A medication review and deprescribing method for hospitalised older patients receiving multiple medications.

BACKGROUND: Prescribing of multiple medications in older patients poses risk of adverse drug events. AIM: To determine whether a structured approach to deprescribing - identifying and discontinuing unnecessary medications - in the inpatient setting is feasible and reduces medication burden. METHODS: Prospective pilot study of a convenience sample of patients aged ≥65 years admitted acutely to general medicine units in a tertiary hospital and receiving eight or more regular medications on presentation. The intervention comprised an education programme and a paper-based or computerised proforma listing clinical and medication data linked with a five-step decision support tool for selecting drugs eligible for discontinuation, which were then ceased or were being weaned by the time of discharge. RESULTS: Among 50 patients of median age 82.5 years and six co-morbidities, 186 of 542 (34.3%) regular medications were discontinued, representing a significant decrease in the median (interquartile range) number of medications per patient at discharge compared with presentation (7 (5-9) vs 10 (9-12), P < 0.001). Medication lists were reduced by at least two medications in 84% of patients, and by four or more in 50%. Statins, gastric acid suppressive agents, angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists and inhaled bronchodilators were the most frequently ceased medications. Of 39 patients in whom follow-up status at a median of 78 days was ascertained, only 5 of 413 (1.2%) ceased medications were recommenced among three patients because of symptom relapse. CONCLUSION: A standardised method of medication review and deprescribing may significantly reduce medication burden in a cohort of older hospitalised patients.

New oral anticoagulants: appropriateness of prescribing in real-world setting.

BACKGROUND: The new oral anticoagulants (NOAC) have been extensively studied in the clinical trial setting; however, concerns remain about the safety of prescribing in the elderly and patients with renal impairment. AIM: The aim of this study was to assess the appropriateness of NOAC prescribing in a real-world setting in terms of patient selection and to compare patient demographics to those included in pivotal clinical trials. METHODS: One hundred and seventy-six patients from three tertiary university teaching hospitals were identified over 3 months in 2014. RESULTS: Median age of the cohort was 74 years (interquartile range: 61-81 years), with a range of 23-96 years. Overall, 34% of the study population were prescribed a NOAC inappropriately. Of these, treatment was contraindicated in 40%, predominantly due to severe renal impairment, 22% were prescribed an excessively high dose, while 38% were under dosed. Although community-initiated patients had poorer renal function (glomerular filtration rate 91.7 ± 55.7 vs 69.3 ± 38.9, P = 0.024), appropriateness of prescription was no different compared to hospital-initiated patients (78% during admission cf. 61% prior, P = 0.061). Appropriate prescribing was better in patients with venous thromboembolism compared to AF (85% appropriate cf. 60%, P = 0.021). CONCLUSION: Our findings imply that there remains considerable uncertainty about appropriate prescribing and dosing of NOAC, particularly in patients with impaired renal function. We recommend judicious prescribing and regular monitoring of renal function in patients at high risk of complications from NOAC therapy.

Adherence to guideline-based antibiotic treatment for acute exacerbations of chronic obstructive pulmonary disease in an Australian tertiary hospital.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are an important cause of acute hospital admissions and incur significant costs, which include antibiotic costs. AIMS: This study aimed to (i) define antibiotic prescribing practice in patients admitted to a tertiary hospital with AECOPD and compare this with current locally and nationally recognised antibiotic prescribing guidelines and (ii) correlate variations in guideline-concordant antibiotic prescribing with mean length of stay (LOS) and rates of unplanned readmission to hospital. METHODS: Retrospective case series of 84 consecutive patients with uncomplicated AECOPD who met pre-specified selection criteria. RESULTS: Seventy-two of 84 participants (85.7%) received guideline-discordant antibiotics, of whom the majority (76%) received intravenous antibiotics. Mean LOS was significantly lower among patients receiving guideline-concordant therapy compared with those receiving guideline-discordant therapy (mean 1.6 days vs 3.7 days; P = 0.002). There was no significant difference between groups in rates of readmission. Estimated excess costs per patient associated with guideline-discordant therapy equalled $2642 which, if eliminated, would save approximately $300 000 per annum. CONCLUSION: In a tertiary hospital, Australian guidelines for treating patients with an AECOPD were rarely followed. The use of guideline-discordant therapy resulted in longer hospital stays and incurred greater costs. Studies are required to determine the reasons behind such discordant practice and to develop initiatives to improve antibiotic prescribing.

Prospective parallel randomized trial of the MultiCyte™ ThinPrep(®) imaging system: the Scottish experience.

BACKGROUND: Computer-assisted screening of cervical liquid-based cytology (LBC) preparations using the ThinPrep® Imaging System (TIS) has shown improved qualitative and quantitative gains. The use of Multicyte™ has not been described in a well-established national screening programme with a low incidence of high-grade dyskaryosis. OBJECTIVES: To assess the impact of computer-assisted screening within the Scottish Cervical Screening Programme (SCSP). METHODS: Two groups of three laboratories, each sharing a ThinPrep® Imager, screened 79 366 slides randomized to test and 90 551 to control arms by laboratory accession. Screeners were not blinded. Standard laboratory reporting profiles of the SCSP, sensitivity, specificity and false-negative rates of all grades of LBC abnormalities with respect to final cytology reports, predictive value for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) on histology; and screening rates were compared for both arms. RESULTS: Inadequate and negative reporting rates were significantly lower and low-grade reporting rates significantly higher in the imager arm. Imager-assisted screening showed significantly better specificity than manual screening with respect to the final cytology result. There was no evidence of a significant difference in the detection of CIN2+ or CIN3 +. Positive, abnormal and total predictive values (high-grade, low-grade and all abnormal cytology found to be CIN2+, respectively) were similar in both arms. Productivity was significantly higher in the imager arm. CONCLUSION: Computer-assisted screening in a well established screening programme showed significantly improved productivity without loss of quality. These findings should inform future policy for cervical screening programmes.

Diagnosis of bladder cancer by immunocytochemical detection of minichromosome maintenance protein-2 in cells retrieved from urine.

BACKGROUND: We tested the accuracy of immunocytochemistry (ICC) for minichromosome maintenance protein-2 (MCM-2) in diagnosing bladder cancer, using cells retrieved from urine. METHODS: Adequate samples were obtained from 497 patients, the majority presenting with gross haematuria (GH) or undergoing cystoscopic surveillance (CS) following previous bladder cancer. We performed an initial study of 313 patients, followed by a validation study of 184 patients. In all cases, presence/absence of bladder cancer was established by cystoscopy/biopsy. RESULTS: In the initial study, receiver operator characteristic analysis showed an area under the curve of 0.820 (P<0.0005) for the GH group and 0.821 (P<0.01) for the CS group. Optimal sensitivity/specificity were provided by threshold values of 50+ MCM-2-positive cells in GH samples and 200+ cells in CS samples, based on a minimum total cell number of 5000. Applying these thresholds to the validation data set gave 81.3% sensitivity, 76.0% specificity and 92.7% negative predictive value (NPV) in GH and 63.2% sensitivity, 89.9% specificity and 89.9% NPV in CS. Minichromosome maintenance protein-2 ICC provided clinically relevant improvements over urine cytology, with greater sensitivity in GH and greater specificity in CS (P=0.05). CONCLUSIONS: Minichromosome maintenance protein-2 ICC is a reproducible and accurate test that is suitable for both GH and CS patient groups.

Raised interleukin-17 is immunolocalised to neutrophils in cystic fibrosis lung disease.

Interleukin (IL)-17 is pivotal in orchestrating the activity of neutrophils. Neutrophilic inflammation is the dominant pathology in cystic fibrosis (CF) lung disease. We investigated IL-17 protein expression in the lower airway in CF, its cellular immunolocalisation and the effects of IL-17 on CF primary bronchial epithelial cells. Immunohistochemistry was performed on explanted CF lungs and compared with the non-suppurative condition pulmonary hypertension (PH). Airway lavages and epithelial cultures were generated from explanted CF lungs. Immunoreactivity for IL-17 was significantly increased in the lower airway epithelium in CF (median 14.1%) compared with PH (2.95%, p=0.0001). The number of cells staining positive for IL-17 in the lower airway mucosa was also increased (64 cells·mm(-1) compared with 9 cells·mm(-1) basement membrane, p=0.0005) and included both neutrophils in addition to mononuclear cells. IL-17 was detectable in airway lavages from explanted CF lungs. Treatment of epithelial cultures with IL-17 increased production of IL-8, IL-6 and granulocyte macrophage colony-stimulating factor. In conclusion, immunoreactive IL-17 is raised in the lower airway of people with CF and localises to both neutrophils and mononuclear cells. IL-17 increases production of pro-neutrophilic mediators by CF epithelial cells, suggesting potential for a positive feedback element in airway inflammation.

An investigation of adequate volume for the diagnosis of malignancy in pleural fluids.

OBJECTIVE: The cytological examination of pleural effusions is an important investigation in the diagnosis of malignancy. Maximizing the chances of identifying malignant effusions is therefore desirable. Recent Royal College of Pathologists guidelines, based on the British Society for Clinical Cytology codes of practice, have suggested that a minimum of 20 ml of pleural fluid is required for diagnostic purposes. METHODS & RESULTS: We examined 2155 pleural fluids received over a 6-year period in order to define a minimum required volume for adequacy. By examining the plateau phase of a graph of threshold volumes for initial samples received for each patient (n =1584) we determine that a minimum fluid volume of 25 ml is required and that more than 50 ml does not improve sensitivity. CONCLUSION: Between 25 and 50 ml of fluid are required for the adequate assessment of pleural effusions for malignancy.

Nedocromil sodium for chronic asthma in children.

BACKGROUND: Currently inhaled corticosteroids are the main stay in the maintenance treatment of chronic asthma in children. Although inhaled corticosteroids play a crucial role in the management of childhood asthma, the long-term side effects of inhaled corticosteroids used in the management of chronic asthma in children are not clearly known. OBJECTIVES: The objective of this review is to compare the safety and efficacy of inhaled nedocromil sodium with placebo in the treatment of chronic asthma in children. SEARCH STRATEGY: We searched the Cochrane airway group trials register, Cochrane controlled trials register, Current contents, review articles, reference lists of articles. We also contacted the drug manufacturer and primary authors for additional citations. We also searched abstracts of major respiratory society meetings. The last search was carried out in October 2004 SELECTION CRITERIA: Randomised placebo controlled trials comparing nedocromil sodium to placebo in the treatment of chronic asthma in children (0 to 18 years). DATA COLLECTION AND ANALYSIS: Both authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. MAIN RESULTS: Fifteen trials (twelve parallel group studies; three crossover trials recruiting 1422 children (837 males and 585 females)) were included. The studies were generally of good methodological quality. Two large long term studies used nedocromil for six months and four to six years and showed conflicting results in symptom free days. Short term studies (duration between 4 weeks to 12 weeks) showed that nedocromil sodium produced some improvement in a number of efficacy measures compared to placebo including FEV(1), FVC, FEV(1) % predicted, PC20 FEV(1), evening PEF and symptom scores. The parent's assessment of efficacy was in favour of nedocromil (odds ratio (OR) 0.5 (95% CI 0.3 to 0.8). Nedocromil sodium has a good safety profile. The only significant side effect observed was unpleasant taste. There was little evidence for a clinically dose response effect and only a few studies recruited participants with severe asthma. AUTHORS' CONCLUSIONS: A limited number of small studies have shown that nedocromil is of benefit in improving lung function and some measures of symptoms, but the evidence with regard to the primary outcome of the review was conflicting. Two long-term trials did not show consistent effects on lung function outcomes, whereas several small short-term trials have shown benefit in these outcomes. Differing severities at baseline may explain this difference with milder participants experiencing less benefit, although the discrepancy between study findings may also reflect publication bias. Nedocromil sodium is associated with a very good safety profile with no significant short term or long- term adverse side effects. Although nedocromil may have advantages over inhaled corticosteroids in terms of side effects, there is a need for head to head trials of nedocromil and inhaled corticosteroids to establish whether asthma control is similar, especially in mild asthma. It is not yet clear where nedocromil should sit in relation to other therapies in the treatment of asthma in children.

Interdigitating dendritic cell sarcoma of the parotid gland.

Interdigitating dendritic cell sarcomas (IDCSs) are extremely uncommon tumours that arise predominantly in lymphoid tissue. We report a case of an IDCS arising in the parotid gland of a 73-year-old man. Clinically, a primary salivary gland tumour was suspected but fine needle aspiration cytology suggested a soft tissue tumour. A diagnosis of IDCS was made on histopathological examination of the resection specimen, with subsequent confirmation by electron microscopy. Given the extreme rarity of this tumour at this site, it is unlikely to be a common diagnostic problem, but the importance of multiple diagnostic modalities is emphasized. The findings of cytology, histology, immunohistochemistry and electron microscopy have not previously been described together in a single case report of this tumour.

Branched chain acyltransferase absence due to an Alu-based genomic deletion allele and an exon skipping allele in a compound heterozygote proband expressing maple syrup urine disease.

Branched chain alpha-ketoacid dehydrogenase assembles around a core of the acyltransferase components on the matrix side of the mitochondrial inner membrane. Autosomal recessive mutations in humans are known to decrease the function of this complex resulting in the clinical phenotype of maple syrup urine disease. Within this wide group of mutations are a subset which result in the antigenic absence of the acyltransferase protein of the complex. Here we describe two mutations in a compound heterozygote proband which result in this acyltransferase-negative phenotype. The mutant allele inherited from the father lacks 15-20 kilobases of genomic DNA resulting from a recombinational event between an intronic Alu sequence and coding sequence in the terminal exon. The mother's mutant allele contains a single base substitution in the -1 position of the 5' splice junction following exon 8. This G1002----A transition results in exon skipping producing two different mRNAs. The first lacks only exon 8 while the second lacks exons 8-10. All mRNAs for the acyltransferase found in cells from the proband have the potential to produce proteins ranging in size from 251-395 amino acids, the largest being 26 amino acids short of a full-length acyltransferase. The potential of these transcripts to produce protein is of interest since the patient is clinically responsive to pharmacologic treatment with thiamin, showing a higher tolerance to protein in the diet. The mechanism for this thiamin response remains to be explained.

Nucleotide sequence of the 5' end including the initiation codon of cDNA for the E1 alpha subunit of the human branched chain alpha-ketoacid dehydrogenase complex.

The 5' end including the start AUG codon has been defined for the human E1 alpha subunit of the branched chain alpha-ketoacid dehydrogenase complex by rapid amplification of cDNA ends. Considering conservative substitutions the amino acid sequence in the mitochondrial targeting sequence for the human clone is 73% identical to this sequence in rat and 84% identical to the bovine sequence. This peptide also shows similarity to the targeting sequence for the human beta subunit but not with targeting sequence for the other subunits of the complex.

Import rate of the E1beta subunit of human branched chain alpha-ketoacid dehydrogenase is a limiting factor in the amount of complex formed in the mitochondria.

Components of the mitochondrial branched chain alpha-ketoacid dehydrogenase multienzyme complex are all encoded by nuclear genes. The functional complex is formed with a known stoichiometric relationship of subunits, but how they enter the mitochondria and form the complex is not defined. Although cytosolic precursors for several of the proteins have been identified, the requirements for import and processing have not been described. Here we demonstrate the similar requirements for in vitro import and processing of the three catalytic subunits unique the this complex. Import was not affected by the amount of endogenous BCKD within the mitochondria. No cooperativity or competition among the subunits for import was found when subunits were used in combination. The relative rates of entry are E1alpha>E2>/=E1beta, making E1beta the limiting component supporting previously reported observations.

Palivizumab for preterm infants. Is it worth it?

Respiratory syncytial virus infection is an important cause of morbidity. Although palivizumab prophylaxis is widely used, it is uncertain whether the cost is justified. A systematic review was therefore performed of the safety, efficacy, and the likely cost effectiveness of prophylaxis for preterm infants in the United Kingdom using a standard search strategy. The only randomised controlled trial identified showed a reduction in hospital admission but no benefit on more serious outcomes. None of the United Kingdom cost studies showed economic benefit for palivizumab prophylaxis. New treatments are rarely cost effective, and, in the absence of a comprehensive economic assessment, continued use for high risk infants may appear justified.

Inhaled beta2-agonists for treating non-specific chronic cough in children.

BACKGROUND: The pathophysiology of so called 'cough variant asthma' has not received a great deal of research interest and opinion lies divided as to whether it is really asthma or not. The proponents of cough variant asthma suggest a therapeutic trial of medications usually used to treat asthma OBJECTIVES: To determine the effectiveness of inhaled ss2 agonists in non-specific chronic cough in children over the age of 2 years. SEARCH STRATEGY: The Cochrane Airways Group database (including MEDLINE, EMBASE and CINAHL) and the Cochrane Controlled Trials Register (CCRT) were searched. Additional searching included hand searching of medical journals through the Cochrane Collaboration, references, references of references listed in primary sources and personal communication with authors. In addition "Grey literature" including theses, internal reports, non-peer reviewed journals were sought. SELECTION CRITERIA: All randomised (randomised and quasi-randomised) controlled clinical trials in which inhaled ss2 agonists were given for chronic cough in children over 2 years of age were included. Two reviewers independently assessed articles for inclusion and methodological quality. DATA COLLECTION AND ANALYSIS: Data for trials of salbutamol versus placebo were extracted by both reviewers and entered into the Cochrane Collaboration software program Review Manager, version 4.2 MAIN RESULTS: In children presenting with isolated chronic cough there was no significant difference between salbutamol treated group and placebo group. AUTHORS' CONCLUSIONS: Salbutamol was no different from placebo in reducing the frequency of cough measured objectively or scored subjectively.

Inhaled corticosteroids for non-specific chronic cough in children.

BACKGROUND: Cough in isolation of other clinical features is known as non-specific cough, which has been defined as non-productive cough in the absence of identifiable respiratory disease or any known aetiology. In children with non-specific cough the possibility of asthma being the underlying disorder is often raised (so called cough variant asthma). The proponents of cough variant asthma suggest a therapeutic trial of medications usually used to treat asthma. OBJECTIVES: To determine the efficacy of inhaled corticosteroids in non-specific cough in children over the age of two years. SEARCH STRATEGY: Searches were conducted on Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. Searches were current as of March 2004. SELECTION CRITERIA: All randomised (randomised and quasi-randomised) controlled clinical trials in which an inhaled corticosteroid (beclomethasone (BDP), fluticasone (FP), triamcinalone (TAA) or any other corticosteroid) were given for cough in children over two years of age were included. Two review authors independently assessed articles for inclusion and methodological quality. DATA COLLECTION AND ANALYSIS: Data from trials was extracted by both review authors and entered into the Cochrane Collaboration software program RevMan Analyses 1.0.2. MAIN RESULTS: Two trials met the inclusion criteria (123 participants). One compared inhaled beclomethasone dipropionate (400 micrograms per day) with placebo and the other compared fluticasone propionate (2 mg per day for 3 days followed by 1 mg per day for 11 days) with placebo. Both studies used metered dose inhalers via a spacer. With the lower dose of inhaled corticosteroid there was no significant difference between the beclomethasone and placebo groups. With the higher dose there was a significant improvement in nocturnal cough frequency after two weeks in children presenting with persistent nocturnal cough. However, a significant but smaller improvement was also seen with placebo. AUTHORS' CONCLUSIONS: In one study beclomethasone dipropionate (400 micrograms per day) was no different from placebo in reducing the frequency of cough measured objectively or scored subjectively. There might be a small improvement with very high-dose inhaled corticosteroid but the clinical impact of this is unlikely to beneficial.

[D.L.vo n. 626/94 - Musculoskeletal diseases caused by use of micropipette in laboratory]. / D.L.vo n. 626/94--Malattie muscolo-scheletriche da impiego di micropipette in laboratorio.

The use of manual pipettes has been associated with a high prevalence of upper extremity and neck cumulative trauma disorders (CTD's) and work-related musculoskeletal disorders (WMSD's) among laboratory workers. The primary risk factor for these disorders are poor ergonomics in three specific areas: posture, repetition and force. Federal agencies have issued guidelines for pipetting practices to reduce the risk of injury and WMSD's. Pipette manufacturing have responded to the problem by improving the ergonomics and buttons and plungers that require less forces during operations. Another problem was still open with the traditional axial-design pipette: deviation of body or extremity from an ergonomically favourable neutral position. The new generation of micropipettes solves this problem.

Characterization of the ovariectomized rat model for the evaluation of estrogen effects on plasma cholesterol levels.

Estrogens protect against cardiovascular disease in women through effects on the vascular wall and liver. Here we further characterize the rat as a model for the evaluation of estrogenic effects on plasma lipid levels vs. uterine wet weight. In adult ovariectomized female rats treated for 4 days s.c., 17alpha-ethinyl estradiol (EE) was the most potent agent to lower plasma total and high density lipoprotein cholesterol levels, followed by 17beta-estradiol and 17alpha-estradiol. However, 17alpha-estradiol had the greatest separation of uterotropic vs. cholesterol-lowering effects. EE had the same lipid-lowering potency whether administered s.c. or orally to adult rats. It had no effect on cholesterol levels in immature rats, even though the uterotropic response was dramatic. Testosterone propionate, dexamethasone, and progesterone did not significantly lower cholesterol levels. The antiestrogens tamoxifen and raloxifene lowered cholesterol levels, but with less efficacy and potency than the estrogens. ICI 182780 had no effect on cholesterol levels. When coadministered with EE, ICI 182780 inhibited the cholesterol-lowering and uterotropic activities of EE, suggesting that the estrogen receptor pathway is involved. In conclusion, although the information from the rat is limited as a model of the low density lipoprotein-lowering effects of estrogens in humans, it can be used to study the effects and mechanism of action of estrogen and antiestrogens on plasma cholesterol levels.

The pharmacokinetics of etodolac in serum and synovial fluid of patients with arthritis.

The pharmacokinetics of etodolac have been evaluated in five patients with arthritis given 200 mg etodolac, twice daily, at 12-hour intervals, for 7 days. Albumin and total protein concentrations were markedly lower in synovial fluid than in serum, and etodolac free fraction was significantly higher. Etodolac readily penetrated into the synovial fluid, and in the postdistributive phase the concentration of free etodolac (i.e., the drug responsible for pharmacologic activity) remained higher than that in serum at all times. No differences in the half-life of etodolac elimination were noted.

Formation of diacyl- and alkylacylphosphatidylcholine by the membranes of human platelets.

We have investigated the distribution and fatty acid preference of two acyl-CoA transferase activities in a human platelet mixed membrane fraction and in well-characterised surface and intracellular membrane subfractions prepared from it by high-voltage free-flow electrophoresis. One transferase inserts long-chain unsaturated fatty acids into 1-acyllysophosphatidylcholine (1-acyl-LPC) and the other into lyso-platelet-activating factor (LPAF). Both transferase activities were approx. 4-fold enriched in the intracellular membranes with respect to their specific activities in the mixed membranes. The surface membrane activities were correspondingly depleted. Using 1-acyl-LPC as the acceptor, all the intracellular membrane preparations showed transferase preference for the CoA ester of 8,11,14-eicosatrienoic acid. In contrast when LPAF was the acceptor the CoA esters of linoleic and arachidonic acid were the preferred donors.

Platelet dysfunction in uremia. Multifaceted defect partially corrected by dialysis.

In an attempt to elucidate the nature of the bleeding tendency in uremia, some in vitro functions of platelets from eight patients undergoing long-term hemodialysis were studied. None of the patients had diabetes. All had bleeding times longer than eight minutes. Threshold aggregating concentrations for collagen, adenosine diphosphate, and epinephrine, when used singly or in pairs, were two to three times higher than normal in platelet-rich plasmas from these patients. In contrast, those for arachidonic acid and U-46619, a cyclic endoperoxide/thromboxane A2 analogue, were within the normal ranges. Thromboxane B2 formation was normal in response to arachidonic acid (0.2 to 1 mM), whereas it was decreased by 30 to 50 percent in response to thrombin (0.5 to 10 units/ml), collagen (0.5 to 10 micrograms/ml), and the combination of collagen with adenosine diphosphate or epinephrine. There was a partial (about 35 percent) reduction of the platelet granular content of adenosine diphosphate. Secretion of adenosine triphosphate by 5 units/ml of thrombin was 25 to 50 percent less than in normal subjects. Thus, there was a storage pool defect as well. Similar but less severe defects were found in platelets from uremic patients who had never undergone hemodialysis. Partial correction of aggregation and thromboxane B2 formation was seen after dialysis, although platelet adenosine diphosphate content did not increase. It is concluded that the platelet dysfunction in uremia is multifaceted. There appears to be an aggregation and secretion defect related to impaired arachidonic acid release from platelet phospholipids as well as a storage pool defect. The first is improved with dialysis; the second is not.