placebo-controlled discontinuation study tested the need for continuous treatment. CONCLUSIONS: In the absence of standard pharmacological treatment for children with autistic disorder, a placebo-controlled study remains the most appropriate method of testing efficacy and safety. The clinical relevance of this study is enhanced by the addition of an extended maintenance phase followed by a placebo discontinuation.

Adolescent↗
PubMed2001

Clinical relevance of the primary findings of the MTA: success rates based on severity of ADHD and ODD symptoms at the end of treatment.

OBJECTIVES: To develop a categorical outcome measure related to clinical decisions and to perform secondary analyses to supplement the primary analyses of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA). METHOD: End-of-treatment status was summarized by averaging the parent and teacher ratings of attention-deficit/hyperactivity disorder and oppositional defiant disorder symptoms on the Swanson, Nolan, and Pelham, version IV (SNAP-IV) scale, and low symptom-severity ("Just a Little") on this continuous measure was set as a clinical cutoff to form a categorical outcome measure reflecting successful treatment. Three orthogonal comparisons of the treatment groups (combined treatment [Comb], medication management [MedMgt], behavioral treatment [Beh], and community comparison [CC]) evaluated hypotheses about the MTA medication algorithm ("Comb + MedMgt versus Beh + CC"), multimodality superiority ("Comb versus MedMgt"), and psychosocial substitution ("Beh versus CC"). RESULTS: The summary of SNAP-IV ratings across sources and domains increased the precision of measurement by 30%. The secondary analyses of group differences in success rates (Comb = 68%; MedMgt = 56%; Beh = 34%; CC = 25%) confirmed the large effect of the MTA medication algorithm and a smaller effect of multimodality superiority, which was now statistically significant (p < .05). The psychosocial substitution effect remained negligible and nonsignificant. CONCLUSION: These secondary analyses confirm the primary findings and clarify clinical decisions about the choice between multimodal and unimodal treatment with medication.

Attention Deficit Disorder with Hyperactivity↗
PubMed2001

Impairment and deportment responses to different methylphenidate doses in children with ADHD: the MTA titration trial.

OBJECTIVE: Results of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) were analyzed to determine whether a double-blind, placebo-controlled methylphenidate (MPH) titration trial identified the best MPH dose for each child with attention-deficit/hyperactivity disorder (ADHD). METHOD: Children with ADHD assigned to MTA medication treatment groups (n = 289) underwent a controlled 28-day titration protocol that administered different MPH doses (placebo, low, middle, and high) on successive days. RESULTS: A repeated-measures analysis of variance revealed main effects for MPH dose with greater effects on teacher ratings of impairment and deportment (F3 = 100.6, n = 223, p = .0001; effect sizes 0.8-1.3) than on parent ratings of similar endpoints (F3 = 55.61, n = 253, p = .00001; effect sizes 0.4-0.6). Dose did not interact with period, dose order, comorbid diagnosis, site, or treatment group. CONCLUSIONS: The MTA titration protocol validated the efficacy of weekend MPH dosing and established a total daily dose limit of 35 mg of MPH for children weighing less than 25 kg. It replicated previously reported MPH response rates (77%), distribution of best doses (10-50 mg/day) across subjects, effect sizes on impairment and deportment, as well as dose-related adverse events.

Analysis of Variance↗
PubMed2001

Longitudinal relationships between childhood, adolescent, and adult eating disorders.

OBJECTIVE: This study investigates the longitudinal course of eating problems from childhood though adulthood. The following questions are answered: (1) How stable are eating disorder symptoms and diagnoses over a 17-year interval from childhood to adulthood? (2) Do early childhood eating problems predict the occurrence of eating disorders in adulthood? METHOD: An epidemiologically selected sample of approximately 800 children and their mothers received DSM-based structured psychiatric assessments in 1975, 1983, 1985, and 1992. The stability of full DSM diagnostic criteria for anorexia nervosa and bulimia nervosa, symptom scales derived from DSM criteria, and individual symptoms such as binge eating or dieting between early adolescence, late adolescence, and young adulthood was examined. RESULTS: Early adolescent bulimia nervosa is associated with a 9-fold increase in risk for late adolescent bulimia nervosa and a 20-fold increase in risk for adult bulimia nervosa. Late adolescent bulimia nervosa is associated with a 35-fold increase in risk for adult bulimia nervosa. Symptom scale scores for anorexia nervosa and bulimia nervosa correlate in the 0.3 to 0.5 range from early to late adolescence and young adulthood. For both anorexia nervosa and bulimia nervosa, gender, as well as eating symptoms at early and late adolescence, all predict young-adult eating disorder symptoms. Risk factors for the later development of eating disorders comprise eating conflicts, struggles with food, and unpleasant meals in early childhood. CONCLUSION: The presence of eating problems in early childhood or an eating disorder in adolescence confers a strong risk for an eating disorder in young adulthood.

Adolescent↗
PubMed2001

Early life influences on later health: the role of nutrition.

Individuals who were small at birth have an increased risk of cardiovascular disease in later life. Barker has put forward a hypothesis to explain this and other associations, known as the 'fetal origins theory of adult disease'. It is proposed that chronic disease is the long-term outcome of physiological adaptations the unborn baby makes when it is undernourished, a process referred to as 'programming'. Maternal nutrition is thought to be a major influence on programming, and growth in childhood as well as obesity in later life may modulate the propensity for disease acquired in the womb. While robust evidence to support specific nutritional interventions during pregnancy is currently lacking, the theory in general affirms broader public health nutritional strategies and policies to improve the social and economic status of women.

Adaptation, Physiological↗
PubMed2001

DPC 681 and DPC 684: potent, selective inhibitors of human immunodeficiency virus protease active against clinically relevant mutant variants.

Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of many highly active antiretroviral therapy regimens. However, development of phenotypic and/or genotypic resistance can occur, including cross-resistance to other PIs. Development of resistance takes place because trough levels of free drug are inadequate to suppress preexisting resistant mutant variants and/or to inhibit de novo-generated resistant mutant variants. There is thus a need for new PIs, which are more potent against mutant variants of HIV and show higher levels of free drug at the trough. We have optimized a series of substituted sulfonamides and evaluated the inhibitors against laboratory strains and clinical isolates of HIV type 1 (HIV-1), including viruses with mutations in the protease gene. In addition, serum protein binding was determined to estimate total drug requirements for 90% suppression of virus replication (plasma IC(90)). Two compounds resulting from our studies, designated DPC 681 and DPC 684, are potent and selective inhibitors of HIV protease with IC(90)s for wild-type HIV-1 of 4 to 40 nM. DPC 681 and DPC 684 showed no loss in potency toward recombinant mutant HIVs with the D30N mutation and a fivefold or smaller loss in potency toward mutant variants with three to five amino acid substitutions. A panel of chimeric viruses constructed from clinical samples from patients who failed PI-containing regimens and containing 5 to 11 mutations, including positions 10, 32, 46, 47, 50, 54, 63, 71, 82, 84, and 90 had mean IC(50) values of <20 nM for DPC 681 and DPC 681, respectively. In contrast, marketed PIs had mean IC(50) values ranging from 200 nM (amprenavir) to >900 nM (nelfinavir).

Administration, Oral↗
PubMed2001

A randomised controlled trial of two methods of delivering nasal continuous positive airway pressure after extubation to infants weighing less than 1000 g: binasal (Hudson) versus single nasal prongs.

OBJECTIVES: Primary: to determine whether nasal continuous positive airway pressure (CPAP) delivered through binasal prongs results in a greater proportion of extremely low birthweight infants being successfully extubated, after a period of intermittent positive pressure ventilation, than nasal CPAP delivered by a single nasal prong. Secondary: to evaluate the effect of mode of delivery of nasal CPAP after extubation on the need for endotracheal reintubation, weight gain, rates of feeding intolerance, sepsis, suspected sepsis, cranial ultrasound abnormalities, retinopathy of prematurity, chronic lung disease, and the duration of assisted ventilation and care in the tertiary neonatal unit. DESIGN AND SETTING: Randomised, controlled, clinical trial conducted at the neonatal intensive care unit of the Royal Women's Hospital, Melbourne, Australia. PATIENTS: Infants of birth weight less than 1000 g, ventilated, requiring < 50% oxygen and ventilator rate less than or equal to 20/minute, and considered by the clinical management team to be ready for extubation. INTERVENTION: Infants were randomly allocated to receive nasal CPAP delivered through binasal (Hudson) prongs or a single nasal prong. PRIMARY OUTCOME MEASURE: Failure of extubation as defined by the following criteria: (a) apnoea (more than one episode/hour over a six hour period or one episode requiring bag and mask ventilation); (b) absolute increase in oxygen requirement greater than 15% above that required before extubation; (c) respiratory acidosis (pH < 7.25 with PCO(2) > 6.67 kPa). RESULTS: Ten of the 41 (24%) infants randomised to binasal prongs reached predetermined failure criteria compared with 26 of the 46 (57%) infants randomised to a single nasal prong (p = 0.005). Four of 17 (24%) infants of birth weight less than 800 g extubated to binasal prongs reached failure criteria compared with 14 of 16 (88%) extubated to a single nasal prong (p < 0.001). There were no significant differences in any of the secondary outcomes. CONCLUSIONS: For extremely low birthweight infants ventilated using an endotracheal tube, nasal CPAP delivered through binasal (Hudson) prongs is more effective in preventing failure of extubation than that delivered through a single nasal prong.

Device Removal↗
PubMed2001

Antioxidant enzymes in the developing lungs of egg-laying and metamorphosing vertebrates.

The activities of the pulmonary antioxidant enzymes (AOE), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase, increase in the final 10-20 % of gestation in the mammalian lung, to protect the lung from attack by increasing levels of reactive oxygen species at birth. Whether the increase occurs as a normal 'preparation for birth', i.e. by a genetically determined mechanism, or in response to increased levels of oxygen, i.e. in response to the environment, is not completely understood. We examined the activities of catalase, SOD and GPx in the developing lungs of two oviparous vertebrate species, the chicken (Gallus gallus) and an agamid lizard (Pogona vitticeps), and in a metamorphosing vertebrate, the anuran Limnodynastes terraereginae. During in ovo development embryos come into contact with higher levels of environmental oxygen, and at a much earlier stage of development, compared with the intrauterine development of mammals. Furthermore, in metamorphosing frogs, the lungs are inflated at an early stage to aid in buoyancy, although the gas-exchange function only develops much later upon final metamorphosis. Here, we hypothesise that the activity of the AOE will be elevated relatively much earlier during development in both oviparous and metamorphosing vertebrates. We also examined the effect of mild hypoxia (17 % oxygen) on the development of the pulmonary AOE in the chicken, to test the hypothesis that these enzymes are responsive to environmental oxygen. In the normoxic lung of both Gallus gallus and Pogona vitticeps, catalase and GPx activities were significantly increased in late incubation, whereas SOD activity decreased in late incubation. Catalase and SOD activities were virtually identical in hypoxic and normoxic embryos of the chicken, but GPx activity was significantly affected by hypoxia. In the developing frog, the activities of all enzymes were high at stage 30, demonstrating that the system is active before the lung displays any significant gas-exchange function. SOD and GPx activity did not increase further with development. Catalase activity increased after stage 40, presumably correlating with an increase in air-breathing. In summary, catalase expression in the two oviparous vertebrates appears to be completely under genetic control as the activity of this enzyme does not change in response to changes in oxygen tension. However, in tadpoles, catalase may be responsive to environmental oxygen. SOD also appears to follow a largely genetically determined program in all species. Under normoxic conditions, GPx appears to follow a genetically determined developmental pattern, but this enzyme demonstrated the largest capacity to respond to environmental oxygen fluctuations. In conclusion, it appears that the AOE are differentially regulated. Furthermore, the AOE in the different species appear to have evolved different levels of dependency on environmental variables. Finally, the late developmental increase in AOE activity seen in mammals is not as pronounced in oviparous and metamorphosing vertebrates.

Animals↗
PubMed2001

Irinotecan and taxane combinations for non small-cell lung cancer.

Based on nonoverlapping toxicity profiles and at least additive cytotoxicity in preclinical models, chemo-therapy regimens have been developed that feature the combination of irinotecan and a taxane drug. In the first study, the optimal doses of paclitaxel and irinotecan were 75 mg/m2 and 50 mg/m2, respectively, when chemotherapy was administered weekly for 4 consecutive weeks, followed by a 2-week rest. The dose-limit-ing toxicity for this regimen was neutropenia, and the most prominent nonhematologic toxicities were mild diarrhea and fatigue. Pharmacokinetic studies failed to demonstrate any sequence-dependent interaction be-tween these agents on the metabolism of irinotecan or its major metabolite. This regimen has been modified, with chemotherapy given on day 1 and day 8 every 3 weeks, and is being tested further in previously un-treated advanced non small-cell lung cancer (NSCLC). In a second trial, irinotecan was combined with docetaxel on a weekly schedule. When chemotherapy was given weekly for 4 weeks, followed by a 2-week rest, the recommended doses of docetaxel and irinotecan were 35 mg/m2 and 50 mg/m2, respectively. Low-grade gastrointestinal toxicity and asthenia were the dose-limiting toxicities. The treatment schedule was modified, with chemotherapy given on days 1 and 8 of a 21-day cycle, and patients are currently being treated with docetaxel 35 mg/m2 and irinotecan 65 mg/m2. Among the 10 evaluable patients with NSCLC in this second study, there was one partial response lasting 24 weeks and four patients with stable disease, including one patient who had progressive disease on a prior paclitaxel-containing regimen. The combinations of irinotecan and a taxane on a weekly schedule are active and well tolerated and deserve further evaluation in the treatment of NSCLC.

Journal Article↗
PubMed2001

Electrically active axons degenerate when exposed to nitric oxide.

Axonal degeneration is a major cause of permanent deficit in inflammatory neurological diseases such as multiple sclerosis. Axons undergo degeneration specifically at the site of the inflammatory lesions, suggesting that locally produced inflammatory factors mediate the phenomenon. One such factor is nitric oxide (NO), which we have previously reported can cause reversible conduction block in axons. Here we confirm these observations and extend them to show that axons exhibit the early stages of wallerian degeneration if they are conducting impulses at physiological frequencies while they are exposed to the low micromolar concentrations of NO that are likely to occur at sites of inflammation. Rat dorsal roots were concurrently exposed in vivo to both NO and sustained impulse activity at 1, 50, or 100 Hz. Although our in vivo observations necessarily focused on the more acute responses, morphological examination of exposed roots at the end of the recording period revealed nodal and paranodal changes consistent with acute wallerian degeneration in roots stimulated at 50 or 100 Hz. This interpretation was confirmed in a few experiments that were prolonged to permit more obvious indicators of degeneration to develop. In these experiments the formation of myelin ovoids and frank axonolysis occurred in more than 95% of fibers. Roots stimulated at only 1 Hz appeared normal. We propose that the combination of normal impulse traffic and NO at sites of inflammation may cause axonal degeneration and that electrical activity may therefore be an important factor in causing permanent disability in patients with neuroinflammatory disorders.

Action Potentials↗
PubMed2001

The influence of victim gender and sexual orientation on judgments of the victim in a depicted stranger rape.

This study investigated the impact of respondent gender, victim gender, and victim sexual orientation on judgments toward the victim of a depicted stranger rape. Respondents were required to read a scenario in which victim gender and sexual orientation varied between subjects, and to complete measures of behavioral blame, responsibility, and severity of the attack. Results revealed that male respondents made more anti-victim judgments than female respondents did. Male respondents judged gay male victims more negatively than they did other victims. Female respondents' judgments were pro-victim regardless of victim gender and victim sexual orientation. Results are discussed in relation to the feminist analysis of victim blame, and blame toward male rape victims. Implications for support services, particularly of male victims, are also considered.

Adolescent↗