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BACKGROUND: Gastrointestinal hemorrhage is considered to be a severe complication of von Willebrand disease. The optimal therapy for acquired von Willebrand syndrome and severe gastrointestinal bleeding with hypertrophic cardiomyopathy is undefined. PATIENTS/METHODS: Seventy-seven patients (median age, 67 years; interquartile range [IQR], 56-75 years; 49% women) with hypertrophic cardiomyopathy underwent von Willebrand factor multimer testing and acquisition of bleeding history. Bleeding was detected in 27 (36%) (median age, 74 years; IQR 66-76 years; 74% women), 20 with gastrointestinal bleeding, including 11 women with transfusion dependence. In these 11 women, the median duration of transfusion dependency was 36 months (IQR 18-44 months), and the median number of transfusions required was 25 (IQR 20-38). Two patients had undergone bowel resection for bleeding, one of them twice. Seven patients showed angiodysplasia, and the remainder had no endoscopic lesion. Bleeding recurred after bowel surgery or endoscopic intervention and medical therapy for hypertrophic cardiomyopathy in 10 of 11 patients. Two patients had septal myectomy, and six patients underwent alcohol septal ablation. With the exception of one patient in whom a significant gradient persisted after septal ablation, after the periprocedural period, patients after septal reduction therapy remained free of recurrent bleeding and need for transfusions. CONCLUSION: Acquired von Willebrand syndrome is common in hypertrophic cardiomyopathy. Gastrointestinal bleeding often recurs after endoscopic therapy, but may be relieved by structural cardiac repair.

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BACKGROUND: Mitral valve regurgitation is associated with an acquired hemostatic defect. OBJECTIVE: We sought to assess the prevalence and severity of acquired von Willebrand syndrome in patients with native valve mitral regurgitation (MR). PATIENTS/METHODS: Fifty-three patients were prospectively observed with bleeding questionnaires and laboratory tests when undergoing an echocardiographic assessment of MR. In patients referred for mitral valve surgery, testing was repeated postoperatively. RESULTS: Echocardiography identified 13 patients with mild MR, 14 with moderate MR, and 26 with severe MR. Among patients with mild, moderate or severe MR, loss of the highest molecular weight von Willebrand factor (VWF) multimers occurred in 8%, 64%, and 85%, respectively, median platelet function analyzer collagen ADP closure times (PFA-CADPs) were 84 s (interquartile range [IQR] 73-96 s), 156 s (IQR 104-181 s), and 190 s (IQR 157-279 s), respectively, and the ratios of VWF latex activity to antigen were 0.92 (IQR 0.83-0.97), 0.85 (IQR 0.76-0.89), and 0.79 (IQR 0.75-0.82), respectively (all P < 0.001). Nine patients reported clinically significant bleeding, and seven had intestinal angiodysplasia and transfusion-dependent gastrointestinal bleeding (Heyde syndrome), with the median number of transfusions required being 20 (IQR 10-33; range 4-50). In patients who underwent mitral valve repair (n = 13) or replacement (n = 7), all measures of VWF function reported above improved significantly. CONCLUSION: The high-shear environment of moderate to severe MR is sufficient to produce prevalent perturbations in VWF activity. Acquired von Willebrand syndrome may occur in this setting, and appears to be reversible with mitral valve surgery.

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An essential step in ensuring the toxicological safety of ingredients in consumer products is the evaluation of their skin sensitising potential. Where skin exposure is low, it is possible to conduct a risk assessment using the Dermal Sensitisation Threshold (DST), a process similar to that of the Threshold of Toxicological Concern. This paper describes work building on that previously published, whose aim was to produce a more robust tool for assessing the safety of consumer products. This consisted of expanding the Local Lymph Node Assay dataset used to define the original DST and classifying chemicals in the dataset according to their mechanistic chemistry domains. A DST of 900µg/cm(2) was derived for chemicals classified as non-reactive and non-proreactive. This value was benchmarked against human potency data for 58 fragrance allergens and was lower than the measured No Expected Sensitisation Levels for those classified as non-reactive. Use of this DST will help to eliminate the need for animal testing of non-reactive and non-proreactive chemicals where skin exposure is sufficiently low. For chemicals where a Quantitative Risk Assessment based on the DST does not give an adequate margin of safety, and those classified as reactive, a case-by-case risk assessment will be required.

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Risk assessment for most human health effects is based on the threshold of a toxicological effect, usually derived from animal experiments. The Threshold of Toxicological Concern (TTC) is a concept that refers to the establishment of a level of exposure for all chemicals below which there would be no appreciable risk to human health. When carefully applied, the TTC concept can provide a means of waiving testing based on knowledge of exposure limits. Two main approaches exist; the first of these is a General Threshold of Toxicological Concern; the second approach is a TTC in relation to structural information and/or toxicological data of chemicals. The structural scheme most routinely used is that of Cramer and co-workers from 1978. Recently this scheme was encoded into a software program called Toxtree, specifically commissioned by the European Chemicals Bureau (ECB). Here we evaluate two published datasets using Toxtree to demonstrate its concordance and highlight potential software modifications. The results were promising with an overall good concordance between the reported classifications and those generated by Toxtree. Further evaluation of these results highlighted a number of inconsistencies which were examined in turn and rationalised as far as possible. Improvements for Toxtree were proposed where appropriate. Notable of these is a necessity to update the lists of common food components and normal body constituents as these accounted for the majority of false classifications observed. Overall Toxtree was found to be a useful tool in facilitating the systematic evaluation of compounds through the Cramer scheme.

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The Threshold of Toxicological Concern (TTC) is a useful concept that is becoming of increasing interest as an addition to the arsenal of tools used for characterising the toxicological risk of human exposure to chemicals. Traditionally used for low level indirect additives, flavours and contaminants in foods, the TTC obviates the need for toxicological testing of chemicals where human exposure is low. Proposals have recently been made for the use of the TTC for low level ingredients in cosmetic and personal care products. However, use of the TTC is only protective for systemic toxicity endpoints, and cannot be used for local endpoints such as contact sensitisation. In this paper a probabilistic analysis of available sensitisation data, similar to that used in the development of the TTC, is presented. The incidence of sensitisers in the world of chemicals was estimated using the ELINCS (European List of Notified Chemical Substances) data set, and a distribution for sensitisation potency was established using a recently published compilation of Local Lymph Node Assay data. From the analysis of these data sets it is concluded that a Dermal Sensitisation Threshold (DST) can be established below which there is no appreciable risk of sensitisation, even for an untested ingredient. Use of a DST would preclude the need for sensitisation testing of ingredients where dermal exposure is sufficiently low.

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High-amylose starch is in great demand by the starch industry for its unique functional properties. However, very few high-amylose crop varieties are commercially available. In this paper we describe the generation of very-high-amylose potato starch by genetic modification. We achieved this by simultaneously inhibiting two isoforms of starch branching enzyme to below 1% of the wild-type activities. Starch granule morphology and composition were noticeably altered. Normal, high-molecular-weight amylopectin was absent, whereas the amylose content was increased to levels comparable to the highest commercially available maize starches. In addition, the phosphorus content of the starch was increased more than fivefold. This unique starch, with its high amylose, low amylopectin, and high phosphorus levels, offers novel properties for food and industrial applications.

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Stroke associated with atrial fibrillation (AF) is mainly due to embolism of thrombus formed during stasis of blood in the left atrial appendage (LAA). Pathophysiologic correlates of appendage flow velocity as assessed by transesophageal echocardiography (TEE) in patients with AF have not been defined. To evaluate the hypothesis that reduced velocity is associated with spontaneous echocardiographic contrast and thrombus in the LAA and with clinical embolic events, we measured LAA flow velocity by TEE in 721 patients with nonvalvular AF entering the Stroke Prevention in Atrial Fibrillation (SPAF-III) study. Patient features, TEE findings, and subsequent cardioembolic events were correlated with velocity by multivariate analysis. Patients in AF during TEE displayed lower peak antegrade (emptying) flow velocity (Anu(p)) than those with intermittent AF in sinus rhythm during TEE (33 cm/s vs 61 cm/s, respectively, P <.0001). Anu(p) < 20 cm/s was associated with dense spontaneous echocardiographic contrast (P <.001), appendage thrombus (P <.01), and subsequent cardioembolic events (P <.01). Independent predictors of Anu(p) < 20 cm/s included age (P =.009), systolic blood pressure (P <.001), sustained AF (P =.01), ischemic heart disease (P =.01), and left atrial area (P =.04). Multivariate analysis found both Anu(p) <20 cm/s (relative risk 2.6, P =.02) and clinical risk factors (relative risk 3.3, P =.002) independently associated with LAA thrombus. LAA Anu(p) is reduced in AF and associated with spontaneous echocardiographic contrast, appendage thrombus, and cardioembolic stroke. Systolic hypertension and aortic atherosclerosis, independent clinical predictors of stroke in patients with AF, also correlated with LAA Anu(p). Our results support the role of reduced LAA Anu(p) in the generation of stasis, thrombus formation, and embolism in patients with AF, although other mechanisms also contribute to stroke.

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Changes in medical practice that limit instruction time and patient availability, the expanding options for diagnosis and management, and advances in technology are contributing to greater use of simulation technology in medical education. Four areas of high-technology simulations currently being used are laparoscopic techniques, which provide surgeons with an opportunity to enhance their motor skills without risk to patients; a cardiovascular disease simulator, which can be used to simulate cardiac conditions; multimedia computer systems, which includes patient-centered, case-based programs that constitute a generalist curriculum in cardiology; and anesthesia simulators, which have controlled responses that vary according to numerous possible scenarios. Some benefits of simulation technology include improvements in certain surgical technical skills, in cardiovascular examination skills, and in acquisition and retention of knowledge compared with traditional lectures. These systems help to address the problem of poor skills training and proficiency and may provide a method for physicians to become self-directed lifelong learners.

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Full length cDNAs encoding a second starch branching enzyme (SBE A) isoform have been isolated from potato tubers. The predicted protein has a molecular mass of 101 kDa including a transit peptide of 48 amino acids. Multiple forms of the SBE A gene exist which differ mainly in the length of a polyglutamic acid repeat at the C-terminus of the protein. Expression of the mature protein in Escherichia coli demonstrates that the gene encodes an active SBE. Northern analysis demonstrates that SBE A mRNA is expressed at very low levels in tubers but is the predominant isoform in leaves. This expression pattern was confirmed by Western analysis using isoform specific polyclonal antibodies raised against E. coli expressed SBE A. SBE A protein is found predominantly in the soluble phase of tuber extracts, indicating a stromal location within the plastid. Transgenic potato plants expressing an antisense SBE A RNA were generated in which almost complete reductions in SBE A were observed. SBE activity in the leaves of these plants was severely reduced, but tuber activity was largely unaffected. Even so, the composition and structure of tuber starch from these plants was greatly altered. The proportion of linear chains was not significantly increased but the average chain length of amylopectin was greater, resulting in an increase in apparent amylose content as judged by iodine binding. In addition, the starch had much higher levels of phosphorous.

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BACKGROUND: The left atrium (LA) is usually enlarged in patients with nonvalvular atrial fibrillation (AF), but factors associated with LA diameter are incompletely defined. METHODS AND RESULTS: This transthoracic echocardiographic cohort study includes 3465 participants with nonvalvular AF in 3 multicenter clinical trials. LA diameter determined by M-mode echocardiography was correlated with clinical and echocardiographic features by cross-sectional multivariate regression analyses. The mean LA diameter was 47 +/- 8 mm, on average 6 mm larger in those with AF at the time of echocardiography than in those with sinus rhythm (48 vs 42 mm, P <. 001). Patient age and body weight were independently predictive of LA diameter (P <.0001), but sex, body surface area, and body mass index were not. The estimated independent contribution of atrial rhythm to LA diameter was approximately 2.5 mm. Prolonged duration of AF, left ventricular dilatation and increased muscle mass, mitral regurgitation, annular calcification, and hypertension were additional independent predictors of LA diameter. CONCLUSIONS: Multiple factors appear to contribute to LA enlargement in patients with nonvalvular AF, including the presence and persistence of the dysrhythmia.

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BACKGROUND: Left ventricular ejection fraction (EF) is a valuable prognostic index in patients with congestive heart failure (CHF). Although EF can be readily measured, many clinicians use roentgenographic heart size as a clue to differentiate systolic from diastolic dysfunction, even in the absence of solid supportive data. OBJECTIVE: To test the hypothesis that the cardiothoracic ratio (CTR) measured from the chest roentgenogram can be used to estimate left ventricular EF in individuals with CHF. METHODS: To answer this question, the database of the Digitalis Investigation Group trial was used. The CTR, determined using the Danzer method, and quantitative EF, measured locally using angiographic, radionuclide, or 2-dimensional echocardiographic techniques, were compared in 7476 patients with clinical CHF (New York Heart Association functional classes I-IV) due to acquired left-sided cardiac disease of ischemic, hypertensive, idiopathic, and alcohol-related causes. RESULTS: Mean (+/-SD) CTR for the cohort was 0.53+/-.07. Mean (+/-SD) EF was 31.7%+/-12.2%. A weak, negative correlation between CTR and EF was observed (r=-0.176). Similar findings were obtained when the results were stratified by cause of CHF, presence of clinically defined right ventricular dysfunction, and method of EF measurement. Categorical analysis failed to yield a CTR cutoff point that facilitated useful segregation of individuals with an EF greater than 35% or 35% and below; greater than 40% or 40% and below; and greater than 45% or 45% and below in any patient group. CONCLUSIONS: Although a weak, negative correlation exists between CTR and EF, this relationship does not allow for accurate determination of systolic function in individual patients with CHF. Considering the morbidity and mortality associated with CHF, and the clinical implications of systolic function in this syndrome, direct measurement of EF is recommended.

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BACKGROUND: Reduced left atrial appendage velocity (LAAV) has been identified as a marker for thromboembolism in patients with atrial fibrillation. HYPOTHESIS: It was postulated that electrocardiographic (ECG) F-wave amplitude would correlate with LAAV, and inversely with the risk of thromboembolism in patients with atrial fibrillation. METHODS: In all, 53 patients with nonrheumatic (NRAF) and 7 patients with rheumatic (RAF) atrial fibrillation underwent assessment of maximum LAAV, which was correlated to the maximum ECG F-wave voltage from lead V1 (F(max)). In 450 NRAF patients on neither aspirin nor warfarin, the relationship between F(max) and thromboembolic risk was assessed over an average follow-up of 1.3 years. RESULTS: F(max) did not correlate with LAAV (r = 0.2, p = 0.07). Patients with intermittent atrial fibrillation (n = 123) had smaller F(max) amplitude than patients with constant atrial fibrillation (n = 327) (mean 0.73 vs. 0.88 mV-1, p = 0.001). F(max) amplitude was not related to a history of hypertension, systolic blood pressure, duration of NRAF, abnormal transthoracic echocardiographic left ventricular (LV) systolic function or left atrial (LA) diameter. There was a strong trend for increased LV mass being related to smaller F(max) amplitude after adjusting for body surface area (p = 0.06). F(max) amplitude was not correlated with risk of embolic events, including only those events presumed by a panel of case-blinded neurologists to be cardioembolic. CONCLUSIONS: F(max) amplitude in NRAF is smaller in patients with intermittent versus constant AF. It does not correlate with LAAV, LA size, increased LV mass, or systolic dysfunction, hypertension, or risk of embolism. Therefore, F(max) amplitude may not be used as a surrogate for LAAV, or as a measure of thromboembolic risk in NRAF.

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Because of its prevalence in the population and its associated underlying diseases and morbidity, atrial fibrillation (AF) is an important and costly health problem. Advancing age, diabetes, heart failure, valvular disease, hypertension, and myocardial infarction predict the occurrence of AF within a population. The management of AF is complex and involves prevention of thromboembolic complications and treatment of arrhythmia-related symptoms. Stroke occurs in 4.5% of untreated patients with AF per year. Independent risk factors for stroke in nonrheumatic patients with AF are advanced age; a history of prior embolism, hypertension, or diabetes; and echocardiographic findings of left atrial enlargement and left ventricular dysfunction. Warfarin decreases stroke by two-thirds and death by one-third; aspirin is only about half as effective overall and is insufficient therapy for those with risk factors for stroke. Options for thromboembolic prophylaxis are use of warfarin for all in whom it is safe or, alternatively, warfarin for those with risk factors and aspirin for those without risk factors. One-half of the patients with AF are 75 years of age or older. The uniform applicability and relative safety of warfarin therapy in this age-group are controversial. Specific therapy for the arrhythmia should be dictated by the need to control symptoms. Symptomatic treatments include rate-control medications and strategies designed to terminate and prevent arrhythmia recurrence. Digoxin, beta-adrenergic blockers, verapamil, and diltiazem slow excessive ventricular rates in patients with AF and may favorably manage comorbid conditions. The efficacy of anti-arrhythmic medications is only 40 to 70% per year in preventing recurrences of AF, and these agents, except amiodarone, may increase the risk of sudden death in patients with certain types of organic heart disease and AF. The use of nonpharmacologic symptomatic therapies such as atrioventricular node modification or ablation with a rate-response pacemaker or surgical intervention is increasing.

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BACKGROUND: Cheyne-Stokes respirations have frequently been noted in highly selected groups of patients with congestive heart failure, but their prevalence in an unselected population with congestive heart failure is undefined. METHODS: One hundred consecutive unselected outpatients or stable inpatients with clinical congestive heart failure encountered by three clinical cardiologists during a 6-month period were screened for Cheyne-Stokes respirations with overnight oximetry. RESULTS: The mean age (+/- SD) of the patients was 70 +/- 8.6 years. Of the 100 patients, 33% had had previous coronary bypass surgery, 77% were men, 57% had hypertension, and 32% had atrial fibrillation. The mean ejection fraction (+/- SD) was 34% +/- 13%. Periodic breathing was assessed qualitatively as Cheyne-Stokes respirations in 27% of patients, nonspecific sleep-disordered breathing (apneas and/or hypopneas) in 43%, and normal in 30%. For patients with Cheyne-Stokes respirations, patients with nonspecific sleep-disordered breathing, and normal subjects, the mean numbers of oxyhemoglobin desaturation events per hour were 24, 10, and 2, and the total numbers of desaturations of 4% or more that lasted less than 3 minutes were 172, 74, and 13. Independent predictors of Cheyne-Stokes respirations vs non-Cheyne-Stokes respirations included a history of nocturnal dyspnea (odds ratio, 4.00; 95% confidence interval, 1.33 to 12.04; P = .01) and atrial fibrillation (odds ratio, 3.24; 95% confidence interval, 1.21 to 8.48; P = .02). CONCLUSIONS: Cheyne-Stokes respirations and nonspecific sleep-disordered breathing are common in unselected patients with congestive heart failure, and Cheyne-Stokes respirations are predicted by a history of nocturnal dyspnea and the presence of atrial fibrillation. Techniques designed to modify the nocturnal breathing pattern of patients with congestive heart failure may be applicable to a large portion of the congestive heart failure population.

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OBJECTIVE: To compare a microprocessor-driven real-time 12-lead electrocardiographic monitoring device with Holter monitoring for detection of ischemia. DESIGN: Electrocardiographic monitoring was conducted in 110 patients at bed rest or undergoing surgical procedures. MATERIAL AND METHODS: In three groups of patients, simultaneous monitoring with a 12-lead real-time device and a 2-channel Holter system was performed to detect ischemic episodes. The differences in the number of ischemic events and the total time of ischemia revealed by the two devices were analyzed statistically. RESULTS: In patients with coronary artery disease, more ischemic ST-segment shifts were detected by the 12-lead device than by Holter monitoring (44 versus 16 events; P < 0.05). Total time of ischemia was also greater with the 12-lead device (879 versus 273 minutes; P < 0.05). Ischemia was detected by both techniques in 6 patients, only by the 12-lead device in 12, and only by Holter monitoring in 1. Neither device detected ischemia in control subjects. The 12-lead device had an advantage in detecting inferior ischemia, and it identified an additional 13 patients with unstable angina who had changes in T-wave polarity but did not exhibit ST-segment shifts. CONCLUSION: The 12-lead real-time electrocardiographic monitoring device is superior to Holter monitoring in detecting and facilitating real-time identification of myocardial ischemia in patients at bed rest.

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BACKGROUND: Medical education faces problems caused by increasing restraints on resources. A multicenter consortium combined simulation and multimedia computer-assisted instruction (MCAI) to develop unique interactive teaching programs that can address a number of these problems. We describe the consortium, the MCAI system, the programs, and a multicenter evaluation of technical and educational performance. METHODS: The MCAI system uses computer-controlled access to full-screen, full-motion, and full-color laser disc video in combination with digitized sound, images, and graphics stored on removable media. The Socratic teaching method enhances interaction and guides learners through the patient's history, cardiovascular physical examination, laboratory evaluation, and therapy. Self-instruction and instructor-led modes of function are possible. The first five programs, based on simulations of specific cardiology problems, were distributed to four medical centers. Questionnaires evaluated technical function and medical student opinions, while behaviors and scores were automatically tracked and tabulated by program administration software. RESULTS: The MCAI system functioned reliably and accurately in all modes and at all sites. The programs were highly rated. Student ratings, scores, and behaviors were independent of institution and mode of use. CONCLUSION: A multicenter educational consortium developed a system to produce unique, sophisticated MCAI programs in cardiology. Both system and programs functioned reliably at four institutions and were highly rated by fourth-year medical students. With this enthusiastic reception, the economies and strengths associated with MCAI make it an attractive solution to a number of problem areas, and it will likely play an increasingly important role.

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Acyl-ACP thioesterases are involved in regulating chain termination of fatty acid biosynthesis in plant systems. Previously, acyl-ACP thioesterase purified from Brassica napus seed tissue has been shown to have a high preference for hydrolysing oleoyl-ACP. Here, oligonucleotides derived from B. napus oleoyl-ACP thioesterase protein sequence data have been used to isolate two acyl-ACP thioesterase clones from a B. napus embryo cDNA library. The two clones, pNL2 and pNL3, contain 1642 bp and 1523 bp respectively and differ in the length of their 3' non-coding regions. Both cDNAs contain open reading frames of 366 amino acids which encode for 42 kDa polypeptides. Mature rape thioesterase has an apparent molecular weight of 38 kDa on SDS-PAGE and these cDNAs therefore encode for precursor forms of the enzyme. This latter finding is consistent with the expected plastidial location of fatty acid synthase enzymes. Northern blot analysis shows thioesterase mRNA size to be ca. 1.6 kb and for the thioesterase genes to be highly expressed in seed tissue coincident with the most active phase of storage lipid synthesis. There is some sequence heterogeneity between the two cDNA clones, but overall they are highly homologous sharing 95.7% identity at the DNA level and 98.4% identity at the amino acid level. Some sequence heterogeneity was also observed between the deduced and directly determined thioesterase protein sequences. Consistent with the observed sequence heterogeneity was Southern blot data showing B. napus thioesterase to be encoded by a small multi-gene family.

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