Arrhythmogenic Antitussive: A Case of Pediatric Benzonatate Overdose With Torsades de Pointes, Cardiac Arrest, and Complete Recovery Without Neurologic Deficits.

Benzonatate is a commonly prescribed antitussive with rapid and deadly effects in overdose. We report a 14-year-old female who ingested 14 capsules containing 200 mg benzonatate. Her case represents the only reported benzonatate overdose with torsades de pointes, as well as the only reported pediatric benzonatate ingestion complicated by cardiac arrest with full recovery.

SB 234551 selective ET(A) receptor antagonism: perfusion/diffusion MRI used to define treatable stroke model, time to treatment and mechanism of protection.

Mismatches between tissue perfusion-weighted imaging (PWI; an index of blood flow deficit) and cellular diffusion-weighted imaging (DWI; an index of tissue injury) provide information on potentially salvageable penumbra tissue in focal stroke and can identify "treatable" stroke patients. The present pre-clinical studies were conducted to: a.) Determine PWI (using perfusion delay) and DWI measurements in two experimental stroke models, b.) Utilize these measurements to characterize selective ET(A) receptor antagonism (i.e., determine efficacy, time-to-treatment and susceptibility to treatment in the different stroke models), and c.) Determine if increasing the reduced blood flow following a stroke is a mechanism of protection. Permanent middle cerebral artery occlusion (MCAO) or sham surgeries were produced in Sprague Dawley rats (SD; proximal MCAO; hypothesized to be a model of slowly evolving brain injury with a significant penumbra) and in spontaneously hypertensive rats (SHR; distal MCAO; hypothesized to be a model of rapidly evolving brain injury with little penumbra). Infusions of vehicle or SB 234551 (3, 10, or 30 microg/kg/min) were initiated at 0, 75, and/or 180 min post-surgery and maintained for the remainder of 24 h post-surgery. Hyper-intense areas of perfusion delay (PWI) in the forebrain were measured using Gadolinium (Gd) bolus contrast. DWI hyper-intense areas were also measured, and the degree of forebrain DWI-PWI mismatch was determined. Region specific analyses (ROI) were also conducted in the core ischemic and low perfusion/penumbra areas to provide indices of perfusion and changes in the degree of tissue perfusion due to SB 234551 treatment. At 24 h post-surgery, final infarct volume was measured by DWI and by staining forebrain slices. Following SD proximal MCAO, there was a significant mismatch in the ischemic forebrain PWI compared to DWI (PWI>DWI) at 60 min which was maintained up to 150 min (all p<0.05). By 24 h post-stroke, infarct volume was identical to the area of early perfusion deficit/PWI, suggesting a slow progression of infarct development that expanded into the significant, earlier cortical penumbra (i.e., model with salvageable tissue with potential for intervention). When SB 234551 was administered within the period of peak mismatch (i.e., at 75 min post-stroke), SB 234551 provided significant dose-related reductions in cortical (penumbral) progression to infarction (p<0.05). Cortical protection was related to an increased/normalization of the stroke-induced decrease in tissue perfusion in cortical penumbra areas (p<0.05). No SB 234551-induced changes in reduced tissue perfusion were observed in the striatum core ischemic area. Also, when SB-234551 was administered beyond the time of mismatch, no effect on cortical penumbra progression to infarct was observed. In comparison and strikingly different, following SHR distal MCAO there was no mismatch between PWI and DWI (PWI=DWI) as early as 60 min post-stroke, with this early change in SHR DWI being identical to the final infarct volume at 24 h, suggesting a rapidly occurring brain injury with little cortical penumbra (i.e., model with little salvageable tissue or potential for intervention). In distal MCAO, SB 234551 administered immediately at the time of stroke did not have any effect on infarct volume in SHR. These data demonstrate that selective blockade of ET(A) receptors is protective following proximal MCAO in SD (i.e. a model similar to "treatable" clinical patients). The protective mechanism appears to be due to enhanced collateral blood flow and salvage of penumbra. Therefore, the use of PWI-DWI mismatch signatures can identify treatable stroke models characterized by a salvageable penumbra and can define appropriate time to treatment protocols. In addition, tissue perfusion information obtained under these conditions might clarify mechanism of protection in the evaluation of protective compounds for focal stroke.

Comorbidity in patients with cancer: prevalence and severity measured by cumulative illness rating scale.

Comorbidity is defined as the presence of one or more diseases in addition to an index disease. In elderly people, the number and severity of comorbidity increase with age. We report the comorbidity data of 536 patients treated as in-patients: 231 elderly cancer patients (ECP), 172 younger cancer patients (YCP) and 133 elderly patients admitted for non-cancer reasons (EMP). Comorbidity was assessed with the cumulative illness rating scale geriatric version (CIRS-G). Data on number of affected organ systems (levels 1-4), number of affected organ systems with severe disease (levels 3-4), and sum score of levels per patient are reported. The number of comorbidities increases with age. A 76% of ECP, 51% of YCP, and 79% of EMP have severe comorbidity. Palliative treatment approach is not associated with higher levels of comorbidity in ECP. Vascular disorders were the most common comorbidity. The difficulty to rate haematological comorbidity in cancer patients is reflected. This is the first report on detailed results of assessment of comorbidity measured by CIRS-G in cancer patients. In addition, we provide a comparison to an elderly group of patients admitted for non-cancer reasons.

Simultaneous assessment of left-ventricular infarction size, function and tissue viability in a murine model of myocardial infarction by cardiac manganese-enhanced magnetic resonance imaging (MEMRI).

Owing to its signal-enhancing characteristics in viable well-perfused tissue, divalent manganese (Mn2+) has been used as a myocardial imaging contrast agent. Because Mn2+ can enter excitable cells through the voltage-gated L-type calcium channels, manganese-enhanced MRI (MEMRI) has been used to determine the viability and the inotropic state of the heart. In this study, we examined the correlation between left ventricular infarction zone as assessed by cardiac MEMRI and function in mice with permanent coronary artery occlusion. At an Mn2+ infusion dose of 1.72+/-0.47 nmol/min/g body weight, the steady-state signal intensity (SI) enhancement 20-26 min post-Mn2+ infusion of the normal septum and left-ventricular wall during diastole was 128.2+/-14.4 and 127.9+/-26.5%, respectively, whereas the infarction zone was 56.0+/-7.1%. During systole, the SI enhancement was 144.6+/-33.0, 116.0+/-18.7 and 48.3+/-20.0% for the normal septum, left-ventricular wall and infarction zone, respectively. A good correlation was obtained between the MEMRI determined infarction volume and conventional histological TTC staining (r = 0.9582, p<0.01). There was also a strong negative correlation between MEMRI determined infarction percentage (compared with whole left ventricle) and ejection fraction (r = -0.94, p<0.05). These data suggest that the Mn2+ concentration at steady state in the heart may reflect altered tissue viability in the infarcted tissue as well as surrounding region following myocardial infarction. In conclusion, in vivo cardiac MEMRI offers a manner in which functional, pathologic and viability data may be obtained simultaneously in myocardial tissue.

p38 MAPK inhibitors ameliorate target organ damage in hypertension: Part 2. Improved renal function as assessed by dynamic contrast-enhanced magnetic resonance imaging.

Recent evidence suggests p38 mitogen-activated protein kinase (MAPK) signal transduction plays an important role in the pathogenesis of progressive renal disease. Using dynamic contrast enhanced magnetic resonance imaging (MRI), we evaluated chronic treatment with a p38 MAPK inhibitor, trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl-methoxypyridimidin-4-yl)imidazole (SB-239063), on renal function in a hypertension model of progressing renal dysfunction. Spontaneously hypertensive-stroke prone rats were placed on a high salt/fat diet (SFD) or maintained on normal chow diet (ND). SFD animals with albuminuria at 4 to 8 weeks (> or =10 mg/day inclusion criteria), were randomized into p38 MAPK inhibitor treatment (SB-239063, 1200 ppm in diet) or vehicle groups. The progression of blood pressure and albuminuria during the treatment period (approximately 6 weeks) was decreased by 12 and 60%, respectively, in the SFD + SB-239063 versus SFD control group. Renal perfusion and filtration were assessed by in vivo MRI at the end of the study. Relative cortical perfusion was increased in the SFD + SB-239063 group compared with the SFD control group as reflected by a 29% decrease in time to peak of contrast agent in the cortex. Additionally, the regional renal glomerular filtration rate index (Kcl) was increased by 39% in the SFD + SB-239063 versus SFD control group and was normalized to the ND control group. Greater functional heterogeneity was observed in the SFD control versus SFD + SB-239063 or ND control group. All alterations of renal function were supported by histopathological findings. In conclusion, chronic treatment with a p38 MAPK inhibitor, SB-239063, attenuates functional and structural renal degeneration in a hypertensive model of established renal dysfunction.

Strain-dependent response to cerebral ischemic preconditioning: differences between spontaneously hypertensive and stroke prone spontaneously hypertensive rats.

Ischemic preconditioning (PC) is a phenomenon whereby a brief exposure to ischemia renders a tissue more tolerant to a subsequent sustained ischemic insult. Animals of the Spontaneously Hypertensive (SHR) and the Spontaneously Hypertensive Stroke-Prone (SHR-SP) rat strains produce cerebral infarcts that are larger and more reproducible in size than infarcts of normotensive rats. This study compared the effects of PC in SHR and SHR-SP rats, under the hypothesis that PC may not be as effective in the SHR-SP, a strain genetically predisposed to stroke. There were two groups per strain, with between eight and ten animals each. The Precondition group (PC) had a 10 min occlusion of the middle cerebral artery on day -1. On the same day the Sham group (Sham) received sham surgery. On day 0, both groups underwent permanent occlusion of the middle cerebral artery. The ischemic lesion was measured on day 1 using T(2)-weighted magnetic resonance imaging. Percent hemispheric infarct was significantly reduced in SHR PC vs. SHR Sham, SHR-SP PC vs. SHR-SP Sham, and SHR PC vs. SHR-SP PC. Thus, rats of the SHR-SP strain respond to PC less markedly than SHR animals. Both models may now be used to elucidate the mechanisms underlying PC.

Reduction of intramyocellular lipid following short-term rosiglitazone treatment in Zucker fatty rats: an in vivo nuclear magnetic resonance study.

The aim of the study was to characterize the effects of rosiglitazone, an oral insulin sensitizer, on intramyocellular lipid (IMCL) content in tibialis anterior muscle and whole body lipid deposition in Zucker fatty rats using in vivo (1)H nuclear magnetic resonance (NMR) spectroscopy. The IMCL/EMCL (extramyocellular) ratio was significantly lower in the rosiglitazone (FRSG) group at 7, 14, 21, and 28 days of treatment at 3 mg/kg/d (0.04 +/- 0.01, 0.09 +/- 0.03, 0.11 +/- 0.02, and 0.07 +/- 0.02, respectively) versus baseline (0.43 +/- 0.12, P <.01 v all time points), whereas there was no difference in the control (FC) group at these time points (0.31 +/- 0.08, 0.36 +/- 0.08, 0.40 +/- 0.14, and 0.49 +/- 0.18, respectively) versus baseline (0.37 +/- 0.07). Absolute IMCL content was also lower at 28 days in the FRSG (0.41 +/- 0.09 micromol/g) versus FC (2.13 +/- 0.40 micromol/g, P <.005) group. To further characterize the temporal nature of this change, the IMCL/EMCL ratio was examined in the FRSG group on each of the first 4 days of treatment, and a steady decline was observed (0.38 +/- 0.12, 0.21 +/- 0.08, 0.12 +/- 0.04, 0.09 +/- 0.04, 0.05 +/- 0.03 at baseline and days 1, 2, 3, and 4 respectively, P <.05 baseline v all time points). To examine the relationship between IMCL and insulin sensitivity, a euglycemic-hyperinsulinemic clamp and IMCL measurement was performed on 7-day treated FRSG and FC groups. There was a negative correlation between absolute IMCL content and glucose infusion rate (r = -0.47, P <.04). The FRSG and the FC groups had similar whole body lipid content (expressed as a percentage of whole body water content) at baseline (48% +/- 5% and 44% +/- 2%, respectively), but the value was greater in the FRSG group following 28 days of treatment (103% +/- 4 v 84% +/- 6%, respectively, P <.02). In summary, there was a rapid (days) and pronounced reduction ( downward arrow approximately 70%) in IMCL content in tibialis anterior muscle following rosiglitazone treatment. Additionally, the increase in whole body lipid in the FRSG group suggests that there was increased adipocyte lipid storage following long-term rosiglitazone treatment. These results support the hypothesis that rosiglitazone indirectly increases peripheral insulin sensitivity by decreasing adipocyte lipolysis, thereby lowering IMCL content.

Normalization of skeletal muscle glycogen synthesis and glycolysis in rosiglitazone-treated Zucker fatty rats: an in vivo nuclear magnetic resonance study.

The aim of this study was to characterize insulin-stimulated skeletal muscle glucose metabolism in Zucker fatty rats and to provide insight into the therapeutic mechanism by which rosiglitazone increases insulin-stimulated glucose disposal in these rats. Metabolic parameters were measured using combined in vivo (13)C nuclear magnetic resonance (NMR) spectroscopy to measure skeletal muscle glucose uptake and its distributed fluxes (glycogen synthesis and glycolysis), and (31)P NMR was used to measure simultaneous changes in glucose-6-phosphate (G-6-P) during a euglycemic-hyperinsulinemic clamp in awake Zucker fatty rats. Three groups of Zucker fatty rats (fatty rosiglitazone [FRSG], fatty control [FC], lean control [LC]) were treated for 7 days before the experiment (3 mg/kg rosiglitazone or vehicle via oral gavage). Rates of glycolysis and glycogen synthesis were assessed after treatment by monitoring 1,6-(13)C(2) glucose label incorporation into 1-(13)C glycogen, 3-(13)C lactate, and 3-(13)C alanine during a euglycemic ( approximately 7-8 mmol/l)-hyperinsulinemic (10 mU. kg(-1). min(-1)) clamp. The FRSG group exhibited a significant increase in insulin sensitivity, reflected by an increased whole-body glucose disposal rate during the clamp (24.4 +/- 1.9 vs. 17.6 +/- 1.4 and 33.2 +/- 2.0 mg. kg(-1). min(-1) in FRSG vs. FC [P < 0.05] and LC [P < 0.01] groups, respectively). The increased insulin-stimulated glucose disposal in the FRSG group was associated with a normalization of the glycolytic flux (52.9 +/- 9.1) to LC (56.2 +/- 16.6) versus FC (18.8 +/- 8.6 nmol. g(-1). min(-1), P < 0.02) and glycogen synthesis flux (56.3 +/- 11.5) to LC (75.2 +/- 15.3) versus FC (16.6 +/- 12.8 nmol. g(-1). min(-1), P < 0.05). [G-6-P] increased in the FRSG and LC groups versus baseline during the clamp (13.0 +/- 11.1 and 16.9 +/- 5.8%, respectively), whereas [G-6-P] in the FC group decreased (-23.3 +/- 13.4%, P < 0.05). There were no differences between groups in intramyocellular glucose, as measured by biochemical assay. These data suggest that the increased insulin-stimulated glucose disposal in muscle after rosiglitazone treatment can be attributed to a normalization of glucose transport and metabolism.