Cyclin-dependent kinases as a therapeutic target for stroke

Cyclin-dependent kinases (CDKs) are commonly known to regulate cell proliferation. However, previous reports suggest that in cultured postmitotic neurons, activation of CDKs is a signal for death rather than cell division. We determined whether CDK activation occurs in mature adult neurons during focal stroke in vivo and whether this signal was required for neuronal death after reperfusion injury. Cdk4/cyclin D1 levels and phosphorylation of its substrate retinoblastoma protein (pRb) increase after stroke. Deregulated levels of E2F1, a transcription factor regulated by pRb, are also observed. Administration of a CDK inhibitor blocks pRb phosphorylation and the increase in E2F1 levels and dramatically reduces neuronal death by 80%. These results indicate that CDKs are an important therapeutic target for the treatment of reperfusion injury after ischemia.

Toward a new generation of vaccines: The anti-cytokine therapeutic vaccines

Pathological conditions, such as cancers, viral infections, and autoimmune diseases, are associated with abnormal cytokine production, and the morbidity associated with many medical disorders is often directly a result of cytokine production. Because of the absence of negative feedback control occurring in some pathophysiologic situations, a given cytokine may flood and accumulate in the extracellular compartment of tissues or tumors thereby impairing the cytokine network homeostasis and contributing to local pathogenesis. To evaluate whether the rise of anti-cytokine Abs by vaccination is an effective way to treat these pathological conditions without being harmful to the organism, we have analyzed each step of the cytokine process (involving cytokine production, target response, and feedback regulation) and have considered them in the local context of effector–target cell microenvironment and in the overall context of the macroenvironment of the immune system of the organism. In pathologic tissues, Abs of high affinity, as raised by anti-cytokine vaccination, should neutralize the pool of cytokines ectopically accumulated in the extracellular compartment, thus counteracting their pathogenic effects. In contrast, the same Abs should not interfere with cytokine processes occurring in normal tissues, because under physiologic conditions cytokine production by effector cells (induced by activation but controlled by negative feedback regulation) does not accumulate in the extracellular compartment. These concepts are consistent with results showing that following animal and human anti-cytokine vaccination, induction of high-affinity Abs has proven to be safe and effective and encourages this approach as a pioneering avenue of therapy.

Toward the therapeutic editing of mutated RNA sequences.

If RNA editing could be rationally directed to mutated RNA sequences, genetic diseases caused by certain base substitutions could be treated. Here we use a synthetic complementary RNA oligonucleotide to direct the correction of a premature stop codon mutation in dystrophin RNA. The complementary RNA oligonucleotide was hybridized to a premature stop codon and the hybrid was treated with nuclear extracts containing the cellular enzyme double-stranded RNA adenosine deaminase. When the treated RNAs were translated in vitro, a dramatic increase in expression of a downstream luciferase coding region was observed. The cDNA sequence data are consistent with deamination of the adenosine in the UAG stop codon to inosine by double-stranded RNA adenosine deaminase. Injection of oligonucleotide-mRNA hybrids into Xenopus embryos also resulted in an increase in luciferase expression. These experiments demonstrate the principle of therapeutic RNA editing.

L-arginine may mediate the therapeutic effects of low protein diets.

We have previously shown beneficial effects of dietary protein restriction on transforming growth factor beta (TGF-beta) expression and glomerular matrix accumulation in experimental glomerulonephritis. We hypothesized that these effects result from restriction of dietary L-arginine intake. Arginine is a precursor for three pathways, the products of which are involved in tissue injury and repair: nitric oxide, an effector molecule in inflammatory and immunological tissue injury; polyamines, which are required for DNA synthesis and cell growth; and proline, which is required for collagen production. Rats were fed six isocaloric diets differing in L-arginine and/or total protein content, starting immediately after induction of glomerulonephritis by injection of an antibody reactive to glomerular mesangial cells. Mesangial cell lysis and monocyte/macrophage infiltration did not differ with diet. However, restriction of dietary L-arginine intake, even when total protein intake was normal, resulted in decreased proteinuria, decreased expression of TGF-beta 1 mRNA and TGF-beta 1 protein, and decreased production and deposition of matrix components. L-Arginine, but not D-arginine, supplementation to low protein diets reversed these effects. These results implicate arginine as a key component in the beneficial effects of low protein diet.

The Utility of Therapeutic Assessment Style Fables During the Termination Stage of Psychotherapy

Stories, fables, and myths have been used for a long time in human history. They serve as a way for cultures and people to communicate, preserve important cultural values, and create meaning. The use of narratives has been recognized as a helpful technique in the field of psychology and can be found in many orientations and intervention techniques (Dwivedi, 2006; Roberts, 2000). Narrative therapy, bibliotherapy, trauma narratives, and Therapeutic Assessment (TA) are some of the areas in which the benefits of using written stories are incorporated into work with clients. In this paper, the clinical utility of using Therapeutic Assessment style fables in the termination phase of psychotherapy is explored. The termination phase is a challenging time for both therapists and clients. The use of rituals in the process of termination has been found to have a positive impact on the experience (Gutheil, 1993). This paper presents several case studies and examines the subsequent impact and clinical benefits of using termination fables in psychotherapy.

Leading With the Relationship: The Role of the Therapeutic Relationship in Motivational Interviewing

Motivational Interviewing (MI) is a brief evidence-based treatment that is most commonly used to treat addictive behaviors and to encourage diet and lifestyle changes and treatment adherence in health care settings. In recent years MI's use has been expanded to multiple other client populations in clinical psychology, as well as to other sectors, such as in education, and international non-profit work (Hettema at al., 2005). MI was inspired by research that demonstrated a high correlation between therapist application of the client-centered skill of accurate empathy and a reduction in drinking behaviors (Miller et al., 1980). MI contains both relational and technical components that are intended to operate synergistically. Despite a large body of research on MI treatment outcomes, variation in effectiveness has been found among studies, and the active ingredients of MI, particularly the relational aspects, are not well understood. As a result, the use of MI in many treatment settings is limited to the technical components of MI without a theory-based integration of the therapeutic relationship. This paper focuses on the contribution of the relational component to the effectiveness of MI, and explores the synergistic relationship between the technical and relational components of MI. A literature review of MI and the trans-theoretical literature on the therapeutic relationship is followed by two case illustrations. The paper concludes with recommendations for the field.

Establishing Culturally Sensitive Therapeutic Communities in Ghana for Individuals with Severe and Persistent Mental Illnesses

This paper makes a proposal for the establishment of therapeutic communities for people with severe and persistent mental illnesses in Ghana. It discusses the history and features of therapeutic communities, as well as the elements that make it compatible with the agenda of the new 2012 Ghana mental health bill. This paper also discusses the present state of mental health care in this West African country and how the establishment of therapeutic communities will promote recovery of people with severe and persistent mental illness, and change the perception of chronic mental illness in Ghana. A discussion of potential modifications of the therapeutic community is offered as well as justifications for maintaining other structural aspects should this establishment materialize in Ghana. The costs of setting up therapeutic communities in this third world country are addressed with the offered conclusion that costs far outweigh the benefits. Finally, given the endeavor of the proposed therapeutic communities to assist in deinstitutionalization of care, cautions are made in this paper to ensure that the trends experienced in the United States with deinstitutionalization are not replicated in Ghana. A proposal is made in the conclusion for Ghana to move past therapeutic communities when developmentally able- to community mental health centers which were in part established to account for some of the fallouts of deinstitutionalization by providing a comprehensive and extensive range of services for people with severe and persistent mental illness.