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Background: The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted. Methods: Seventy-one adults with advanced STS who received ⩽2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS). Results: There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm ( N =11) over single agent ( N =10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P =0.01). Four-month PFS rate was 50% (95% confidence interval 0.19–0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each). Conclusions: While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.

Objective: To assess the haemodynamic effect of simultaneously adjusting atrioventricular (AV) and interventricular (VV) delays. Method: 35 different combinations of AV and VV delay were tested by using digital photoplethysmography (Finometer) with repeated alternations to measure relative change in systolic blood pressure (SBPrel) in 15 patients with cardiac resynchronisation devices for heart failure. Results: Changing AV delay had a larger effect than changing VV delay (range of SBPrel 21 v 4.2 mm Hg, p < 0.001). Each had a curvilinear effect. The curve of response to AV delay fitted extremely closely to a parabola (average R2  =  0.99, average residual variance 0.8 mm Hg2). The response to VV delay was significantly less curved (quadratic coefficient 67 v 1194 mm Hg/s2, p  =  0.003) and therefore, although the residual variance was equally small (0.8 mm Hg2), the R2 value was 0.7. Reproducibility at two months was good, with the SD of the difference between two measurements of SBPrel being 2.5 mm Hg for AV delay (2% of mean systolic blood pressure) and 1.5 mm Hg for VV delay (1% of mean systolic blood pressure). Conclusions: Changing AV and VV delays results in a curvilinear acute blood pressure response. This shape fits very closely to a parabola, which may be valuable information in developing a streamlined clinical protocol. VV delay adjustment provides an additional, albeit smaller, haemodynamic benefit to AV optimisation.

Background:The complications and limitations of biventricular pacing largely relate to left ventricular (LV) pacing. An alternative approach was tested of simultaneously pacing the right ventricular (RV) apex and outflow tract (RVOT) or using bifocal right ventricular pacing (BRVP) to provide cardiac resynchronisation.Methods:21 consecutive patients with heart failure and severely impaired left ventricular function were studied. Ejection fraction and tissue Doppler data were collected at baseline, during BRVP, and during biventricular pacing, using a temporary pacing protocol.Results:BRVP was achieved in all patients without complication. BRVP significantly reduced mean baseline intra-LV, inter-LV–RV, and global mechanical dyssynchrony from (mean (SD)) 71 (35) to 44 (18) ms, p = 0.003; 86 (42) to 57 (33) ms, p = 0.029; and 157 (67) to 101 (42) ms, p = 0.005, respectively. It increased the ejection fraction from 21 (8)% to 29 (7)%, p = 0.002. Compared with BRVP, reductions in intra-LV, inter-LV–RV, and global mechanical dyssynchrony were superior with biventricular pacing (31 (12) ms, p = 0.014; 36 (27) ms, p = 0.008; and 67 (34) ms, p = 0.01 compared with BRVP, respectively); improvements in ejection fraction were similar (26 (9)%, NS).Conclusions:In patients with heart failure, superior mechanical resynchronisation is achieved with biventricular pacing compared with BRVP. BRVP may be useful when left ventricular lead placement is not possible.

Objective:To determine the effects of interventricular pacing interval and left ventricular (LV) pacing site on ventricular dyssynchrony and function at baseline and during biventricular pacing, using tissue Doppler imaging.Methods:Using an angioplasty wire to pace the left ventricle, 20 patients with heart failure and left bundle branch block underwent temporary biventricular pacing from lateral (n = 20) and inferior (n = 10) LV sites at five interventricular pacing intervals: +80, +40, synchronous, −40, and −80 ms.Results:LV ejection fraction (EF) increased (mean (SD) from 18 (8)% to 26 (10)% (p = 0.016) and global mechanical dyssynchrony decreased from 187 (91) ms to 97 (63) ms (p = 0.0004) with synchronous biventricular pacing compared to unpaced baseline. Sequential pacing with LV preactivation produced incremental improvements in EF and global mechanical dyssynchrony (p<0.0001 and p = 0.0026, respectively), primarily as a result of reductions in inter-LV–RV dyssynchrony (p = 0.0001) rather than intra-LV dyssynchrony (NS). Results of biventricular pacing from an inferior or lateral LV site were comparable (for example, synchronous biventricular pacing, global mechanical dyssynchrony: lateral LV site, 97 (63) ms; inferior LV site, 104 (41) ms (NS); EF: lateral LV site, 26 (10)%; inferior LV site, 27 (10)% (NS)). ECG morphology was identical during biventricular pacing through an angioplasty wire and a permanent lead.Conclusions:Sequential biventricular pacing with LV preactivation most often optimises LV synchrony and EF. An inferior LV site offers a good alternative to a lateral site. Pacing through an angioplasty wire may be useful in assessing the acute effects of pacing.

In a double-blind, multicenter trial, 541 febrile granulocytopenic patients were randomized to receive either intravenous (iv) clinafloxacin (200 mg every 12 h) or iv imipenem (500 mg every 6 h) as empirical monotherapy. More baseline pathogens were susceptible to clinafloxacin (259 [99%] of 262 organisms) than to imipenem (253 [95%] of 265; P = .03). Initial favorable clinical response rates for clinafloxacin (88 [32%] of 272 patients) and imipenem (89 [33%] of 269) were similar. After addition of other antimicrobial agents, overall response rates were 259 (95%) of 272 for clinafloxacin and 251 (93%) of 269 for imipenem. During the study, only 13 clinafloxacin (5%) and 18 imipenem (7%) recipients died. Both drugs were generally well tolerated. Drug-related skin rash occurred more often with clinafloxacin (11% vs. 6%; P = .07), whereas nausea (2% vs. 5%; P = .16), Clostridium-difficile-associated diarrhea (3% vs. 8%; P = .02), and seizures (0% vs. 2%; P = .06) occurred more often with imipenem. These results suggest that clinafloxacin and imipenem have similar efficacy as empirical monotherapy in febrile granulocytopenic patients.

Life-threatening infections of the head and neck have become less common in the postantibiotic ear. Furthermore, with widespread use of antibiotics and the development of profound immunosuppression in some patients, the classic manifestations of these infections are often altered. In this review, the key clinical manifestations of several life-threatening infections of the head and neck are highlighted, and the anatomic relationships that underlie their diagnosis and management are emphasized.

Rhabdomysarcoma is the most common soft tissue tumour in children under the age of 15. Although the introduction of multimodal treatment programmes, including chemotherapy, radiation therapy and excision have increased the overall survival, the chemotherapeutic agents currently used for the treatment of rhabdomyosarcoma exhibit considerable toxicity. The aim of this study was to investigate the effects and possible mechanism(s) of action of resveratrol on human embryonal rhabdomyosarcoma (RD) cells. Resveratrol is a natural polyphenolic compound produced in a number of edible plants and has received considerable attention as a potential chemopreventive and/or chemotherapeutic agent against various types of cancers. In the present study, resveratrol was shown to inhibit cell proliferation of RD cells in a dosedependent manner with an IC₅₀ of 48.1 μmol/1 and induce an arrest in the S/G₂ phase of the cell cycle. As evident from immunocytochemical data, resveratrol treatment increased the size of the RD cells. Furthermore, resveratrol treatment resulted in a significant downregulation of cyclin expression as demonstrated by western blot analyses. In conclusion, the present study shows that resveratrol exerts a strong inhibition of rhabdomyosarcoma cell proliferation in part by arresting cells in S/G₂ phase of the cell cycle. These findings warrant further investigation to establish potential use of resveratrol as a relatively non-toxic chemotherapeutic agent for the treatment of rhabdomyosarcoma.

Random mutagenesis with hydroxylamine was done on toxic shock syndrome toxin-1 (TSST-1) to identify the amino acid residues critical for binding to major histocompatibility complex (MHC) class II molecules of human monocytes. A double mutant with amino acid substitutions of glycine 31→arginine and aspartic acid 184→asparagine (G31R.D184N) demonstrated markedly reduced binding to human monocytes and induction of mitogenesis or cytokine secretion. Site-directed mutagenesis revealed that G31R, but not D184N, was at least 4 orders of magnitude less active than wild type recombinant (r) TSST-1 in these biologic activities and did not induce lethal shock in mice. The global structure of G31R remained highly similar to wild type rTSST-1 as evidenced by circular dichroism spectroscopy and binding to anti - TSST-1 polyclonal and monoclonal antibodies. These studies identified TSST-1 residue 31 as critical for binding to MHC class II molecules and for the consequent superantigenic and lethal properties of TSST-1.

Toxic shock syndrome toxin (TSST)-1 is a superantigen known to profoundly induce proinflammatory cytokines by activation of V beta -specific alpha beta T cells, but its effect on gamma delta T cells, which normally constitute 1%-5% of peripheral blood mononuclear cells (PBMCs), is unclear. Here, we demonstrate that TSST-1 induced significantly higher levels of interferon (IFN)- gamma, tumor necrosis factor (TNF)- alpha, and interleukin (IL)-2, and a lower level of IL-10 in human PBMCs when the gamma delta subpopulation has been primed by isopentylpyrophosphate, compared with that in control PBMCs. Furthermore, depletion of the gamma delta subpopulation completely abrogated this effect. Thus, peripheral gamma delta T cells markedly modulate both the proinflammatory and anti-inflammatory cytokine responses of TSST-1.

Genetic relationships among 315 isolates of the bacterium Staphylococcus aureus expressing toxic shock syndrome toxin-1 (TSST-1) recovered primarily from humans with toxic shock syndrome (TSS) in five countries on two continents were determined by analyzing electrophoretically demonstrable allelic variation at 20 chromosomal enzyme loci. Forty-nine distinctive electrophoretic types (ETs), representing multilocus enzyme genotypes, were identified. Cluster analysis of the ETs revealed two major phylogenetic divisions separated at a genetic distance of 0.35 and seven branches diverging from one another at distances ≥ 0.20. A single clone (ET 41) accounted for 88% of cases of TSS with a female urogenital focus and 53% of TSS cases involving nonurogenital (predominantly wound) infections. With few exceptions, strains representing different phylogenetic lines had characteristic TSST-1 gene (tst) restriction fragment length polymorphism patterns obtained by digestion of genomic DNA with Cla I. Strains recovered from ovine and bovine hosts with mastitis were genotypically distinct from the major human TSS clone. The expression of TSST-1 in cell lineages representing the total breadth of multilocus genotypic diversity in the species S. aureus as a whole is interpreted as evidence that the TSST-1 gene is evolutionarily old. The recovery of a single clone from the majority of individuals afflicted with TSS having a urogenital focus and from the genital tract of a large proportion of asymptomatic female carriers strongly suggests that this clone is especially well adapted for colonization of these anatomic sites.