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Biomedical subjects

Mark Miller

Publications and source records attributed to Mark Miller.

27 records · Page 2Linked to original sources
PubMed2004

Exploring nitrilase sequence space for enantioselective catalysis.

Nitrilases are important in the biosphere as participants in synthesis and degradation pathways for naturally occurring, as well as xenobiotically derived, nitriles. Because of their inherent enantioselectivity, nitrilases are also attractive as mild, selective catalysts for setting chiral centers in fine chemical synthesis. Unfortunately, <20 nitrilases have been reported in the scientific and patent literature, and because of stability or specificity shortcomings, their utility has been largely unrealized. In this study, 137 unique nitrilases, discovered from screening of >600 biotope-specific environmental DNA (eDNA) libraries, were characterized. Using culture-independent means, phylogenetically diverse genomes were captured from entire biotopes, and their genes were expressed heterologously in a common cloning host. Nitrilase genes were targeted in a selection-based expression assay of clonal populations numbering 10(6) to 10(10) members per eDNA library. A phylogenetic analysis of the novel sequences discovered revealed the presence of at least five major sequence clades within the nitrilase subfamily. Using three nitrile substrates targeted for their potential in chiral pharmaceutical synthesis, the enzymes were characterized for substrate specificity and stereospecificity. A number of important correlations were found between sequence clades and the selective properties of these nitrilases. These enzymes, discovered using a high-throughput, culture-independent method, provide a catalytic toolbox for enantiospecific synthesis of a variety of carboxylic acid derivatives, as well as an intriguing library for evolutionary and structural analyses.

Aminohydrolases↗
PubMed2003

Adequacy of early empiric antibiotic treatment and survival in severe sepsis: experience from the MONARCS trial.

As part of the Monoclonal Anti-TNF: A Randomized Controlled Sepsis (MONARCS) trial, which enrolled patients with suspected sepsis, we sought to determine whether adequate antibiotic therapy was associated with a decreased mortality rate. The study enrolled 2634 patients, 91% of whom received adequate antibiotic therapy. The mortality rate among patients given adequate antibiotic treatment was 33%, versus 43% among patients given inadequate treatment (P<.001). We conclude that adequate antibiotic therapy results in a significant decrease in the crude mortality rate among patients suspected of sepsis.

Anti-Bacterial Agents↗
PubMed2003

Electroporation enables plasmid vaccines to elicit CD8+ T cell responses in the absence of CD4+ T cells.

In vivo electroporation dramatically enhances plasmid vaccine efficacy. This enhancement can be attributed to increased plasmid delivery and, possibly, to some undefined adjuvant properties. Previous reports have demonstrated CD8(+) T cell priming by plasmid vaccines is strongly dependent upon CD4(+) T cell help. Indeed, the efficacy of a plasmid vaccine expressing Escherichia coli beta-galactosidase was severely attenuated in MHC class II-deficient (C2D) mice. To determine whether electroporation could compensate for the absence of CD4(+) T cell help, C2D mice were immunized by a single administration of plasmid in combination with electroporation using two conditions which differed only by the duration of the pulse (20 or 50 msec). Both conditions elicited robust cellular and humoral responses in wild-type mice, as measured by IFN-gamma ELISPOT, anti-beta-galactosidase ELISA, and protection from virus challenge. In C2D mice, the cellular response produced by the vaccine combined with the 50-msec pulse, as measured by ELISPOT, was identical to the response in wild-type mice. The 20-msec pulse elicited a milder response that was approximately one-fifth that of the response elicited by the 50-msec pulse. By contrast, the 20-msec conditions provided comparable protection in both wild-type and C2D recipients whereas the protection elicited by the 50-msec conditions in C2D mice was weaker than in wild-type mice. Further investigation is required to understand the discordance between the ELISPOT results and outcome of virus challenge in the C2D mice. Nonetheless, using this technique to prime CD8(+) T cells using plasmid vaccines may prove extremely useful when immunizing hosts with limiting CD4(+) T cell function, such as AIDS patients.

Animals↗
PubMed2003

Super-activated interferon-regulatory factors can enhance plasmid immunization.

We have been investigating the adjuvant properties of two super-activated interferon-regulatory factors (IRFs), IRF-3(5D) and IRF7/3A, identified in our previous studies of structure-function relationships, for enhancing plasmid vaccines. Intramuscular injection of plasmid cocktails encoding IRF-3(5D) and IRF7/3A molecules elicited cytotoxic T cell responses in over 80% of mice following a single immunization compared to a 20% response-rate using a control cocktail. Most interestingly, greater than 60% of mice immunized with the super-activated IRFs developed antigen-specific antibodies compared to 0% of the mice in the control group. Finally, vaccines which incorporated the super-activated IRFs provided greater protection against challenge with a recombinant vaccinia virus. These results support further investigation of the potential of these agents as adjuvants for genetic immunization.

Animals↗
PubMed2003

Environmental risk communication for the clinician.

Although they are accustomed to discussing risks in the medical arena through the process of informed consent, primary care clinicians may have difficulty communicating with their patients and communities about environmental health risks. Clinicians are generally trusted and can play important roles as educators, alert practitioners, or even advocates talking about environmental health risks with individuals and groups. Communication of risk requires an understanding of how scientists and clinicians assess risk--the process of quantitative or qualitative risk assessment. Risk is never a purely scientific issue; risk is perceived differently depending on some well-understood characteristics of the hazard, the individual perceiving the risk, and the social context. Many low-income communities of color have faced and continue to face disproportionate environmental exposures and disease burdens. The issue of environmental justice can significantly affect the context of a discussion about a specific environmental risk. The essence of risk communication has been well described and requires careful evaluation of the science and the social context, honesty, listening to and partnering with the community, and a clear, compassionate team approach.

Communication↗
PubMed2002

Depression after cardiac transplant treated with interpersonal psychotherapy and paroxetine.

This case study discusses the treatment of a 67-year-old man with no prior history of psychiatric illness diagnosed with major depression following cardiac transplantation. Shortly after surgery, the patient demonstrated depressive symptoms, including weight loss, emotional instability, and social isolation. Psychiatric consultation revealed that the patient first experienced these symptoms after learning that the donor heart he had received belonged to a woman. The patient had preconceived, stereotypical ideas that a woman's heart would inhibit his physical recovery and transform him into a more emotional man. The patient was prescribed the selective serotonin reuptake inhibitor paroxetine and began interpersonal psychotherapy. Results from this case study indicate that treatment with paroxetine, combined with interpersonal psychotherapy, may be successful in treating patients who had transplants and suffer from postsurgical depression.

Aged↗
PubMed2002

Using a psychoeducational approach to increase the self-esteem of adolescents at high risk for dropping out.

The effectiveness of an ecologically oriented approach in changing the self-concepts of 80 high-risk adolescents was investigated. Participants were administered a self-esteem scale before and after an eight-week psychoeducational program designed for dropout prevention. Results indicated significant reductions in dropout rates and increased self-esteem among participants.

Adolescent↗