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Biomedical subjects

M R Edwards

Publications and source records attributed to M R Edwards.

At least 19 recordsLinked to original sources
PubMed2006

Proximal anterior cruciate ligament avulsion fracture in a skeletally immature athlete: a case report and method of physeal sparing repair.

Traumatic rupture of the anterior cruciate ligament (ACL) in adulthood is relatively common and surgical reconstruction is frequently required to allow return to high-level activities. There is growing evidence to suggest that ACL rupture in children is more common than previously thought and a poor outcome is associated with conservative management. The site of rupture in childhood is predominantly tibial avulsion, but mid-substance tears have also been reported. We report a case of a proximal ACL avulsion in an 11-year-old athlete and discuss a method of extra-physeal repair. There are very few previous reports of proximal avulsion fractures in skeletally immature patients.

Anterior Cruciate Ligament↗
PubMed2004

Patello-femoral joint pain due to unusual location of localised pigmented villonodular synovitis-a case report.

Localised pigmented villonodular synovitis (PVNS) is a rare condition usually affecting the knee. It can be a difficult condition to manage with an average delay in diagnosis of 4.4 years. We describe a case of a localised PVNS lesion interposed between the patello-femoral joint, presenting as 'anterior knee pain'. To our knowledge this has not previously been reported. The lesion was completely excised at arthroscopy resulting in complete resolution of symptoms. Solitary lesions of PVNS should also be considered in the differential diagnosis of unexplained 'anterior knee pain'.

Adult↗
PubMed2004

The plasma membrane of microaerophilic protists: oxidative and nitrosative stress.

The trans-plasma-membrane electrochemical potential of microaerophilic protists was monitored by the use of voltage-sensitive charged lipophilic fluorophores; of the many available probes, the anionic oxonol dye bis(1,3-dibarbituric acid)-trimethine oxonol [DiBAC(4)(3)] is an example of one which has been successfully employed using fluorescence microscopy, confocal laser-scanning microscopy and flow cytometry. Several microaerophilic protists have been investigated with this dye; these were Giardia intestinalis, Trichomonas vaginalis, Tritrichomonas foetus, Hexamita inflata and Mastigamoeba punctachora. Under conditions where they exhibit normal vitality, these organisms exclude DiBAC(4)(3) by virtue of their maintenance of a plasma-membrane potential (negative inside). Uptake of the fluorophore is indicative of disturbance to this membrane (i.e. by inhibition of pump/leak balance, blockage of channels or generation of ionic leaks), and is indicative of metabolic perturbation or environmental stress. Here, it is shown that oxidative or nitrosative stress depolarizes the plasma membranes of the aforementioned O(2)-sensitive organisms and allows DiBAC(4)(3) influx. Oxonol uptake thereby provides a sensitive and early indication of plasma-membrane perturbation by agents that may lead to cytotoxicity and eventually to cell death by necrotic or apoptotic pathways.

Animals↗
PubMed2003

Immunoglobulin gene rearrangement, repertoire diversity, and the allergic response.

The immunoglobulin repertoire arises as a consequence of combinatorial diversity, junctional diversity, and the process of somatic point mutation. Each of these processes involves biases that limit and shape the available immunoglobulin repertoire. The expressed repertoire is further shaped by selection, to the extent that biased gene usage can become apparent in many disease states. The study of rearranged immunoglobulin genes therefore may not only provide insights into the molecular processes involved in the generation of antibody diversity but also inform us of pathogenic processes and perhaps identify particular lymphocyte clones as therapeutic targets. Partly as a consequence of the low numbers of circulating IgE-committed B-cells, studies of rearranged IgE genes in allergic individuals have commenced relatively recently. In this review, recent advances in our understanding of the processes of immunoglobulin gene rearrangement and somatic point mutation are described, and biases inherent to these processes are discussed. The evidence that some diseases may be associated with particular gene rearrangements is then considered, with a particular focus on allergic disease. Reviewed data suggest that an important contribution to the IgE response may come from cells that use relatively rare heavy chain V (V(H)) segment genes, which display little somatic point mutation. Some IgE antibodies also seem to display polyreactive binding. In other contexts, these 3 characteristics have been associated with antibodies of the B-1 B-cell subset, and the possibility that B-1 B-cells contribute to the allergic response is therefore considered.

Antibody Diversity↗
PubMed2003

Nitrosative stress induced cytotoxicity in Giardia intestinalis.

AIMS: To investigate the antigiardial properties of the nitrosating agents: sodium nitrite, sodium nitroprusside and Roussin's black salt. METHODS AND RESULTS: Use of confocal laser scanning microscopy and flow cytometry indicated permeabilization of the plasma membrane to the anionic fluorophore, DiBAC4(3) [bis(1,3-dibutylbarbituric acid) trimethine oxonol]. Loss of plasma membrane electrochemical potential was accompanied by loss of regulated cellular volume control. Changes in ultrastructure revealed by electron microscopy and capacity for oxygen consumption, were also consequences of nitrosative stress. Roussin's black salt (RBS), active at micromolar concentrations was the most potent of the three agents tested. CONCLUSIONS: These multitargeted cytotoxic agents affected plasma membrane functions, inhibited cellular functions in Giardia intestinalis and led to loss of viability. SIGNIFICANCE AND IMPACT OF THE STUDY: Nitrosative damage, as an antigiardial strategy, may have implications for development of chemotherapy along with suggesting natural host defence mechanisms.

Animals↗
PubMed2001

Na(+)-dependent pH regulation by the amitochondriate protozoan parasite Giardia intestinalis.

Giardia intestinalis is a pathogenic fermentative parasite, which inhabits the gastrointestinal tract of animals and humans. G. intestinalis trophozoites are exposed to acidic fluctuations in vivo and must also cope with acidic metabolic endproducts. In this study, a combination of independent techniques ((31)P NMR spectroscopy, distribution of the weak acid pH marker 5,5-dimethyl-2,4-oxazolidinedione (DMO) and the fluorescent pH indicator 2',7'-bis (carboxyethyl)-5,6-carboxyfluorescein (BCECF)) were used to show that G. intestinalis trophozoites exposed to an extracellular pH range of 6.0--7.5 maintain their cytosolic pH (pH(i)) within the range 6.7--7.1. Maintenance of the resting pH(i) was Na(+)-dependent but unaffected by amiloride (or analogs thereof). Recovery of pH(i) from an intracellular acidosis was also Na(+)-dependent, with the rate of recovery varying with the extracellular Na(+) concentration in a saturable manner (K(m) = 18 mm; V(max) = 10 mm H(+) min(-1)). The recovery of pH(i) from an acid load was inhibited by amiloride but unaffected by a number of its analogs. The postulated involvement of one or more Na(+)/H(+) exchanger(s) in the regulation of pH(i) in G. intestinalis is discussed.

Amiloride↗
PubMed2001

Valency or wählency: is the epitope diversity of the B-cell response regulated or chemically determined?

For almost a century, the humoral immune response has been monitored principally by the measurement of antibody concentrations, although antibody affinity and isotype have also long been acknowledged as critical to their biological activity. In this report, it is argued that these measures alone may provide a poor measure of the activity of serum antibodies. A B-cell response that is directed against multiple epitopes on a protein can form immune complexes bearing multiple antibody molecules. This is essential for the efficient initiation of processes such as the complement cascade and the activation of leucocytes via Fc receptors. These processes can be dramatically enhanced when B cells target a greater number of epitopes on any antigen. Evidence that the epitope diversity of an immune response may vary between individuals, and that it may vary in an individual over time, is reviewed. This variability is likely to be influenced by a number of host-specific factors in addition to antigen chemistry. The appropriateness of the chemically deterministic term 'antigen valency' to describe the number of epitopes recognized by an individual's B-cell response is discussed, and the term 'wählency' to emphasize the situational nature of B-cell epitopes is introduced.

Animals↗
PubMed2001

The antioxidant potential of pyruvate in the amitochondriate diplomonads Giardia intestinalis and Hexamita inflata.

Giardia intestinalis and Hexamita inflata are microaerophilic protozoa which rely on fermentative metabolism for energy generation. These organisms have developed a number of antioxidant defence strategies to cope with elevated O(2) tensions which are inimical to survival. In this study, the ability of pyruvate, a central component of their energy metabolism, to act as a physiological antioxidant was investigated. The intracellular pools of 2-oxo acids in G. intestinalis were determined by HPLC. With the aid of a dichlorodihydrofluorescein diacetate-based assay, intracellular reactive oxygen species generation by G. intestinalis and H. inflata suspensions was monitored on-line. Addition of physiologically relevant concentrations of pyruvate to G. intestinalis and H. inflata cell suspensions was shown to attenuate the rate of H(2)O(2)- and menadione-induced generation of reactive oxygen species. In addition, pyruvate was also shown to decrease the generation of low-level chemiluminescence arising from the oxygenation of anaerobic suspensions of H. inflata. In contrast, addition of pyruvate to suspensions of respiring Saccharomyces cerevisiae was shown to increase the generation of reactive oxygen species. These data suggest that (i) in G. intestinalis and H. inflata, pyruvate exerts antioxidant activity at physiological levels, and (ii) it is the absence of a respiratory chain in the diplomonads which facilitates the observed antioxidant activity.

Animals↗
PubMed2001

Influence of inhaled nitric oxide on gas exchange during normoxic and hypoxic exercise in highly trained cyclists.

This study tested the effects of inhaled nitric oxide [NO; 20 parts per million (ppm)] during normoxic and hypoxic (fraction of inspired O(2) = 14%) exercise on gas exchange in athletes with exercise-induced hypoxemia. Trained male cyclists (n = 7) performed two cycle tests to exhaustion to determine maximal O(2) consumption (VO(2 max)) and arterial oxyhemoglobin saturation (Sa(O(2)), Ohmeda Biox ear oximeter) under normoxic (VO(2 max) = 4.88 +/- 0.43 l/min and Sa(O(2)) = 90.2 +/- 0.9, means +/- SD) and hypoxic (VO(2 max) = 4.24 +/- 0.49 l/min and Sa(O(2)) = 75.5 +/- 4.5) conditions. On a third occasion, subjects performed four 5-min cycle tests, each separated by 1 h at their respective VO(2 max), under randomly assigned conditions: normoxia (N), normoxia + NO (N/NO), hypoxia (H), and hypoxia + NO (H/NO). Gas exchange, heart rate, and metabolic parameters were determined during each condition. Arterial blood was drawn at rest and at each minute of the 5-min test. Arterial PO(2) (Pa(O(2))), arterial PCO(2), and Sa(O(2)) were determined, and the alveolar-arterial difference for PO(2) (A-aDO(2)) was calculated. Measurements of Pa(O(2)) and Sa(O(2)) were significantly lower and A-aDO(2) was widened during exercise compared with rest for all conditions (P < 0.05). No significant differences were detected between N and N/NO or between H and H/NO for Pa(O(2)), Sa(O(2)) and A-aDO(2) (P > 0.05). We conclude that inhalation of 20 ppm NO during normoxic and hypoxic exercise has no effect on gas exchange in highly trained cyclists.

Administration, Inhalation↗
PubMed2001

Critical analysis of cerebrovascular autoregulation during repeated head-up tilt.

BACKGROUND AND PURPOSE: Cerebrovascular autoregulation has been described with a phase lead of cerebral blood flow preceding changes in cerebral perfusion pressure (CPP), but there has been less focus on the effect of CPP on cerebral vascular resistance. We investigated these relations during spontaneous fluctuations (control) and repeated head-up tilt. METHODS: Eight healthy adults were studied in supine rest and repeated tilt with 10-second supine, 10 seconds at 45 degrees head-up tilt for a total of 12 cycles. Cerebral blood flow was estimated from mean flow velocity (MFV) by transcranial Doppler ultrasound, CPP was estimated from corrected finger pressure (CPP(F)), and cerebrovascular resistance index (CVRi) was calculated in the supine position from CPP(F)/MFV. Gain and phase relations were assessed by cross-spectral analysis. RESULTS: In the supine position, MFV preceded CPP(F), but changes in CVRi followed CPP(F). Gain and phase relations for CPP(F) as input and MFV as output were similar in supine and repeated tilt experiments. Thus, changes in cerebrovascular resistance must have had a similar pattern in the supine and tilt experiments. CONCLUSIONS: Cerebrovascular autoregulation is achieved by changes in resistance in response to modulations in perfusion pressure whether spontaneous or induced by repeated tilt. The phase lead of MFV before CPP(F) is a mathematical and physiological consequence of the relation the input variable (CPP(F)) and the manipulated variable (cerebrovascular resistance) that should not be taken as an indication of independent control of cerebral blood flow.

Adult↗
PubMed2001

The application of phage display in allergy research: characterization of IgE, identification of allergens and development of novel therapeutics.

The ability to display IgE antibody fragments, allergens and peptides upon filamentous phage has increasingly been used in allergy research. This technique offers the opportunity to isolate and produce IgE antibody fragments specific for allergens. These antibody fragments can then be used to address fundamental issues regarding the development of IgE antibodies in allergic patients, at both the molecular and structural level. Random peptide display has greatly facilitated the discovery of epitopes recognized by serum IgE antibodies from allergic patients, and it is a definitive tool for investigating the IgE-epitope interaction. Whole allergens can also be displayed on phage. Selecting IgE binding phage from diverse cDNA libraries of allergens has assisted in the identification of new allergens and provided a source of purified allergens for the diagnosis of allergic diseases. Finally, phage display of antibody fragments and random peptides is currently providing a means by which the IgE antibody can be targeted as a potential treatment for allergy. This review highlights several studies which have utilized phage display methodology in the area of allergy research, and it discusses how the therapeutic potential of this approach may be exploited.

Allergens↗
PubMed2000

The membrane potential of Giardia intestinalis.

Giardia intestinalis is a primitive microaerophilic protozoan parasite which colonises the upper intestine of humans. Despite the evolutionary and medical significance of this organism, its physiology is very poorly understood. In this study we have used a novel flow cytometric technique to make quantitative measurements of the electrical potential across the plasma membrane of G. intestinalis trophozoites. In media lacking both K(+) and Na(+), G. intestinalis trophozoites maintained a high negative plasma membrane potential (Psi(m)) of -134+/-3 mV. The Psi(m) was unaffected by the addition of Na(+) to the extracellular medium, whereas the addition of K(+) resulted in a significant membrane depolarisation, consistent with the G. intestinalis trophozoite plasma membrane having a significant (electrophoretic) permeability to K(+). The membrane was also depolarised by the H(+) ionophore m-chlorophenylhydrazone and by the H(+) ATPase inhibitors dicyclohexylcarbodiimide and N-ethylmaleimide. These results are consistent with G. intestinalis trophozoites maintaining a high resting Psi(m), originating at least in part from an electrogenic H(+) pump acting in concert with a K(+) diffusion pathway.

Animals↗
PubMed2000

Studies on C-phycocyanin from Cyanidium caldarium, a eukaryote at the extremes of habitat.

C-Phycocyanin, a biliprotein, was purified from the red alga, Cyanidium caldarium. This alga grows at temperatures up to 57 degrees C, a very high temperature for a eukaryote, and at pH values down to 0.05. Using the chromophores on C-phycocyanin as naturally occurring reporter groups, the effects of temperature on the stability of the protein were studied by circular dichroism and absorption spectroscopy. The protein was unchanged from 10 to 50 degrees C, which indicates that higher temperatures are not required to cause the protein to be photosynthetically active. At 60 and 65 degrees C, which are above the temperatures at which the alga can survive, the protein undergoes irreversible denaturation. Gel-filtration column chromatography demonstrated that the irreversibility is caused by the dissociation of the trimeric protein to its constitutive polypeptides. Upon cooling, the alpha and beta polypeptides did not reassemble to the trimer. Unlike phycocyanins 645 and 612, the C-phycocyanin does not show a reversible conformational change at moderately high temperatures. At constant temperature, the C-phycocyanin was more stable than a mesophilic counterpart. It is designated a temperature-resistant protein.

Circular Dichroism↗