Motive-oriented therapeutic relationship building for patients diagnosed with schizophrenia

Treatment options for patients with schizophrenia demand further improvement. One way to achieve this improvement is the translation of findings from basic research into new specific interventions. Beyond that, addressing the therapy relationship has the potential to enhance both pharmacological and non-pharmacological treatments. This paper introduces motive-oriented therapeutic relationship (MOTR) building for schizophrenia. MOTR enables therapists to proactively adapt to their patient’s needs and to prevent problematic behaviors. For example, a patient might consider medication as helpful in principle, but the rejection of medication might be one of his few remaining means for his acceptable motive to stay autonomous despite hospitalization. A therapist who is motiveoriented proactively offers many degrees of freedom to this patient in order to satisfy his need for autonomy and to weaken the motivational basis for not taking medication. MOTR makes use of findings from basic and psychotherapy research and is generic in this respect, but at the same time guides therapeutic action precisely and flexibly in a patient oriented way.

Application, tolerance and safety of fondaparinux therapy in a German hospital: a prospective single-centre experience.

INTRODUCTION The pentasaccharide fondaparinux is widely approved for prophylaxis and treatment of thromboembolic diseases and therapy of acute coronary syndrome. It is also used off-label in patients with acute, suspected or antecedent heparin-induced thrombocytopenia (HIT). The aim of this prospective observational cohort study was to document fondaparinux' prescription practice, tolerance and therapy safety in a representative mixed German single-centre patient cohort. PATIENTS AND METHODS Between 09/2008 - 04/2009, 231 consecutive patients treated with fondaparinux were enrolled. Medical data were obtained from patient's records. The patients were clinically screened for thrombosis (Wells score), sequelae of HIT (4T's score), and bleeding complications (ISTH-criteria) and subjected to further assessment (i.e. sonography, HIT-diagnostics), if necessary. The mortality rate was assessed 30 days after therapy start. RESULTS Overall, 153/231 patients had a prophylactic, 74/231 patients a therapeutic, and 4/231 patients a successive prophylactic/therapeutic indication. In 11/231 patients fondaparinux was used due to suspected/antecedent HIT, in 5/231 patients due to a previous cutaneous delayed-type hypersensitivity to heparins. Other indications were rare. Three new/progressive thromboses were detected. No cases of HIT, major bleedings, or fatalities occurred. CONCLUSIONS Fondaparinux was well tolerated and was safe in prophylaxis and therapy; prescriptions mostly followed the current approval guidelines and were rarely related to HIT-associated indications (<5% of prescriptions), which is in contrast to previous study results in the U.S. (>94% of prescriptions were HIT-associated). A trend towards an individualised fondaparinux use based on the compound's inherent properties and the patients' risk profiles, i.e., antecedent HIT, bone fractures, heparin allergy, was observed.

Olfactory bulb volume predicts therapeutic outcome in major depression disorder

The volume of the olfactory bulb (OB) is strongly reduced in patients with major depressive disorder (MDD) and this group exhibits markedly decreased olfactory function. It has been suggested that olfactory input is important for maintaining balance in limbic neurocircuits. The aim of our study was to investigate whether reduced OB volume is associated with response to therapy in MDD. Twenty-four inpatients (all women, age 21-49 years, mean 38 ± 10 years SD) with MDD and 36 healthy controls (all women, age 20-52 years, mean 36 ± 10 years SD) underwent structural MRI. OB volume was compared between responders (N = 13) and non-responders (N = 11) to psychotherapy. Retest of OB volume was performed about 6 months after the end of therapy in nine of the patients. Therapy responders exhibited no significant difference in OB volume compared to healthy controls. However, average OB volume of non-responders was 23 % smaller compared to responders (p = .0011). Furthermore, OB volume was correlated with the change of depression severity (r = .46, p = .024). Volume of the OB did not change in the course of therapy. OB volume may be a biological vulnerability factor for the occurrence and/or maintenance of depression, at least in women.

The shorter the better? A follow-up analysis of 10-session psychiatric treatment including the motive-oriented therapeutic relationship for borderline personality disorder

OBJECTIVE: There is little research on short-term treatments for borderline personality disorder (BPD). While the core changes may occur only in long-term treatments, short-term treatments may enable the study of early generic processes of engagement in therapy and thus inform about effective treatment components. It was shown that a 10-session version of a psychiatric treatment was effective in reducing borderline symptoms at the end of this treatment [Kramer, U., Kolly, S., Berthoud, L., Keller, S., Preisig, M., Caspar, F., … Despland, J.-N. (2014). Effects of motive-oriented therapeutic relationship in a ten-session general psychiatric treatment for borderline personality disorder: A randomized controlled trial. Psychotherapy and Psychosomatics, 83, 176-186.]. Also, it was demonstrated in a randomized design that adding the motive-oriented therapeutic relationship (MOTR), following an individualized case formulation based on Plan Analysis, further increased general outcome after session 10 and had a positive effect on the early changes in self-esteem and alliance. METHOD: The present study focuses on the follow-up period after this initial treatment, examining treatment density and outcomes after 6 months and service utilization after 12 months. Outcome was measured using the OQ-45. RESULTS: Results on a sub-sample of N = 40 patients with available OQ-45 data at follow-up (n = 21 for MOTR-treatment, n = 19 for comparison treatment) showed maintenance of gains over the follow-up period, which did not differ between both conditions. It appeared for this sample that MOTR treatments, while using the same number of sessions, lasted more weeks (i.e., lower treatment density, defined as the number of sessions per week), when compared to the treatments without MOTR. Density marginally predicted symptom reduction at follow-up. Patients in MOTR treatments had a greater likelihood of entering structured psychotherapy after the initial sessions than patients in the comparison group. CONCLUSIONS: These results are overall consistent with earlier studies on short-term treatments for BPD and underline the importance of individualizing interventions, by using case formulations that rely on idiographic methods and integrative concepts.

Directional DBS improves therapeutic window: from model prediction to human use

Deep brain stimulation of different targets has been shown to drastically improve symptoms of a variety of neurological conditions. However, the occurrence of disabling side effects may limit the ability to deliver adequate amounts of current necessary to reach the maximal benefit. Computed models have suggested that reduction in electrode size and the ability to provide directional stimulation could increase the efficacy of such therapies. This has never been demonstrated in humans. In the present study, we assess the effect of directional stimulation compared to omnidirectional stimulation.

Conceptualizing Success in Therapeutic Wilderness Experiences: The Creation and Maintenance of Instructor-Participant Relationships

Researchers have noted that relationships created between instructors and clients in therapeutic wilderness experiences are unique (Russell, 2003; Russell & Phillips-Miller, 2001; Sklar, Anderson, & Autry, 2007; Taniguchi et al., 2009), but little research has been done to explore these relationships. The present study is an investigation of how instructors build and maintain relationships with participants, conceptualize these relationships, and define success in these tasks. Nine instructors from a wilderness program for at-risk youth participated in interviews. Data were analyzed using a line-by-line coding technique. Results of this study add to existing research on wilderness therapy and therapeutic wilderness experiences, provide models of successful instructing, and guide programs and instructors in the services they provide to their participants.

Therapeutic Use of Ginkgo Biloba

Gingko biloba, one of the most popular herbs in the USA is known for its various therapeutic uses and is now well researched for its various active compounds. Although originally grown in Asia, the tree is distributed all over the world. Leaves, bark, roots all have therapeutic properties and are used for various illnesses like asthma, circulatory ailments and cognitive support or dysfunction.

A new fork for clinical application: Targeting forkhead transcription factors in cancer therapy

RAS-ERK-MAPK (Mitogen-activated protein kinase) pathway plays an essential role in proliferation, differentiation, and tumor progression. In this study, we showed that ERK downregulated FOXO3a through directly interacting with and phosphorylating FOXO3a at Serine 294, Serine 344, and Serine 425. ERK-phosphorylated FOXO3a was degraded by MDM2-mediated ubiquitin-proteosome pathway. FOXO3a phosphorylation and degradation consequently promoted cell proliferation and tumorigenesis. However, the non-phosphorylated FOXO3a mutant, which was resistant to the interaction and degradation by MDM2, resulted in inhibition of tumor formation. Forkhead O transcription factors (FOXOs) are important in the regulation of cellular functions including cell cycle arrest and cell death. Perturbation of FOXOs function leads to deregulated cell proliferation and cancer. Inactivation of FOXO proteins by activation of cell survival pathways, such as PI3K/AKT/IKK, is associated with tumorigenesis. Our study will further highlight FOXOs as new therapeutic targets in a broad spectrum of cancers. ^ Chemotherapeutic drug resistance is the most concerned problem in cancer therapy as resistance ultimately leads to treatment failure of cancer patients. In another study, we showed that blocking ERK activity with AZD6244, an established MEK1/2 inhibitor currently under human cancer clinical trials, enhances FOXO3a expression in various human cancer cell lines in vitro, and also in human colon cancer cell xenografts in vivo. Knocking down FOXO3a and its downstream gene Bim impaired AZD6244-induced growth suppression, whereas restoring activation of FOXO3a sensitized human cancer cell to AZD6244-induced growth arrest and apoptosis. More importantly, AZD6244-resistant cancer cells showed impaired endogenous FOXO3a nuclear translocation, reduced FOXO3a-Bim promoter association and significantly decreased Bim expression in response to AZD6244. AZD6244-resistant cancer cells can be sensitized to API-2 (an AKT inhibitor) and LY294002 (a PI3K inhibitor) in suppressing cell growth and colony formation, these inhibitors were known to enhance FOXO3a activity/nuclear translocation through inhibiting PI3K-AKT pathway. This study reveals novel molecular mechanism contributing to AZD6244-resistance through regulation of FOXO3a activity, further provides significant clinical implication of combining AZD6244 with PI3K/AKT inhibitors for sensitizing AZD6244-resistant cancer cells by activating FOXO3a. FOXO3a activation can be an essential pharmacological target and indicator to mediate and predict AZD6244 efficacy in clinical use. ^

The impact of social support networks on compliance with hypertensive therapeutic regimens among noninstitutionalized black adults

A conceptual framework based on the Health Belief Model was proposed which identified those factors most significant in the prediction of compliance behavior. The hypothesized model was applied to analyze the effects of sociodemographic characteristics, self-assessed health status, and social support networks on compliance with antihypertensive regimens, focusing on black adults.^ The study population was selected from the National Health and Examination Survey II (NHANES II) which produced a sample of 3,957 eligible persons 35-74 years of age.^ The study addressed the following research questions: (a) what is the relationship between demographic variables and self-assessed health status, (b) what is the relationship between social support network and self-assessed health status, (c) what is the compliance, (d) what factors, e.g., demographic characteristics, social support network, self-assessed health status, are most related to compliance, and (e) does the effect of these factors on compliance differ between black and white adults?^ The results of the study found that blacks: (a) had poorer health than whites, and education and income were significantly related to self-assessed health status, (b) the stronger social support networks of blacks, the better their health status, and (c) older blacks and those in poorer health were more likely to comply with recommended treatment. The hypothesized conceptual model for the prediction of compliance behavior was partially substantiated for both blacks and whites.^ Implications for the application of the conceptual model are also discussed. ^

LOW REACTIVE OXYGEN SPECIES AND HIGH GLYCOLYSIS IN GLIOBLASTOMA STEM CELLS:MECHANISMS AND THERAPEUTIC IMPLICATIONS

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with poor prognosis due in part to drug resistance and high incidence of tumor recurrence. The drug resistant and cancer recurrence phenotype may be ascribed to the presence of glioblastoma stem cells (GSCs), which seem to reside in special stem-cell niches in vivo and require special culture conditions including certain growth factors and serum-free medium to maintain their stemness in vitro. Exposure of GSCs to fetal bovine serum (FBS) can cause their differentiation, the underlying mechanism of which remains unknown. Reactive oxygen species (ROS) play an important role in normal stem cell differentiation, but their role in affecting cancer stem cell fate remains unclear. Whether the metabolic characteristics of GSCs are different from other glioblastoma cells and can be targeted are also unknown. In this study, we used several stem-like glioblastoma cell lines derived from clinical tissues by typical neurosphere culture system or orthotopic xenografts, and showed that addition of fetal bovine serum to the medium induced an increase of ROS, leading to aberrant differentiation and decreases of stem cell markers such as CD133. We found that exposure of GSCs to serum induced their differentiation through activation of mitochondrial respiration, leading to an increase in superoxide (O2-) generation and a profound ROS stress response manifested by upregulation of oxidative stress response pathway. This increase in mitochondrial ROS led to a down-regulation of molecules including SOX2, and Olig2, and Notch1 that are important for stem cell function and an upregulation of mitochondrial superoxide dismutase SOD2 that converts O2- to H2O2. Neutralization of ROS by antioxidant N-acetyl-cysteine in the serum-treated GSCs suppressed the increase of superoxide and partially rescued the expression of SOX2, Olig2, and Notch1, and prevented the serum-induced differentiation phenotype. Additionally, GSCs showed high dependence on glycolysis for energy production. The combination of a glycolytic inhibitor 3-BrOP and a chemotherapeutic agent BCNU depleted cellular ATP and inhibited the repair of BCNU-induced DNA damage, achieving strikingly synergistic killing effects in drug resistant GSCs. This study uncovers the metabolic properties of glioblastoma stem cells and suggests that mitochondrial function and cellular redox status may profoundly affect the fates of glioblastoma stem cells via a ROS-mediated mechanism, and that the active glycolytic metabolism in cancer stem cells may provide a biochemical basis for developing novel therapeutic strategies to effectively eliminate GSCs.

Differential Activity of the KRAS Oncogene by Method of Activation: Implications for Signaling and Therapeutic Intervention

Despite having been identified over thirty years ago and definitively established as having a critical role in driving tumor growth and predicting for resistance to therapy, the KRAS oncogene remains a target in cancer for which there is no effective treatment. KRas is activated b y mutations at a few sites, primarily amino acid substitutions at codon 12 which promote a constitutively active state. I have found that different amino acid substitutions at codon 12 can activate different KRas downstream signaling pathways, determine clonogenic growth potential and determine patient response to molecularly targeted therapies. Computer modeling of the KRas structure shows that different amino acids substituted at the codon 12 position influences how KRas interacts with its effecters. In the absence of a direct inhibitor of mutant KRas several agents have recently entered clinical trials alone and in combination directly targeting two of the common downstream effecter pathways of KRas, namely the Mapk pathway and the Akt pathway. These inhibitors were evaluated for efficacy against different KRAS activating mutations. An isogenic panel of colorectal cells with wild type KRas replaced with KRas G12C, G12D, or G12V at the endogenous loci differed in sensitivity to Mek and Akt inhibition. In contrast, screening was performed in a broad panel of lung cell lines alone and no correlation was seen between types of activating KRAS mutation due to concurrent oncogenic lesions. To find a new method to inhibit KRAS driven tumors, siRNA screens were performed in isogenic lines with and without active KRas. The knockdown of CNKSR1 (CNK1) showed selective growth inhibition in cells with an oncogenic KRAS. The deletion of CNK1 reduces expression of mitotic cell cycle proteins and arrests cells with active KRas in the G1 phase of the cell cycle similar to the deletion of an activated KRas regardless of activating substitution. CNK1 has a PH domain responsible for localizing it to membrane lipids making KRas potentially amenable to inhibition with small molecules. The work has identified a series of small molecules capable of binding to this PH domain and inhibiting CNK1 facilitated KRas signaling.