Creation of drug-specific herpes simplex virus type 1 thymidine kinase mutants for gene therapy.

Herpes simplex virus type 1 (HSV-1) thymidine kinase is currently used as a suicide agent in the gene therapy of cancer. This therapy is based on the preferential phosphorylation of nucleoside analogs by tumor cells expressing HSV-1 thymidine kinase. However, the use of HSV-1 thymidine kinase is limited in part by the toxicity of the nucleoside analogs. We have used random sequence mutagenesis to create new HSV-1 thymidine kinases that, compared with wild-type thymidine kinase, render cells much more sensitive to specific nucleoside analogs. A segment of the HSV-1 thymidine kinase gene at the putative nucleoside binding site was substituted with random nucleotide sequences. Mutant enzymes that demonstrate preferential phosphorylation of the nucleoside analogs, ganciclovir or acyclovir, were selected from more than one million Escherichia coli transformants. Among the 426 active mutants we have isolated, 26 demonstrated enhanced sensitivity to ganciclovir, and 54 were more sensitive to acyclovir. Only 6 mutant enzymes displayed sensitivity to both ganciclovir and acyclovir when expressed in E. coli. Analysis of 3 drug-sensitive enzymes demonstrated that 1 produced stable mammalian cell transfectants that are 43-fold more sensitive to ganciclovir and 20-fold more sensitive to acyclovir.

Toward antibody-directed "abzyme" prodrug therapy, ADAPT: carbamate prodrug activation by a catalytic antibody and its in vitro application to human tumor cell killing.

Antibody-directed enzyme prodrug therapy, ADEPT, is a recent approach to targeted cancer chemotherapy intended to diminish the nonspecific toxicity associated with many commonly used chemotherapeutic agents. Most ADEPT systems incorporate a bacterial enzyme, and thus their potential is reduced because of the immunogenicity of that component of the conjugate. This limitation can be circumvented by the use of a catalytic antibody, which can be "humanized," in place of the bacterial enzyme catalyst. We have explored the scope of such antibody-directed "abzyme" prodrug therapy, ADAPT, to evaluate the potential for a repeatable targeted cancer chemotherapy. We report the production of a catalytic antibody that can hydrolyze the carbamate prodrug 4-[N,N-bis(2-chloroethyl)]aminophenyl-N-[(1S)-(1,3- dicarboxy)propyl]carbamate (1) to generate the corresponding cytotoxic nitrogen mustard (Km = 201 microM, kcat = 1.88 min-1). In vitro studies with this abzyme, EA11-D7, and prodrug 1 lead to a marked reduction in viability of cultured human colonic carcinoma (LoVo) cells relative to appropriate controls. In addition, we have found a good correlation between antibody catalysis as determined by this cytotoxicity assay in vitro and competitive binding studies of candidate abzymes to the truncated transition-state analogue ethyl 4-nitrophenylmethylphosphonate. This cell-kill assay heralds a general approach to direct and rapid screening of antibody libraries for catalysts.

Switch from a type 2 to a type 1 T helper cell response and cure of established Leishmania major infection in mice is induced by combined therapy with interleukin 12 and Pentostam.

Successful treatment in allergic, autoimmune, and infectious diseases often requires altering the nature of a detrimental immune response mediated by a particular CD4+ T helper (Th) cell subset. While several factors contribute to the development of CD4+ Th1 and Th2 cells, the requirements for switching an established response are not understood. Here we use infection with Leishmania major as a model to investigate those requirements. We report that treatment with interleukin 12 (IL-12), in combination with the antimony-based leishmanicidal drug Pentostam, induces healing in L. major-infected mice and that healing is associated with a switch from a Th2 to a Th1 response. The data suggest that decreasing antigen levels may be required for IL-12 to inhibit a Th2 response and enhance a Th1 response. These observations are important for treatment of nonhealing forms of human leishmaniasis and also demonstrate that in a chronic infectious disease an inappropriate Th2 response can be switched to an effective Th1 response.

Acceptance and Commitment Therapy with Forensic Inpatients

This paper provides a preliminary exploration of the application of Acceptance and Commitment Therapy (ACT) within the context of a forensic hospital. ACT has a reputation for being a clinically flexible and empirically sound therapeutic intervention, which appears uniquely suited for forensic hospital settings. However, no research has been published to date on the use of ACT as a treatment for forensic inpatients. The ACT approach directly aims to help people let go of the unwinnable struggles to control symptoms of mental illness, and instead focus on constructing a "life worth living." ACT interventions can equip forensic patients with the values and flexible behavioral repertoires necessary to lead lives that are personally meaningful and satisfying and do not involve inflicting harm to others. The ACT model also attempts to minimize the therapist-patient hierarchy through an emphasis on the ubiquitous nature of human suffering. This approach can be particularly useful when working with marginalized, treatment-resistant patients. Continued research on the application of ACT with forensic inpatients is recommended.

Therapeutic Personality Assessment with Couples: A Short-Term Therapy Model

This paper focuses on the importance of psychological assessment as a short-term therapeutic tool for use in couples therapy. Personality assessment, when used collaboratively, can be a vital contribution to the therapeutic environment and can help couples can insight into each other's character traits and behavior patterns. This paper addresses the need for a short-term model of couples therapy for couples where one partner is incarcerated. The author proposes using a slightly modified version of Finn's Therapeutic Assessment for couples - Therapeutic Personality Assessment for Couples for a Prison Setting (TPAC-PS). A future research paradigm is suggested to test the validity of the TPAC-PS model.

Acceptance and Commitment Therapy-Based Exposure Treatment of Choking Phobia: A Case Study

One might choke if they observed the lack of research on choking phobia. McNally's (1994) review of the literature on choking phobia found only 25 studies addressing the treatment of choking phobia. The vast majority of these were case studies and none were randomized controlled trials. A search of the literature since then yielded only a few more studies. Given the dearth of information available about choking phobia and its treatment, it is important to document cases treated successfully with novel approaches. My goal in this paper is therefore to illustrate the use of exposure therapy augmented by Acceptance and Commitment Therapy (ACT; e.g., see Hayes, Strosahl, & Wilson, 1999; Hayes and Strosahl, 2004) in the treatment of an adult male presenting with fear of choking and to offer suggestions for the optimal treatment of choking phobia. To my knowledge, there are no documented cases of elements of ACT being used in the treatment of choking phobia to be found in the literature.

Art and play therapy.

Mode of access: Internet.

Existence and therapy; an introduction to phenomenological psychology and existential analysis.

Bibliography: p. 362-366.

Gene therapy for human patients : information for the general public.

Mode of access: Internet.

Managing interleukin-2 therapy /

Mode of access: Internet.

Radioactive iodine therapy for inpatients.

Mode of access: Internet.

Group psychotherapy with children : the theory and practice of play-therapy.

Mode of access: Internet.

National training course, emergency medical technician - paramedic. Instructor's lesson plans. Module III: shock and fluid therapy.

Mode of access: Internet.

Reimbursement principles concerning integrated therapy.

Mode of access: Internet.

Vitamin therapy, a résumé of clinical experience.

Includes bibliographies.