Multidisciplinary approaches in progressive neurological disease: can we do better?
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Disease Progression↗
Biomedical subjects
M Phillips
Publications and source records attributed to M Phillips.
Effect of oxygen on breath markers of oxidative stress.
Supplemental oxygen is often administered to induce hyperoxia in nonhypoxic patients for indications such as chest pain, despite lack of evidence of clinical benefit. Induced hyperoxia is potentially toxic, since it may increase oxidative stress and peroxidative damage to deoxyribonucleic acid, lipids and proteins. The aim of this study was to establish whether supplemental oxygen induces oxidative stress in nonhypoxic subjects. Breath markers of oxidative stress were measured in 31 healthy subjects before and after breathing 28% oxygen at 2.0 L x min(-1) via nasal prongs for 30 min while resting. The criterion standard of oxidative stress was the breath methylated alkane contour (BMAC), a three-dimensional plot of the alveolar gradients of C4-C20 alkanes and monomethylated alkanes produced by lipid peroxidation. Volatile organic compounds (VOCs) in breath were assayed by gas chromatography and mass spectroscopy, and the BMACs before and after oxygenation were compared. Following oxygenation, there was a significant increase in mean volume under the curve of the BMAC and in alveolar gradients of three VOCs: 3-methyltridecane, 3-methylundecane and 5-methylnonane. Breath markers of oxidative stress were significantly increased in normal volunteers breathing supplemental oxygen for 30 min.
Adult↗
A whole blood bactericidal assay for tuberculosis.
The bactericidal activity of orally administered antituberculosis (anti-TB) drugs was determined in a whole blood culture model of intracellular infection in which microbial killing reflects the combined effects of drug and immune mechanisms. Rifampin (Rif) was the most active compound studied and reduced the number of viable bacilli by >4 logs. Isoniazid (INH), 2 quinolones, and pyrazinamide (PZA) showed intermediate levels of activity. Ethambutol exerted only a bacteristatic effect; amoxicillin/clavulanate was inactive. The combination of INH-Rif-PZA showed strong activity against 11 drug-sensitive isolates (mean, -3.8 log) but no activity against 12 multidrug-resistant (MDR) strains. The combination of levofloxacin-PZA-ethambutol had intermediate bactericidal activity against MDR isolates (mean, -1.2 log) but failed to equal that of INH-Rif-PZA against sensitive isolates (P<.001). The whole blood BACTEC method (Becton Dickinson) may be useful for the early clinical evaluation of new anti-TB drugs and in the management of individual patients.
Anti-Infective Agents↗
Redox and ligand exchange reactions of potential gold(I) and gold(III)-cyanide metabolites under biomimetic conditions.
Biomimetic pathways for the oxidation of [Au(CN)(2)](-), a gold metabolite, and further cyanation of the gold(III) products to form Au(CN)(4)(-) were investigated using 13C NMR and UV-Visible spectroscopic methods. Hypochlorite ion, an oxidant released during the oxidative burst of immune cells, was employed. The reaction generates mixed dicyanoaurate(III) complexes, trans-[Au(CN)(2)X(2)](-), where X(-) represents equilibrating hydroxide and chloride ligands, and establishes the chemical feasibility of dicyanoaurate oxidation by OCl(-) to gold(III) species. This oxidation reaction suggests a new procedure for synthesis of H[Au(CN)(2)Cl(2)]. Reaction of trans-[Au(CN)(2)X(2)](-) (X(-)=Cl(-) and Br(-)) or [AuCl(4)](-) with HCN in aqueous solution at pH 7.4 leads directly to [Au(CN)(4)](-) without detection of the anticipated [Au(CN)(x)X(4-x)](-)intermediates, which is attributed to the cis- and trans-accelerating effects of the cyanides. The reduction of [Au(CN)(4)](-) by glutathione and other thiols is a complex, pH-dependent process that proceeds through two intermediates and ultimately generates [Au(CN)(2)](-). These studies provide further insight into the possible mechanisms of an immunogenically generated gold(I)/gold(III) redox cycle in vivo.
Cyanates↗
Synthesis of a new bisphosphonic acid ligand (SEDP) and preparation of a (188)Re-(Sn)SEDP bone seeking radiotracer.
The new bisphosphonate ligand SEDP (2-sulfonato-1,1-ethylidene bisphosphonic acid) has been synthesized and characterized, including the determination of the protonation constants, and used to form (188)Re-(Sn)SEDP from Na(188)ReO4. The title compound (188)Re-(Sn)SEDP shows slightly greater bone uptake and less kidney uptake than (188)Re-(Sn)HEDP in rat biodistribution studies.
Animals↗
Deconfounding the effects of dominance and social acceptance on self-esteem.
Three studies examined the independent effects of social acceptance and dominance on self-esteem. In Studies 1 and 2, participants received false feedback regarding their relative acceptance and dominance in a laboratory group, and state self-esteem was assessed. Results indicated that acceptance and dominance feedback had independent effects on self-esteem. Study 2 showed that these effects were not moderated by individual differences in participants' self-reported responsivity to being accepted versus dominant. In Study 3, participants completed multiple measures of perceived dominance, perceived acceptance, and trait self-esteem. Results showed that both perceived dominance and perceived acceptance accounted for unique variance in trait self-esteem, but that perceived acceptance consistently accounted for substantially more variance than perceived dominance. Also, trait self-esteem was related to the degree to which participants felt accepted by specific people in their lives, but not to the degree to which participants thought those individuals perceived them as dominant.
Adult↗
Comparison of clozapine and haloperidol on some autonomic and psychomotor functions, and on serum prolactin concentration, in healthy subjects.
AIMS: To compare the autonomic, neuroendocrine and psychomotor effects of single doses of the 'atypical' antipsychotic clozapine and the 'classical' antipsychotic haloperidol, in healthy male volunteers. METHODS: Clozapine (50 mg), haloperidol (3 mg) and placebo were administered to 12 healthy male volunteers at weekly intervals, according to a balanced double-blind design. Resting pupil diameter, salivary output, heart rate, blood pressure, plasma prolactin concentration, critical flicker fusion frequency and subjective 'alertness', 'contentedness' and 'anxiety' were measured at baseline and 2, 3, 4 and 5 h after drug ingestion. Data were analysed by analysis of variance with individual comparisons (Dunnett's test) with a significance criterion of P < 0.05. RESULTS: Significant treatment effects (difference from placebo [mean, 95% CI] 5 h after drug ingestion) were as follows: clozapine reduced pupil diameter (mm; -3.02 [-3.56, -2.47]), salivary output (g; -0.34 [-0.60, -0.08]), mean arterial blood pressure (mm Hg; -8.7 [-14.3, -3.1]), critical flicker fusion frequency (Hz; -3.26 [-3.94, -2.58]), and subjectively-rated 'alertness' (mm; -20.94 [-29.21, -12.67]) and 'contentedness' (mm; -12.98 [-17.90, -8.06]), whereas haloperidol increased prolactin concentration (mU l(-1); 301.3 [196.7, 405.8]) and caused small reductions in pupil diameter (mm; -0.68 [-1.23, -0.14]), mean arterial blood pressure (mm Hg; -7.0 [-12.6, -1.4]) and critical flicker fusion frequency (Hz; -1.15 [-1.83, -0.47]). CONCLUSIONS: The effects of the antipsychotics are in agreement with their receptor binding profiles: alpha(1)-adrenoceptor blockade by clozapine may contribute to reductions in pupil diameter, salivation, mean arterial blood pressure and sedation, and muscarinic cholinoceptor blockade by the drug may underlie the reduction in salivation. Conversely, D(2) dopamine receptor blockade by haloperidol is likely to be responsible for the increase in prolactin secretion evoked by the drug.
Adult↗
Opsonizing antibodies (IgG1) up-regulate monocyte proinflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and IL-6 but not anti-inflammatory cytokine IL-10 in mycobacterial antigen-stimulated monocytes-implications for pathogenesis.
Cachexia is one of the prominent features of advanced tuberculosis (TB) seen in association with increased expression of the monokine TNF-alpha. Several mycobacterial proteins, including PPD, stimulate TNF-alpha secretion from monocytes. Host factors that may play a role in cytokine expression from monocytes remain largely unknown. One such factor is the opsonizing antibodies. Monocytes have high-affinity receptors (FcgammaI and FcgammaIII) for IgG1 and IgG3 antibodies that mediate antigen uptake. We have reported selective up-regulation of IgG1 (which bind to Fcgamma receptors) in advanced TB and have recently shown the ability of PPD-specific IgG1 antibodies to augment TNF-alpha expression in PPD-stimulated monocytes. These observations have now been extended to other cytokines with semipurified fractions from secreted antigens of Mycobacterium tuberculosis (containing 30 kD and 58 kD) that were devoid of lipids, glycolipids and carbohydrates. In the presence of heat-inactivated TB plasma containing known amounts of antigen-specific IgG1 antibodies, these fractions induced significantly increased TNF-alpha, IL-6 and IL-10 secretion. Absorption of IgG1 with Protein 'A' removed the augmenting activity for TNF-alpha and IL-6 secretion from the TB plasma samples. In the case of IL-10, removal of IgG1 resulted in increased rather than decreased IL-10 secretion. These results suggest a possible pathogenic role for antibodies in TB by enhancing proinflammatory and blocking down-regulatory cytokines such as IL-10 cytokines during the chronic phase of TB.
Antigens, Bacterial↗
Outcomes measurement for asthma following acute presentation to an emergency department.
The Asthma Management Plan (AMP) was developed by the Thoracic Society of Australia and New Zealand in 1989 to provide a more uniform approach to asthma care, aimed at reducing mortality, morbidity and emergency presentations. The AMP is often supplemented with Asthma Clinical Pathways (CPs) within the emergency department and hospital setting. This study was designed to evaluate the impact of these two instruments on asthma outcomes one month after presentation to the emergency department. The AMP and CP were both found to have had positive influences on asthma management. However, the study illustrates that there continue to be problems with asthma management, which would be improved by a more consistent use of these instruments.
Acute Disease↗
Factors influencing patients' length of stay.
This study was conducted to evaluate the ability of AN-DRG version 3.1 to predict variation in patients' length of stay in hospital (LOS) and identify other factors that can influence the LOS by using routinely collected hospital morbidity data. A total of 18 DRGs that comprised 4,589 episodes were analysed. Multiple regression was used to model length of stay as a function of a number of independent variables. Overall only 37.6% of variation in mean length of stay could be explained. DRGs predicted 30% of the total variation. Other factors such as age, payment classification, source of referral, specialty of doctor, and ethnic group also influenced patient length of stay. It was concluded that the limited explanation was a consequence of a lack of a better indicator of severity within DRGs.
Diagnosis-Related Groups↗
A multi-project systems approach to developing community trust and building capacity.
Community characteristics are being recognized as important determinants for effective community-based programs. Community capacity to collaboratively identify issues, establish collective goals, and mobilize resources is built on experience with such interactions and trust among collaborators. Conceptual approaches and methods to develop community capacity rarely have been a focus of research programs, at least in part due to categorical funding, which often limits the scope and duration of interventions, thereby limiting capacity development. This approach uses multiple categorical funding sources to create sustained community programs involving multiple systems to increase capacity. Quasi-experimental evidence of increases in community capacity within two Alabama communities is presented.
Adult↗
Inhibition of isoniazid-induced expression of Mycobacterium tuberculosis antigen 85 in sputum: potential surrogate marker in tuberculosis chemotherapy trials.
Mycobacterium tuberculosis antigen 85 is induced in vitro by isoniazid (INH); its sustained induction in sputum during tuberculosis (TB) therapy predicts relapse. In this trial, rifampin or rifalazil inhibited the induction of sputum antigen 85 by INH in a dose-dependent fashion. This approach may facilitate the evaluation of new TB drugs.
Acyltransferases↗
"Haemoxygenase-1 induction and exhaled markers of oxidative stress in lung diseases", summary of the ERS Research Seminar in Budapest, Hungary, September, 1999.
In recent years, there has been increasing interest in noninvasive monitoring of airway inflammation and oxidative stress. Several volatile and nonvolatile substances can be measured in exhaled breath and have been suggested as potential biomarkers of these events. Exhaled gases, including carbon monoxide (CO), alkanes (ethane, pentane), and substances measured in breath condensate, such as hydrogen peroxide (H2O2) and isoprostanes were all suggested as potential markers of oxidative stress in the lung. A European Respiratory Society (ERS) International Research Seminar entitled "Haemoxygenase-1 induction and exhaled markers of oxidative stress in lung diseases" was organized by the Airway Regulation and Provocation Group of the Clinical Allergy and Immunology Assembly in Budapest, Hungary in September, 1999 to integrate the latest knowledge on these issues and accelerate further improvement in this area. During this 2-day event several issues were raised about: the use and standardization of measurements in exhaled breath; problems of measuring expired H2O2 and other mediators in breath condensate; role and regulation of haemoxygenase (HO)-1 in the lung; and conditions and factors influencing exhaled CO. This report is a summary of the main presentations at the seminar, together with the current areas of research in this rapidly expanding field.
Antioxidants↗
Transdermal fentanyl for pain relief in a paediatric palliative care population.
This multicentre, observational study examined the efficacy of the therapeutic transdermal fentanyl system (TTS-fentanyl) in children requiring opioids for pain in life-threatening disease. Forty-one children receiving oral morphine (median dose 60 mg/day) transferred to transdermal fentanyl (median dose 25 micrograms/h according with the manufacturer's dose conversion guidelines). Twenty-six children completed the 15-day treatment phase, seven died due to disease progression and eight were withdrawn because of adverse events, inadequate analgesia or a change to parenteral opioids. After 15 days, the median fentanyl dose was 75 micrograms/h (range 25-250). No serious adverse events were attributed to fentanyl. There was a trend toward improved side-effects and convenience with fentanyl. Twenty-three of 26 parents (three missing) and 25 of 26 investigators considered transdermal fentanyl to be better than previous treatment. For all records available (at 15 days or on withdrawal if earlier), 75% (27/36) reported that fentanyl treatment was 'good' or 'very good'. The findings suggest that transdermal fentanyl is both effective and acceptable for children and their families.
Administration, Cutaneous↗
Pharmacological characterization of locomotor sensitization induced by chronic phencyclidine administration.
Phencyclidine (PCP) administration in rats acutely in high doses or chronically in lower doses causes neurotoxicity characterized by neuronal vacuolization and apoptotic neuronal death, respectively. The purpose of this study was to determine whether drugs that previously had been reported to prevent either type of neurotoxicity were also able to prevent locomotor sensitization following chronic PCP administration. PCP (5 or 20 mg/kg) was administered once a day for 5 days following drug pretreatment. After withdrawal, rats were challenged with 3.2 mg/kg PCP and locomotor activity was assessed. Haloperidol and clozapine significantly attenuated sensitization elicited by PCP (20 mg/kg). The D(1)-like antagonist SCH23390 was much less effective than clozapine, showing a marginal inhibition. Risperidone, a D(2)/serotonin (5-HT(2)) antagonist, also resulted in a marginal attenuation of 15%. Ketanserin, a 5-HT(2) antagonist, had no effect. Atropine retarded sensitization by 35% and (+)-sulpiride caused a 50% reduction. The AMPA/kainate antagonist, 6,7-dinitroquinoxaline-2,3-dione, had no effect, but barbital sodium reduced sensitization by 54%. These data suggest that gamma-aminobutyric acid A, D(2), and muscarinic receptors play a major role in the complex pathway underlying sensitization to PCP, whereas D(1), 5-HT(2) and AMPA receptors have little or no relevance in the behavioral sensitization produced by 20 mg/kg PCP. In a model using 5 mg/kg PCP, the effects of sulpiride and SCH23390 replicated those observed with 20 mg/kg PCP and further showed that acute locomotor activation is not a strict requirement for the development of sensitization. These data argue that there is overlap, but nonidentity, between the mechanisms underlying PCP-induced sensitization and neurotoxicity.
Animals↗
Developing community capacity and improving health in African American communities.
Community-based programs have produced mixed results. Community capacity is thought to be a major determinant of program effectiveness. Thus, enhancing community capacity may increase the beneficial effects of existing programs and enhance future program effectiveness. This highlights the need to focus on understanding the components of capacity and the methods of enhancing capacity. Although we are just beginning to examine and understand key concepts, community capacity is probably influenced by both relatively nonmodifiable characteristics (such as demographic factors, institutional resources, and social structures) and relatively modifiable characteristics (such as knowledge, skills, and the ability and willingness of members and agencies to work collaboratively). In their relationships with community members and agencies, academicians and public health practitioners may help acquire categorical funding to enhance opportunities to build community capacity and their own capacity as well. The relationship between academicians/practitioners and community members/agencies probably is influenced by a host of characteristics which determine the degree to which capacity can be built. This paper discusses: the key components of capacity; the factors that influence building capacity through collaborations; a community health advisor (CHA) model which both builds on sociocultural aspects of African American culture and is consistent with methods for building community capacity; and how modifications to this model allow it to be compatible with categorically funded projects.
Black or African American↗
Developing community capacity and improving health in African American communities.
Community-based programs have produced mixed results. Community capacity is thought to be a major determinant of program effectiveness. Thus, enhancing community capacity may increase the beneficial effects of existing programs and enhance future program effectiveness. This highlights the need to focus on understanding the components of capacity and the methods of enhancing capacity. Although we are just beginning to examine and understand key concepts, community capacity is probably influenced by both relatively nonmodifiable characteristics (such as demographic factors, institutional resources, and social structures) and relatively modifiable characteristics (such as knowledge, skills, and the ability and willingness of members and agencies to work collaboratively). In their relationships with community members and agencies, academicians and public health practitioners may help acquire categorical funding to enhance opportunities to build community capacity and their own capacity as well. The relationship between academicians/practitioners and community members/agencies probably is influenced by a host of characteristics which determine the degree to which capacity can be built. This paper discusses: the key components of capacity; the factors that influence building capacity through collaborations; a community health advisor (CHA) model which both builds on sociocultural aspects of African American culture and is consistent with methods for building community capacity; and how modifications to this model allow it to be compatible with categorically funded projects.
Black or African American↗
Cross-linking constraints on F-actin structure.
The DNase I binding loop (residues 38-52), the hydrophobic plug (residues 262-274), and the C terminus region are among the structural elements of monomeric (G-) actin proposed to form the intermonomer interface in F-actin. To test the proximity and interactions of these elements and to provide constraints on models of F-actin structure, cysteine residues were introduced into yeast actin either at residue 41 or 265. These mutations allowed for specific cross-linking of F-actin between C41 and C265, C265 and C374, and C41 and C265 using dibromobimane and disulfide bond formation. The cross-linked products were visualized on SDS-PAGE and by electron microscopy. Model calculations carried out for the cross-linked F-actins revealed that considerable flexibility or displacement of actin residues is required in the disulfide cross-linked segments to fit these filaments into model F-actin structures. The calculated, cross-linked structures showed a better fit to the Holmes rather than the refined Lorenz model of F-actin. It is predicted on the basis of such calculations that image reconstruction of electron micrographs of disulfide cross-linked C41-C374 F-actin should provide a conclusive test of these two similar models of F-actin structure.
Actins↗