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Biomedical subjects

T Keenan

Publications and source records attributed to T Keenan.

At least 19 recordsLinked to original sources
PubMed2001

Nonlinear ligament viscoelasticity.

Ligaments display time-dependent behavior, characteristic of a viscoelastic solid, and are nonlinear in their stress-strain response. Recent experiments (25) reveal that stress relaxation proceeds more rapidly than creep in medial collateral ligaments, a fact not explained by linear viscoelastic theory but shown by Lakes and Vanderby (17) to be consistent with nonlinear theory. This study tests the following hypothesis: nonlinear viscoelasticity of ligament requires a description more general than the separable quasilinear viscoelasticity (QLV) formulation commonly used. The experimental test for this hypothesis involves performing both creep and relaxation studies at various loads and deformations below the damage threshold. Freshly harvested, rat medial collateral ligaments (MCLs) were used as a model. Results consistently show a nonlinear behavior in which the rate of creep is dependent upon stress level and the rate of relaxation is dependent upon strain level. Furthermore, relaxation proceeds faster than creep; consistent with the experimental observations of Thornton et al. (25) The above results from rat MCLs are not consistent with a separable QLV theory. Inclusion of these nonlinearities would require a more general formulation.

Animals↗
PubMed2000

A ligand-reversible dimerization system for controlling protein-protein interactions.

Chemically induced dimerization provides a general way to gain control over intracellular processes. Typically, FK506-binding protein (FKBP) domains are fused to a signaling domain of interest, allowing crosslinking to be initiated by addition of a bivalent FKBP ligand. In the course of protein engineering studies on human FKBP, we discovered that a single point mutation in the ligand-binding site (Phe-36 --> Met) converts the normally monomeric protein into a ligand-reversible dimer. Two-hybrid, gel filtration, analytical ultracentrifugation, and x-ray crystallographic studies show that the mutant (F(M)) forms discrete homodimers with micromolar affinity that can be completely dissociated within minutes by addition of monomeric synthetic ligands. These unexpected properties form the basis for a "reverse dimerization" regulatory system involving F(M) fusion proteins, in which association is the ground state and addition of ligand abolishes interactions. We have used this strategy to rapidly and reversibly aggregate fusion proteins in different cellular compartments, and to provide an off switch for transcription. Reiterated F(M) domains should be generally useful as conditional aggregation domains (CADs) to control intracellular events where rapid, reversible dissolution of interactions is required. Our results also suggest that dimerization is a latent property of the FKBP fold: the crystal structure reveals a remarkably complementary interaction between the monomer binding sites, with only subtle changes in side-chain disposition accounting for the dramatic change in quaternary structure.

Dimerization↗
PubMed2000

Regulation of protein secretion through controlled aggregation in the endoplasmic reticulum.

A system for direct pharmacologic control of protein secretion was developed to allow rapid and pulsatile delivery of therapeutic proteins. A protein was engineered so that it accumulated as aggregates in the endoplasmic reticulum. Secretion was then stimulated by a synthetic small-molecule drug that induces protein disaggregation. Rapid and transient secretion of growth hormone and insulin was achieved in vitro and in vivo. A regulated pulse of insulin secretion resulted in a transient correction of serum glucose concentrations in a mouse model of hyperglycemia. This approach may make gene therapy a viable method for delivery of polypeptides that require rapid and regulated delivery.

Animals↗
PubMed2000

A theory of mind perspective on cognitive, affective, and intimacy deficits in child sexual offenders.

Previous work in the area of sexual offending has suggested that factors such as intimacy deficits, problems empathizing with victims, and cognitive distortions have all been associated with the genesis and maintenance of sexual abuse. While researchers have constructed theories to account for the role of these variables in sexual offending, a framework that unites their study is lacking. Recently Ward, Keenan, and Hudson have proposed that sexual offenders may suffer from a deficit in their ability to understand and attribute mental states to others. Their review of the literature on the etiology of sexual offending suggested that intimacy deficits, empathy deficits, and cognitive distortions all point to a lack of awareness of other peoples' beliefs, desires, perspectives, and needs, what is commonly referred to in the developmental literature as a theory of mind. In this paper, we expand on this argument, illustrating some of the developmental pathways by which deficits in one's theory of mind can explain the pattern of deficits exhibited by many sexual offenders.

Child↗
PubMed1999

Chronic inhalation carcinogenicity study of commercial hexane solvent in F-344 rats and B6C3F1 mice.

The carcinogenic and chronic toxicity potential of commercial hexane solvent was evaluated in F-344 rats and B6C3F1 mice (50/sex/concentration/species) exposed by inhalation for 6 h/day, 5 days/week for 2 years. Target hexane vapor concentrations were 0, 900, 3000, and 9000 ppm. There were no significant differences in survivorship between control and hexane-exposed groups, and clinical observations were generally unremarkable. Small, but statistically significant decreases in body weight gain were seen in rats of both sexes in the mid- and high-exposure groups and in high-expsoure female mice. The only noteworthy histopathological finding in rats was epithelial cell hyperplasia in the nasoturbinates and larynx of exposed groups. This response was judged to be indicative of upper respiratory tract tissue irritation. No significant differences in tumor incidence between control and hexane-exposed rats were found. In mice, uterine tissue from the high-exposure females exhibited a significant decrease in the severity of cystic endometrial hyperplasia compared to controls. An increase in the combined incidence of hepatocellular adenomas and carcinomas was observed in high-exposure female mice. The incidence of liver tumors was not increased in the mid- or low-exposure female mice or in male mice exposed to hexane. An increased incidence of pituitary adenomas was observed in female, but not male mice. This finding was not believed to have been treatment-related because the incidence in the control group was unusually low, and the incidence in exposed groups was not dose-related and was within the historical control range. No other neoplastic changes judged to be treatment-related were observed in tissues from male or female mice. In conclusion, chronic exposure to commercial hexane solvent at concentrations up to 9000 ppm was not carcinogenic to F-344 rats or to male B6C3F1 mice, but did result in an increased incidence of liver tumors in female mice.

Adenoma, Liver Cell↗
PubMed1998

Synthesis and activity of bivalent FKBP12 ligands for the regulated dimerization of proteins.

The total synthesis and in vitro activities of a series of chemical inducers of dimerization (CIDs) is described. The use of small-molecule CIDs to control the dimerization of engineered FKBP12-containing fusion proteins has been demonstrated to have broad utility in biological research as well as potential medical applications in gene and cell therapies. The facility and flexibility of preparation make this new class of wholly synthetic compounds exceptionally versatile tools for the study of intracellular signaling events mediated by protein-protein interactions or protein localization. While some congeners possess potency comparable to or better than the first generation natural product-derived CID, FK1012, structure-activity relationships are complex and underscore the need for application-specific compound optimizations.

Apoptosis↗
PubMed1997

A versatile synthetic dimerizer for the regulation of protein-protein interactions.

The use of low molecular weight organic compounds to induce dimerization or oligomerization of engineered proteins has wide-ranging utility in biological research as well as in gene and cell therapies. Chemically induced dimerization can be used to activate intracellular signal transduction pathways or to control the activity of a bipartite transcription factor. Dimerizer systems based on the natural products cyclosporin, FK506, rapamycin, and coumermycin have been described. However, owing to the complexity of these compounds, adjusting their binding or pharmacological properties by chemical modification is difficult. We have investigated several families of readily prepared, totally synthetic, cell-permeable dimerizers composed of ligands for human FKBP12. These molecules have significantly reduced complexity and greater adaptability than natural product dimers. We report here the efficacies of several of these new synthetic compounds in regulating two types of protein dimerization events inside engineered cells--induction of apoptosis through dimerization of engineered Fas proteins and regulation of transcription through dimerization of transcription factor fusion proteins. One dimerizer in particular, AP1510, proved to be exceptionally potent and versatile in all experimental contexts tested.

Apoptosis↗
PubMed1997

Care of patients with type II diabetes: a study of family physicians' compliance with clinical practice guidelines.

BACKGROUND: Most patients with type II diabetes mellitus receive care by family physicians. The goals of this study were to determine the level of diabetes care provided by family physicians; to assess family physicians' compliance with the Canadian Diabetes Association (CDA) guidelines; and to examine relationships between various aspects of diabetes care and glycemic control. METHODS: A retrospective medical chart review was conducted of 118 patients with type II diabetes mellitus in 10 family practice clinics in Newfoundland. The study population consisted of 55 male and 63 female patients with a mean age of 64 (range 29 to 88) years. Using standardized forms based on the CDA guidelines, information about plasma glucose and lipid levels, presence of diabetes complications, and physician management practices were extracted from patient charts. The main outcome measure was glycosylated hemoglobin (HbA1c) levels. RESULTS: Only 53% patients had HbA1c measurements done in the previous year; these persons had a significantly longer duration of diabetes that those who did not have their HbA1c measured. Eighty-seven percent of patients had optimal or good plasma glucose levels. Compliance with CDA guidelines by physicians was poor; physicians were doing about half the recommended checks and procedures. CONCLUSIONS: Data from the present study seem to suggest that family physicians are doing a good job of providing care for their patients with type II diabetes. The results, however, should be interpreted with caution until further research is done to replicate our findings because of the limitations of this small retrospective study.

Adult↗
PubMed1996

A humanized system for pharmacologic control of gene expression.

Gene therapy was originally conceived as a medical intervention to replace or correct defective genes in patients with inherited disorders. However, it may have much broader potential as an alternative delivery platform for protein therapeutics, such as cytokines, hormones, antibodies and novel engineered proteins. One key technical barrier to the widespread implementation of this form of therapy is the need for precise control over the level of protein production. A suitable system for pharmacologic control of therapeutic gene expression would permit precise titration of gene product dosage, intermittent or pulsatile treatment, and ready termination of therapy by withdrawal of the activating drug. We set out to design such a system with the following properties: (1) low baseline expression and high induction ratio; (2) positive control by an orally bioavailable small-molecule drug; (3) reduced potential for immune recognition through the exclusive use of human proteins; and (4) modularity to allow the independent optimization of each component using the tools of protein engineering. We report here the properties of this system and demonstrate its use to control circulating levels of human growth hormone in mice implanted with engineered human cells.

Animals↗
PubMed1991

Adolescent health care and school-based clinics.

School-based adolescent health centers are emerging as a promising means of dealing comprehensively with the health needs, risks, and behaviors of the community's youth. This article reports on the initial experience of The Robert Wood Johnson Foundation in working jointly with communities, schools, and local medical institutions (hospitals, health centers, health departments) in establishing adolescent health clinics of this kind. The Foundation has helped to fund approximately one quarter of all such clinics nationwide.

Adolescent↗
PubMed1990

Myoclonus, seizures, and paratonia in Alzheimer disease.

Twenty-eight patients with the clinical diagnosis of probable Alzheimer disease (AD) were followed longitudinally until death. The presence of myoclonus, seizures, and paratonia was monitored as part of this process. At autopsy, 22 of the patients met pathologic criteria for AD and 6 had other degenerative neurologic diseases. Myoclonus was present in 55% of the AD patients and none of the non-AD patients. Seizures were present in 64% of the AD patients, and only 17% of the non-AD patients. Paratonia was found frequently in all patient groups. In most patients, symptoms developed late in the course of their illness. The incidence of myoclonus, seizures, and paratonia in our patients was higher than in most previous studies. The reasons for this finding are discussed.

Adult↗