Search

Background: The focus of much Intensive Care research has been on short-term survival, which has demonstrated clear improvements over time. Less work has investigated long-term survival, and its correlates. This study describes long-term survival and identifies factors associated with time to death, in patients who initially survived an Intensive Care admission in Victoria, Australia., Methods: We conducted a retrospective cohort study of adult patients discharged alive from hospital following admission to all Intensive Care Units (ICUs) in the state of Victoria, Australia between July 2007 and June 2018. Using the Victorian Death Registry, we determined survival of patients beyond hospital discharge. Comparisons between age matched cohorts of the general population were made. Cox regression was employed to investigate factors associated with long-term survival., Results: A total of 130,775 patients from 23 ICUs were included (median follow-up 3.6 years post-discharge). At 1-year post-discharge, survival was 90% compared to the age-matched cohort of 98%. All sub-groups had worse long-term survival than their age-matched general population cohort, apart from elderly patients admitted following cardiac surgery who had better or equal survival. Multiple demographic, socio-economic, diagnostic, acute and chronic illness factors were associated with long-term survival., Conclusions: Australian patients admitted to ICU who survive to discharge have worse long-term survival than the general population, except for the elderly admitted to ICU following cardiac surgery. These findings may assist during goal-of-care discussions with patients during an ICU admission., Competing Interests: The authors have declared that no competing interests exist.

Different approaches for the determination of the 87 Sr/ 86 Sr isotope ratio of high-Rb glass are compared in this work to assess the suitability of minimally invasive approaches for applications on medieval stained glass (from the ancient Abbey of Stavelot in Belgium). It was found that pneumatic nebulization multicollector inductively coupled plasma-mass spectrometry (PN-MC-ICP-MS) after acid digestion and chromatographic isolation of the target analyte out of the sample matrix can still be seen as the preferred method for the high-precision isotopic analysis of Sr in glass with high Rb and rare-earth element (REE) concentrations. Alternatively, the use of laser ablation (LA) for sample introduction is a powerful technique for the direct analysis of solid samples. However, both the high Rb/Sr ratios in the samples of interest and the presence of REEs at sufficiently high concentrations lead to a large bias in LA-MC-ICP-MS, which cannot be corrected for, even by operating the MC-ICP-MS instrument at higher mass resolution and/or using mathematical corrections. It was demonstrated that LA tandem-ICP-MS (LA-ICP-MS/MS) using CH 3 F/He as the reaction gas to overcome spectral overlap in a mass-shift approach (chemical resolution) provides a viable alternative when (quasi) nondestructive analysis is required. This approach relies on the monitoring of Sr + ( m/z = 86, 87, and 88) ions as the corresponding SrF + reaction product ions ( m/z = 105, 106, and 107), thus avoiding the occurrence of spectral interference. Self-evidently, the isotope ratio precision attainable using sequential quadrupole-based ICP-MS instrumentation (0.3% RSD) was found to be significantly worse than that of high-precision MC-ICP-MS (0.03% RSD) with simultaneous detection, although it was still fit for the purpose of current applications. In addition to Sr isotopic analysis, the REE patterns and their potential influence on the Sr isotopic composition were evaluated by LA-ICP-MS., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

We document the utility for in situ Rb-Sr dating of a one-of-a-kind tribrid mass spectrometer, 'Proteus', coupled to a UV laser ablation system. Proteus combines quadrupole mass-filter, collision cell and sector magnet with a multicollection inductively-coupled plasma mass spectrometer (CC-MC-ICPMS/MS). Compared to commercial, single collector, tribrid inductively-coupled plasma mass spectrometers (CC-ICPMS/MS) Proteus has enhanced ion transmission and offers simultaneous collection of all Sr isotopes using an array of Faraday cups. These features yield improved precision in measured 87 Sr/ 86 Sr ratios, for a given mass of Sr analysed, approximately a factor of 25 in comparison to the Thermo Scientific™ iCAP TQ™ operated under similar conditions. Using SF 6 as a reaction gas on Proteus, measurements of Rb-doped NIST SRM (standard reference material) 987 solutions, with Rb/Sr ratios from 0.01-100, yield 87 Sr/ 86 Sr that are indistinguishable from un-doped NIST SRM 987, demonstrating quantitative 'chemical resolution' of Rb from Sr. We highlight the importance of mass-filtering before the collision cell for laser ablation 87 Sr/ 86 Sr analysis, using an in-house feldspar standard and a range of glass reference materials. By transmitting only those ions with mass-to-charge ratios 82-92 u/e into the collision cell, we achieve accurate 87 Sr/ 86 Sr measurements without any corrections for atomic or polyatomic isobaric interferences. Without the pre-cell mass-filtering, measured in situ 87 Sr/ 86 Sr ratios are inaccurate. Combining in situ measurements of Rb/Sr and radiogenic Sr isotope ratios we obtain mineral isochrons. We utilise a sample from the well-dated Dartmoor granite (285 ± 1 Ma) as a calibrant for our in situ ages and, using the same conditions, produce accurate Rb-Sr isochron ages for samples of the Fish Canyon tuff (28 ± 2 Ma) and Shap granite pluton (397 ± 1 Ma). Analysing the same Dartmoor granite sample using identical laser conditions and number of spot analyses using the Thermo Scientific™ iCAP TQ™ yielded an isochron slope 5× less precise than Proteus. We use an uncertainty model to illustrate the advantage of using Proteus over single collector CC-ICPMS/MS for in situ Rb-Sr dating. The results of this model show that the improvement is most marked for samples that have low Rb/Sr (<10) or are young (<100 Ma). We also report the first example of an in situ , internal Rb-Sr isochron from a single potassium-feldspar grain. Using a sample from the Shap granite, we obtained accurate age and initial 87 Sr/ 86 Sr with 95% confidence intervals of ±1.5% and ±0.03% respectively. Such capabilities offer new opportunities in geochronological studies., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1 , identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement factor D inhibitor and exhibited submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1' pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.

Matrix metalloproteinases (MMP) are a family of more than 25 zinc-dependent enzymes that are centrally involved in cellular migration, tissue remodeling, cancer invasion and metastasis. Besides degrading extracellular matrix proteins, MMPs are crucial for growth factor and cytokine release and activation. At the same time, they can inactivate inflammatory mediators and enzymes themselves through protein degradation. Subclasses of MMPs include collagenases, gelatinases, stromelysins, membrane-bound MMPs, and others. With regard to the stromelysin subfamily, three members exist, e.g., stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11). MMP-3, and MMP-10 share extensive similarities at the amino acid level that made it difficult to develop specific antibodies distinguishing between MMP-3 and MMP-10. Scrutinizing published data on and performing different analyses with detection of both stromelysins with commercially available or lab-made antibodies showed ambiguous results with regard to specificity of antibodies used to date. We developed new specific antibodies against the most divergent parts of the active forms of both proteins. We assessed the specificity of our novel specific anti-human and anti-mouse MMP-3 and MMP-10 antibodies in cell lysates and different human and murine skin tissues. Tests analyzing specificity of the novel antibodies included Western immunoblotting, immunofluorescence, and immunohistochemistry on paraffin sections. Analyses demonstrated specific detection of respective protein for human or mouse samples except for the anti-human MMP-3 antibody. The aim of this summary was to call attention the MMP research community to distinguish clearly between both enzymes. Our new specific anti-mouse MMP-3 and both MMP-10 antibodies allow us to address this detection problem and to enable comparative studies between both stromelysins with regard to their respective location and function in the tissue., (© 2019 by the Wound Healing Society.)

Objectives: To estimate the potential impact of the addition of culture-based screening for group B streptococcus (GBS) carriage in pregnancy to a risk-based prevention policy in the UK. We aimed to establish agreement within a multidisciplinary group of key stakeholders on the model input parameters., Design: Deterministic model using a consensus approach for the selection of input parameters., Setting and Participants: A theoretical annual cohort of 711 999 live births in the UK (excluding births by elective caesarean section)., Interventions: Culture-based screening for GBS at 35-37 weeks of pregnancy added to the recommended risk-based prevention policy in place on the date of modelling., Outcome Measures: Outcomes assessed included use of intrapartum antibiotic prophylaxis (IAP), early onset GBS (EOGBS), EOGBS mortality, severe EOGBS-related morbidity and maternal penicillin anaphylaxis., Results: With no prophylaxis strategy, the model estimated that there would be 421 cases of culture positive EOGBS in a year (0.59/1000 live births). In the risk-based prophylaxis scenario, 30 666 women were estimated to receive IAP and 70 cases of EOGBS were prevented. Addition of screening resulted in a further 96 260 women receiving IAP and the prevention of an additional 52 to 57 cases of EOGBS. This resulted in the prevention of three EOGBS deaths and four cases of severe disability. With screening, an additional 1675 to 1854 women receive IAP to prevent one EOGBS case and 24 065 to 32 087 receive IAP to prevent one EOGBS death., Conclusions: The evidence base available for a broad range of model input parameters was limited, leading to uncertainty in the estimates produced by the model. Where data was limited, the model input parameters were agreed with the multidisciplinary stakeholder group, the first time this has been done to our knowledge. The main impact of screening is likely to be on the large group of low-risk women where the clinical impact of EOGBS tends to be less severe. This model suggests that the reduction in mortality and severe disability due to EOGBS with antenatal GBS screening is likely to be very limited, with a high rate of overdetection and overuse of antibiotics., Competing Interests: Competing interests: CP chaired the expert group. JM and DB were both employees of the UK National Screening Committee at the time of preparation of the model. AW is an employee of Bazian Ltd. who received payment to develop the model and write up the project through contracts with the UK National Screening Committee. Bazian Ltd. have also been paid to carry out other literature searches, reviews and models for the National Screening Committee, including reviews of the evidence on antenatal GBS screening. Bazian Ltd. is part of The Economist Group, and holds contracts with public and private organisations within the healthcare industry., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The Blood-Brain Barrier (BBB) is a highly specialised interface separating the Central Nervous System (CNS) from circulating blood. Dysregulation of the BBB is a key early event in pathological conditions such as inflammation, in which the entry of activated leukocytes into the CNS is facilitated by BBB breakdown. The metzincin family of metalloproteinases (MPs) is one of the major contributors to BBB permeability as they cleave endothelial cell-cell contacts and underlying basal lamina components. However, the mechanisms by which MPs regulate BBB integrity has not yet been fully elucidated. The aim of this review is to provide an overview of pathways by which MPs could regulate the BBB in the context of neuroinflammation.

Think back; think wayyy back: before laptops, internet and smartphones. Bank machines didn't exist, tele-phones were permanently plugged into the wall, airport security meant only checking that you paid for your ticket and medical journals came in the mail (as did the bills for the journals). As it turned out, the 1970s was not a kind decade for medical journals, and several were struggling financially. Even the New England Journal of Medicine (NEJM), desperate for cash, was forced to offer a lifetime subscription to anyone who could pay the princely sum of $350! (A colleague of ours, now retired, still receives the weekly NEJM by mail, 45 years later!).

Soluble guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases associated with oxidative stress. In a pathological oxidative environment, the heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the production of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing to elevated intraocular pressure associated with glaucoma. Herein we describe the discovery of molecules specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the production of cGMP. These efforts culminated in the identification of compound (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clinical evaluation.

Non-alcoholic fatty liver disease (NAFLD) affects 25% of adults and at present no licensed medication has been approved. Despite its complex patho-physiology, dietary strategies aiming at delaying or preventing NAFLD have taken a reductionist approach, examining the impact of single components. Accumulating evidence suggests that n-3 LC-PUFAs are efficacious in regulating lipogenesis and fatty acid oxidation. In addition, plant derived flavonoids are also emerging as a dietary strategy for NAFLD prevention, with efficacy attributed to their insulin sensitising and indirect antioxidant effects. Based on knowledge of their complementary molecular targets, we aimed to demonstrate that the combination of n-3 LC-PUFA (n-3) and flavan-3-ols (FLAV) prevents NAFLD. In a high-fat high-fructose (HF/HFr) fed C57Bl/6J mouse model, the independent and interactive impact of n-3 and FLAV on histologically defined NAFLD, insulin sensitivity, weight gain, intestinal and hepatic gene expression, intestinal bile acids were examined. Only the combination of FLAV and n-3 (FLAVn-3) prevented steatosis as evidenced by a strong reduction in hepatocyte ballooning. While FLAV reduced body (-28-30%), adipose tissue (-45-50%) weights and serum insulin (-22-25%) as observed following an intra-peritoneal glucose tolerance test, n-3 downregulated the expression of Srebf1 and the lipogenic genes (Acaca, Fasn). Significant impacts of interventions on intestinal bile acid metabolism, farnesoid X receptor (Fxr) signalling in the intestine and liver, and hepatic expression of fatty acid transporters (Fabp4, Vldlr, Cd36) were also evident. FLAVn-3 may be a novel intervention for NAFLD. Future research should aim to demonstrate its efficacy in the prevention and treatment of human NAFLD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations., Methods: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran., Results: No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants., Conclusions: Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

Background: Osteogenesis imperfecta (OI) is an inherited disorder, which causes brittle bones resulting in recurrent fractures. The associated poor mobility of children with OI increases susceptibility to obesity, and obesity further dramatically limits mobility and increases fracture risk., Objectives: The aim of this report is to describe outcomes of weight loss surgery (WLS) in 2 adolescents with severe obesity and OI., Setting: Two University Hospitals (in the United Kingdom and in the United States)., Methods: Two cases of OI treated with WLS were identified. Pre- and postoperative anthropometric and biochemical data and clinical course were reviewed., Results: In these 2 cases, preoperative Body Mass Index (BMI) values were 38 and 46 kg/m 2 . Following laparoscopic sleeve gastrectomy (LSG), BMI decreased by 55% and 60% by 26 and 24 months, respectively. There were no surgical complications, and both patients experienced improvement in their mobility and ability to perform activities of daily living., Conclusion: WLS effectively treated severe obesity in 2 OI patients and substantially improved mobility and quality of life, theoretically reducing fracture risk., (Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

The ATPase subunit of DNA gyrase B is an attractive antibacterial target due to high conservation across bacteria and the essential role it plays in DNA replication. A novel class of pyrazolopyridone inhibitors was discovered by optimizing a fragment screening hit scaffold using structure guided design. These inhibitors show potent Gram-positive antibacterial activity and low resistance incidence against clinically important pathogens.

The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design. These inhibitors show potent minimum inhibitory concentrations against fluoroquinolone resistant MRSA and other Gram-positive bacteria.

Antibacterials with a novel mechanism of action offer a great opportunity to combat widespread antimicrobial resistance. Bacterial DNA Gyrase is a clinically validated target. Through physiochemical property optimization of a pyrazolopyridone hit, a novel class of GyrB inhibitors were discovered. Guided by structure-based drug design, indazole derivatives with excellent enzymatic and antibacterial activity as well as great animal efficacy were discovered.

Background: Effective treatment of acute bleeding episodes in patients with hemophilia B relies on factor IX recovery, with higher levels being more desirable, whereas prevention of bleeds with a prophylactic regimen depends on the half-life of the product. Lower recovery values have been reported following administration of recombinant FIX (rFIX) than following administration of plasma-derived FIX (pdFIX)., Objectives: To compare the pharmacokinetic and pharmacodynamic properties of rFIX and pdFIX in patients with hemophilia B., Methods: A prospective crossover study of nine patients with moderate to severe hemophilia B was performed. Following a washout period, 50 U kg(-1) FIX was administered, and blood samples were taken as per protocol up to 48 h postinfusion. Paired data were analyzed with the Wilcoxon signed rank test., Results: Mean peak recovery at 10 min postinfusion was 62.14 IU dL(-1) with pdFIX and 52.7 IU dL(-1) with rFIX (P = 0.08). Mean half-life was 16.6 h with pdFIX and 17.5 h with rFIX (P = 0.55). Maximum peak thrombin generation (PTG) was 35.9 nm with pdFIX and 28.9 nm with rFIX (P = 0.21). Administration of rFIX resulted in early PTG, whereas administration of pdFIX resulted in slightly later and sustained PTG. At 48 h, PTG was similar with pdFIX (19.0 nm) and rFIX (19.4 nm) (P = 0.91)., Conclusions: Patients experienced better recovery with pdFIX than with rFIX. pdFIX and rFIX had similar half-lives. Maximum PTG was higher for pdFIX; however, this difference did not reach statistical significance. The clinical impact of the slightly increased, delayed and sustained PTG with pdFIX requires further investigation., (© 2014 International Society on Thrombosis and Haemostasis.)

Background: In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity., Methods: We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×10(12) vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring., Results: A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment., Conclusions: In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.).

Vitamin B₁₂ is found almost exclusively in animal-based foods and is therefore a nutrient of potential concern for those following a vegetarian or vegan diet. Vegans, and anyone who significantly limits intake of animal-based foods, require vitamin B₁₂-fortified foods or supplements. Vitamin B₁₂ deficiency has several stages and may be present even if a person does not have anaemia. Anyone following a vegan or vegetarian diet should have their vitamin B₁₂ status regularly assessed to identify a potential problem. A useful process for assessing vitamin B₁₂ status in clinical practice is the combination of taking a diet history, testing serum vitamin B₁₂ level and testing homocysteine, holotranscobalamin II or methylmalonic acid serum levels. Pregnant and lactating vegan or vegetarian women should ensure an adequate intake of vitamin B₁₂ to provide for their developing baby. In people who can absorb vitamin B₁₂, small amounts (in line with the recommended dietary intake) and frequent (daily) doses appear to be more effective than infrequent large doses, including intramuscular injections. Fortification of a wider range of foods products with vitamin B₁₂, particularly foods commonly consumed by vegetarians, is likely to be beneficial, and the feasibility of this should be explored by relevant food authorities.

The various superstructure phases that occur with the anion-deficient compositions of binary oxides MO(2-x) with the fluorite structure as parent are explored here in terms of the original 'coordination defect' (or CD) concept in which each vacant oxygen site, □, is 'coordinated' by six O atoms thereby creating the octahedral 'structure-determining' entity [M(3.5)□O(6)]. It emerges that the structure and composition of each anion-deficient (polymorph) phase can be described in terms of crystallographic `motifs' which comprise sets of parallel coplanar polygons based on ½<210>(F) and ½<111>(F) CD linkages.

Introduction: Postpartum depression is a disabling psychological disorder that, if left untreated, may have negative consequences for the mother, her partner, and the child. Although women with postpartum depression often experience symptoms of anxiety as well as depression, this has been underresearched. As metacognitive therapy assumes that the underlying mechanisms for both anxiety and depression are the same, it is a potentially useful psychological treatment for postpartum depression., Methods: A pilot study was carried out using a multiple-baseline single case series to examine the effects associated with metacognitive therapy in the treatment of depression. Six women with postpartum depression were assigned to no-treatment baselines of 3 to 6 weeks, followed by 8 to 12 sessions of metacognitive therapy. Follow-up with participants took place at 3 and 6 months posttreatment., Results: All participants experienced clinically significant reductions in symptoms of depression and anxiety, with corresponding reductions in metacognitive beliefs consistent with the idea that this may be the mechanism by which change occurred. Furthermore, all scores fell within the normal range posttreatment, and effect sizes were large. Treatment gains were maintained at 3 and 6 months posttreatment by all participants., Discussion: This pilot study suggests that metacognitive therapy may be an effective psychological treatment for postpartum depression., (© 2013 by the American College of Nurse-Midwives.)

Objective: Wnt-1-inducible signaling pathway protein 3 (WISP-3)/CCN6 is mutated in progressive pseudorheumatoid dysplasia and may have effects on cartilage homeostasis. The aim of this study was to ascertain additional roles for WISP-3/CCN6 by determining its expression in osteoarthritic (OA) cartilage and by investigating its effects on cartilage-relevant metalloproteinase expression in immortalized (C-28/I2) and primary chondrocytes., Methods: Cartilage steady-state levels of WISP-3/CCN6 messenger RNA and protein production were determined by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. WISP-3/CCN6 was overexpressed in C-28/I2 cells, and the resultant clones were analyzed by quantitative RT-PCR. The stable clones were analyzed by RT-PCR for metalloproteinase expression, and the signaling pathways involved were investigated using pharmacologic inhibition. The effects of WISP-3/CCN6 on metalloproteinase expression in primary chondrocytes were investigated using a small interfering RNA approach., Results: WISP-3/CCN6 was highly expressed in OA cartilage compared with undamaged cartilage, at both the RNA and protein levels. WISP-3/CCN6 overexpression in C-28/I2 cells resulted in unexpected dual regulation of metalloproteinases; expression of the potent aggrecanase ADAMTS-5 was down-regulated 9-fold, while expression of MMP-10 was up-regulated 14-fold, and these responses were accentuated in the WISP-3/CCN6 clones grown in suspension. MMP-10 up-regulation was dependent on several MAPKs, but WISP-3/CCN6-mediated ADAMTS-5 repression was independent of these pathways and was partially relieved by activation of β-catenin signaling. WISP-3/CCN6 also suppressed ADAMTS-5 expression in C-28/I2 cells treated with cytokines. In cytokine-treated primary chondrocytes, gene silencing of WISP-3/CCN6 resulted in enhanced ADAMTS-5 expression, while MMP-10 expression was suppressed., Conclusion: WISP-3/CCN6 was highly expressed in end-stage OA cartilage, suggesting a role for this growth factor in cartilage homeostasis. WISP-3/CCN6-induced repression of ADAMTS-5 expression and regulation of MMP-10 expression suggest complex and context-dependent roles for WISP-3/CCN6 in cartilage biology., (Copyright © 2012 by the American College of Rheumatology.)

Defective hemostasis in haemophilia patients with FVIII inhibitors results in a dramatic decrease in thrombin generation forming unstable fibrin clots that are susceptible to fibrinolyisis. In this study we tested whether the combination of plasma derived activated prothrombin complex concentrate (pd-aPCC) with tranexamic acid (TXA) may improve fibrin clot stability in FVIII inhibitor plasma. A microplate assay for clot lysis time was used to assess clot stability in FVIII inhibitor plasma. The effect of pd-aPCC on clot stability was first tested using the commercial FVIII inhibitor plasma. TXA (5 ~ 10 mg mL⁻¹) increased clot lysis time, but pd-aPCC (0.25 ~ 1.0 U mL⁻¹) had no effect on it. The combination of pd-aPCC and TXA significantly increased clot lysis time compared with TXA alone. The effect appeared to be limited to fibrin clot resistance to fibrinolysis, as TXA was found to have no effect on thrombin generation induced by pd-aPCC. The effect of pd-aPCC and TXA on clot stability was then tested and verified in plasma samples from ten patients with severe haemophilia A and inhibitors. The combination of TXA (10 mg mL⁻¹) and pd-aPCC (0.5 U mL⁻¹) significantly increased clot lysis time compared to TXA alone. Our results suggest that the combination of pd-aPCC with TXA improves clot stability in FVIII inhibitor plasma without additional increases in thrombin generation., (© 2011 Blackwell Publishing Ltd.)

We evaluated the effectiveness of full-session differential reinforcement of low rates of behavior (DRL) on 3 primary school children's rates of requesting attention from their teacher. Using baseline rates of responding and teacher recommendations, we set a DRL schedule that was substantially lower than baseline yet still allowed the children access to teacher assistance. The DRL schedule was effective in reducing children's requests for assistance and approval, and the teacher found the intervention highly useful and acceptable. The possible mechanisms that account for behavior change using full-session DRL schedules are discussed.

Maintaining the plasma fibrinogen concentration is important to limit excessive perioperative blood loss. This article considers the evidence for this statement, and questions the justification for using cryoprecipitate rather than virus-inactivated fibrinogen concentrate to support plasma fibrinogen levels. Haemophilia was historically treated with cryoprecipitate, but specific coagulation factor concentrates are now preferred. In contrast, primary fractions of allogeneic donor blood, including cryoprecipitate, are still commonly used to treat perioperative bleeding. When compared with cryoprecipitate and fresh-frozen plasma (FFP), freeze-dried fibrinogen concentrate offers standardized fibrinogen content, faster reconstitution and improved efficacy. Pasteurization and purification processes employed in the preparation of fibrinogen concentrate reduce the risk of pathogen transmission and immune-mediated complications, in comparison with cryoprecipitate and FFP. When all costs associated with administration are taken into consideration, the cost of fibrinogen concentrate is not substantially different to that of cryoprecipitate. In conclusion, wider availability and use of fibrinogen concentrate may improve the management of perioperative bleeding. Further benefits may accrue from more rapid and accurate techniques for monitoring fibrinogen levels. Clinical studies are needed to evaluate methods of measuring fibrinogen and assessing fibrin polymerization, and to define critical haemostatic plasma fibrinogen concentrations in different perioperative situations.

Introduced into clinical practice in the 1960s, the analgesic fentanyl is 100 times more potent than morphine. Various methods of administration exist including the transdermal Duragesic patch system, widely used in chronic pain and palliative care settings. Numerous, often imaginative methods of abuse of fentanyl patches have been reported; the majority of fatal fentanyl overdose cases resulting from deliberate abuse or suicide. We describe the accidental overdose of a young black male with sickle cell/beta-thalassemia who had been using the Duragesic system for almost 2 years.At autopsy the macroscopic findings were of nonspecific opiate overdose with congested heavy lungs. Histopathological examination revealed severe sickling of red blood cells in the lungs (acute chest syndrome). Toxicological examination revealed blood and urine fentanyl levels of 40 microg/L and 400 microg/L (10 fold and 100 fold higher than therapeutic levels). The mast cell tryptase was also significantly elevated at 76 microg/L, (Normal 2-14 microg/L). We discuss the relevance of these findings with regard to the cause of death, and stress the need to consider fentanyl when confronted with nonspecific signs of opiate overdose as it is not detected in routine toxicological drug screens.

Thrombotic thrombocytopenic purpura (TTP) may be idiopathic or secondary. We report seven TTP cases precipitated by pancreatitis. The patients were admitted with acute pancreatitis and at that time had no clinical or laboratory features of TTP. The median time to develop TTP after pancreatitis was 3 d. The patients had moderately reduced ADAMTS13 activity (mean activity 49%; normal range 66-126%) with no evidence of anti-ADAMTS13 inhibitory autoantibodies. The median number of plasma exchanges to remission was 10 (range 7-14) and no additional treatment with immunosuppression was required to maintain remission. There have been no relapses to date.

The bixbyite structure (Mn(2)O(3)) (Ia3) is often described as a distorted face-centered cubic (f.c.c.) array of Mn atoms, with O atoms occupying 3/4 of the tetrahedral holes. The empty M(4) tetrahedra are centred at 16c. In anti-bixbyite structures (Mg(3)N(2)), cation vacancies are centred in empty N(4) tetrahedra. If 16 hypothetical atoms were located at this site they would form the structure of gamma-Si. This means that anti-bixbyite structures are ideally prepared to accommodate Si(Ge) atoms at these holes. Several compounds (Li(3)AlN(2) and Li(3)ScN(2)) fully satisfy this expectation. They are really anti-bixbyites 'stuffed' with Al(Sc). The presence of these atoms in 16c is illuminated in the light of the extended Zintl-Klemm concept (EZKC) [Vegas & García-Baonza (2007). Acta Cryst. B63, 339-345], from which a compound would be the result of 'multiple resonance' pseudo-structures, emerging from electron transfers between any species pair (like or unlike atoms, cations or anions). The coordination-defect (CD) concept [Bevan & Martin (2008). J. Solid State Chem. 181, 2250-2259] is also consistent with the EZKC description of the pseudo-structures. A more profound insight into crystal structures is gained if one is not restricted to the contemplation of classical anions and cations in their conventional oxidation states.

Thrombotic thrombocytopenic purpura (TTP) is an acute, rare, life-threatening disorder. This report presents the South East (SE) England registry for TTP, from April 2002 to December 2006, which included 176 patients and 236 acute episodes; 75% of patients were female and 25% were male, overall median age at presentation was 42 years. Mortality was 8.5%, most cases died before treatment was instigated. The main ethnic groups were Caucasian (64%) and Afro Caribbean (27%). Seventy-seven percent of cases were idiopathic, 5% were congenital and the remaining cases had a defined precipitant. Neurological features were the most prevalent, but cardiac involvement accounted for 42% of presenting features. The overall median number of plasma exchanges (PEXs) to remission was 15; between April 2002 and December 2003, the median number of PEXs was 19 and it was 12 between January 2004 and December 2006 (P < 0.0001). In the latter period, adjuvant therapies were reduced, but Rituximab was increased. ADAMTS 13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was <10% in 74% and 95% of these cases had positive IgG antibodies to ADAMTS 13. Renal impairment and delayed normalisation of platelet count were the main differences between idiopathic and secondary TTP.

Background: The aim of this prospective study was to establish the prevalence of thrombophilia and hyperhomocysteinaemia using a comprehensive screen in patients with peripheral vascular disease., Methods: A total of 150 patients with peripheral vascular disease (with an ankle brachial pressure index of less than 0.8) underwent thrombophilia screening (protein C and protein S, antithrombin, lupus anticoagulant, activated protein C resistance and factor V Leiden and prothrombin mutations). Fasting homocysteine assays were also performed., Results: A thrombophilia defect was found in 41 patients (27.3 per cent). The commonest was protein S deficiency, found in 17 patients (11.3 per cent). Others included factor V Leiden mutation, found in 10 (6.7 per cent) and protein C deficiency, found in six (4.0 per cent). Lupus anticoagulant and prothrombin mutation were both found in six (4.0 per cent). One patient had an antithrombin deficiency. Only the presence of critical ischaemia was associated with a positive thrombophilia screen on single variable analysis (P = 0.03). Hyperhomocysteinaemia was present in over a third of the study group (37.3 per cent): 45 defined as moderate and 11 as intermediate., Conclusion: A quarter of patients with peripheral vascular disease had evidence of thrombophilia, and a third had hyperhomocysteinaemia.

Objectives: Research is needed to enable more effective assessment and treatment of analgesic addiction among patients with painful chronic illnesses and to improve our understanding of the staff-patient interactions that give rise to pseudoaddiction. This study tested predictions that certain drug-use behaviors and pain-coping strategies were associated with analgesic addiction, and that certain were associated with risk of pseudoaddiction., Methods: Analgesic addiction and risk of pseudoaddiction among patients with sickle cell disease were measured by symptom counts, using an interview method for classifying symptoms as pain-related (pseudoaddiction) or non-pain-related (analgesic addiction). Concern-raising drug-use behaviors and treatment requirements for pain were also assessed, and participants completed the pain-coping strategies questionnaire. Qualitative case descriptions of patients meeting criteria for analgesic addiction and pseudoaddiction were examined to identify common and distinctive features of the two groups., Results: Consistent with predictions, multiple regression analyses showed that disputes about analgesics were independently associated with risk of pseudoaddiction. Physiological dependence and illicit drug use were both associated with analgesic addiction, independently of other factors. The qualitative data showed that analgesic addiction was not an obvious, clear-cut phenomenon: addiction and pseudoaddiction were superficially similar, and even symptoms of genuine addiction originated in patients' experiences of pain and illness., Conclusions: These tentative findings were broadly consistent with what is known about analgesic addiction and pseudoaddiction in other painful conditions. They also suggested that current recommendations about addiction in pain patients could understate the potential importance of physiological dependence. The findings could inform staff training programs to improve pain management and reduce the incidence of pseudoaddiction. The classification of pain-related and non-pain-related symptoms could be used in further research on the development of analgesic addiction and the factors that influence staff attributions about addiction in patients with pain.

Abdominal pain of presumed vasocclusive origin, often termed 'girdle syndrome' because of the circumferential distribution of the pain, is common in sickle cell anaemia (SCA). Evidence of progression to bowel infarction is rare. A 27-year-old man with SCA developed chest and abdominal pain unresponsive to opiate analgesia. Abdominal X-ray showed dilated bowel loops because of partial obstruction. Despite reduction of HbS to 23% by automated red cell exchange, abdominal pain worsened. A CT scan was the most informative investigation and showed free peritoneal air. He underwent emergency hemicolectomy and reversible ileostomy formation. Histology of the resected colon was consistent with acute ischaemic colitis. Early surgical intervention remains essential in SCA when abdominal pain does not respond to maximal therapy including red cell exchange: as this case illustrates, sickle girdle syndrome has the capacity to progress to irreversible ischaemic colitis and necrotic perforation of the bowel wall.

Background: Factor VII polymorphisms have been suggested in some studies to show an association with some aspects of coronary disease, and there is a known association between FVII levels and polymorphic variants in the gene. The aim of the study was to assess whether Factor VII polymorphism R353Q is associated with the extent of coronary artery disease in patients with chronic stable angina., Methods and Results: There is evidence that Factor VII polymorphisms are markers of susceptibility to coronary artery disease (CAD), but two studies have suggested that there is no association between the degree of vessel disease and these polymorphisms. One of these studies did not exclude patients with unstable angina or MI. We therefore set up a prospective cohort study to determine Factor VIIa, VIIc and VIIAg levels, genotype for R353Q, lipid status, smoking history and the degree of vessel disease, in patients attending the hospital for routine day case angiography over a 20 month period. From 519 cases, 400 had no previous MI or revascularisation, including 153 with zero vessel disease, and were successfully genotyped: 9 (2%) QQ, 78 (20%) RQ and 313 (78%) RR. Compared with RR subjects, heterozygotes were 2.7 years older (95% CI: 0.3, 5.0; p=0.027), but were not significantly different regarding gender, cholesterol, extent of vessel disease or smoking history. If those with vessel disease were considered, then the heterozygotes were 3.5 years older than the RR homozygotes (95% CI: 0.6-6.4, p=0.016). There was a significant association between all measures of Factor VII and the R353Q polymorphism, with the Q allele associating with lower levels. There was no significant association between the degree of vessel disease and genotype., Conclusions: The degree of vessel disease as seen at day case angiography is independent of polymorphism status, but there appears nonetheless to be a moderate protective effect of the Q allele against stable angina, in that angiographic investigation occurs a few years later for RQ heterozygotes than RR homozygotes. The effect may be mediated by reduced levels of Factor VII.

Epidemiology data on multiple myeloma (MM) occurrence and outcome is inconsistent whilst a major limitation of randomized controlled trials is selection bias. We present a population-based analysis of patients diagnosed with MM in the South Thames area, which comprises 5.4 million adult inhabitants. A total of 855 cases of MM were ascertained between 1999 and 2000 in a collaborative project involving haematologists and the Thames Cancer Registry. The age-standardized rate was 3.29 per 100 000 and 4.82 cases per 100 000 (World Standard and European Population respectively). The median age was 73 years. The median survival for the whole group was 24 months whist it was 42 and 18 months in those aged less than 65 years and greater than 65 years respectively (P < 0.001). This population study has shown a higher incidence than previously reported in the UK and Europe and provides a benchmark for future studies. If survival is to be improved, future clinical trials and health care planning should consider patients over 65 years of age.

This paper reviews the available data on the prevalence of thrombophilia defects in patients with peripheral vascular disease (PVD) and attempts to delineate the risk of failure of vascular intervention in these patients. The prevalence of thrombophilia in stable claudicants is 25% and increases to 40% in those requiring revascularisation, compared to only 11% in the control group. The overall prevalence of thrombophilia defects in patients with premature atherosclerosis appears to be between 15 and 30%. The prevalence in the typical cohort of patients with PVD appears to be similar. All these studies have recruited patients with symptoms significant enough to warrant intervention. The overall prevalence of thrombophilia calculated from these trials, therefore, may not be truly indicative of the general vascular population who may not even present primary or secondary healthcare. The risk of thrombotic occlusion following arterial revascularisation in patients with an identified thrombophilia defect appears to be almost three times that of patients with no evidence of a thrombophilia defect. The best management of these patients has not been determined and needs to be evaluated by prospective randomized trials.

Genetic studies in the mouse have highlighted essential roles for several growth factors in skin repair and have offered a rationale for their use in therapy. The present study shows that the plasminogen-related growth factor HGF/SF (hepatocyte growth factor/scatter factor) promotes wound repair in homozygous diabetic db/db mice by recruiting neutrophils, monocytes, and mast cells to the wound; by promoting the migration of endothelial cells to the injured area; and by enhancing keratinocyte migration and proliferation. As a result, granulation tissue formation, wound angiogenesis, and re-epithelialization are all increased. The results demonstrate that HGF/SF affects and sustains all key cellular processes responsible for wound repair and point to a unique potential of this molecule for the therapy of chronic skin wounds., (Copyright 2004 Pathological Society of Great Britain and Ireland.)

In plants, Glycoside Hydrolase (GH) Family 1 beta -glycosidases are believed to play important roles in many diverse processes including chemical defense against herbivory, lignification, hydrolysis of cell wall-derived oligosaccharides during germination, and control of active phytohormone levels. Completion of the Arabidopsis thaliana genome sequencing project has enabled us, for the first time, to determine the total number of Family 1 members in a higher plant. Reiterative database searches revealed a multigene family of 48 members that includes eight probable pseudogenes. Manual reannotation and analysis of the entire family were undertaken to rectify existing misannotations and identify phylogenetic relationships among family members. Forty-seven members (designated BGLU1 through BGLU47 ) share a common evolutionary origin and were subdivided into approximately 10 subfamilies based on phylogenetic analysis and consideration of intron-exon organizations. The forty-eighth member of this family ( At3g06510; sfr2 ) is a beta -glucosidase-like gene that belongs to a distinct lineage. Information pertaining to expression patterns and potential functions of Arabidopsis GH Family 1 members is presented. To determine the biological function of all family members, we intend to investigate the substrate specificity of each mature hydrolase after its heterologous expression in the Pichia pastoris expression system. To test the validity of this approach, the BGLU44 -encoded hydrolase was expressed in P. pastoris and purified to homogeneity. When tested against a wide range of natural and synthetic substrates, this enzyme showed a preference for beta -mannosides including 1,4- beta -D-mannooligosaccharides, suggesting that it may be involved in A. thaliana in degradation of mannans, galactomannans, or glucogalactomannans. Supporting this notion, BGLU44 shared high sequence identity and similar gene organization with tomato endosperm beta -mannosidase and barley seed beta -glucosidase/ beta -mannosidase BGQ60.

Treatment of painful episodes in sickle cell disease (SCD) is sometimes complicated by disputes between patients and staff and patient behaviors that raise concerns about analgesic misuse. Those concern-raising behaviors could indicate either drug seeking caused by analgesic dependence or pseudoaddiction caused by undertreatment of pain. To make a systematic assessment of concern-raising behaviors and examine their associations with other factors, including DSM-IV symptoms of substance dependence, individual, in-depth interviews with SCD patients were conducted to apply pre-established criteria for concern-raising behaviors. These included disputes with staff tampering with analgesic delivery systems, passing prescribed analgesics from one person to another, being suspected or accused of analgesic misuse, self-discharging from hospital, obtaining analgesic prescriptions from multiple sources, using illicit drugs, and injecting analgesics. Assessments were also made of pain-related symptoms of substance dependence (where behaviors resemble substance dependence but reflect attempts to manage pain, increasing the risk of pseudoaddiction), non-pain-related symptoms of substance dependence (where substance dependence reflects analgesic use beyond pain management), and pain coping strategies (using the Pain Coping Strategies Questionnaire). Inter-rater reliability for the assessment of concern-raising behaviors was high, with Kappa coefficients of 0.63 to 1.0. The most frequent concern-raising behaviors were disputes with staff about pain or analgesics. The least frequent were tampering with analgesic delivery systems and passing analgesics between patients in hospital. The odds of concern-raising behaviors in hospital were raised eightfold by less use of ignoring pain as a coping strategy, and more than doubled by each additional pain-related symptom of substance dependence. Non-pain-related symptoms of substance dependence had no independent effect on concern-raising behaviors. Concern-raising behaviors were more closely associated with pain behaviors that make patients vulnerable to misperceptions of substance dependence than they were with genuine substance dependence. The results show how pseudoaddiction can adversely influence hospital pain management, and suggest that more emphasis should be placed on patients' pain and analgesic needs when responding to concern-raising behaviors in hospital.

Purpose: To describe the outbreak of severe acute respiratory syndrome (SARS) in Toronto, its impact on anesthesia practice and the infection control guidelines adopted to manage patients in the operating room (OR) and to provide emergency intubation outside the OR., Clinical Features: The SARS outbreak in Toronto was the result of a single index patient. The causative virus, SARS-CoV, is moderately contagious, and is spread by droplets and contact. The virus gains access to host through the mucosa of the respiratory tract and the eyes. It can affect both healthy and compromised patients. The use of several precautionary measures such as goggles, gloves, gowns and facemasks and the application of various infection control strategies designed to minimize the spread of the virus are discussed., Conclusion: In containing the spread of SARS, vigilance and strict infection control are important. This results in the rediscovery of standards of infection control measures in daily anesthesia practice.

Concerns about dependence on prescribed analgesia may compromise pain management, but there was previously little reliable evidence about substance dependence among patients with sickle cell disease (SCD). We conducted in-depth, semi-structured interviews with SCD patients in London, UK, to assess DSM-IV symptoms of substance dependence and abuse. Criteria were applied to differentiate between pain-related symptoms, which corresponded to the DSM-IV symptoms but involved analgesics used to control pain, and non-pain-related symptoms, which involved analgesic use beyond pain management. Pain-related symptoms are informative about how the pattern of recurrent acute pain in SCD may make patients vulnerable to perceptions of drug dependence. Non-pain-related symptoms are informative about more stringently defined dependence on analgesia in SCD. Inter-rater reliability was high, with mean Kappa coefficients of 0.67-0.88. The criteria could be used to assess analgesic dependence in other painful conditions. Pain-related symptoms were more frequent, accounting for 88% of all symptoms reported. When pain-related symptoms were included in the assessment, 31% of the sample met the DSM-IV criteria for substance dependence, compared with only 2% when the assessment was restricted to non-pain-related symptoms. Qualitative analysis of participants' descriptions of analgesic use showed that active coping attempts (attempts to anticipate pain and avoid hospital admissions) and awareness of dependence were themes in descriptions of both pain-related and non-pain-related symptoms. Seeking a more normal lifestyle and impaired activities were themes associated with pain-related symptoms. Psychological disturbance was a theme associated with non-pain-related symptoms. The implications are for more responsive treatment of pain in SCD and greater awareness of how patients' pain coping may be perceived as analgesic dependence. Further research could examine ways that pain-related and non-pain-related symptoms of dependence may be associated with other pain coping strategies and with the outcomes of treatment for painful episodes in hospital.

A number of studies have shown elevated matrix metalloproteinase expression in chronic wound fluid compared to an acute wound; however, little has been done to characterize animal models in a similar manner and thus determine their usefulness. The diabetes mouse is an animal model of type II diabetes that shows impaired dermal wound healing and has been proposed as a model of human impaired wound healing. In this study we have determined the mRNA and protein expression profiles of matrix metalloproteinases 2, 3, and 9 during the first 10 d of dermal healing for the diabetes mouse and its normally healing littermate. Additionally, human wound fluid from diabetic chronic wounds and acute surgical wounds were studied to enable a comparison of the model to the human condition. We show that during the early stages of wound healing the diabetes mouse possesses significantly reduced protein levels of pro-matrix metalloproteinases 2 and 9 within the wound tissue and active matrix metalloproteinase 3 within the fluid. Pro-matrix metalloproteinase 3 levels are also significantly reduced in the diabetes mouse during the later stages of healing. These differences may be contributing to the impaired healing of the diabetes mouse; however, they differ from the human data presented here, which show elevated matrix metalloproteinase 2 and reduced matrix metalloproteinase 9 in human diabetic chronic wound fluid compared to acute wound fluid. Therefore, although clearly showing the importance of appropriate matrix metalloproteinase regulation for normal acute wound healing to occur, the diabetes mouse may not be an ideal model for study of matrix metalloproteinase involvement in human chronic wound healing.

Objective: To examine whether specific platelet pheresis (minimal plasma harvested) would contribute toward reduced blood loss and allogenic blood requirements after cardiac surgery., Design: A prospective randomized trial., Setting: A large cardiothoracic surgical center., Participants: Consenting patients undergoing routine coronary artery or valve surgery (n = 54)., Interventions: Patients in the pheresis group underwent platelet pheresis in the anesthetic preparation room before general anesthesia. Pheresed platelets were stored during cardiopulmonary bypass and were returned to the patients after reversal of heparin with protamine toward the end of surgery. Control patients underwent their operations without this intervention., Measurements and Main Results: Primary endpoints were blood loss and transfusion requirements. There were no differences between the 2 groups (pheresis v control: median loss, 960 mL v 1100 mL, p = 0.15; median blood transfused, 896 mL v 635 mL, p = 0.71). Secondary endpoints included analysis of platelet counts, platelet function, and surface markers. Counts remained the same after retransfusion of platelets up to 2 hours after surgery. Platelet aggregation to ristocetin was well preserved, but adenosine diphosphate caused almost no aggregation of the harvested platelets. Flow cytometry revealed the platelets to have a reduced surface density of the glycoprotein 1b receptor, and 13% of them were irreversibly activated., Conclusion: Platelet pheresis activates a proportion of the harvested platelets and impairs the function of the remainder; this may explain its failure to reduce postoperative blood loss and transfusion requirements., (Copyright 2002, Elsevier Science (USA). All rights reserved.)