Functional tyrosine kinase inhibitor profiling: a generally applicable method points to a novel role of platelet-derived growth factor receptor-beta in tuberous sclerosis

A ubiquitous herpesvirus that establishes life-long infection, the Epstein-Barr virus (EBV) has yielded little insight into how a single agent in general accord with its host can produce diverse pathologies ranging from oral hairy leukoplakia to nasopharyngeal carcinoma, from infectious mononucleosis to Hodgkin's disease (HD) and Burkitt's lymphoma. Its pathogenesis is further confounded by the less than total association of virus with histologically similar tumors. In other viral systems, defective (interfering) viral genomes are known to modulate outcome of infection, with either ameliorating or intensifying effects on disease processes initiated by prototype strains. To ascertain whether defective EBV genomes are present in HD, we examined paraffin-embedded tissue from 56 HD cases whose EBV status was first determined by cytohybridization for nonpolyadenylated EBV RNAs (EBERs). Using both standard polymerase chain reaction (PCR) and PCR in situ hybridization, we successfully amplified sequences that span abnormally juxtaposed BamHI W and Z fragments characteristic of defective heterogeneous (het) EBV DNA from 10 of 32 (31%) EBER-positive tumors. Of 24 EBER-negative HD, 8 yielded PCR products indicating presence of het EBV DNA. Two of these contained defective EBV in the apparent absence of the prototype virus. Of the 42 tumors analyzed for defective EBV by both PCR techniques, there was concordance of results in 38 (90%). Detection of defective EBV genomes with the potential to disrupt viral gene regulation suggests one mechanism for pathogenic diversity that may also account for loss of prototypic EBV from individual tumor cells.     

Heat shock protein 90alpha-dependent translocation of annexin II to the surface of endothelial cells modulates plasmin activity in the diabetic rat aorta

The goals of this article were (1) to identify cell surface proteins whose expression was regulated by diabetes and (2) to assess their contribution to diabetic complications. We purified heat shock protein 90alpha (Hsp90alpha) from the membrane fraction of high glucose-treated endothelial cells (ECs) as a binding partner for a diabetes-specific phage. Further investigation revealed that high glucose elevated cell surface Hsp90alpha in cultured cells, and that diabetes increased the amount of Hsp90alpha on the luminal surface of the aorta. We also found that high glucose or diabetes promoted the association of Hsp90alpha with annexin II and increased the expression of annexin II on the surface of aortic ECs. Finally, plasmin activity was increased by high glucose or diabetes, and this change was partially reversed with an annexin II antibody. These findings reveal a novel glucose-regulated interaction between Hsp90alpha and annexin II, and raise the possibility that increased expression of annexin II, which promotes the generation of plasmin, is linked to clotting abnormalities associated with the diabetic state.     

Postoperative pain management in pediatric patients undergoing minimally invasive repair of pectus excavatum: The role of intercostal block

Purpose

There are no published data regarding value of intercostal block following pectus excavatum repair. Our aim was to evaluate the efficacy of intercostal block in children following minimally invasive repair of pectus excavatum (MIRPE).

Methods

Forty-five patients given patient-controlled analgesia (PCA) with morphine postoperatively were studied. Twenty-six patients were given bilateral intercostal blocks after induction of anesthesia (PCA-IB group), and nineteen patients were retrospective controls without regional blockade (PCA group). All patients were followed up 24 h postoperatively.

Results

A loading dose of morphine (0,1 ± 0,49 mg/kg) before starting PCA was used in seventeen patients in PCA group vs. no patient in PCA-IB group. Cumulative used morphine doses were lower up to 12 h after surgery in PCA-IB group (0,29 ± 0,08 μg/kg) than in the PCA group (0,46 ± 0,18 μg/kg), p < 0,01. There were no differences in pain scores, oxygen saturation values, sedation scores, and the incidence of pulmonary adverse events between the two groups. There was a tendency towards less morphine-related adverse effects in PCA-IB group compared to PCA group (p < 0,05). No complications related to the intercostal blocks were observed.

Conclusion

Bilateral intercostal blocks following MIRPE are safe and easy to perform and can diminish postoperative opioid requirement. Double-blind randomized study is required to confirm the potential to diminish opioid related side effects.     

Value of adipokines in predicting the severity of acute pancreatitis: Comprehensive review

AIM: To analyze the prognostic value of adipokines in predicting the course, complications and fatal outcome of acute pancreatitis (AP).METHODS: We performed the search of PubMed database and the systemic analysis of the literature for both experimental and human studies on prognostic value of adipokines in AP for period 2002-2012. Only the papers that described the use of adipokines for prediction of severity and/or complications of AP were selected for further analysis. Each article had to contain information about the levels of measured adipokines, diagnosis and verification of AP, to specify presence of pancreatic necrosis, organ dysfunction and/or mortality rates. From the very beginning, study was carried out adhering to the PRISMA checklist and flowchart for systemic reviews. To assess quality of all included human studies, the Quality Assessment of Diagnostic Accuracy Studies tool was used. Because of the high heterogeneity between the studies, it was decided to refrain from the statistical processing or meta-analysis of the available data.RESULTS: Nine human and three experimental studies were included into review. In experimental studies significant differences between leptin concentrations at 24 and 48 h in control, acute edematous and acute necrotizing pancreatitis groups were found (P = 0.027 and P < 0.001). In human studies significant differences between leptin and resitin concentrations in control and acute pancreatitis groups were found. 1-3 d serum adiponectin threshold of 4.5 μg/mL correctly classified the severity of 81% of patients with AP. This threshold yielded a sensitivity of 70%, specificity 85%, positive predictive value 64%, negative predictive value88% (area under curve 0.75). Resistin and visfatin concentrations differ significantly between mild and severe acute pancreatitis groups, they correlate with severity of disease, need for interventions and outcome. Both adipokines are good markers for parapancreatic necrosis and the cut-off values of 11.9 ng/mL and 1.8 ng/mL respectively predict the high ranges of radiological scores. However, the review revealed that all nine human studies with adipokines are very different in terms of methodology and objectives, so it is difficult to generalize their results. It seems that concentrations of the leptin and resistin increases significantly in patients with acute pancreatitis compared with controls. Serum levels of adiponectin, visfatin and especially resitin (positive correlation with Acute Physiology and Chronic Health Evaluation II, Ranson and C-reactive protein) are significantly different in mild acute pancreatitis and severe acute pancreatitis patients, so, they can serve as a markers for the disease severity prediction. Resistin and visfatin can also be used for pancreatic and parapancreatic necrosis prediction, interventions needs and possible, outcome.CONCLUSION: High levels of adipokines could allow for prediction of a severe disease course and outcome even in small pancreatic lesions on computed tomography scans.     

Application of the Pareto principle to identify and address drug-therapy safety issues

Purpose

Adverse drug events (ADE) and medication errors (ME) are common causes of morbidity in patients presenting at emergency departments (ED). Recognition of ADE as being drug related and prevention of ME are key to enhancing pharmacotherapy safety in ED. We assessed the applicability of the Pareto principle (～80 % of effects result from 20 % of causes) to address locally relevant problems of drug therapy.

Methods

In 752 cases consecutively admitted to the nontraumatic ED of a major regional hospital, ADE, ME, contributing drugs, preventability, and detection rates of ADE by ED staff were investigated. Symptoms, errors, and drugs were sorted by frequency in order to apply the Pareto principle.

Results

In total, 242 ADE were observed, and 148 (61.2 %) were assessed as preventable. ADE contributed to 110 inpatient hospitalizations. The ten most frequent symptoms were causally involved in 88 (80.0 %) inpatient hospitalizations. Only 45 (18.6 %) ADE were recognized as drug-related problems until discharge from the ED. A limited set of 33 drugs accounted for 184 (76.0 %) ADE; ME contributed to 57 ADE. Frequency-based listing of ADE, ME, and drugs involved allowed identification of the most relevant problems and development of easily to implement safety measures, such as wall and pocket charts.

Conclusions

The Pareto principle provides a method for identifying the locally most relevant ADE, ME, and involved drugs. This permits subsequent development of interventions to increase patient safety in the ED admission process that best suit local needs.     

Predictors of health-related quality of life in neurosurgical brain tumor patients: focus on patient-centered perspective

Background

In brain tumor (BT) patients, the association between health-related quality of life (HRQoL) and psychological characteristics remains largely unknown. We evaluated the association of personality traits, clinical factors, psychological distress symptoms, and cognitive state with HRQoL in BT patients.

Methods

On admission for BT surgery, 200 patients (69 % women; age 55.8?±?14.5 years) were evaluated for HRQoL (SF-36 scale), Big-Five personality traits (Ten-Item Personality Inventory), psychological distress symptoms (Hospital Anxiety and Depression Scale or HADS), cognitive function (Mini-Mental State Examination or MMSE) and clinical characteristics, including functional status (Barthel index or BI). The most common BT diagnoses were meningioma (39 %) and high-grade glioma (18 %).

Results

Only factors significantly associated with SF-36 domains in univariable regression analyses were included in their respective multivariable models and predicted from 6 %–49 % of the total variance of SF-36 scores. Greater TIPI emotional stability score was independently associated with greater SF-36 emotional well-being (β?=?0.23, p?<?0.001) and general health (β?=?0.18, p?=?0.01) scores, and greater TIPI consciousness score, with greater SF-36 emotional well-being score (β?=?0.13, p?=?0.02). HADS-anxiety and HADS-depression scores were the strongest independent determinants of all, except physical functioning, SF-36 scores (β-values range from 0.14 to 0.56; p values?≤?0.03). BI score was the strongest independent determinant of SF-36 physical functioning score (β?=?0.36, p?<?0.001). MMSE score was associated with all but emotional well-being and social functioning SF-36 scores.

Conclusions

Consciousness and emotional stability should be considered important personality-related determinants of HRQoL in BT patients. Psychological distress, functional disability, and cognitive impairment are also important predictors of HRQoL.     

The priming/completion paradigm to explain growth factor-dependent cell cycle progression

Approximately 50 years ago, researchers established conditions to maintain cells in tissue culture: Likely et al. (1952), Scherer et al. (1953), Eagle (1955). This simple model system set the stage for discovery of growth factors and the signaling systems that they engage to mediate cellular responses such as proliferation. The purpose of this review is to present the original view of how growth factors regulate cell cycle progression and an updated (priming/completion) version of how growth factors advance resting cells through the cell cycle.