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Biomedical subjects

M A Wheatley

Publications and source records attributed to M A Wheatley.

At least 19 recordsLinked to original sources
PubMed2001

Optimization of spray drying by factorial design for production of hollow microspheres for ultrasound imaging.

A process for producing hollow microcapsules as ultrasound contrast agents was optimized using a 2(3) factorial experimental design method with two replicates. Spray drying, a conveniently scalable encapsulation technique, was used to encapsulate a volatile core material, such as ammonium carbonate, using biodegradable 50-50 poly(D,L-lactide-co-glycolide). Various effects due to changes in processing variables and their interactions were studied using the factorial grid. The high- and low-incremented variables examined included the temperature difference between the inlet and outlet of the spray dryer (5 degrees and 15 degrees C), air atomization pressure (80 and 100 psi), and polymer concentration in solvent (0.005 and 0.025 g/mL). Responses analyzed for computing the main effects and interactions were microcapsule morphology, yield, mean size, and zeta potential. Experimental results showed that polymer concentration was most important for determining microcapsule morphology. The temperature difference for drying prominently affected mean size, and atomization pressure was the main effect for microcapsule yield. Interactions among variables were not present in this case. The best conditions for producing PLGA microcapsules was a temperature difference of 5 degrees C, an initial polymer concentration of 0.005 g/mL, and an atomization pressure of 80 psi. The microcapsule zeta potentials were unaffected by spray-drying conditions.

Biocompatible Materials↗
PubMed2001

Generation of ultraharmonics in surfactant based ultrasound contrast agents: use and advantages.

A unique distinction between surfactant stabilized ultrasound contrast agent ST68 and water (or tissue), is the enhanced ability of the agent to generate non-linear frequencies such as sub-harmonics (f0/2), higher harmonics (2fo, 3fo, 4fo,...), and ultraharmonics (3f0/2, Sf0/2, 7f0/2,...), when insonated with fundamental frequency f0. Currently, second harmonics (2f0) have been predominantly researched, to exploit the diagnostic benefits of the contrast-specific non-linear imaging. However, we found that at normal imaging pressures (100 kPa-1 MPa), ST68 agent-generated second harmonic enhancements dropped to approximately 8 dB at 100 kPa and approximately 2 dB at 1 MPa. Moreover, at these pressures water (or tissue) produced strong second harmonics due to non-linear propagation. Ultraharmonics and sub-harmonics on the other hand, were generated only by the agent, and were not produced due to the non-linear propagation of ultrasound in either water or tissue. Additionally, ultraharmonic (3f0/2) enhancements of approximately 23 dB at 100 kPa, approximately 35 dB at 0.5 MPa and approximately 41dB at 1.1 MPa for ST68-PFC, offer much greater signal to noise ratio than higher harmonics.

Contrast Media↗
PubMed2001

Grafting of encapsulated BDNF-producing fibroblasts into the injured spinal cord without immune suppression in adult rats.

Grafting of genetically modified cells that express therapeutic products is a promising strategy in spinal cord repair. We have previously grafted BDNF-producing fibroblasts (FB/BDNF) into injured spinal cord of adult rats, but survival of these cells requires a strict protocol of immune suppression with cyclosporin A (CsA). To develop a transplantation strategy without the detrimental effects of CsA, we studied the properties of FB/BDNF that were encapsulated in alginate-poly-L-ornithine, which possesses a semipermeable membrane that allows production and diffusion of a therapeutic product while protecting the cells from the host immune system. Our results show that encapsulated FB/BDNF, placed in culture, can survive, secrete bioactive BDNF and continue to grow for at least one month. Furthermore, encapsulated cells that have been stored in liquid nitrogen retain the ability to grow and express the transgene. Encapsulated FB/BDNF survive for at least one month after grafting into an adult rat cervical spinal cord injury site in the absence of immune suppression. Transgene expression decreased within two weeks after grafting but resumed when the cells were harvested and re-cultured, suggesting that soluble factors originating from the host immune response may contribute to the downregulation. In the presence of capsules that contained FB/BDNF, but not cell-free control capsules, there were many axons and dendrites at the grafting site. We conclude that alginate encapsulation of genetically modified cells may be an effective strategy for delivery of therapeutic products to the injured spinal cord and may provide a permissive environment for host axon growth in the absence of immune suppression.

Alginates↗
PubMed2000

Methylmercury and the health of indigenous peoples: a risk management challenge for physical and social sciences and for public health policy.

Methylmercury in aquatic ecosystems and bio-accumulated in aquatic biota, especially fish, is a major public health concern internationally. Precautionary efforts are currently underway internationally to reduce the anthropogenic release of mercury, which in turn, over time, will reduce human exposure. However, at the present time, it is important to address the issue of management of the risks of exposure as they exist now. Of particular concern are the impacts of methylmercury on indigenous populations which depend on fish as a subsistence food source, both in remote areas of developed countries, such as Canada, and in developing countries such as Brazil. Research into these impacts over the past two or three decades has shown that, other than in very severe pollution situations such as occurred in Minamata, Japan, the direct impacts on human health are difficult to prove. On the other hand, the indirect negative effects of methylmercury on health, mediated through the disruption of lifestyle and eating patterns and the associated socio-cultural and socio-economic consequences among the affected native populations, have, in many cases, been significant. These social factors have raised serious challenges in determining practical public health policies on the issue. Policy development relating to environmental contaminants has been presented, with the problem of assessing the role of the various factors which contribute to the impact on health as a result of socio-cultural disruption. These factors include changes in diet and lifestyle due to methylmercury in the environment and its real or perceived risk. The standard physical sciences risk assessment process, based on the lowest observed adverse effects level (LOAEL) or no observed adverse effects level (NOAEL) used in defining health policies may be seen as over-simplistic theoretical extrapolations when viewed in the context of the concerns of the social sciences. Both approaches, however, have relevance to health policies that address the risks posed by environmental methylmercury. Therefore, the standard physical sciences approach of the past three decades now needs to be linked with the social sciences approach, with its focus on the indirect impacts of exposure to methylmercury, to provide a comprehensive approach to public health policy development. With this objective in mind, this paper reviews methylmercury-related data from both physical and social sciences. It attempts to draw on the findings in both disciplines to provide suggestions for an integrated approach in policy development relating to human health and human exposure to methylmercury, especially among indigenous peoples in remote areas and in developing countries. An integrated approach such as this may help to limit adverse health effects in the indigenous communities affected.

Canada↗
PubMed2000

Influence of environmental conditions on a new surfactant-based contrast agent: ST68.

Environmental influences on the new surfactant-stabilized bubbles, ST68, were investigated. We have developed a new surfactant-based contrast agent ST68, which is prepared by insonating buffered mixtures of Span 60 and Tween 80 in the presence of either air, PFC, or SF(6) gas. The effect of dilution, shear, and sonication on size distribution of ST68 showed that PFC-containing bubbles (ST68-PFC) were most stable. ST68-PFC bubbles lasted more than 15 min with approximately 30 dB backscatter enhancement in degassed phosphate-buffered saline, (pH 7.4), and air bubbles lasted approximately 3 s, suggesting the effects of diffusion. Additionally, it was found that the ionic strength of the suspending medium (for example, PBS), did not have any effect on ST68 bubbles containing SF(6) or PFC, but had a dramatic impact on bubbles containing air.

Contrast Media↗
PubMed2000

Effects of pediatric head trauma for children, parents, and families.

Severe pediatric head injury has negative consequences for children of all ages. Even mild and moderate head injury results in residual impairment for school-age children and adolescents. Data are needed on the effects of these less severe insults, especially for preschoolers. Although research on the impact of the child's head injury on the parent-child relationship and family functioning is limited, the experience is likely to be very stressful for the parent and the family. Indeed, family integrity may be at risk. Research is needed that examines the effects of a child's head injury for the parent and the family over time and identifies factors related to these outcomes.

Adult↗
PubMed1999

ERGIC-53 gene structure and mutation analysis in 19 combined factors V and VIII deficiency families.

Combined factors V and VIII deficiency is an autosomal recessive bleeding disorder associated with plasma levels of coagulation factors V and VIII approximately 5% to 30% of normal. The disease gene was recently identified as the endoplasmic reticulum-Golgi intermediate compartment protein ERGIC-53 by positional cloning, with the detection of two founder mutations in 10 Jewish families. To identify mutations in additional families, the structure of the ERGIC-53 gene was determined by genomic polymerase chain reaction (PCR) and sequence analysis of bacterial artificial chromosome clones containing the ERGIC-53 gene. Nineteen additional families were analyzed by direct sequence analysis of the entire coding region and the intron/exon junctions. Seven novel mutations were identified in 10 families, with one additional family found to harbor one of the two previously described mutations. All of the identified mutations would be predicted to result in complete absence of functional ERGIC-53 protein. In 8 of 19 families, no mutation was identified. Genotyping data indicate that at least two of these families are not linked to the ERGIC-53 locus. Taken together, these results suggest that a significant subset of combined factors V and VIII deficiency is due to mutation in one or more additional genes.

Amino Acid Substitution↗
PubMed1999

Effect of filling gases on the backscatter from contrast microbubbles: theory and in vivo measurements.

Two surfactant-based contrast agents, ST44 and ST68, were produced according to US Patent # 5,352,436 and filled with either air, C4F10 (perfluorobutane) or SF6 (sulfur hexaflouride). Ten rabbits received i.v. injections of each agent/gas combination with 5 repetitions of each dose (range: 0.005-0.13 mL/kg). A custom-made 10-MHz cuff transducer was placed around the surgically exposed distal aorta and audio Doppler signals were acquired in vivo. Quantitative in vivo dose responses were calculated off-line using spectral power analysis and compared to a theoretical model of microbubble dissolution and enhancement. For qualitative comparisons, 10 rabbits were imaged pre- and postcontrast administration (dose: 0.1 mL/kg) in gray-scale and colour. All agent/gas combinations produced marked Doppler enhancement with air bubbles enhancing least of all (p < 0.0001) and ST68-SF6 best of all (maximum: 27.6 +/- 2.04 dB; p < 0.012). There were no significant differences between other agent/gas combinations (0.30 < p < 0.70). Theoretical enhancement was within 1 order of magnitude of the experimental observations (i.e., deviations of up to 10 dB). The duration of contrast enhancement was 1-2 min for air-filled bubbles, 3-5 min for SF6-filled bubbles and more than 7 min for C4F10-filled bubbles. In conclusion, ST68-SF6 microbubbles produced most in vivo enhancement of the agent/gas combinations studied. Theory matched the measurements within an order of magnitude.

Animals↗
PubMed1999

Subharmonic imaging with microbubble contrast agents: initial results.

The subharmonic emission from insonified contrast microbubbles was used to create a new imaging modality called Subharmonic Imaging. The subharmonic response of contrast microbubbles to ultrasound pulses was first investigated for determining adequate acoustic transmit parameters. Subharmonic A-lines and gray scale images were then obtained using a laboratory pulse-echo system in vitro and a modified ultrasound scanner in vivo. Excellent suppression of all backscattered signals other than from contrast microbubbles was achieved for subharmonic A-lines in vitro while further optimization is required for in vivo gray scale subharmonic images.

Animals↗
PubMed1998

Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII.

Combined deficiency of factors V and VIII is an autosomal recessive bleeding disorder resulting from alterations in an unknown gene on chromosome 18q, distinct from the factor V and factor VIII genes. ERGIC-53, a component of the ER-Golgi intermediate compartment, was mapped to a YAC and BAC contig containing the critical region for the combined factors V and VIII deficiency gene. DNA sequence analysis identified two different mutations, accounting for all affected individuals in nine families studied. Immunofluorescence and Western analysis of immortalized lymphocytes from patients homozygous for either of the two mutations demonstrate complete lack of expression of the mutated gene in these cells. These findings suggest that ERGIC-53 may function as a molecular chaperone for the transport from ER to Golgi of a specific subset of secreted proteins, including coagulation factors V and VIII.

Amino Acid Sequence↗
PubMed1998

Social and cultural impacts of environmental change on aboriginal Peoples in Canada.

Environmental change, often the result of Western industrial development, has had a major impact on Canadian Aboriginal people. Even when there are no provable direct health effects, Aboriginal peoples' holistic concepts of health, balance, and harmony, and the interrelatedness of health and environment lead them to regard social and cultural effects as health effects. This paper explores the links between environmental change and the social and cultural and, hence, health effects these changes produce. It is argued that factors such as Aboriginal holistic concepts of environment and health, perceptions of risk, and difficulties in communication contribute to these social and cultural effects and their subsequent health effects-effects which frequently present a greater problem in Canadian Aboriginal communities than do the direct health effects of environmental change.

American Indian or Alaska Native↗
PubMed1997

Quantitative acoustic characterization of a new surfactant-based ultrasound contrast agent.

The acoustic properties of a new ultrasound contrast agent, ST68, have been investigated. ST68 is a sonicated mixture of nonionic surfactants (Span-type and Tween-type) consisting of stabilized microbubbles with a mean diameter of 3.8 microns and a concentrations of 7.1 x 10(8) bubbles/mL. A pulsatile flow system was used to acquire data in vitro. The acoustic properties of ST68, as a function of time, frequency and dose, were calculated. Enhancement changed nonlinearly with contrast agent dose; maximum was 13.1 dB +/- 1.0 dB for a dose of 0.30 microL/mL of suspending medium. Attenuation reached approximately 11 dB/cm for dosages above 0.27 microL/mL and for frequencies between 2.5 and 6.0 MHz. In vivo, i.v. injections of ST68 were given to 4 rabbits (doses from 0.01 to 0.23 mL/kg). A clear increase in flow signal intensity was observed for 1 to 2 min. An in vivo dose-response curve was calculated from audio Doppler signals obtained with a 10-MHz cuff transducer placed around the distal aorta. Maximum enhancement was 18.3 dB +/- 3.13 dB for a 0.13 mL/kg dose. Moreover, ST68 appears to follow a simple relationship between in vivo enhancement and dose. In conclusion, ST68 is capable of producing marked vascular enhancement. Its acoustic properties have been characterized in vitro and in vivo.

Acoustics↗
PubMed1996

Polymorphism of adhesion molecule CD31 is not a significant risk factor for graft-versus-host disease.

Mismatch between bone marrow transplant (BMT) patient and donor for an amino acid polymorphism within the adhesion molecule CD31 has recently been reported to increase risk for the development of graft-versus-host disease (GVHD). We further examined this association in a larger series of 301 BMT patients (227 with grade III/IV GVHD and 74 with grade 0 GVHD) and their HLA-identical sibling donors. CD31 genotypes were determined by polymerase chain reaction and restriction endonuclease digestion. The role of mismatch at the CD31 locus in the development of GVHD was assessed by analyzing the extent of CD31 identity and CD31 compatibility among the grade 0 GVHD and grade III/IV GVHD sibling pairs. No significant association between CD31 mismatch and the development of severe GVHD was detected in our overall patient population. Sixty-three percent of grade III/IV GVHD sibling pairs and 69% of grade 0 GVHD sibling pairs had CD31 genotypes that were identical (P = .36, odds ratio = 1.30). In addition, neither the grade 0 GVHD group (P = .10) nor the grade III/IV GVHD group (P = .27) differed significantly from the expected probability of identity between sibling pairs. Mismatch at the CD31 polymorphism between recipients and donors showed no consistent association with the development of GVHD. Current evidence does not support the value of CD31 mismatch in the selection of BMT donors.

Alleles↗
PubMed1996

The importance of social and cultural effects of mercury on aboriginal peoples.

Environmental contaminants, including mercury, often by-products of industrialization land development projects, frequently have far-reaching consequences for Aboriginal people, who often receive little benefit from such projects. In trying to understand the full impact of environmental mercury on Aboriginal people, therefore, research endeavours must consider the social and cultural impacts, and not simply focus on the direct clinical effects resulting from exposure. This paper explores some of the key areas in developing such an understanding. Aboriginal peoples' understanding of mercury contamination is influenced by their holistic concepts of health and environment. Whether or not scientific assessment reveals direct clinical health effects from exposure to mercury, this holistic viewpoint may lead to an effect on both individuals and communities. Perceptions of changes and the disruption of the special relationship that Aboriginal people perceive themselves to have with the environment have a considerable impact on their social, cultural, spiritual and economic well-being. These qualitative impacts are not easily measured with standard social indicators. The involvement of communities in the identification and measurement of Aboriginal community indicators which reflect the reality of their situation is essential in order to establish a better understanding of the extent and importance of social and cultural effects of exposure to mercury. Toxicologists, policy makers and others concerned with setting risk levels which may lead to formal guidelines should be aware of the impacts that their actions and decisions may have on the lifestyle, and therefore on the health, of Aboriginal peoples.

American Indian or Alaska Native↗
PubMed1991

Developing an integrated traditional/clinical health system in the Yukon.

The introductory steps have been taken in Yukon. Elders have met and voiced their concerns and initial contacts have been made with government officials, medical and legal consultants. A proposal is now being developed to obtain funding to design a suitable model for an integrated Yukon Indian/clinical health care system. One of the next steps, following on the advice of the Elders, should be for communities to establish their own projects to record the plants and practices used, with the assistance of their Elders. The communities should also identify people who use traditional practices who are willing to come forward. They could then come together with the Elders to discuss their concerns. Beyond that, representatives from the traditional system will need to meet with representatives of the mainstream system, to discuss areas of co-operation. Once the "content" has been identified, the model for integrating the two health systems can be addressed. This will necessitate further meetings of Yukon Territorial Government officials, legal advisors, medical advisors, and Yukon First Nations representatives. The proposal currently being developed will build on the initial steps which have been taken. The Yukon Territorial Government has indicated a willingness to look at ways of including traditional health care practices for patients who wish to use them. The receptivity of government and Yukon medical profession and the expressed concerns of the Elders indicate that now is the time to proceed.

Health Services↗
PubMed1990

Contrast agents for diagnostic ultrasound: development and evaluation of polymer-coated microbubbles.

Although the concept of an ultrasound contrast agent dates from Gramiak's work in 1968 in which indocyanine green was injected into the ascending aorta and heart, no universally accepted contrast agent for ultrasound now exists. This is primarily due to problems with stability, size and/or toxicity of the agents which have been investigated. Development of an effective ultrasound contrast agent would be highly significant for the health care industry, since it would greatly expand the scope of ultrasound (a noninvasive and safe procedure) as a diagnostic technique. While encapsulated gas bubbles offer particular advantages in stability over hand-agitated systems, they frequently present problems with size. Capsules larger than 10 microns in diameter become entrapped in the capillary bed of the lung. This paper describes the use of ionotropic gelation of the naturally occurring polysaccharide, alginate, for microencapsulation of air. Two procedures have been investigated. A novel jet head has been developed which allows co-extrusion of a solution of sodium alginate and air to produce nascent microencapsulated air bubbles which fall into a hardening solution of calcium ions. A second method employs ultrasound to introduce cavitation-induced bubbles into the alginate before capsule formation by spraying. Power spectra of these preparations demonstrate echogenicity (that is strong scatter of the incident ultrasound wave back to the emitting transducer, which also acts as a receiver), with resonant peaks that are a function of capsule size and wall characteristics.

Alginates↗
PubMed1990

Enzymatically activated microencapsulated liposomes can provide pulsatile drug release.

A system for the delayed or pulsed release of biologically active substances was achieved by encapsulating liposomes containing the substance of interest inside microcapsules. The microcapsules retain the liposomes but allow controlled diffusion of the active substance when it is released from the liposomes. Furthermore, by coating the liposomes with phospholipase A2 (an enzyme that removes an acyl group from the 2 position of phospholipids) before placing them within the microcapsule, a pulsatile release pattern was achieved both in vitro and in vivo. The time of onset of the pulse as well as the release rate can be controlled by the amount of phospholipase A2, the molecular weight of the poly(L-lysine) that is used to coat the microencapsulated liposomes, and the composition of the phospholipid bilayer membrane. Even at 37 degrees C the system would protect a model enzyme (horseradish peroxidase). When not placed inside the microencapsulated liposomes, the enzyme lost its activity in solution at 37 degrees C in a few days, whereas it retained 40% of the initial activity after 30 days of incubation at 37 degrees C inside the microencapsulated liposomes.

Capsules↗