3-Bromopyruvate antagonizes effects of lactate and pyruvate, synergizes with citrate and exerts novel anti-glioma effects.

Oxidative stress-energy depletion therapy using oxidative stress induced by D-amino acid oxidase (DAO) and energy depletion induced by 3-bromopyruvate (3BP) was reported recently (El Sayed et al., Cancer Gene Ther., 19, 1-18, 2012). Even in the presence of oxygen, cancer cells oxidize glucose preferentially to produce lactate (Warburg effect) which seems vital for cancer microenvironment and progression. 3BP is a closely related structure to lactate and pyruvate and may antagonize their effects as a novel mechanism of its action. Pyruvate exerted a potent H(2)O(2) scavenging effect to exogenous H(2)O(2), while lactate had no scavenging effect. 3BP induced H(2)O(2) production. Pyruvate protected against H(2)O(2)-induced C6 glioma cell death, 3BP-induced C6 glioma cell death but not against DAO/D-serine-induced cell death, while lactate had no protecting effect. Lactate and pyruvate protected against 3BP-induced C6 glioma cell death and energy depletion which were overcome with higher doses of 3BP. Lactate and pyruvate enhanced migratory power of C6 glioma which was blocked by 3BP. Pyruvate and lactate did not protect against C6 glioma cell death induced by other glycolytic inhibitors e.g. citrate (inhibitor of phosphofructokinase) and sodium fluoride (inhibitor of enolase). Serial doses of 3BP were synergistic with citrate in decreasing viability of C6 glioma cells and spheroids. Glycolysis subjected to double inhibition using 3BP with citrate depleted ATP, clonogenic power and migratory power of C6 glioma cells. 3BP induced a caspase-dependent cell death in C6 glioma. 3BP was powerful in decreasing viability of human glioblastoma multiforme cells (U373MG) and C6 glioma in a dose- and time-dependent manner.

D-Amino acid oxidase-induced oxidative stress, 3-bromopyruvate and citrate inhibit angiogenesis, exhibiting potent anticancer effects.

Angiogenesis is critical for cancer growth and metastasis. Steps of angiogenesis are energy consuming, while vascular endothelial cells are highly glycolytic. Glioblastoma multiforme (GBM) is a highly vascular tumor and this enhances its aggressiveness. D-amino acid oxidase (DAO) is a promising therapeutic protein that induces oxidative stress upon acting on its substrates. Oxidative stress-energy depletion (OSED) therapy was recently reported (El Sayed et al., Cancer Gene Ther, 19, 1-18, 2012). OSED combines DAO-induced oxidative stress with energy depletion caused by glycolytic inhibitors such as 3-bromopyruvate (3BP), a hexokinase II inhibitor that depleted ATP in cancer cells and induced production of hydrogen peroxide. 3BP disturbs the Warburg effect and antagonizes effects of lactate and pyruvate (El Sayed et al., J Bioenerg Biomembr, 44, 61-79, 2012). Citrate is a natural organic acid capable of inhibiting glycolysis by targeting phosphofructokinase. Here, we report that DAO, 3BP and citrate significantly inhibited angiogenesis, decreased the number of vascular branching points and shortened the length of vascular tubules. OSED delayed the growth of C6/DAO glioma cells. 3BP combined with citrate delayed the growth of C6 glioma cells and decreased significantly the number and size of C6 glioma colonies in soft agar. Human GBM cells (U373MG) were resistant to chemotherapy e.g. cisplatin and cytosine arabinoside, while 3BP was effective in decreasing the viability and disturbing the morphology of U373MG cells.

Usefulness of a mobile phone with video telephony in identifying the correct landmark for performing needle thoracocentesis.

BACKGROUND: A needle thoracocentesis should be performed with maximal safety and optimal efficacy in mind. Mobile video telephony (VT) could be used to facilitate instructions for the accurate performance of needle thoracocentesis in an emergency setting. This new communication method will increase the accuracy of identifying the relevant anatomical site during the decompression technique. METHODS: A prospective randomised manikin study was performed to investigate the effectiveness of using VT as a method of instruction for the identification of anatomical landmarks during the performance of needle thoracocentesis. RESULTS: The overall success rate was significantly higher in the VT group which performed needle thoracocentesis under the guidance of VT than in the non-VT group who performed the procedure without VT-aided instruction. The instrument difficulty score and procedure satisfaction score were significantly lower in the VT group than in the non-VT group. CONCLUSION: Identification of the correct anatomical landmark for needle thoracocentesis can be performed with instructions provided via VT because a dispatcher can monitor every step and provide correct instructions. This new technology will improve critical care medicine.

The usefulness of the GlideScope video laryngoscope in the education of conventional tracheal intubation for the novice.

The aim of this study is to evaluate the usefulness of the GlideScope video laryngoscope (GVL) as a tool to educate novice users in conventional tracheal intubation. 41 premedical students with no previous experience in tracheal intubation participated in this prospective, randomised and controlled study. Group M (n = 20) was instructed in tracheal intubation by using the Macintosh laryngoscope and group G (n = 21) was instructed by using both the GVL and the Macintosh laryngoscope. There was no significant difference in tracheal intubation performance using the Macintosh laryngoscope between the two groups. However, the GVL facilitates the education of tracheal intubation because it shows the same anatomical structure for both instructor and trainee simultaneously on a real-time basis. This aspect makes the trainee feel more comfortable learning the material with a high degree of satisfaction. Introducing GVL to conventional intubation education for novice users could increase the satisfaction of trainees during the procedure, especially as a way to understand critical anatomical structures.

Effects of bed height on the performance of chest compressions.

OBJECTIVES: The correct chest compression technique was emphasised to enhance the result of cardiopulmonary resuscitation in the 2005 guidelines. The present study compared the effects of different bed heights, including a bed at knee height, on the performance of chest compressions. METHODS: Twenty-four healthcare providers participated in this study. Knee height was defined as the baseline bed height. Bed heights were adjusted to 10 and 20 cm above the baseline and 10 and 20 cm below the baseline. At the five bed heights, chest compressions were performed for 2 minutes, and the compression rate was maintained at 100 per minute, with audible feedback. RESULTS: The mean compression depths (MCD) were 28.3 mm (SD 10.7; knee height +20 cm), 32.3 mm (SD 9.2; knee height +10 cm), 32.7 mm (SD 8.5; knee height), 32.3 mm (SD 9.0; knee height -10 cm) and 31.1 mm (SD 8.5; knee height -20 cm). The MCD was significantly lower at knee height plus 20 cm (p<0.001). CONCLUSION: The performance of chest compressions decreased when the bed height was 20 cm higher than the knee height of the rescuer.

Performance of cellular phones with video telephony in the use of automated external defibrillators by untrained laypersons.

AIM: To evaluate the hypothesis that using an automated external defibrillator (AED) with video telephony-directed cellular phone instructions for untrained laypersons would increase the probability of successful performance of AEDs. Real-time communication with visual images can provide critical information and appropriate instructions to both laypersons and dispatchers. METHODS: A prospective observational study was undertaken. 52 public officers with no previous experience in the use of a defibrillator were presented with a scenario in which they were asked to use an AED on a manikin according to the instructions given to them by cellular phones with video telephony. The proportion who successfully delivered a shock and the time interval from cardiac arrest to delivery of the shock were recorded. RESULTS: Placement of the electrode pads was performed correctly by all 52 participants and 51 (98%) delivered an accurate shock. The mean (SD) time to correct shock delivery was 131.8 (20.6) s (range 101-202). CONCLUSION: Correct pad placement and shock delivery can be performed using an AED when instructions are provided via video telephone because a dispatcher can monitor every step and provide correct information.

Accuracy of Web-based recording program for in-hospital resuscitation: laboratory study.

OBJECTIVE: The purpose of this study was to assess the accuracy of a Web-based resuscitation recording program compared with the handwritten method. METHODS: A Web site was developed to record in-hospital resuscitation events and a mock resuscitation was recorded using both the Web site and handwritten method by emergency nurses. Accurate recorded events and times were compared between the two methods through the use of a video clip. Paired t tests were used to compare differences in absolute timing error, the number of omitted events out of 11 reference events and total recorded events. RESULTS: Twenty-one emergency nurses recorded simulated resuscitation events using both the handwritten and Web-based computerised recording system. The mean absolute timing errors were significantly lower using the computerised recording program (37.3 s (SD 17.1) versus 8.3 s (SD 5.3), p<0.001). The mean number of omissions for the computerised program was 1.8 (SD 0.8) compared with 1.4 (SD 1.1) for the handwritten method (p = 0.202). The mean number of total recorded events for the computerised program was 16.5 (SD 3.5) compared with 15.0 (SD 3.8) for the handwritten method (p = 0.063). CONCLUSIONS: This study suggests that a Web-based recording program decreased timing error while causing no differences in the number of recorded or omitted events in a laboratory setting.

Comparison of the GlideScope video laryngoscope and Macintosh laryngoscope in simulated tracheal intubation scenarios.

OBJECTIVE: To compare the GlideScope video laryngoscope (GVL) with the classic Macintosh laryngoscope in simulated airway scenarios of varying difficulty. MATERIALS AND METHODS: A prospective, crossover and randomised study was performed. Four airway scenarios were simulated using the Airsim model as follows: normal; cervical spine immobilisation; tongue oedema and combined cervical spine immobilisation with tongue oedema. Emergency physicians performed tracheal intubations using both devices in each of the scenarios. The time required to intubate, the success rate and the number of intubation attempts were recorded. At the end of each scenario, participants scored vocal cord visualisation using the percentage of glottic opening (POGO) visible and the subjective ease of intubation on a visual analogue scale (VAS). RESULTS: All 25 participants successfully completed the study. There was no difference in the time required for successful tracheal intubation using the GVL compared with using the Macintosh laryngoscope in the four airway scenarios. Only one participant failed to intubate the trachea with the Macintosh laryngoscope for the combined scenario. There was a significant increase in POGO when using the GVL in the cervical spine immobilisation group (p = 0.027). The VAS score of the subjective ease of intubation was lower for the GVL than for the Macintosh laryngoscope device in difficult scenarios but this difference was not significant. CONCLUSION: This study suggests that the GVL could be an option for airway management even by emergency physicians with little experience and no training in its use.

Emergency department experience of primary diffusion weighted magnetic resonance imaging for the patient with lacunar syndrome.

BACKGROUND: The purpose of this study was to evaluate the usefulness of a particular magnetic resonance imaging technique known as primary diffusion weighted imaging (DWI) for patients with lacunar syndrome in the emergency department (ED). METHODS: Patients with one of five classic lacunar syndromes underwent DWI as primary imaging modality. The DWI findings were classified into groups: (a) having a lesion with high signal intensity, (b) having a lesion with mixed signal intensity, and (c) unremarkable. The final clinical diagnoses were extracted from the patients' medical records, and used as a reference standard. RESULTS: Of 151 DWI images, 120 (79%) were interpreted as high signal lesions, 21 (14%) as mixed signal lesions, and 10 (7%) as unremarkable. All patients with high signal lesions or unremarkable findings were diagnosed with ischaemic stroke. The patients with mixed signal lesions were diagnosed with haemorrhagic stroke with an exception of one ischaemic stroke. CONCLUSION: Primary DWI is a feasible and useful neuroimaging tool for patients with lacunar syndrome in the ED.

Usefulness of mean platelet volume as a marker for clinical outcomes after out-of-hospital cardiac arrest: a retrospective cohort study.

Essentials It is unknown whether mean platelet volume (MPV) estimates outcomes after cardiac arrest (CA). We investigated whether MPV was associated with 30-day neurologic outcome and mortality after CA. Elevated MPV at admission was associated with poor neurological outcomes and mortality at 30 days. Identifying levels of MPV is helpful for estimating disease severity among resuscitated patients. SUMMARY: Background Whole-body ischemia followed by reperfusion during cardiac arrest and after return of spontaneous circulation (ROSC) triggers systemic sterile inflammatory responses, inducing a sepsis-like state during post-cardiac arrest syndrome. Activated platelets are enlarged, and contain vasoactive and prothrombic factors that aggravate systemic inflammation and endothelial dysfunction. Objectives To investigate whether mean platelet volume (MPV) is useful as a marker for early mortality and neurologic outcomes in patients who achieve ROSC after out-of-hospital cardiac arrest (OHCA). Methods OHCA records from the Emergency Department Cardiac Arrest Registry were retrospectively analyzed. Patients who survived for > 24 h after ROSC were included. We evaluated mortality and cerebral performance category scores after 30 days. Results We analyzed records from 184 patients with OHCA. Increased 30-day mortality among patients who achieved ROSC after OHCA was associated with MPV at admission (hazard ratio [HR] 1.36; 95% confidence interval [CI] 1.06-1.75). An elevated MPV at admission was also associated with poor neurologic outcomes (HR 1.28; 95% CI 1.06-1.55). Conclusions An elevated MPV was independently associated with increased 30-day mortality, with the highest discriminative value being obtained upon admission after OHCA. An elevated MPV on admission was associated with poor neurologic outcomes. High MPVs are helpful for estimating 30-day mortality and neurologic outcomes among patients who achieve ROSC after OHCA.

Delayed postanoxic encephalopathy after carbon monoxide poisoning.

Delayed postanoxic encephalopathy causes deterioration and relapse of cognitive ability and behavioural movement a few weeks after complete recovery from initial hypoxic injury. A case is reported of delayed postanoxic encephalopathy after carbon monoxide poisoning, which was diagnosed with diffusion weighted magnetic resonance imaging. The literature is also reviewed.

D-amino acid oxidase gene therapy sensitizes glioma cells to the antiglycolytic effect of 3-bromopyruvate.

Glioma tumors are refractory to conventional treatment. Glioblastoma multiforme is the most aggressive type of primary brain tumors in humans. In this study, we introduce oxidative stress-energy depletion (OSED) therapy as a new suggested treatment for glioblastoma. OSED utilizes D-amino acid oxidase (DAO), which is a promising therapeutic protein that induces oxidative stress and apoptosis through generating hydrogen peroxide (H2O2). OSED combines DAO with 3-bromopyruvate (3BP), a hexokinase II (HK II) inhibitor that interferes with Warburg effect, a metabolic alteration of most tumor cells that is characterized by enhanced aerobic glycolysis. Our data revealed that 3BP induced depletion of energetic capabilities of glioma cells. 3BP induced H2O2 production as a novel mechanism of its action. C6 glioma transfected with DAO and treated with D-serine together with 3BP-sensitized glioma cells to 3BP and decreased markedly proliferation, clonogenic power and viability in a three-dimensional tumor model with lesser effect on normal astrocytes. DAO gene therapy using atelocollagen as an in vivo transfection agent proved effective in a glioma tumor model in Sprague-Dawley (SD) rats, especially after combination with 3BP. OSED treatment was safe and tolerable in SD rats. OSED therapy may be a promising therapeutic modality for glioma.

The effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia.

D-Amino acid oxidase (DAO) has been established to be involved in the oxidation of D-serine, an allosteric activator of the N-methyl-D-aspartate-type glutamate receptor in the brain, and to be associated with the onset of schizophrenia. The effect of risperidone, a benzisoxazole derivative, atypical antischizophrenic drug, on the activity of human DAO was tested using an in-vitro oxygraph system and rat C6, stable C6 transformant cells overexpressing mouse DAO (designated as C6/DAO) and pig kidney epithelial cells (LLC-PK(1)). Risperidone has a hyperbolic mixed-type inhibition, designated as 'partial uncompetitive inhibition effect', with K(i) value of 41 microM on human DAO. Risperidone exhibited a protective effect from D-amino acid induced cell death in both C6/DAO and LLC-PK(1) cells with 10% increase in viability. These data indicate the involvement of DAO activity in D-serine metabolism and also suggest a new mechanism of action to risperidone as antischizophrenic drug.