Psychosocial treatments for negative symptoms in schizophrenia: current practices and future directions.

Schizophrenia can be a chronic and debilitating psychiatric disorder. Though advancements have been made in the psychosocial treatment of some symptoms of schizophrenia, people with schizophrenia often continue to experience some level of symptoms, particularly negative symptoms, throughout their lives. Because negative symptoms are associated with poor functioning and quality of life, the treatment of negative symptoms is a high priority for intervention development. However, current psychosocial treatments primarily focus on the reduction of positive symptoms with comparatively few studies investigating the efficacy of psychosocial treatments for negative symptoms. In this article, we review and evaluate the existing literature on three categories of psychosocial treatments--cognitive behavioral therapy (CBT), social skills training (SST), and combined treatment interventions--and their impact on the negative symptoms of schizophrenia. Of the interventions reviewed, CBT and SST appear to have the most empirical support, with some evidence suggesting that CBT is associated with maintenance of negative symptom improvement beyond six months after treatment. It remains unclear if a combined treatment approach provides improvements above and beyond those associated with each individual treatment modality. Although psychosocial treatments show promise for the treatment of negative symptoms, there are many unanswered questions about how best to intervene. We conclude with a general discussion of these unanswered questions, future directions and methodological considerations, and suggestions for the further development of negative symptom interventions

The power to resist: the relationship between power, stigma, and negative symptoms in schizophrenia.

Stigmatizing beliefs about mental illness can be a daily struggle for people with schizophrenia. While investigations into the impact of internalizing stigma on negative symptoms have yielded mixed results, resistance to stigmatizing beliefs has received little attention. In this study, we examined the linkage between internalized stigma, stigma resistance, negative symptoms, and social power, or perceived ability to influence others during social interactions among people with schizophrenia. Further, we sought to determine whether resistance to stigma would be bolstered by social power, with greater power in relationships with other possibly buffering against motivation/pleasure negative symptoms. Fifty-one people with schizophrenia or schizoaffective disorder completed measures of social power, internalized stigma, and stigma resistance. Negative symptoms were assessed using the Clinical Assessment Interview for Negative Symptoms (CAINS). Greater social power was associated with less internalized stigma and negative symptoms as well as more stigma resistance. Further, the relationship between social power and negative symptoms was partially mediated by stigma resistance. These findings provide evidence for the role of stigma resistance as a viable target for psychosocial interventions aimed at improving motivation and social power in people with schizophrenia

Social Cognitive Deficits in Schizophrenia, Schizoaffective Disorder and Bipolar Disorder: Similarities and Differences

Impairments in social functioning are characteristic of several severe mental illnesses. Efforts have been made to understand the nature of these social functioning deficits. However, there is still much to learn about the role of social functioning in individuals with mental illness. This study aims to investigate one aspect of social functioning --social cognitive functioning-- for each of three clinical groups of outpatients with severe mental illness [individuals with schizophrenia (N=16), bipolar disorder (N=19), and schizoaffective disorder (N=18)], as compared to that of healthy controls (N=15). Participants were evaluated on three social cognitive assessments: 1) a traditional Theory of Mind-False Belief Task (ToM), an inferential thinking task and a measure of receptive social cognition; 2) the Movie Clips Task, a social reasoning and affect understanding task that also measures receptive social cognition; and 3) The Interpersonal Block Assembly Task (IBAT), an interpersonal communication task that measures expressive social cognition. Results indicated that all three clinical groups performed significantly worse on the IBAT as compared to the healthy control group. Only one significant clinical group versus control group difference was found on the receptive social cognition tasks (the Movie Clips Task and the ToM Task): the bipolar disorder group performed worse than the healthy control group on the Movie Clips Task. Clinical group comparisons on the three tasks indicated that there were significant differences on the Movie Clip Task only, with individuals in the schizoaffective group performing better than individuals in the bipolar disorder group. These findings suggest that expressive social cognitive functioning is impaired in schizophrenia, schizoaffective disorder, and bipolar disorder, as compared to healthy individuals; in contrast, deficits in receptive social cognition were found for the bipolar disorder group alone, suggesting that impairments in receptive social cognitive abilities may be limited and specific to individuals with bipolar disorder

Controllability on the group of diffeomorphisms

Given a compact manifold M, we prove that any bracket generating family of vector fields on M, which is invariant under multiplication by smooth functions, generates the connected component of the identity of the group of dieomorphisms of M

A liver angioma colonized by colon cancer cells in a patient with two primitive localizations by colon adenocarcinoma: biologic, diagnostic and therapeutic implications

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The RNase Rny1p cleaves tRNAs and promotes cell death during oxidative stress in Saccharomyces cerevisiae

The cellular response to stress conditions involves a decision between survival or cell death when damage is severe. A conserved stress response in eukaryotes involves endonucleolytic cleavage of transfer RNAs (tRNAs). The mechanism and significance of such tRNA cleavage is unknown. We show that in yeast, tRNAs are cleaved by the RNase T2 family member Rny1p, which is released from the vacuole into the cytosol during oxidative stress. Rny1p modulates yeast cell survival during oxidative stress independently of its catalytic ability. This suggests that upon release to the cytosol, Rny1p promotes cell death by direct interactions with downstream components. Thus, detection of Rny1p, and possibly its orthologues, in the cytosol may be a conserved mechanism for assessing cellular damage and determining cell survival, analogous to the role of cytochrome c as a marker for mitochondrial damage

Insights into the molecular determinants involved in cap recognition by the vaccinia virus D10 decapping enzyme

Decapping enzymes are required for the removal of the 5′-end m7GpppN cap of mRNAs to allow their decay in cells. While many cap-binding proteins recognize the cap structure via the stacking of the methylated guanosine ring between two aromatic residues, the precise mechanism of cap recognition by decapping enzymes has yet to be determined. In order to get insights into the interaction of decapping enzymes with the cap structure, we studied the vaccinia virus D10 decapping enzyme as a model to investigate the important features for substrate recognition by the enzyme. We demonstrate that a number of chemically modified purines can competitively inhibit the decapping reaction, highlighting the molecular features of the cap structure that are required for recognition by the enzyme, such as the nature of the moiety at positions 2 and 6 of the guanine base. A 3D structural model of the D10 protein was generated which suggests amino acids implicated in cap binding. Consequently, we expressed 17 mutant proteins with amino acid substitutions in the active site of D10 and found that eight are critical for the decapping activity. These data underscore the functional features involved in the non-canonical cap-recognition by the vaccinia virus D10 decapping enzyme

13C labeling experiments at metabolic nonstationary conditions: An exploratory study

<p>Abstract</p> <p>Background</p> <p>Stimulus Response Experiments to unravel the regulatory properties of metabolic networks are becoming more and more popular. However, their ability to determine enzyme kinetic parameters has proven to be limited with the presently available data. In metabolic flux analysis, the use of ¹³C labeled substrates together with isotopomer modeling solved the problem of underdetermined networks and increased the accuracy of flux estimations significantly.</p> <p>Results</p> <p>In this contribution, the idea of increasing the information content of the dynamic experiment by adding ¹³C labeling is analyzed. For this purpose a small example network is studied by simulation and statistical methods. Different scenarios regarding available measurements are analyzed and compared to a non-labeled reference experiment. Sensitivity analysis revealed a specific influence of the kinetic parameters on the labeling measurements. Statistical methods based on parameter sensitivities and different measurement models are applied to assess the information gain of the labeled stimulus response experiment.</p> <p>Conclusion</p> <p>It was found that the use of a (specifically) labeled substrate will significantly increase the parameter estimation accuracy. An overall information gain of about a factor of six is observed for the example network. The information gain is achieved from the specific influence of the kinetic parameters towards the labeling measurements. This also leads to a significant decrease in correlation of the kinetic parameters compared to an experiment without ¹³C-labeled substrate.</p

Oxaliplatin plus raltitrexed and leucovorin-modulated 5-fluorouracil i.v. bolus: a salvage regimen for colorectal cancer patients

The aim of the present study was to define the activity and tolerability of a triplet regimen including oxaliplatin 130 mg m−2 (2 h i.v. infusion) and raltitrexed 3.0 mg m−2 (15 min i.v. infusion) given on day 1, followed by levo-folinic acid 250 mg m−2 (2 h i.v. infusion) and 5-fluorouracil 1050 mg m−2 i.v. bolus on day 2, every 2 weeks, in pretreated colorectal cancer patients. From April 1999 to December 2000, 50 patients were enrolled: 26 were males and 24 females, their median age was 63 (range, 43–79) years; ECOG performance status was 0 in 26 patients, ⩾1 in 24 patients; 26 patients had received previous adjuvant chemotherapy, 40 patients had been exposed to one or two lines of palliative chemotherapy (including irinotecan in 31 cases); 18 patients were considered chemo-refractory. A total of 288 cycles were administered, with a median number of 6 (range 1–12) courses per patient. A complete response was obtained in three patients, and a partial response in nine patients, giving a major response rate of 24% (95% confidence interval, 13–38%), while 15 further patients showed a stable disease, for an overall control of tumour growth in 60% of patients. Three complete responses and three partial responses were obtained in patients pretreated with irinotecan (response rate, 19%); among refractory patients, three achieved partial responses (response rate, 13%). After a median follow-up of 18 (range, 10–30) months, 40 patients showed a progression of disease: the growth modulation index ranged between 0.2 and 2.5: it was ⩾1.33 (showing a significant delay of tumour growth) in 16 (40%) patients. Actuarial median progression-free survival time was 7.6 months, and median survival time was 13.6 months: estimated probability of survival was 55% at 1 year. Main severe toxicity was neutropenia: World Health Organisation grade 4 affected 32% of patients; non-haematological toxicity was mild: World Health Organisation grade 3 diarrhoea was complained of by 8%, and grade 3 stomatitis by 4% of patients; neurotoxicity (according to Lévi scale) was scored as grade 3 in 8% of patients. In conclusion, this regimen was manageable and active as salvage treatment of advanced colorectal cancer patients; it showed incomplete cross-resistance with irinotecan-based treatments, and proved to delay the progression of disease in a relevant proportion of treated patients

Combined effects of bevacizumab with erlotinib and irradiation: a preclinical study on a head and neck cancer orthotopic model

Clinical benefit has been demonstrated in patients with head and neck tumours receiving an anti-epidermal growth factor receptor (EGFR) agent in combination with radiotherapy (RT). Recent preclinical and clinical studies suggest beneficial effects from combining anti-angiogenic drugs with RT. To investigate the effect of combining these approaches, we evaluated in vivo the anti-tumour efficacy of the anti-angiogenic compound bevacizumab, a highly specific monoclonal antibody directed against the vascular endothelial growth factor (VEGF), erlotinib, an EGFR tyrosine kinase inhibitor, and irradiation given alone and in combination. Investigations were performed using a VEGF-secreting human head and neck tumour cell line, CAL33, with a high EGFR content, injected as orthotopic xenografts into the mouth floor of nude mice. Three days after tumour cell injection, bevacizumab (5 mg kg−1, 5 days a week, i.p.), erlotinib (100 mg kg−1, 5 days a week, orally) and irradiation (6 Gy, 3 days a week) were administered alone and in combination for 10 days. As compared with the control, concomitant administration of drugs produced a marked and significant supra-additive decrease in tumour mass; the addition of irradiation almost completely abolished tumour growth. The drug association markedly reduced the number of metastatic nodes and the triple combination significantly reduced the total number of pathologically positive lymph nodes as compared with controls. The RT-induced proliferation, reflected by Ki67 labelling, was reduced to control level with the triple combination. Radiotherapy induced a strong and very significant increase in tumour angiogenesis, which was no longer observed when combined with erlotinib and bevacizumab. The efficacy of the combination of bevacizumab+erlotinib and RT may be of clinical importance in the management of head and neck cancer patients