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Biomedical subjects

Kevin King

Publications and source records attributed to Kevin King.

8 recordsLinked to original sources

Antibody structure, instability, and formulation.

The number of therapeutic monoclonal antibody in development has increased tremendously over the last several years and this trend continues. At present there are more than 23 approved antibodies on the US market and an estimated 200 or more are in development. Although antibodies share certain structural similarities, development of commercially viable antibody pharmaceuticals has not been straightforward because of their unique and somewhat unpredictable solution behavior. This article reviews the structure and function of antibodies and the mechanisms of physical and chemical instabilities. Various aspects of formulation development have been examined to identify the critical attributes for the stabilization of antibodies.

Antibodies, Monoclonal↗

Effects of chronic ethanol administration on brain interstitial fluid levels of Methionine-enkephalin as measured by microdialysis in vivo.

The level of Met-enkephalin in the brain is inversely correlated with ethanol consumption and is controlled partially through efflux activity of peptide transport system-1 (PTS-1) at the blood-brain barrier (BBB). Prolonged alcohol drinking can perturb aspects of this system, including a loss of control of Met-enkephalin levels at the transcriptional and translational levels, and impaired release of Met-enkephalin from tissue sources. Met-enkephalin levels in whole brain homogenates often first paradoxically increase after a few days of ethanol drinking and then decrease with the development of physical dependence. Which of those various changes drives the others is unclear. To clarify these interactions, we here determined the levels of Met-enkephalin in striatal interstitial fluid (ISF) by microdialysis, striatal tissue homogenates, and serum after chronic ethanol treatment and alcohol withdrawal. Mice received ethanol (5%) in liquid diet for 7 days (ethanol-treated) and others withdrawn for a day following 7-day treatment (withdrawal). There was a significant (P<0.05) difference in the levels of Met-enkephalin in striatal microdialysate between the control (79.1+/-5.9 pg/ml) and ethanol-treated group (94.9+/-4.3 pg/ml), which was lost by withdrawing ethanol (83.9+/-3.8 pg/ml). In contrast, ethanol treatment did not affect Met-enkephalin levels in the striatal tissue. In the ethanol-treated group, there was a significant (P<0.05) reduction of the levels of Met-enkephalin in serum to 70.5% of control levels. This decrease was restored to the level of control by withdrawing ethanol. These reversible changes in ISF and serum are readily explained by the known changes in the efflux activity of PTS-1 at the BBB.

Animals↗

Pancreatitis with didanosine and tenofovir disoproxil fumarate [corrected].

Pancreatitis occurs in up to 7% of patients infected with human immunodeficiency virus who are treated with standard doses of didanosine. Tenofovir disoproxil fumarate increases the plasma levels of didanosine and, thus, the combination of these agents may increase the risk of pancreatitis. Four cases of pancreatitis that occurred during administration of this drug combination are examined, including 1 that resulted in death.

Adenine↗

Estimating domain orientation of two human antibody IgG4 chimeras by crystallohydrodynamics.

A modified crystallohydrodynamic approach introduced in 2001 is applied to two human IgG4 constructs from mouse IgG1. The constructs were point mutants of the chimeric antibody molecule cB72.3(gamma4): cB72.3(gamma4A), devoid of inter-chain disulfide bridging, and cB72.3(gamma4P), which has full inter-chain bridging. As before, the known crystallographic structures for the Fab and Fc domains were combined with the measured translational frictional ratios to obtain an estimate for the apparent time-averaged hydration of the domains and hence for that of the intact molecule. The original approach was modified with the hydrated dimensions of the domains being applied, rather than the anhydrous crystallographic dimensions, for assessing the inter-domain orientations using the algorithms HYDROSUB and SOLPRO. Both chimeric IgG4 molecules were found to have open, rather than compact, structures, in agreement with the previous study on wild-type human IgG4. The insertion of a frictionless connector between the domains was necessary, however, for representing the cB72.3(gamma4A) chimera. It therefore appears that the inter-chain disulfide bonds act as physical constraints in the cB72.3(gamma4P) chimera, forcing the antibody domains together and producing a less elongated structure than that of cB72.3(gamma4A). The open structures produced for the two IgG4 chimeras showed similarity to those structures identified for murine IgG1 and IgG2a molecules through X-ray crystallography.

Animals↗

Chondrosarcoma of bone complicating Ollier's disease: report of a favourable response to radiotherapy.

Because chondrosarcoma of bone is traditionally thought to be a radioresistant malignancy, it is usually managed surgically. We report a case of multifocal chondrosarcoma arising in Ollier's disease for which the patient declined surgery. He was given a course of radical radiotherapy that resulted in symptom palliation and a radiologically confirmed response before he died of disseminated disease. In patients with inoperable chondrosarcoma, radiotherapy can provide palliative benefit.

Bone Neoplasms↗

Medical support for emergency relief workers after typhoon Sudal in Yap, Micronesia.

INTRODUCTION: On 09 April 2004, Typhoon Sudal struck the Island of Yap in the Federated States of Micronesia (FSM). Over 90% of homes, public utilities, and public property were damaged or destroyed. Nearly 10% of the population was displaced to shelters, and the majority of the population was without drinking water or power. United States disaster workers were deployed to Yap for three months to assist in the recovery and relief efforts. OBJECTIVE: The objective of this study was to evaluate the acute healthcare needs of the US disaster relief population serving in a remote setting with limited medical resources. METHODS: A retrospective chart review of all disaster relief workers presenting to an emergency clinic in Yap during the disaster relief effort from April 2004-July 2004 was performed. Investigators extracted demographic data, chief complaints, medical histories, medical management, disposition, and outcome data from the clinic charts. RESULTS: Together, the 60 disaster workers present on Yap during the relief effort made 163 patient contacts in the disaster emergency clinic. A total of 92% of patient contacts were for minor medical complaints or minor trauma, 13% were for upper-respiratory infections, 9% were for gastrointestinal illness, and 9% were for dermatological problems. Eight percent of visits were for serious medical problems or trauma. Life-threatening illnesses or injuries did not occur. CONCLUSIONS: Disaster relief workers on Yap frequently utilized the disaster relief clinic. In general, disaster workers remained healthy during the relief effort in Yap, and most injuries and illnesses were minor. On-site medical providers resulted in rapid care and stabilization, and after treatment, disaster workers were able to return to duty.

Disasters↗

Paramedic performance in calculating drug dosages following stressful scenarios in a human patient simulator.

BACKGROUND: Paramedics face many stressors in their work environment. Studies have shown that stress can have a negative effect on the psychological well-being of health professionals. However, there is little published research regarding the effects of stress on the cognitive skills necessary for optimal patient care. OBJECTIVES: The primary purpose of this study was to investigate the effects of acute stress on the emotional response and performance of paramedics. Furthermore, the authors explored whether a paramedic's level of training or years of experience would mediate the effects of stress on performance. METHODS: Paramedic performances in calculating drug dosages were compared in two stress conditions. In the low-stress condition, 30 paramedics calculated the drug dosages in a quiet classroom free of any stressor. In the high-stress condition, the same paramedics calculated comparable drug dosages immediately after working through a challenging scenario with a human patient simulator. RESULTS: The paramedics obtained lower accuracy scores in the high-stress condition than in the low-stress condition [43% (95% confidence interval [CI]: 36.9-49.2) vs. 58% (95% CI: 48.6-67.1), p < 0.01 based on univariate analysis]. Neither work experience nor level of training predicted the individual differences in the stress-induced performance decrements. CONCLUSION: These results suggest that the types of stressors encountered in clinical situations can increase medical errors, even in highly experienced individuals. These findings underline the need for more research to determine the mechanisms by which stress influences clinical performance, with the ultimate goal of targeting education or technologic interventions to those tasks, situations, and individuals most likely to benefit from such interventions.

Adaptation, Psychological↗

Parallel MR imaging: a user's guide.

Parallel imaging is a recently developed family of techniques that take advantage of the spatial information inherent in phased-array radiofrequency coils to reduce acquisition times in magnetic resonance imaging. In parallel imaging, the number of sampled k-space lines is reduced, often by a factor of two or greater, thereby significantly shortening the acquisition time. Parallel imaging techniques have only recently become commercially available, and the wide range of clinical applications is just beginning to be explored. The potential clinical applications primarily involve reduction in acquisition time, improved spatial resolution, or a combination of the two. Improvements in image quality can be achieved by reducing the echo train lengths of fast spin-echo and single-shot fast spin-echo sequences. Parallel imaging is particularly attractive for cardiac and vascular applications and will likely prove valuable as 3-T body and cardiovascular imaging becomes part of standard clinical practice. Limitations of parallel imaging include reduced signal-to-noise ratio and reconstruction artifacts. It is important to consider these limitations when deciding when to use these techniques.

Artifacts↗