Hypothermia-induced platelet aggregation in heparinized flowing human blood: identification of a high responder subpopulation

Cold-induced platelet aggregation (CIPA) in PRP has previously been documented in connection with platelet preservation (4-15 degrees C). This report describes hypothermia-induced platelet aggregation (HIPA) in whole blood and at temperatures used in open-heart surgery (24-32 degrees C). HIPA (specifically, the formation of occlusive aggregates) was studied in human whole blood. Fresh heparinized (1.5 U/ml) human blood was cooled and maintained at target temperatures (15, 20, 24, 28, 32, or 37 degrees C) as it flowed (1 ml/min) through 75-cm long 1/32 inches internal diameter polymer conduit. The formation of aggregates in the tubing was verified using optical video microscopy and was quantified by a light-scattering method and a constant-pressure filtration method. Donors were tested at least twice at each target temperature and were classified into three separate response regimes (Low, Medium, and High) on the basis of the number of aggregates and the duration of their appearance. The screening of 121 donors (average age 22.3 +/- 4.3 years) for HIPA at 24 degrees C (the temperature of maximum response) indicated 14% High Responders, 18% Medium Responders, and 68% Low Responders. HIPA was inhibited by EDTA, citrate, PGE1, and Tirofiban, but not by aspirin, and it was enhanced by elevated heparin levels. HIPA was consistently noted in the blood of a subpopulation of donors, and the associated platelet aggregates in the blood of High Responders were rigid and occlusive. It is postulated that such aggregates may contribute to cognitive dysfunction noted in patients undergoing hypothermic open-heart surgery, and that postulus is being investigated.     

Asthma

Asthma is one of the commonest chronic diseases of affluent societies. The striking increase in prevalence of asthma over recent decades and the rarity of this disease in less affluent populations confirms the importance of environmental factors in the cause of asthma--although which environmental factors are responsible is still not clear. Family studies show that genetic factors are also important in determining individual susceptibility to asthma, with results of genetic studies suggesting that there are many genes with moderate effects rather than a few major genes. Asthmatic airways show inflammation and remodelling, with CD4+ helper cells, mast cells, and eosinophils characterising the inflammatory response. Inhaled corticosteroids remain the cornerstone of treatment with the addition of long-acting beta agonists as the next step if symptoms continue. Leukotriene antagonists, the only new drugs to reach the market in the past decade, have modest effects. However, a better understanding of the mechanisms underlying asthma and the genetic and environmental factors that predispose individuals to asthma should lead to better preventative strategies and new therapeutic approaches.     

Transfusion for coagulopathy after heart surgery: efficacy of laboratory studies

Limited information exists regarding transfusions specifically for coagulopathy following cardiac surgery and the value of pre- and postoperative coagulation tests. Procedures (86% coronary bypass, 7.5% valve, and 6.5% combined valve and bypass) on 478 patients were reviewed; 101 patients (21%) were transfused for postoperative coagulopathy. Compared to those not transfused, patients with coagulopathy were significantly older and smaller, and they had more combined valve procedures, emergency operations, and preoperative heparin treatment as well as longer crossclamp and bypass times. Three preoperative tests showed significant differences in the coagulopathy group: activated clotting time, partial thromboplastin time, and antithrombin-III level. Four postoperative tests showed significant differences between the groups: prothrombin time, partial thromboplastin time, fibrinogen level, and fibrin split products at 10 dilutions. Patient characteristics and pre- and postoperative testing can identify patients at high risk of transfusion specifically related to coagulopathy.     

Specificity of mammography and US in the evaluation of a palpable abnormality: retrospective review

PURPOSE: To determine the number of patients who received a diagnosis of breast cancer after having an area of clinical concern at presentation and combined negative mammographic and ultrasonographic (US) findings. MATERIALS AND METHODS: During a 4-year period, 829 patients with a palpable abnormality at presentation and combined negative mammographic and US findings were identified. The number of women who went on to receive a diagnosis of breast cancer was determined retrospectively. The authors searched the breast imaging database and the pathology database, sent a contact letter to the referring physicians, and linked their data to the State Cancer Registry. They also analyzed the breast parenchymal density among all patients who had more than 2 years of follow-up. RESULTS: Of the 829 women, 374 had follow-up information. Two-hundred thirty-three patients had negative imaging findings with more than 2 years of follow-up. The other 141 women were presumed to be cancer free, as they were not identified by the State Cancer Registry. Six (2.6%) of the 233 women had a diagnosis of breast cancer in the area of the palpable abnormality. The six cancers were diagnosed among the 156 women who had radiographically dense breast tissue (Breast Imaging Reporting and Data System category 3 or 4). Among the 77 women with predominantly fatty tissues, no cancers were diagnosed. CONCLUSION: A negative mammographic and US finding of a palpable abnormality does not exclude breast cancer, but the likelihood of breast cancer is low, approximately 2.6%-2.7%. It may be higher if the breast tissues are dense and lower if they are predominantly fatty.     

The demise of a planned randomised controlled trial in an urban Aboriginal medical service

To fill a gap in knowledge about the effectiveness of brief intervention for hazardous alcohol use among Indigenous Australians, we attempted to implement a randomised controlled trial in an urban Aboriginal Medical Service (AMS) as a joint AMS-university partnership. Because of low numbers of potential participants being screened, the RCT was abandoned in favour of a two-part "demonstration project". Only 16 clients were recruited for follow-up in six-months, and the trial was terminated. Clinic, patient, Aboriginal health worker, and GP factors, interacting with study design factors, all contributed to our inability to implement the trial as designed. The key points to emerge from the study are that alcohol misuse is a difficult issue to manage in an Indigenous primary health care setting; RCTs involving inevitably complex study protocols may not be acceptable or sufficiently adaptable to make them viable in busy, Indigenous primary health care settings; and "gold-standard" RCT-derived evidence for the effectiveness of many public health interventions in Indigenous primary health care settings may never be available, and decisions about appropriate interventions will often have to be based on qualitative assessment of appropriateness and evidence from other populations and other settings.     

Selective metabolism of vincristine in vitro by CYP3A5.

Clinical outcomes of vincristine therapy, both neurotoxicity and efficacy, are unpredictable, and the reported pharmacokinetics of vincristine have considerable interindividual variability. In vitro and in vivo data support a dominant role for CYP3A enzymes in the elimination of vincristine. Consequently, genetic polymorphisms in cytochrome P450 (P450) expression may contribute to the interindividual variability in clinical response, but the contributions of individual P450s and the primary pathways of vincristine metabolism have not been defined. In the present study, vincristine was incubated with a library of cDNA-expressed P450s, and the major oxidative metabolites were identified. CYP3A4 and CYP3A5 were the only P450s to support substantial loss of parent drug and formation of the previously unidentified, major metabolite (M1). The structure of M1, arising as a result of an oxidative cleavage of the piperidine ring of the dihydro-hydroxycatharanthine unit of vincristine, was conclusively established after conversion to suitable derivatives followed by spectroscopic analysis, and a new pathway for vincristine metabolism is proposed. CYP3A5 was more efficient in catalyzing the formation of M1 compared with CYP3A4 (9- to 14-fold higher intrinsic clearance for CYP3A5). The formation of M1 was stimulated (3-fold) by the presence of coexpressed cytochrome b5, but the relative efficiencies of M1 formation by CYP3A4 and CYP3A5 were unaffected. Our findings demonstrate that in contrast to most CYP3A biotransformations, the oxidation of vincristine is considerably more efficient with CYP3A5 than with CYP3A4. We conclude that common genetic polymorphisms in CYP3A5 expression may contribute to the interindividual variability in the systemic elimination of vincristine.