Biomedical subjects

C Oliver

Publications and source records attributed to C Oliver.

At least 19 recordsLinked to original sources

PubMed2007

Highly concentrated monoclonal antibody solutions: direct analysis of physical structure and thermal stability.

Virtually all current analytical methods employed in the development of highly concentrated monoclonal antibody (MAb) formulations require dilution of the sample before acquiring data. Thus, there is an unmet need for methods to study proteins directly at high concentration, since extrapolation of stability indicating parameters obtained from dilute studies may not be representative of the high concentration solution. Only slight or no modifications of biophysical methods including fluorescence, UV absorbance, circular dichroism, and FTIR (ATR and transmittance) spectroscopies as well as differential scanning calorimetry (DSC) are described here that permit the direct study of immunoglobulins (and other proteins) at high concentrations. Although FTIR spectra show differences that are dependent upon sampling geometry, other spectroscopic data from two different recombinant MAbs suggests that structure of each antibody exists in a physically similar state in the concentration range of 0.1-190 mg/mL in 40 mM pH 6 citrate-phosphate buffer. Upon thermally stressing these proteins, spectroscopic techniques that probe tertiary structure demonstrate a decrease in the apparent thermal melting temperature of approximately 5-20 degrees C of both proteins with increasing concentration. In contrast, DSC thermograms and CD thermal experiments suggest a minor degree of stabilization (approximately 2 degrees C) for both antibodies although protein association could be responsible for these observations. Empirical phase diagrams produced from spectroscopic data also suggest (1) the existence of similar structural states at low temperatures independent of concentration and (2) a decrease in the temperature at which phase changes are observed with increasing concentration. The decrease in structural stability observed in these studies is probably the result of aggregation or self-association of the recombinant MAbs upon heating in crowded solutions and not due to a decrease in the intrinsic structural stability of the MAbs.

Antibodies, Monoclonal↗

PubMed2007

Standardizing lung function laboratories for multicenter trials.

Multi-center studies provide advantages in clinical research but differences between centers can introduce bias. Three specialist pediatric respiratory laboratories standardized their methodology and examined differences between centers. The specific aims were to (i) assess the variability of measurements on adults within and between centers and (ii) to exchange and cross-analyze data from children to assess the extent of agreement between centers. Each laboratory used identical equipment and software. Inter-laboratory visits were used to (i) standardize protocols for data collection and analysis and (ii) make spirometric and plethysmographic measurements on participating staff at each location. Staff also had repeat measurements in their home laboratories. Measurements from children in each laboratory were exchanged on disk, cross-analyzed, and data compared by ANOVA. There were no significant within-subject, between-center differences in FVC, FEV1, FEF50, FRCpleth, or VC. There was a slight trend for TLC and RV (P=0.07) to be higher at one center. The 95% limits of agreement within and between centers were similar for all parameters. There were no differences between centers in cross-analyzed data from 10 children. By standardizing hardware, software, and protocol, potential inter-laboratory differences can be minimized. We recommend that this approach be adopted prior to multi-center studies.

Adult↗

PubMed2006

Chloroplast DNA phylogeography of the arctic-montane species Saxifraga hirculus (Saxifragaceae).

The genetic structure of populations of an arctic-montane herb, Saxifraga hirculus (Saxifragaceae), was analysed by means of chloroplast restriction fragment-length polymorphism. Sampled populations were distributed across Europe and North America (Alaska and Colorado). There was no evidence for geographically structured genetically divergent lineages, and although no haplotypes were shared between North America and Europe, the haplotypes from different continents were intermixed on a minimum spanning tree. European populations were much more highly differentiated and had much lower levels of haplotype diversity than their Alaskan counterparts. Centres of haplotype diversity were concentrated in those Alaskan populations located outside the limits of the last (Wisconsin) glaciation, suggesting that they may have acted as refugia during the Pleistocene. It was not possible to identify putative migration routes or corresponding refugia in the European genepool. One British population, from the Pentland Hills, was genetically very distant from all the others, for reasons that are as yet unknown.

Alaska↗

PubMed2006

The behavioural phenotype of Angelman syndrome.

BACKGROUND: The purpose of this review is to examine the notion of a behavioural phenotype for Angelman syndrome and identify methodological and conceptual influences on the accepted presentation. METHODS: Studies examining the behavioural characteristics associated with Angelman syndrome are reviewed and methodology is described. RESULTS: Potential bias in the description of the phenotype emerges with the use of case and cohort studies with the absence of comparison groups. A trend in the literature from a direct gene effect to a socially mediated effect on laughter is evident. CONCLUSION: Evidence for a behavioural phenotype of Angelman syndrome has begun to emerge. However, by adopting the concept of a 'behavioural phenotype', attention may become biased towards the underlying biological basis of the syndrome, with developmental and environmental factors being overlooked.

Adolescent↗

PubMed2006

Effect of long-term atorvastatin treatment on the electrophysiological and mechanical functions of muscle.

OBJECTIVE: To study alterations in muscle function combining physiological, electrophysiological and metabolic measurements in patients receiving a statin at various dosages during long-term therapy. MATERIAL: A 3-month (D0, D30 and D90) longitudinal physiological and electrophysiological muscle study was performed in 26 patients receiving 10, 40 or 80 mg/day atorvastatin. METHOD: All subjects performed maximal (MVC) and submaximal (60% MVC) isometric thumb adduction, handgrip and knee extension exercises during the recording of surface electromyograms (EMG) of the adductor pollicis (AP), flexor digitorum (FD) and vastus lateralis (VL). The compound muscle potential (M-wave) evoked by direct muscle stimulation was measured at rest and after 60% MVCs and the EMG power spectrum was analyzed during sustained effort. Blood was sampled from an antecubital vein for measurements of pH, lactate and potassium levels after thumb adduction and handgrip exercises. The measurements were repeated on Day 0 (D0), D30 and D90. RESULTS: Atorvastatin did not affect the MVC and endurance time to fatigue. Post-exercise M-wave alterations in the AP began at D30 with the 80 mg/day treatment and there was a reduced or suppressed leftward shift in the EMG power spectrum in the AP and VL with all 3 dosages. In the AP, the EMG changes appeared earlier (D30) with 80 mg/day whereas they only occurred at D90 on the lower dosages. Atorvastatin had no effect on the maximal postexercise variations in pHv and lactate but it significantly reduced the maximal increase in plasma potassium concentration after thumb adduction and handgrip exercise, the effects being only present at D90 on 10 mg/day but occurring as early as D30 with higher dosages. CONCLUSION: A 3-month atorvastatin treatment did not affect the maximal performance of skeletal muscle during voluntary efforts but EMG analysis revealed a reduced muscle excitability and an attenuated adaptation to fatigue. These effects prevailed in muscles containing the largest proportion of slow-oxidative fibers and were associated with a reduced outward flow of potassium.

Anticholesteremic Agents↗

PubMed2006

The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent.

L-theanine (N-ethyl-L-glutamine) or theanine is a major amino acid uniquely found in green tea. L-theanine has been historically reported as a relaxing agent, prompting scientific research on its pharmacology. Animal neurochemistry studies suggest that L-theanine increases brain serotonin, dopamine, GABA levels and has micromolar affinities for AMPA, Kainate and NMDA receptors. In addition has been shown to exert neuroprotective effects in animal models possibly through its antagonistic effects on group 1 metabotrophic glutamate receptors. Behavioural studies in animals suggest improvement in learning and memory. Overall, L-theanine displays a neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans.

Animals↗

PubMed2005

[Corticotropic axis and chronic stress in abdominal obesity and metabolic syndrome].

Several indicators of corticotropic axis hyperactivity have been observed in common abdominal obesity, which is clinically similar to the obesity found in Cushing's syndrome. Corticotropic axis hyperactivity may be involved in the development and metabolic and cardiovascular complications of abdominal obesity. Several mechanisms may be responsible for this hormonal dysregulation: genetic, lifestyle, and nutritional factors, and chronic stress. We note the necessity of methodologically-impeccable clinical studies for an objective evaluation of the role of stress in obesity.

Abdominal Fat↗

PubMed2005

Arterial distensibility in adolescents: the influence of adiposity, the metabolic syndrome, and classic risk factors.

BACKGROUND: Atherosclerosis develops from childhood, but the determinants of this preclinical stage remain uncertain. We examined the relations of classic coronary risk factors, adiposity and its associated metabolic disturbances, to arterial distensibility (a marker of early arterial disease) in 13- to 15-year-olds, some of whom had previously been studied at ages 9 to 11 years. METHODS AND RESULTS: Brachial artery distensibility was measured by a noninvasive ultrasound technique in 471 British children in whom measures of adiposity, blood pressure, fasting blood lipids, and insulin had been made. All adiposity measures showed strong graded inverse relationships with distensibility. Inverse associations with distensibility were also observed for insulin resistance (homeostasis model assessment), diastolic pressure, C-reactive protein, and the number of metabolic syndrome components present, which had a graded relation to distensibility. Total and LDL cholesterol levels were also inversely related to distensibility, but less strongly than adiposity; homocysteine had no relation to distensibility. Although the relations of total and LDL cholesterol and diastolic pressure to distensibility had been present at 9 to 11 years of age, those of adiposity and insulin resistance were only apparent at 13 to 15 years. CONCLUSIONS: Adiposity and its metabolic consequences are associated with adverse changes in the arterial wall by the teenage years. The graded relation with increasing adiposity was stronger than that for cholesterol and was seen at body mass index levels well below those considered to represent "obesity." This emphasizes the importance of population-based strategies to control adiposity and its metabolic consequences in the young.

Adipose Tissue↗

PubMed2005

Ultrasonically nebulized distilled water prevents exogenous histamine hyperreactivity in Toxocara canis-infected mice.

OBJECTIVE: This study examines the effect of ultrasonically nebulized distilled water inhalation on the systemic histamine hyperreactivity of Toxocara canis-infected mice. METHODS: Uninfected and T. canis-infected mice received an intravenous sublethal dose of histamine and lethality rates were documented. At 24 days post infection, infected mice received ultrasonically nebulized distilled water inhalation for 1 h. Twenty-four hours later histamine levels were determined in bronchoalveolar lavage fluid as well as histamine lethality and toluidine blue-stained mast cell number in the lung. RESULTS: T. canis-infected mice showed increased lethality after exposure to histamine in comparison to uninfected mice. Ultrasonically nebulized distilled water inhalation prevented histamine-induced lethality and reduced toluidine blue-stained mast cell numbers in the lung. CONCLUSIONS: The correlation between decreases in stained mast cells in the lung after ultrasonically nebulized distilled water inhalation and inhibition of histamine-induced lethality in these animals suggests participation of mast cells in the phenomenon and could be helpful in understanding the mechanisms of hyperreactivity during helminth parasite infections.

Anaphylaxis↗

PubMed2005

The association between environmental events and self-injurious behaviour in Cornelia de Lange syndrome.

BACKGROUND: There has been limited empirical research into the environmental causes of self-injury in Cornelia de Lange syndrome. The present study examined the variability of self-injurious behaviour in Cornelia de Lange syndrome across environmental setting events. Additionally, the association between setting events and more specific environmental events was examined. METHOD: A descriptive analysis of observational data on eight children with Cornelia de Lange syndrome aged between 4 and 14 years was carried out. The association between self-injurious behaviour and four environmental setting events and between specific environmental events and setting events was examined using established statistical methods for observational data. RESULTS: Seven out of eight of the participants showed at least one form of self-injurious behaviour that was associated with a particular setting event. The study also demonstrated that the relationship between setting events and environmental events is extremely variable across individuals. CONCLUSIONS: Self-injurious behaviour in some individuals with Cornelia de Lange syndrome is associated with environmental events although the precise nature of the association warrants clarification. Using broad setting events as a methodological tool in isolation provides some insight into the role of specific environmental factors in maintaining self-injurious behaviour but the integrity of setting events must be established.

Adolescent↗

PubMed2005

The early development of self-injurious behaviour: evaluating the role of social reinforcement.

BACKGROUND: The potential role of social reinforcement in the development of self-injury has not yet been subjected to empirical analysis. In this 2-year prospective study, the pattern of social interactions related to the early presentation of self-injury were examined to identify a potential association with an increase in self-injury. METHODS: The self-injurious behaviour and social contact with adults of 16 children with intellectual disability (ID) with self-injury of recent onset were observed at 3-month intervals over 2 years. RESULTS: Increase in self-injury over a 2-year period was positively correlated with a distribution of social contact relative to episodes of self-injury that is consistent with a mutual social reinforcement paradigm. When this paradigm was operative, self-injury was evoked under stable antecedent conditions over time but tended to evoke increasing levels of social interaction. CONCLUSIONS: These results support the hypothesis that increases in the frequency of early self-injury in children with ID may be determined by social reinforcement with implications for early intervention and proactive identification of children at risk for increases in self-injury.

Adolescent↗

PubMed2004

[Cardiovascular symptoms and risks of subclinical dysthyroidism].

PURPOSE: To clarify the importance of cardiovascular symptoms and risks in subclinical dysthyroidism in order to define the best way of treatment and follow-up. CURRENT KNOWLEDGE AND KEY POINTS: Subclinical dysthyroidism is defined by abnormal circulating TSH values in face and normal free thyroid hormones levels, in asymptomatic individuals. If the cardiovascular effects of overt hyperthyroidism are well documented, the relation between subclinical dysthyroidism and the heart is not well established. Subclinical hyperthyroidism may be caused by the same thyroid disorders that results in overt hyperthyroidism, but the most common cause is excessive dosage in levothyroxine. The most frequent cardias complication of subclinical hyperthyroidism is atrial fibrillation. Recently minimal alterations of myocardial function have also been described. In most patients, one tries to return to euthyroidism in order to prevent cardiovascular complications. Subclinical hypothyroidism is 3 to 10 times more frequent, especially in women after 60 years. Subtle modifications of cardiac function and lipid metabolism and an increased risk of atherosclerosis have been described in this condition. There is still debate about the decision to treat or not to treat these patients. FUTURE PROSPECTS AND PROJECTS: Until now, treatment of subclinical dysthyroidism is mainly based upon experiences and convictions to physicians. Prospective studies are necessary to assess the true benefits and risks of either early treatment or therapeutic abstention with regular clinical and biological follow up. In such studies, patients should be separated according to age and the nature (endogenous or exogenous) of dysthyroidism.

Cardiovascular Diseases↗

PubMed2004

Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis.

BACKGROUND: Multiple breath inert gas washout (MBW) has been suggested as a tool for detecting early cystic fibrosis (CF) lung disease. A study was undertaken to compare the relative sensitivity of MBW and spirometry for detecting abnormal lung function in school age children with CF and to compare MBW results obtained from healthy children in the UK with those recently reported from Sweden. METHODS: Forced expiratory volume in 1 second (FEV1) and maximal expiratory flow when 25% of forced vital capacity remains to be expired (MEF25) were compared with the lung clearance index (LCI) derived from sulphur hexafluoride MBW in 22 children with CF aged 6-16 years and in 33 healthy controls. RESULTS: LCI was higher in children with CF than in healthy controls (mean difference 5.1 (95% CI of difference 4.1 to 6.1) and FEV1 and MEF25 z-scores were lower (mean difference -2.3 (95% CI -2.9 to -1.7) and -1.8 (95% CI -2.4 to -1.3), respectively; p<0.001 for all). There was a significant negative correlation between LCI and FEV1 (r2 = 0.62) and MEF25 (r2 = 0.46). However, while normal (> or =-1.96 z-scores) FEV1 and MEF25 results were seen in 11 (50%) and 12 (53%) children with CF, respectively, all but one of these children had an abnormally increased LCI. LCI was repeatable in both groups (within subject CV for three measurements 6% for CF and 5% for healthy children). In healthy subjects LCI was independent of age and virtually identical in the British and Swedish children (mean difference 0.1 (95% CI -0.1 to 0.4), p = 0.38) CONCLUSIONS: MBW is reproducible between laboratories, generates normal ranges which are constant over childhood, and is more frequently abnormal than spirometry in children with CF.

Adolescent↗

PubMed2003

Differential expression of integrin subunits on adherent and nonadherent mast cells.

Mast cell progenitors arise in bone marrow and then migrate to peripheral tissues where they mature. It is presumed that integrin receptors are involved in their migration and homing. In the present study, the expression of various integrin subunits was investigated in three systems of adherent and nonadherent mast cells. Mesentery mast cells, freshly isolated bone marrow-derived mast cells (BMMC) and RBL-2H3 cells grown attached to tissue culture flasks are all adherent mast cells and peritoneal mast cells, and cultured BMMC and RBL-2H3 cells grown in suspension represent nonadherent mast cell populations. Pure populations of mast cells were immunomagnetically isolated from bone marrow, mesentery and peritoneal lavage using the mast cell-specific monoclonal antibody AA4. By immunomicroscopy, we could demonstrate that all of these mast cells expressed alpha 4, alpha 5, alpha 6, beta 1 and beta 7 integrin subunits. The expression of the alpha 4 integrin subunit was 25% higher in freshly isolated mesentery mast cells and BMMC. Consistent with the results obtained by immunomicroscopy, mesentery mast cells expressed 65% more mRNA for the alpha 4 integrin subunit than peritoneal mast cells. In vitro studies were also conducted using the rat mast cell line RBL-2H3. RBL-2H3 cells grown attached to the tissue culture flasks or as suspension cultures expressed the same integrin subunits identified in bone marrow, mesenteric and peritoneal mast cells ex vivo. Similarly, the expression of alpha 4 integrin was higher in adherent cells. Therefore, alpha 4 integrins may play a critical role in the anchorage of mast cells to the extracellular matrix in bone marrow and in peripheral tissues.

Animals↗

PubMed2003

Hypothalamo-pituitary-adrenal axis in acute myocardial infarction treated by percutaneous transluminal coronary angioplasty: effect of time of presentation.

Acute myocardial infarction (AMI) is associated with a stimulation of cortisol which lasts 24 hours in patients treated by thrombolysis. Percutaneous transluminal coronary angioplasty (PTCA) is an alternative treatment for AMI which reduces the length of myocardial ischemia. Our objective was the determination of the amplitude and duration of cortisol and other hormones of the hypothalamo-pituitary-adrenal (HPA) axis release in patients undergoing PTCA. These responses were also analyzed in relation with the time of onset of AMI. The effect of coronarography with or without angioplasty in patients without AMI was also studied. Plasma ACTH, cortisol, corticotropin-releasing hormone and arginine vasopressin levels were determined during the first 48 hours in 20 patients with first AMI, treated by PTCA and in 10 patients without AMI undergoing coronarography (and angioplasty in five of them). A strong stimulation of the HPA axis was observed in AMI patients, but the duration of cortisol secretion was significantly reduced (less than 8 hours) as compared with previous studies in patients treated with thrombolysis. A clear-cut ACTH-cortisol dissociation was also observed after the third hour. ACTH and cortisol stimulation was higher in patients admitted between 04:00 h and 16:00 h than in patients admitted between 16:00 h and 04:00 h In patients without AMI, coronarography induced a moderate, but significant short-lasting ACTH and cortisol stimulation. In conclusion, our data suggest that the degree of stimulation of the HPA axis may depend upon the type of treatment and the circadian rhythm of this axis.

Adrenocorticotropic Hormone↗

PubMed2003

Risk markers associated with challenging behaviours in people with intellectual disabilities: a meta-analytic study.

A meta-analysis of prevalence and cohort studies conducted over the last 30 years was carried out to identify risk markers for challenging behaviour shown by individuals with intellectual disabilities (IDs). A total of 86 potential studies was identified from the review, with 22 (25.6%) containing sufficient data to enable a statistical analysis to be conducted. Results indicated that males were significantly more likely to show aggression than females, and that individuals with a severe/profound degree of ID were significantly more likely to show self-injury and stereotypy than individuals with a mild/moderate degree of ID. Individuals with a diagnosis of autism were significantly more likely to show self-injury, aggression and disruption to the environment whilst individuals with deficits in receptive and expressive communication were significantly more likely to show self-injury. In most cases, tests for heterogeneity were statistically significant, as expected. The meta-analysis highlighted the paucity of methodologically robust studies of risk markers for challenging behaviours and the lack of data on incidence, prevalence and chronicity of challenging behaviour in this population.

Adolescent↗

PubMed2003

Mast cell degranulation induced by lectins: effect on neutrophil recruitment.

The mammalian lectin macrophage-derived neutrophil chemotactic factor (MNCF) and the plant lectin KM+ were characterized for their ability to activate and degranulate mast cells. The association between mast cell activation and the induction of neutrophil migration was also investigated. Incubation of rat peritoneal mast cells with these lectins resulted in degranulation and mediator release. By confocal microscopy, both lectins were evenly distributed on the cell surface. MNCF activated RBL-2H3 mast cells only if the cells had been sensitized with IgE. KM+ was able to activate either unsensitized or IgE sensitized RBL-2H3 cells. In microplate assays MNCF, but not KM+, bound to rat IgE. In rats that were depleted of mast cells, neutrophil recruitment by MNCF and KM+ were significantly reduced indicating that mast cell activation provides an amplification loop for the neutrophil recruitment induced by these lectins. The present study supports the concept that mammalian lectins play a fundamental role in innate immunity.

Animals↗

PubMed2002

Sm60, a mannose-binding protein from Schistosoma mansoni with inflammatory property.

We demonstrate here that a mannose-binding protein from Schistosoma mansoni, termed Sm60, was recovered in the mannose-eluted fraction (Man(+)) upon affinity chromatography on immobilised mannose of the soluble antigen fraction from adult worm tegument and cercariae. Sm60 was detected in the Man(+) fraction as a prominent doublet with an apparent molecular mass of 60-66 kDa by SDS-PAGE and appeared as a single band with a pI of approximately 6.9 by isoelectrofocusing. Sm60 was also detected in preparations of schistosomula extract and soluble egg antigens using a mouse polyclonal anti-Sm60 serum on immunoblotting assay. This antiserum demonstrated that Sm60 was localised on the tegument of S. mansoni adult worm. In order to determine the role of Sm60 in host-parasite interactions, we showed that Sm60 induced in vitro migration of human neutrophil in a dose-dependent manner and in vitro mast cell degranulation. Sm60 triggered these activities through its carbohydrate-binding site, since these activities were selectively inhibited by 0.2 M D-mannose, but not by 0.2 M D-galactose. Furthermore, Sm60 induced in vivo neutrophil migration. In contrast, mast cell-depleted rats presented a significant reduction of the neutrophil migration induced by Sm60 as compared with non-depleted controls. These data suggest that in vivo neutrophil migration induced by Sm60 is modulated by mast cell-dependent mechanisms. Sm60 might play a key role in the host-parasite interaction, and its characterization opens perspective to examine the role of this molecule in the biology of S. mansoni.

Animals↗