Cognitive remediation combined with an early intervention service in first episode psychosis.

OBJECTIVE: This randomised clinical trial assessed the effects of a 16-week cognitive remediation programme (NEUROCOM) combined with an early intervention service (EIS) vs. EIS alone. METHOD: One hundred and seventeen patients with first episode psychosis were randomly assigned to 4 months cognitive remediation combined with EIS vs. EIS alone. Statistical analysis of effect was based on intention to treat. RESULTS: A total of 98 patients (83.8%) participated in post-training assessments at 4 months and 92 (78.6%) in 12-month follow-up assessments. No effects were found on the primary outcome measure functional capacity. At the post-training assessment, the intervention group had improved significantly on Rosenberg Self-Esteem Scale (Cohen's d=0.54, P=0.01), Positive and Negative Symptoms Scale (PANSS), General Psychopathology Scale (Cohen's d=0.51, P=0.05) and the verbal learning domain (Cohen's d=0.46, P=0.02). At follow-up assessment, the intervention group retained the significant improvements on the verbal learning domain (Cohen's d=0.58, P<0.05). Furthermore, significant improvements were observed on the working memory domain (Cohen's d=0.56, P=0.01) and PANSS positive symptoms (Cohen's d=0.44, P=0.04), while improvement on the composite score was marginally significant (Cohen's d=0.34, P=0.05). CONCLUSION: In accordance with other cognitive remediation programmes, this programme demonstrates some immediate and long-term effect on cognitive functioning, symptoms and self-esteem.

Regulation of DNA-dependent protein kinase by protein kinase CK2 in human glioblastoma cells.

The DNA-dependent protein kinase (DNA-PK) is a nuclear serine/threonine protein kinase composed of a large catalytic subunit (DNA-PKcs) and a heterodimeric DNA-targeting subunit Ku. DNA-PK is a major component of the nonhomologous end-joining pathway of DNA double-strand breaks repair. Although DNA-PK has been biochemically characterized in vitro, relatively little is known about its functions in the context of DNA repair and how its kinase activity is precisely regulated in vivo. Here, we report that cellular depletion of the individual catalytic subunits of protein kinase CK2 by RNA interference leads to significant cell death in M059K human glioblastoma cells expressing DNA-PKcs, but not in their isogenic counterpart, that is M059J cells, devoid of DNA-PKcs. The lack of CK2 results in enhanced DNA-PKcs activity and strongly inhibits DNA damage-induced autophosphorylation of DNA-PKcs at S2056 as well as repair of DNA double-strand breaks. By the application of the in situ proximity ligation assay, we show that CK2 interacts with DNA-PKcs in normal growing cells and that the association increases upon DNA damage. These results indicate that CK2 has an important role in the modulation of DNA-PKcs activity and its phosphorylation status providing important insights into the mechanisms by which DNA-PKcs is regulated in vivo.

The regulatory beta-subunit of protein kinase CK2 regulates cell-cycle progression at the onset of mitosis.

Cell-cycle transition from the G(2) phase into mitosis is regulated by the cyclin-dependent protein kinase 1 (CDK1) in complex with cyclin B. CDK1 activity is controlled by both inhibitory phosphorylation, catalysed by the Myt1 and Wee1 kinases, and activating dephosphorylation, mediated by the CDC25 dual-specificity phosphatase family members. In somatic cells, Wee1 is downregulated by phosphorylation and ubiquitin-mediated degradation to ensure rapid activation of CDK1 at the beginning of M phase. Here, we show that downregulation of the regulatory beta-subunit of protein kinase CK2 by RNA interference results in delayed cell-cycle progression at the onset of mitosis. Knockdown of CK2beta causes stabilization of Wee1 and increased phosphorylation of CDK1 at the inhibitory Tyr15. PLK1-Wee1 association is an essential event in the degradation of Wee1 in unperturbed cell cycle. We have found that CK2beta participates in PLK1-Wee1 complex formation whereas its cellular depletion leads to disruption of PLK1-Wee1 interaction and reduced Wee1 phosphorylation at Ser53 and 121. The data reported here reinforce the notion that CK2beta has functions that are independent of its role as the CK2 regulatory subunit, identifying it as a new component of signaling pathways that regulate cell-cycle progression at the entry of mitosis.

UV light blocks EGFR signalling in human cancer cell lines.

UV light excites aromatic residues, causing these to disrupt nearby disulphide bridges. The EGF receptor is rich in aromatic residues near the disulphide bridges. Herein we show that laser-pulsed UV illumination of two different skin-derived cancer cell lines i.e. Cal-39 and A431, which both overexpress the EGF receptor, leads to arrest of the EGFR signaling pathway. The phosphorylation status of the receptor and the level of phosphorylated downstream signaling molecules i.e. AKT and the mitogen activated protein kinases (MAPKs) ERK1 and 2 is detected by Western blotting using phosphospecific antibodies. There was a threshold level, below which the receptor could not be blocked. In addition, illumination caused the cells to upregulate the cyclin-dependent kinase inhibitor p21WAF1, irrespective of the p53 status. Since the EGF receptor is often overexpressed in cancers and other proliferative skin disorders, it might be possible to significantly reduce the proliferative potential of these cells making them good targets for laser-pulsed UV light treatment.

Decreasing incidence of major amputations in people with diabetes.

AIMS/HYPOTHESIS: To assess the results of the strategy used in avoiding major amputations in patients with diabetes mellitus. METHODS: A retrospective study for the years 1981 to 1995 in a central district hospital in Copenhagen with a catchment area population of about 178,000. RESULTS: There were 463 major leg amputations and the incidence decreased from 27.2 to 6.9/100,000 population (75%). The decrease in patients with Type I (insulin-dependent) diabetes mellitus was from 10.0 to 4.1 (59%) and in Type II (non-insulin-dependent) diabetes mellitus from 17.2 to 2.8/100,000 people (84%). Analysis showed that the diabetic population remained constant despite a considerable fall in the number of older people. During the study period infra-popliteal arterial bypass was introduced for the treatment of critical lower limb ischaemia and in diabetic patients the number of bypasses increased from zero to 13/100,000 population. The total number of revascularisation procedures in people with diabetes increased from 2.6 to 19.2/100,000 population. Moreover, a multidisciplinary diabetic foot clinic was established. CONCLUSION/INTERPRETATION: A 75% reduction in the incidence of major amputations coincided with a sevenfold increase in revascularization procedures and the establishment of a multidisciplinary diabetic foot clinic suggesting these measures are important in the prevention of diabetic leg amputations.

Drawbacks of traction-absorbing wiring (TAW) in displaced fractures of the olecranon.

Drawbacks of traction-absorbing wiring (TAW) in displaced fractures of the olecranon were observed in 29 out of 55 consecutive patients. Sliding of the K wires, with resulting skin troubles in 24 patients (10 patients with perforation of the skin), required premature removal of the implant. Minor operative modifications in the TAW technique are suggested in order to avoid these drawbacks.