Nanoencapsulation of ABT-737 and camptothecin enhances their clinical potential through synergistic antitumor effects and reduction of systemic toxicity.

The simultaneous delivery of multiple cancer drugs in combination therapies to achieve optimal therapeutic effects in patients can be challenging. This study investigated whether co-encapsulation of the BH3-mimetic ABT-737 and the topoisomerase I inhibitor camptothecin (CPT) in PEGylated polymeric nanoparticles (NPs) was a viable strategy for overcoming their clinical limitations and to deliver both compounds at optimal ratios. We found that thrombocytopenia induced by exposure to ABT-737 was diminished through its encapsulation in NPs. Similarly, CPT-associated leukopenia and gastrointestinal toxicity were reduced compared with the administration of free CPT. In addition to the reduction of dose-limiting side effects, the co-encapsulation of both anticancer compounds in a single NP produced synergistic induction of apoptosis in both in vitro and in vivo colorectal cancer models. This strategy may widen the therapeutic window of these and other drugs and may enhance the clinical efficacy of synergistic drug combinations.

Cranial computed tomography in trauma: the accuracy of interpretation by staff in the emergency department.

OBJECTIVES: Cranial computed tomography (CT) is replacing skull radiography in head trauma. Rapid radiological opinions on these images may not always be available. We assessed the ability of our permanent emergency department staff to interpret the images. METHODS: A retrospective series of 100 consecutive cases was reviewed and interpreted by five permanent emergency department medical staff, and their interpretation compared with the consensus opinion of two radiologists. RESULTS: An overall agreement of 86.6% (95% confidence interval (CI) 83.4 to 89.9) was achieved, with a false negative rate of 4.2% (95% CI 3.9 to 4.3). No findings that would have changed the overnight management of any patient were missed. CONCLUSIONS: Our results for CT scans are similar to studies of interpretation of other radiographic images in emergency departments. Our emergency staff could safely make the initial interpretation of cranial CT images in trauma out of hours, and formal reporting may wait until a suitably experienced radiologist is available.

Domain-specific spectroscopy of 5-hydroxytryptophan-containing variants of Escherichia coli DnaJ.

Tryptophan-containing variants of Escherichia coli DnaJ protein were constructed in order to examine the hypothetical domain structure by fluorescence quenching and denaturant-induced unfolding. Two residues in the J-domain and one in the Gly/Phe-rich region were targeted for replacement and the proteins were expressed in a tryptophan auxotrophic strain in the presence of 5-hydroxytryptophan (5-HW). Fluorescence quenching with iodide of 5-HW in the variant proteins suggests that the Gly/Phe-rich region is more accessible to solvent than the J-domain. This is consistent with the proposal that the Gly/Phe-rich region is unstructured. Unfolding of the 5-HW-containing variants was monitored by fluorescence, and the results showed that the unfolding of the J-domain is cooperative and the unfolding of the Gly/Phe-rich region is not cooperative.

Role of the J-domain in the cooperation of Hsp40 with Hsp70.

The Escherichia coli Hsp40 DnaJ and Hsp70 DnaK cooperate in the binding of proteins at intermediate stages of folding, assembly, and translocation across membranes. Binding of protein substrates to the DnaK C-terminal domain is controlled by ATP binding and hydrolysis in the N-terminal ATPase domain. The interaction of DnaJ with DnaK is mediated at least in part by the highly conserved N-terminal J-domain of DnaJ that includes residues 2-75. Heteronuclear NMR experiments with uniformly 15N-enriched DnaJ2-75 indicate that the chemical environment of residues located in helix II and the flanking loops is perturbed on interaction with DnaK or a truncated DnaK molecule, DnaK2-388. NMR signals corresponding to these residues broaden and exhibit changes in chemical shifts in the presence of DnaK(MgADP). Addition of MgATP largely reversed the broadening, indicating that NMR signals of DnaJ2-75 respond to ATP-dependent changes in DnaK. The J-domain interaction is localized to the ATPase domain of DnaK and is likely to be dominated by electrostatic interactions. The results suggest that the J-domain tethers DnaK to DnaJ-bound substrates, which DnaK then binds with its C-terminal peptide-binding domain.

Infant with irritability, feeding problems, and progressive developmental abnormalities presenting repeatedly to a pediatric emergency department.

Emergency physicians often deal with diagnostically elusive cases that may present repeatedly over the course of illness. The infant presented here had a chronic history, prompting multiple physician contacts for initially seemingly common problems. Assessing the patient's progression of symptoms over time and eliciting a brief developmental history in the emergency department (ED) helped guide decision-making toward admission and appropriate diagnostic workup.

Efficacy of metaiodobenzylguanidine as a scintigraphic agent for the detection of neuroblastoma.

RATIONALE AND OBJECTIVES: Metaiodobenzylguanidine (MIBG) has been shown to be both sensitive and highly specific for the detection of neuroblastoma. However, controversy surrounds its sensitivity in detecting neuroblastoma when compared with radionuclide (technetium 99m-methylene diphosphonate [99mTc]-MDP) bone scans. Because a diagnostic test ideally should be easy to interpret in addition to being sensitive and specific, this study aims to determine the most efficacious scintigraphic agent for diagnostic use in neuroblastoma. METHODS: Twenty patients with neuroblastoma had a total of 26 paired MIBG and 99mTc-MDP bone scans obtained less than 4 weeks apart. Each study was evaluated independently of its counterpart by six separate observers (3 experienced and 3 inexperienced in MIBG scintigraphy) to determine the presence or absence of disease and the tumor burden. RESULTS: Inexperienced observers reported more confidence in their interpretations of 99mTc-MDP bone scans; however, seven false-positive bone scans were reported. Using MIBG, all true-positive and true-negative scans, as well as significantly more sites of both primary and metastatic disease, were identified by all observers. CONCLUSION: This study suggests that MIBG is the more efficacious agent for the scintigraphic evaluation of neuroblastoma.

The laryngeal mask airway. Two cases of prehospital trauma care.

Two cases of emergency prehospital airway control using the laryngeal mask are described. The patients were trapped following road traffic accidents and limited access prevented tracheal intubation. The laryngeal mask airway may be a useful alternative to tracheal intubation in some cases of prehospital trauma care.

A comparison of the efficacy of gastric lavage, ipecacuanha and activated charcoal in the emergency management of paracetamol overdose.

The aim of this prospective trial was to compare the efficacy of gastric lavage, activated charcoal and ipecacuanha at limiting the absorption of paracetamol in overdose and to assess the significance of the continued absorption of paracetamol following treatment. Patients aged 16 and over who had ingested 5 gms or more of paracetamol within 4h of admission were entered into the trial. The percentage fall in plasma paracetamol level was used as the measure of the success of a treatment at limiting absorption. The mean percentage fall was 39.3 for gastric lavage, 52.2 for activated charcoal and 40.7 for ipecacuanha, with a significant difference between the treatment methods (p = 0.03). Activated charcoal was more effective at limiting the absorption of paracetamol following overdose than either gastric lavage or ipecacuanha induced emesis. In treated patients continuing paracetamol absorption is not significant if more than 2h have elapsed since ingestion.

Acetazolamide in prevention of acute mountain sickness: a double-blind controlled cross-over study.

Twenty-four amateur climbers took part in a double-blind controlled cross-over trial of acetazolamide versus placebo for the prevention of acute mountain sickness. They climbed Kilimanjaro (5895 m) and Mt Kenya (5186 m) in three weeks with five rest days between ascents. The severity of acute mountain sickness was gauged by a score derived from symptoms recorded daily by each subject. On kilimanjaro those taking acetazolamide reached a higher altitude (11 v 4 reached the summit) and had a lower symptom score than those taking placebo (mean 4.8 v 14.3). Those who had taken acetazolamide on Kilimanjaro maintained their low symptom scores while taking placebo on Mt Kenya (mean score 1.9), whereas those who had taken placebo on Kilimanjaro experienced a pronounced improvement when they took acetazolamide on Mt Kenya (mean score 2.5). Acute mountain sickness prevented one subject for completing either ascent. Acetazolamide was acceptable to 23 of the 24 subjects. Acetazolamide is recommended as an acceptable and effective prophylactic for acute mountain sickness.