PCK2 activation mediates an adaptive response to glucose depletion in lung cancer.

Cancer cells are reprogrammed to utilize glycolysis at high rates, which provides metabolic precursors for cell growth. Consequently, glucose levels may decrease substantially in underperfused tumor areas. Gluconeogenesis results in the generation of glucose from smaller carbon substrates such as lactate and amino acids. The key gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK), has been shown to provide metabolites for cell growth. Still, the role of gluconeogenesis in cancer is unknown. Here we show that the mitochondrial isoform of PEPCK (PCK2) is expressed and active in three lung cancer cell lines and in non-small cell lung cancer samples. PCK2 expression and activity were enhanced under low-glucose conditions. PEPCK activity was elevated threefold in lung cancer samples over normal lungs. To track the conversion of metabolites along the gluconeogenesis pathway, lung cancer cell lines were incubated with (13)C3-lactate and label enrichment in the phosphoenolpyruvate (PEP) pool was measured. Under low glucose, all three carbons from (13)C3-lactate appeared in the PEP pool, further supporting a conversion of lactate to pyruvate, via pyruvate carboxylase to oxaloacetate, and via PCK2 to phosphoenolpyruvate. PCK2 small interfering RNA and the pharmacological PEPCK inhibitor 3-mercaptopicolinate significantly enhanced glucose depletion-induced apoptosis in A549 and H23 cells, but not in H1299 cells. The growth of H23 multicellular spheroids was significantly reduced by 3-mercaptopicolinate. The results of this study suggest that lung cancer cells may utilize at least some steps of gluconeogenesis to overcome the detrimental metabolic situation during glucose deprivation and that in human lung cancers this pathway is activated in vivo.

Thiolated polyacrylic acid-modified iron oxide nanoparticles for in vitro labeling and MRI of stem cells.

PURPOSE: The purpose of this study was to develop and characterize new surface-modified iron oxide nanoparticles demonstrating the efficiency to be internalized by human endothelial progenitor cells (EPCs) from umbilical cord blood. METHODS: Iron oxide nanoparticles were coated with polyacrylic acid-cysteine (PAA-Cys) by either in situ precipitation or postsynthesis. The nanoparticles were characterized by X-ray powder diffraction. EPCs were labeled with PAA-Cys-modified iron oxide nanoparticles or with uncoated nanoparticles. The relaxivity of uncoated and coated iron oxide nanoparticles as well as EPCs labeled with PAA-Cys-modified iron oxide were determined. RESULTS: Addition of PAA-Cys increased the particle size from 10.4 to 144 and 197 nm, respectively. The X-ray powder diffraction pattern revealed that the particles consist of Fe(3)O(4) with a spinal structure. Postsynthesis coated particles showed a cellular uptake of 85% and 15.26 pg iron/cell. For both types of particles the relaxivity ratio was at least 2-fold higher than that of the gold standard Resovist(®). CONCLUSION: The PAA-Cys coated iron oxide nanoparticles are a promising tool for labeling living cells such as stem cells for diagnostic and therapeutic application in cell-based therapies due to their high relaxivities and their easy uptake by cells.

Development and in vivo bioavailability study of an oral fondaparinux delivery system.

Fondaparinux is an agent of choice for the prevention and initial treatment of venous thromboembolism (VTE) as well as myocardial infarction. Nevertheless, as a negatively charged molecule fondaparinux can pass the intestinal epithelial barrier after oral administration only partially. It was therefore the aim of this study to design a highly efficient small-intestinal-targeted oral delivery system for fondaparinux based on thiolated polycarbophil (PCP-Cys) and glutathione (GSH) combined with sodium decanoate. The formulations were tested in vitro with regard to their release, cytotoxicity profiles and their permeation-enhancing properties across small-intestinal mucosa. For the in vivo study, rats were treated with a single oral dose of fondaparinux gels or mini-tablets (5mg/kg) and the subcutaneous and intravenous groups with a dose of 200µg/kg fondaparinux. The anti-factor Xa activity in the plasma was measured. In the presence of PCP-Cys/GSH/sodium decanoate the uptake of fondaparinux from the intestinal mucosa was 4.1-fold improved. The area under concentration-time curve in rat plasma from 0 to 24h with PCP-Cys/GSH/sodium decanoate gel was 135.3µgmin/ml and 1.3-fold improved with the tablets. C(max) value of mini-tablets was 0.23µg/ml and the absolute bioavailability of 4.4% was 6.2-fold improved, while the control solution was not absorbed orally. PCP-Cys/GSH/sodium decanoate demonstrated potential for increasing the oral bioavailability of the indirect factor Xa inhibitor as an alternative to currently used subcutaneous delivery.

Prenatal magnetic resonance imaging: towards optimized patient information.

OBJECTIVES: To investigate the perception of fetal magnetic resonance imaging (MRI) by women confronted with the necessity of a targeted prenatal examination because of suspicion of an abnormality, in order to develop a pre-scan information leaflet tailored to the information requirements of these women. METHODS: Sixty-two women were assessed by qualitative interview immediately before and after scanning. Data were analyzed by means of a qualitative content analysis. The transcribed interviews were coded within established categories, including knowledge of the purpose of the exam, understanding of the procedure, expectation of the baby's reaction, satisfaction with pre-information, experience of fetal MRI, distressing conditions during scanning, anxiety and suggestions for improvement of the scanning procedure. RESULTS: Pre-scan interviews indicated 66% of our sample to be well-informed about the purpose of fetal MRI. A realistic, detailed description of the examination was given by 37%. Only 32% expected the scanning to be safe for their baby. Despite the overall good tolerance of fetal MRI (63%), post-scan interviews revealed that 58% of women had experienced anxiety during MRI, which was partly due to the fearful perception of intensified fetal body movements during scanning. The quality of the pre-information leaflet was rated as sufficiently informative by 68% of the women. Suggestions for improvement were centered on physical conditions, the presence of the partner during scanning, and the availability of pre-scan briefings. CONCLUSIONS: Based on women's needs, detailed information about the fetal MRI procedure should be provided, containing clear-cut explanations about the purpose, course, method and possible distressing conditions. A leaflet describing these details should be given to women by the referring physician well in advance of the examination, and the woman given the opportunity to discuss unclear points.

[Predictors for patients' starting psychotherapy]. / Prädiktoren für die Inanspruchnahme einer Psychotherapie.

BACKGROUND: The aim of this study was to discover prognostic criteria for outpatients' making use of psychotherapy. Data from patients and therapists were collected. SUBJECTS AND METHODS: After initial psychoanalytic interviews, 92 patients at a university psychotherapy outpatient department were asked to complete narrative forms and standardized questionnaires (FMP) regarding their motivation to seek psychotherapy. In addition, the therapists contributed a Global Assessment of Functioning (GAF) and estimate of the initial therapeutic working alliance (iTAB) for each patient. In the follow-up, we investigated patients' actual use of psychotherapy. RESULTS: Sociodemographic variables, personality variables, and diagnoses had only minor prognostic relevance, whereas therapists' assessments of patient resources for therapeutic relationship and work proved to be of high predictive value. CONCLUSION: Positive assessment of a patient's ability for therapeutic working alliance in the initial diagnostic interview is shown to be an important prognostic factor of a patient's entering psychotherapy.

Immunohistochemical analysis of desmoid tumours.

BACKGROUND/AIMS: Although the standard treatment for desmoid tumours is complete surgical resection with wide margins, the optimal adjuvant treatment for recurrent or inoperable disease is unclear, often being based on sporadic immunohistochemical reports with a low number of cases. Therefore, a large immunohistochemical study was performed, to provide a theoretical basis for adjuvant treatment regimens. METHODS: One hundred and sixteen tissue samples from 80 patients (49 female, 31 male; mean age, 34 years; range, 0-83) with desmoid tumours (46 extra-abdominal, 21 abdominal, 13 intra-abdominal) were tested for oestrogen receptors alpha and beta, progesterone and androgen receptors, and somatostatin, in addition to HER2, cathepsin D, Ki-67, and c-KIT by immunohistochemistry. RESULTS: All samples were negative for oestrogen receptor alpha, HER2, and the progesterone receptor. Positive staining for the androgen receptor was found in six extra-abdominal cases. Staining for oestrogen receptor beta was positive in four extra-abdominal, two abdominal, and one intra-abdominal case. Staining for somatostatin was positive in six extra-abdominal, two abdominal, and one intra-abdominal case, and staining for cathepsin D was positive in all cases. Positive staining for Ki-67 was found in 14 extra-abdominal, three abdominal, and three intra-abdominal cases. C-KIT was detectable in one abdominal case only. CONCLUSIONS: The data from this immunohistochemical study show that the published effects of antioestrogens and imatinib mesylate in the treatment of aggressive fibromatoses may not be attributable to oestrogen receptor alpha or c-KIT expression.

Affective state of women following a prenatal diagnosis: predictors of a negative psychological outcome.

OBJECTIVE: The benefits of prenatal diagnostic procedures are well documented. However, the investigation of psychological consequences related to these procedures has remained a surprisingly neglected area of research. The main aim of the present study was to investigate the potential relationship between psychological outcome and associated (socio-demographic, psychological and obstetric) variables in women attending a tertiary referral center for prenatal diagnosis and therapy for ultrasound scanning (due to the suspicion of a fetal malformation raised by the gynecologist in private practice), amniocentesis or chorionic villus sampling. METHODS: Affective state was assessed by means of standardized measures of anxiety and depression (State-Trait Anxiety Inventory; Mood Scale) in 77 consecutive, unselected women. A follow-up investigation, including an additional assessment of coping mechanisms, took place 6 months after the first contact. Given the considerable number of intervening and correlating factors, a path analysis was undertaken. RESULTS: We found that all women in our sample experienced acute distress, not only those with proven fetal malformations, genetic disorders or intrauterine fetal death, but also those with the diagnosis of a sonographic sign. At baseline (i.e. immediately after the diagnostic procedure), mood and anxiety scores in our sample were found to be comparable to those of patients with a major depressive episode. A high trait anxiety level, implementation of negative coping strategies and loss of the child during pregnancy were found to be predictive of a negative psychological outcome at follow-up. Socio-demographic variables did not have a significant predictive function for the psychological outcome. CONCLUSIONS: We assume that a considerable number of women undergoing prenatal diagnostic procedures experience psychological distress, which may be underestimated by workers in prenatal care. Establishment of interdisciplinary treatment settings, in which access to psychological support is facilitated, may be extremely beneficial for women following a prenatal diagnosis.

Context-Oriented Model Development in Psychotherapy Planning ('COMEPP'): a useful adjunct to diagnosis and therapy of severe personality disorders.

OBJECTIVE: Pathogenous interpersonal (e.g. interfamilial) relationships and reference styles can compromise treatment efforts in severely disturbed (i.e. psychotic or borderline) patients. The integration of family- and individual-centred starting points may be useful in establishing interdisciplinary treatment concepts in these patients. Context-Oriented Model Development in Psychotherapy Planning (COMEPP) represents a diagnostic and therapy planning process, integrating both systemic and psychoanalytic conceptualizations. METHOD: COMEPP is exemplified by the case of a young man with psychotic personality disorder who had previously been unresponsive to pharmacological and psychological treatment. RESULTS: After psycho-dynamical conflicts (i.e. primitive projective processes from the patient's mother to her son) had been elucidated during the COMEPP process, a sufficient treatment setting could be established. CONCLUSION: COMEPP provides a psychotherapeutical approach to treatment planning on case-specific premises and may serve as an adjunct to concomitant pharmacological and psychological treatment strategies in so-called 'therapy refractory' patients.

Self-report versus interview data of women's subjective theories of illness: concordance and predictive validity in a psychosomatic-gynecological liaison service.

Between-method comparisons of patient data from standardized self-report instruments and corresponding patient interview data frequently have poor agreement. We investigated the concordance and predictive validity of self-report measures and expert-rated interview data of women's subjective theories of illness in a psychosomatic-gynecological consultation liaison service. 31 patients completed two questionnaires (KKG, PATEF) on subjective theories of illness and were interviewed with a semistructured instrument on the same topic at the time of the initial appointment and after 1.5 years. External criteria for assessing the predictive validity of questionnaire versus interview data were: follow-up participation and psychotherapy utilization during the follow-up interval. Questionnaire and interview rating data were only modestly associated. Rater concordance on the interview data was low. Neither the initial-assessment interview nor the questionnaire data had predictive validity for patients' participation in the follow-up. None of the interview rating data but a portion of the questionnaire data, had predictive validity for patients' utilization of psychotherapy during the follow-up interval. The cognitive conceptualization of subjective theories of illness may fail in patients with psychosomatic disorders, due to their very mode of experience. A wider approach that includes assessment of nonverbal communication and countertransference might be useful.

Gender and perversion--what constitutes a "bad mother".

BACKGROUND: There is a need for reconsidering the conceptualisations of female perverse behavior, especially in connection with motherhood. METHODS AND FINDINGS: Based on case material obtained through psychoanalytic psychotherapy with female patients from a psychosomatic gynecological outpatient clinic, the characteristics of the psychic structure of these patients who presented symptoms of deliberate self harm and of misusing and mistreating their children, are outlined. Another common trait is the embeddedness of their perverse behavior in a generational chain of transmission. Female patients who mistreat their children had been victims of traumatising experiences in their own biography, inflicted by their mothers and directed towards their bodies. DISCUSSION: Female perverse behavior, therefore, is fundamentally different from male perversion: the perverse act in women is aimed against themselves and/or their children. Currently used diagnostic statistical manuals lack categories to describe this symptomatology adequately. Further research is requested to understand a mother's perverse actions and thus develop treatment strategies, without marginalizing these patients.

Experiences with a psychological help service for women following a prenatal diagnosis: results of a follow-up study.

The aim of this study is to provide a description of a psychological help service for women following a prenatal diagnosis at the Division of Prenatal Diagnosis and Therapy at Vienna University Hospital. The investigation group consisted of 77 psychologically treated women. The follow-up took place six months after the first contact. For baseline evaluation the State-Trait Anxiety Inventory, a mood scale and a documentation instrument were used. In the follow-up patients were again investigated by the test inventory and the Freiburger Coping Behavior Scale and a special follow-up instrument. The women showed extreme high scores of general mood scale and state anxiety compared with a normal population. After six months the scores had decreased significantly. Approximately 56% of the patients showed former prenatal incidents in their case histories. A significant correlation was found between the use of negative coping strategies and the development of somatic problems and changes in the private life in the follow-up period. In total 97% of the women quoted the psychological treatment as very important for coping with the prenatal incident and 100% of the women stressed the implementation of a permanent psychological help service. In conclusion, psychological treatment should be available in the event of a prenatal diagnosis, if necessary with the partner. Special attention should be given to women traumatized by a former prenatal incident.

[Relationship between psychosomatic medicine and psychotherapy in theory and practice]. / Zum Verhältnis von Psychosomatik und Psychotherapie in Theorie und Praxis.

Initially, the different operationalizations of 'psychosomatic' are presented. Etiological concepts of psychosomatic illness include stressful life events, developmental factors and the individual psychic structure. At the Department for Psychotherapy and Psychoanalysis of Vienna University, the initial diagnostic interview includes subjective illness theories as possible pathway to psychotherapy, motivational factors and the patient's ability to transfer the experience from this interview into psychotherapy proper. The psychotherapeutic method applied to psychosomatic patients should offer a theoretical concept concerning psychosomatic illness, as it is the case in psychoanalytic psychotherapy. Finally, the importance of supervision for psychotherapists working in an institutional setting with in-patients is stressed.

Expression of insulin-like growth factor-I (IGF-I) in aneurysmal bone cyst.

The effects of insulin-like growth factor-I on bone tissue and its role in bone development have been extensively investigated, but there is little information on its role in the pathogenesis of aneurysmal bone cyst. Therefore, using the techniques of immunohistochemistry and in situ hybridization, the authors studied the expression of insulin-like growth factor-I in 19 specimens of aneurysmal bone cyst. Insulin-like growth factor-I or specific mRNA sequences encoding for insulin-like growth factor-I were detectable in all specimens tested and were mainly localized in multinucleate giant cells. In contrast, only insignificant levels of insulin-like growth factor-I expression were detectable in normal human bone tissue. Taken together with the previously reported role of insulin-like growth factor-I in the pathogenesis of giant cell tumor, the findings of this study suggest that insulin-like growth factor-I may play a role in the pathogenesis of aneurysmal bone cyst.

[Application of a context-oriented model for the planning of psychotherapy]. / Kontextorientierte Modellentwicklung in der Psychotherapieplanung.

Since clinical experience has shown that creating a therapeutic setting with borderline or psychotic patients is extremely difficult the Department of Psychoanalysis and Psychotherapy at Vienna University Hospital has developed a method of treatment designed to increase the possibilities to work with this group of patients. This procedure is conceptualised as "context oriented model exploration in psychotherapy planning" COMEPP. Initially the context is explored in which the psychotherapeutic model should be implemented which has so far failed for different reasons. Following this a setting is created in which the therapeutic team and the patient(s) can constructively and creatively reflect on alternative therapeutic models. A clinical case illustrates the problems and the basic structure of COMEPP in a schematic and condensed form.