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Psychosis develops through several phases. Longitudinal high-risk studies and birth cohort studies have shown that persons who later develop schizophrenia have lower cognitive and social function levels, slower neuromotor development and more emotional problems. Almost 20 percent achieve full recovery after a psychotic episode, approximately 25 percent undergo remission, but do not meet the criteria for full recovery, 15 percent need institutional care, and another approx. 40 percent remain chronically psychotic.

The possibilities for intervention in the early phases of schizophrenia and schizophrenia-like psychosis were reviewed. Long duration of untreated psychosis is related to persistent psychotic symptoms. Early detection programmes can reduce the duration of untreated psychosis and thereby probably improve outcome. There is ample evidence that intensive specialised assertive intervention during the early phase of psychotic symptoms is effective in improving several outcomes. Family intervention reduces risk of remission and improve compliance with antipsychotic medication.

Context: Intensive early treatment for first-episode psychosis has been shown to be effective. It is unknown if the positive effects are sustained for 5 years., Objective: To determine the long-term effects of an intensive early-intervention program (OPUS) for first-episode psychotic patients., Design: Single-blinded, randomized, controlled clinical trial of 2 years of an intensive early-intervention program vs standard treatment. Follow-up periods were 2 and 5 years., Setting: Copenhagen Hospital Corporation and Psychiatric Hospital, Aarhus, Denmark. Patients A total of 547 patients with a first episode of psychosis. Of these, 369 patients were participating in a 2-year follow-up, and 301 were participating in a 5-year follow-up. A total of 547 patients were followed for 5 years., Interventions: Two years of an intensive early-intervention program vs standard treatment. The intensive early-intervention treatment consisted of assertive community treatment, family involvement, and social skills training. Standard treatment offered contact with a community mental health center., Main Outcome Measures: Psychotic and negative symptoms were recorded. Secondary outcome measures were use of services and social functioning., Results: Analysis was based on the principles of intention-to-treat. Assessment was blinded for previous treatment allocation. At the 5-year follow-up, the effect of treatment seen after 2 years (psychotic dimension odds ratio [OR], -0.32; 95% confidence interval [CI], -0.58 to -0.06; P = .02; negative dimension OR, -0.45; 95% CI, -0.67 to -0.22; P = .001) had equalized between the treatment groups. A significantly smaller percentage of patients from the experimental group were living in supported housing (4% vs 10%, respectively; OR, 2.3; 95% CI, 1.1-4.8; P = .02) and were hospitalized fewer days (mean, 149 vs 193 days; mean difference, 44 days; 95% CI, 0.15-88.12; P = .05) during the 5-year period., Conclusions: The intensive early-intervention program improved clinical outcome after 2 years, but the effects were not sustainable up to 5 years later. Secondary outcome measures showed differences in the proportion of patients living in supported housing and days in hospital at the 5-year follow-up in favor of the intensive early-intervention program.

Background: Those with first-episode psychosis are at high-risk of suicide., Aims: To identify predictive factors for suicidal thoughts, plans and attempts, and to investigate the rate of suicides and other deaths during the 5 years after first diagnosis and initiation of treatment., Method: A longitudinal, prospective, 5-year follow-up study of 547 individuals with first-episode schizophrenia spectrum psychosis. Individuals presenting for their first treatment in mental health services in two circumscribed urban areas in Denmark were included in a randomised controlled trial of integrated v. standard treatment. All participants were followed in the Danish Cause of Death Register for 5 years. Suicidal behaviour and clinical and social status were assessed using validated interviews and rating scales at entry, and at 1- and 2-year follow-ups., Results: Sixteen participants died during the follow-up. We found a strong association between suicidal thoughts, plans and previous attempts, depressive and psychotic symptoms and young age, and with suicidal plans and attempts at 1- and 2-year follow-up., Conclusions: In this first-episode cohort depressive and psychotic symptoms, especially hallucinations, predicted suicidal plans and attempts, and persistent suicidal behaviour and ideation were associated with high risk of attempted suicide.

Biochemical evidence indicates that TGF-beta-activated kinase 1 (TAK1), a key modulator of the inflammatory response, exists in a complex with various adaptor proteins including the TAK1 binding protein 1 (TAB1). However, the physiological importance of TAB1 in TAK1 activation, and in the subsequent induction of proinflammatory mediators, remains unclear. In this study, a critical role for TAK1 in IL-1alpha or TNFalpha stimulated MAPK and NFkappaB activation was confirmed by inhibition of the nuclear accumulation of NFkappaB p65 and phosphorylated forms of c-Jun and p38 following siRNA mediated TAK1 silencing. These effects were associated with significant reductions in IL-1alpha stimulated levels of secreted IL-6, IL-8, MCP-1 and GM-CSF. In contrast, IL-1alpha or TNFalpha dependent cellular redistribution of NFkappaB p65 and phosphorylated c-Jun and p38 was not affected by 80% siRNA mediated knockdown of TAB1 protein levels. Interestingly, IL-6, IL-8 and GM-CSF release from TAB1 siRNA transfected cells was significantly reduced following IL-1alpha treatment, but was unchanged after TNFalpha stimulation, suggesting differential roles for TAB1 in IL-1alpha and TNFalpha signalling pathways. These findings may imply an as yet unidentified role for TAB1 in the inflammatory response, which is independent of the activation of classical TAK1 associated signalling cascades.

This chapter describes a robust high-content cellular screening assay to simultaneously analyze the spatiotemporal activation of three different kinase-associated signaling pathways involving NF-kappaB, JNK, and p38, all of which are closely implicated in proliferative and proinflammatory responses. Signal transduction is dependent on the translocation of NF-kappaB p65 and phosphorylated c-Jun and p38 from the cytosol to the nucleus, and fluorescent immunolabeling was used to monitor changes in their cellular distribution. Cellular screening, data acquisition, and data interpretation were conducted on the ArrayScan HCS Reader (Cellomics Inc., Pittsburgh, PA). Assay adaptation to various cellular systems is feasible when sufficient separation of the nuclear and cytosolic compartment can be achieved and if cell adhesion properties permit proper attachment to the culture plates. Substitution of NF-kappaB p65 and phosphorylated forms of c-Jun and p38 as targets to analyze other translocating components is possible and is limited primarily by antibody specificity and the risk of fluorescent bleed-through between emission channels. Because assay validity is particularly confounded by inadequate spectral separation of the detection dyes in multicolor labeling assays, means of eliminating or counterbalancing staining artifacts are illustrated. Also, protocol parameter settings important for imaging and image processing are described, including object identification, image exposure settings, separation of cytosolic and nuclear regions, number of cells sufficient for analysis, and the use of gating thresholds critical for cell sorting and subpopulation analysis. This assay is a useful tool to investigate the interplay between signaling pathways and the mode of action, potency, and selectivity of compound inhibition of specific target molecules in a cellular context.

Partial sequences of a novel papillomavirus were amplified from a cutaneous lesion biopsy of a raccoon (Procyon lotor), by using PCR with degenerate papillomavirus-specific primers. The Procyon lotor papillomavirus type 1 (PlPV-1) DNA was amplified with long template PCR in two overlapping fragments, together encompassing the entire genome, and the complete PlPV-1 genomic sequence was determined. The PlPV-1 genome consists of 8170 bp, and contains the typical papillomaviral open reading frames, encoding five early proteins and two late capsid proteins. Besides the classical non-coding region (NCR1) between the end of L1 and the start of E6, PlPV-1 contains an additional non-coding region (NCR2) of 1065 bp between the early and late protein region, which has previously also been described for the canine oral papillomavirus (COPV) and the Felis domesticus papillomavirus (FdPV-1). Phylogenetic analysis places PlPV-1 together with COPV and FdPV-1 in a monophyletic branch which encompasses the Lambda papillomavirus genus.

High content cellular screening assays are useful tools to investigate the interplay between signaling pathways and offer valuable platforms to determine the mode of action, potency, and selectivity of potential drug candidates in a biological setting. We describe a cell-based multiplex fluorescent imaging assay that permits concurrent detection and quantification of the distribution of nuclear factor kappaB (NFkappaB) p65/RelA and phosphorylated forms of p38 and c-Jun between the cytosol and nucleus. Cellular screening, data acquisition, and data interpretation were conducted on the ArrayScan HCS Reader (Cellomics Inc., Pittsburgh, PA). A significant window between untreated and interleukin-1alpha (IL-1alpha) stimulated HeLa cells for all three targets was achieved with low variability. Staining specificity was confirmed with blocking peptides and pharmacological inhibition of p38, c-Jun-N-terminal kinase (JNK), and inhibitory kappaB kinase 2, and channel bleed-through was eliminated or counterbalanced by the use of fixed exposure times together with careful reporter channel selection. The JNK inhibitor SP600125 was used as a demonstration compound because in addition to inhibiting nuclear accumulation of phosphorylated c-Jun it reduced nuclear translocation of phosphorylated p38 and NFkappaB p65/RelA in a dose-dependent manner, indicating a lack of SP600125 selectivity. This was supported by RNA interference where co-transfection of small interfering RNA targeting both JNK1 and JNK2, to limit signaling redundancy, significantly inhibited IL-1alpha-stimulated translocation of phosphorylated c-Jun without altering phosphorylated p38 and NFkappaB p65/RelA redistribution. This image analysis application is a valuable and information-rich screening tool to investigate compound selectivity and/or cross-talk between key signaling pathways involved in the inflammatory response.

Aims/hypothesis: Because oxidative stress has been suggested to be a significant contributing factor in the development of endothelial dysfunction and insulin resistance, we investigated whether reactive oxygen species contribute to insulin resistance by impairing insulin uptake through an effect on endothelial insulin receptor function., Methods: Following a 2-h pro-oxidant challenge with xanthine oxidase, we examined the temporal pattern of insulin processing in the human umbilical endothelial cell line Ea.Hy926 and bovine aortic endothelial cells equilibrated with [125I]-insulin. Insulin receptor mRNA concentrations were analysed by RT-PCR and insulin receptor tyrosine phosphorylation and protein concentrations were estimated by western blotting., Results: Xanthine oxidase exposure resulted in a major reduction in total insulin receptor-mediated [125I]-insulin internalization over a 1-h period in both Ea.Hy926 and bovine aortic endothelial cells. After 15 min, untreated bovine aortic endothelial cells internalized fivefold more cell-bound [125I]-insulin than pro-oxidant treated cells. The [125I]-insulin disappeared from the cell surface at a similar rate in both pro-oxidant and untreated cells, with relatively more [125I]-insulin being released into the medium in pro-oxidant treated cells. Although xanthine oxidase reduced insulin receptor mRNA and protein concentrations, cell surface insulin binding capacity was not affected. Following 5 min insulin exposure, insulin receptor auto-phosphorylation was considerably reduced in cells challenged with xanthine oxidase for 2 h, which could be important for insulin receptor activation and internalization., Conclusion/interpretation: Oxidative stress impairs insulin endocytosis in both arterial and venous endothelial cell lines. This was not a consequence of modified insulin binding capacity but could involve insufficient insulin receptor activation.

The object of the investigation was to compare the effect of three different physiotherapy masks on the incidence of postoperative complications after thoracic surgery. It was carried out as a prospective, consecutive, randomized comparison at a Department of Thoracic and Heart Surgery at a University Hospital. The therapy was performed by experienced and specially trained physiotherapists. One hundred and sixty patients were evaluated; 60 patients undergoing heart surgery, 59 patients having pulmonary resection, and 41 patients with exploratory thoracotomy. In each operative category the patients were treated with one of three face mask systems used in addition to routine chest physiotherapy. These were either continuous positive airway pressure (CPAP), positive expiratory pressure (PEP), or inspiratory resistance--positive expiratory pressure (IR-PEP). Postoperative pulmonary complications were assessed by forced vital capacity (FVC), arterial oxygen tension (PaO2), and chest X-ray examination, all parameters were measured preoperatively and on the fourth and ninth postoperative day. The patients filled in a questionnaire concerning their opinions about their mask treatment. IR-PEP showed a lesser decrease in PaO2 on day nine. Otherwise there was an equal decrease in FVC and PaO2, and equal frequency of atelectasis in the three mask treatments. It is therefore concluded that any of the three therapies: continuous positive airway pressure (CPAP), positive expiratory pressure (PEP), and inspiratory resistance--positive expiratory pressure (IR-PEP) may be used as supplement to standard chest physiotherapy.

Objective: An investigation into the incidence of post-operative complications after thoracic surgery with 3 different physiotherapy masks., Design: A prospective, consecutive, randomized comparison., Setting: Department of Thoracic and Heart Surgery at a University Hospital. The treatments were performed by experienced and specially trained physiotherapists., Patients: 160 patients were evaluated. 60 patients undergoing heart surgery, 59 patients having pulmonary resection, and 41 patients with exploratory thoracotomy., Interventions: In each operative category the patients were treated with one of three face mask systems used in addition to routine chest physiotherapy. These were either continuous positive airway pressure (CPAP), positive expiratory pressure (PEP), or inspiratory resistance - positive expiratory pressure (IR-PEP)., Measurements and Results: Post-operative pulmonary complications were assessed by forced vital capacity (FVC), arterial oxygen tension (PaO2), and chest X-ray examination, all measured pre-operatively and on the fourth and ninth post-operative day. The patients filled in a questionnaire expressing their opinion about their mask treatment. There was an equal decrease in FVC, FVC%, and PaO2, and equal frequency of atelectasis in the 3 mask treatments. More patients with the PEP mask favoured their system than did those with the other 2 systems., Conclusion: There was no statistically significant difference between the treatments: continuous positive airway pressure (CPAP), positive expiratory pressure (PEP), and inspiratory resistance - positive expiratory pressure (IR-PEP) on post-operative complications. Any of the three treatments may be used as supplement to standard chest physiotherapy.