Platelet-activating factor and the release of a platelet-derived coronary artery vasodilator substance in the canine

Platelet-activating factor (acetyl-glyceryl-ether-phosphorylcholine; 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphorylcholine), which is released by stimulated neutrophils and platelets, possesses the ability to alter vascular tone and permeability and to activate various formed blood elements. We have characterized the hemodynamic effects of intracoronary injections of platelet-activating factor and the influences of pharmacological blockade and platelet depletion on its activity. Intracoronary injections of platelet-activating factor produced maximum increases in left circumflex coronary artery blood flow of 55 +/- 8, 52 +/- 8, and 52 +/- 7 ml/min at 0.5, 1.0, and 2.0 nM, respectively. Only modest changes in systemic arterial blood pressure and regional developed isometric contractile force were associated with the intracoronary artery administration of platelet-activating factor over the range of doses studied. The increase in left circumflex coronary artery blood flow in response to platelet-activating factor was attenuated (44%), but not prevented, by pretreatment with diphenhydramine, (4 mg/kg, iv), and was not affected by pretreatment with aspirin (20 mg/kg, iv) or the systemic administration of the serotonin receptor antagonist, methysergide. The coronary vasodilator response to platelet-activating factor was reduced significantly by the induction of thrombocytopenia (95 +/- 3% platelet depletion) through the administration of sheep-derived canine platelet antiserum. The intracoronary artery injection of platelet-rich plasma activated with platelet-activating factor into thrombocytopenic dogs produced a significantly greater increase in coronary artery blood flow than the injection of either non-activated platelet-rich plasma or platelet-depleted plasma to which platelet-activating factor was added. Similar changes in coronary artery blood flow could be obtained with the intracoronary artery injection of cell-free supernates from washed platelets activated with platelet-activating factor. The observed results suggest that circulating platelets, when exposed to platelet-activating factor, can release a coronary dilator substance, and that the coronary artery dilation is not prevented by pharmacological receptor antagonists for histamine, serotonin, or inhibitors of cyclooxygenase.     

The international autoimmune hepatitis score in chronic hepatitis C

SUMMARY. Clinical and laboratory findings of autoimmunity are common in chronic hepatitis C. Autoimmune hepatitis (AIH), a disease of unknown cause, has been defined by use of the International Autoimmune Hepatitis Group Score (AIH score), which quantifies clinical and laboratory parameters. To further validate the specificity of the International AIH score and investigate the similarities between hepatitis C and AIH, we measured the International Autoimmune Hepatitis Group Score in patients with well-defined chronic hepatitis C. Thirty consecutive non-cirrhotic patients with chronic hepatitis C were evaluated. Scoring was performed using both components of the AIH score: a set of minimum required parameters including laboratory and historical data and a second set of additional parameters dominated by histological criteria. Autoantibodies were positive in 21 of 30 hepatitis C patients and associated (patient or first-degree relative) autoimmune diseases were present in eight of 30 patients. Histologically, chronic active hepatitis with periportal piecemeal necrosis was seen in 24 of 30 patients and lymphoid follicles in 16 of 30 patients. No patient scored as probable or definite AIH using the minimum required parameters of the AIH score. When histological parameters were included, four of 30 patients scored as probable AIH but none as definite AIH. Therefore, AIH was excluded by the minimal and additional criteria of the AIH score in 86% of patients with hepatitis C despite a high prevalence of autoantibodies in these patients. We conclude that the criteria set forth by the International AIH scoring system defines a distinct disease although it shares some features with chronic hepatitis C. Modification of the AIH scoring system to include other commonly accepted risk factors for hepatitis C and additional histological parameters would further improve its specificity.     

Clinical evaluation of music perception,appraisal and experience in cochlear implant users

Objectives: The objectives were to evaluate the relationships among music perception, appraisal, and experience in cochlear implant users in multiple clinical settings and to examine the viability of two assessments designed for clinical use. Design: Background questionnaires (IMBQ) were administered by audiologists in 14 clinics in the United States and Canada. The CAMP included tests of pitch-direction discrimination, and melody and timbre recognition. The IMBQ queried users on prior musical involvement, music listening habits pre and post implant, and music appraisals. Study sample: One-hundred forty-five users of Advanced Bionics and Cochlear Ltd cochlear implants. Results: Performance on pitch direction discrimination, melody recognition, and timbre recognition tests were consistent with previous studies with smaller cohorts, as well as with more extensive protocols conducted in other centers. Relationships between perceptual accuracy and music enjoyment were weak, suggesting that perception and appraisal are relatively independent for CI users. Conclusions: Perceptual abilities as measured by the CAMP had little to no relationship with music appraisals and little relationship with musical experience. The CAMP and IMBQ are feasible for routine clinical use, providing results consistent with previous thorough laboratory-based investigations.     

Rate of FKS Mutations among Consecutive Candida Isolates Causing Bloodstream Infection

Precise FKS mutation rates among Candida species are undefined because studies have not systematically screened consecutive, disease-causing isolates. The Sensititre YeastOne (SYO) assay measures echinocandin MICs against Candida with less variability than reference broth microdilution methods. However, clinical breakpoint MICs may overstate caspofungin nonsusceptibility compared to other agents. Our objectives were to determine Candida FKS mutation rates by studying consecutive bloodstream isolates and to determine if discrepant susceptibility results were associated with FKS mutations. FKS hot spots were sequenced in echinocandin-intermediate and -resistant isolates and those from patients with breakthrough candidemia or ≥3 days of prior echinocandin exposure. Overall, 453 isolates from 384 patients underwent susceptibility testing; 16% were echinocandin intermediate or resistant. Intermediate susceptibility rates were higher for Candida glabrata than for other species (P < 0.0001) and higher for caspofungin than for other agents (P < 0.0001). Resistance rates were similar between agents. FKS mutations were detected in 5% of sequenced isolates and 2% of isolates overall. Corresponding rates among C. glabrata isolates were 8% and 4%, respectively. Among Candida albicans isolates, rates were 5% and <1%, respectively. Mutations occurred exclusively with prior echinocandin exposure and were not detected in other species. Isolates with discrepant susceptibility results did not harbor FKS mutations. Mutation rates among isolates resistant to ≥2, 1, and 0 agents were 75%, 13%, and 0%, respectively. In conclusion, FKS mutations were uncommon among non-C. glabrata species, even with prior echinocandin exposure. Discrepancies in echinocandin susceptibility by SYO testing were not driven by mutations and likely reflect imprecise caspofungin clinical breakpoints.