X-ray signs of foreign body aspiration in children

Preoperative chest X-rays were taken in both postanterior and partially lateral views of 94 children with foreign-body aspiration. Additional fluoroscopy was employed in 70 patients. In 7% of the cases, the foreign body was radiopaque; in an equal amount of cases, there were no radiological findings. In the remaining results we observed: emphysema as an indirect radiological sign in two-thirds of the cases; in less than one-third, poststenotic atelectasis; pneumonia in 10%; bronchitis in 9%; pneumothorax in 2%.     

Unmet needs in oral antiplatelet therapy with ADP receptor blocking agents

Antiplatelet agents like aspirin and clopidogrel are treatment cornerstones for acute coronary syndromes (ACS). Drawbacks of dual therapy with these agents include slow onset and offset of effect and wide response variability. Clopidogrel may provide little benefit if administered too close to percutaneous coronary intervention (PCI) and increase major bleeding risk if given too close to coronary artery bypass grafting (CABG) or other surgery. It may not provide sufficient antiplatelet coverage prior to CABG if stopped too long before intervention and leave patients without antiplatelet coverage due to hyporesponsiveness. Prasugrel has made steps towards addressing these limitations by exhibiting more efficient metabolism, more rapid onset of effect, and greater and more consistent platelet inhibition than clopidogrel. The TRITON-TIMI38 trial in ACS patients undergoing PCI showed prasugrel produced greater ischemic event protection than clopidogrel but significantly increased major bleeding risk. AZD6140, the first reversible oral P2Y₁₂ inhibitor, provides more rapid onset of effect and greater and more consistent platelet inhibition than clopidogrel. In DISPERSE2, a phase II trial in ACS patients, AZD6140 did not increase bleeding risk, reduced bleeding risk among CABG patients, and produced numerical reductions in myocardial infarction risk. AZD6140 is being compared with clopidogrel in PLATO, a phase III trial in approximately 18000 ACS patients.     

Succinimide formation at Asn 55 in the complementarity determining region of a recombinant monoclonal antibody IgG1 heavy chain

We investigated the formation and stability of succinimide, an intermediate of deamidation events, in recombinant monoclonal antibodies (mAbs). During the course of an analytical development study of an IgG1 mAbs, we observed that a specific antibody population could be separated from the main product by cation-exchange (CEX) chromatography. The cell-based bioassay measured a ～70% drop in potency for this fraction. Liquid chromatography time-of-flight mass spectrometry (LC–TOF/MS) and tandem mass spectrometry (LC–MS/MS) analyses showed that the modified CEX fraction resulted from the formation of a succinimide intermediate at Asn 55 in the complementarity determining region (CDR) of the heavy chain. Biacore assay revealed a ～50% decrease in ligand binding activity for the succinimide-containing Fab with respect to the native Fab. It was found that the succinimide form existed as a stable intermediate with a half-life of ～3 h at 37°C and pH 7.6. Stress studies indicated that mildly acidic pH conditions (pH 5) favored succinimide accumulation, causing a gradual loss in potency. Hydrolysis of the succinimide resulted in a further drop in potency. The implications of the succinimide formation at Asn 55, a highly conserved residue among IgG1 (mAbs), are discussed. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3509–3521, 2009     

Preoperative plasma plasminogen activator inhibitor type-1 and serum C-reactive protein levels in patients with colorectal cancer

Background: Preoperative plasma plasminogen activator inhibitor-1 (PAI-1) is a prognostic variable in patients with colorectal cancer. It has been suggested, however, that plasma PAI-1 is a nonspecific prognostic parameter similar to the acute-phase reactant C-reactive protein (CRP). In the present study we analyzed the association between plasma PAI-1 and serum CRP in patients scheduled for elective resection of colorectal cancer. In addition, the prognostic value of PAI-1 and CRP was studied in this patient cohort. Methods: PAI-1 and CRP were analyzed in citrated plasma and serum, respectively, obtained preoperatively from 594 patients. Patients who required preoperative blood transfusion received SAGM blood, in which soluble PAI-1 is not present. None of the patients received pre- or postoperative adjuvant chemotherapy, and all were followed in the outpatient clinic for at least 5 years or until death. The association of PAI-1 and CRP, respectively, with survival was tested using the median value of PAI-1 and the upper normal limit for CRP. Analyses were performed by inclusion of all patients, and in the subgroup of patients, who underwent curative resection. Results: The median follow-up period was 6.8 (5.4–7.9) years. The median value of plasma PAI-1 was 35.8 ng/ml, and values greater than 94 nmol/L identified patients with increased CRP levels. Comparison of the molecules showed that PAI-1 was weakly correlated with CRP (r=.26;P<.0001). Both molecules showed a Dukes independent distribution. In univariate survival analyses high levels of PAI-1 were found associated with poor prognosis and low levels with good prognosis (P=.02, HR: 1.3). Similarly, high levels of CRP were found associated with poor prognosis and low levels with good prognosis (P<.0001, HR: 1.9). In a multivariate statistical analysis including Dukes classification, gender, age, tumor location, perioperative blood transfusion, PAI-1 and CRP, plasma PAI-1 was a dependent prognostic variable, while serum CRP (P<.0001; HR: 1.4; 95% CI: 1.3–1.5) was found to be a Dukes independent prognostic variable. Similar analyses, excluding patients with Dukes’ D disease showed serum CRP to be an independent prognostic variable (P<.0001; HR: 1.3: 95% CI: 1.2–1.5). Conclusions: This study did not show a strong correlation between plasma PAI-1 and serum CRP in patients with colorectal cancer. Serum CRP was found to be a Dukes independent prognostic variable in this patient cohort, and was found to identify a subgroup of curatively resected patients at risk for short survival. The study received financial support from The Ingeborg Roikjer Foundation, The Aage and Johanne Louis-Hansen Foundation, The Danish Pharmacy Foundation of 1991, The Agnete and Poul Friis Fund, The Walter and O. Kristiane Christensen Fund, The E. Danielsen Family Fund, The Hede-Nielsen Foundation, The Einar and Vera Hansen Foundation, The Torben and Alice Frimodt Fund, and The Danish Cancer Society (grant # 97 100 21).     

Levels of high energy phosphate in the dorsal skin of the foot in normal and diabetic adults: the role of 31P magnetic resonance spectroscopy and direct quantification with high pressure liquid chromatography

Determining viability of tissues and wound-healing potential in diabetic patients remains a significant challenge. Current methods for preoperative assessment of wound-healing potential (pressures in the ankle, temperature of tissues, transcutaneous measurements of oxygen, and systemic nutritional status) are indirect, in that they characterize the delivery of oxygen or other nutrients to the cells. A noninvasive means to measure adenosine triphosphate (ATP) and phosphocreatine (PCr), the fundamental high energy phosphate substrates of oxidative energy-metabolism in the skin, has been devised by using magnetic resonance spectroscopy (MRS). The signal-to-noise ratio of bioenergetic metabolites in the skin was 86% lower in five patients with diabetes who had ischemia of the lower extremity compared with five control subjects (P < 0.0001), suggesting that the concentration of high energy metabolites in diabetic patients was reduced. The ratio of ATP/phosphocreatine (PCr) in patients with diabetes was also significantly lower than in controls (P < 0.01). Chewing a single piece of nicotine gum reduced the measured concentrations of ATP and PCr in control subjects by an average of 18% and by an average of 75% in subjects with diabetes. To verify these results in a second experiment, skin was harvested from the surgical wound sites in eight patients with diabetes undergoing elective amputation, eight patients with diabetes undergoing elective foot surgery, and ten age-matched control (nondiabetic) patients undergoing elective foot surgery. Analysis of ATP and PCr using high pressure liquid chromatography corroborated MRS findings, showing a significant reduction in ATP and PCr in diabetic skin. Depression of metabolites was more severe in the patients with diabetes undergoing amputation than in the ones undergoing elective surgery. Results demonstrate depression of metabolites in the skin of patients with diabetes and suggest that MRS with 31p may be useful in characterizing metabolites in the skin.