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Immediate-release niacin manifests beneficial effects in cardiovascular disease with respect to dyslipidemic states. It lowers low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein(a), and apoprotein B; at the same time, it increases high-density lipoprotein (HDL) cholesterol, HDL2, and apoprotein A-I. However, use of crystalline niacin has drawbacks: therapy requires multidose regimens, and side effects include flushing and pruritus. Slowing absorption with sustained-release formulations succeeds in decreasing flushing and increasing tolerance, but increases in hepatic enzyme levels have raised safety concerns. A new extended-release, once-daily formulation of niacin (Niaspan) shows promise in minimizing flushing while avoiding hepatotoxicity. A multicenter, randomized, double-blind clinical trial of Niaspan enrolled 122 patients with confirmed diagnosis of primary dyslipidemia (LDL cholesterol >4.14 mmol/L [160 mg/dL] and triglycerides

Crystalline nicotinic acid (immediate-release niacin) is effective therapy for lipoprotein regulation and cardiovascular risk reduction. However, inconvenient regimens and unpleasant side effects decrease compliance. Sustained-release formulations designed to circumvent these difficulties increase hepatotoxicity. Niaspan, a new US Food and Drug Administration (FDA)-approved, once-daily, extended-release form, has been found effective and safe in short-term trials. The long-term efficacy and safety of Niaspan lipid monotherapy was studied in 517 patients (aged 21-75 years) for < or =96 weeks in dosages < or =3,000 mg/day. Primary efficacy endpoints were low-density lipoprotein (LDL) cholesterol and apolipoprotein B (apo B) changes from baseline; secondary efficacy endpoints were changes in total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, lipoprotein(a), and total cholesterol/HDL-cholesterol ratio; safety data included adverse events and laboratory values over the 2-year study period. LDL-cholesterol levels decreased significantly: 18% at week 48 and 20% at week 96; apo B reduction was similar (16% decrease at week 48 and 19% at week 96). Large elevations in HDL cholesterol (26%, week 48; 28%, week 96) allowed only modest decreases in total cholesterol (12% and 13%, respectively), whereas total cholesterol/HDL-cholesterol ratio decreased by almost one third. Triglyceride and lipoprotein(a) levels were decreased by 27% and 30%, respectively (week 48), and by 28% and 40%, respectively (week 96). All changes from baseline were significant (p

Objectives—To assess procedural outcome, complications, and clinical follow up in 218 patients who underwent treatment with 297 Multi-link (Guidant) stents implanted without the use of intravascular ultrasound (IVUS) or quantitative coronary angiography (QCA), and using aspirin alone as antiplatelet therapy. Methods—The case records and angiograms were reviewed and the patients were contacted by telephone to determine their symptoms and any adverse events at follow up. Data were analysed using Fisher's exact test. Results—Of the 218 patients included in the study, 45 had multivessel intracoronary intervention, and 55 had unstable angina. The mean (SD) length of hospital stay following the procedure was 2.0 (2.1) days. There were two early deaths at less than 30 days, and two deaths during follow up at more than 100 days. Ten patients suffered complications during the first 30 days: four had subacute stent thrombosis, of whom two died and two were treated successfully with coronary artery bypass grafting; five had a non-Q wave myocardial infarction; and one had a femoral false aneurysm. Patient outcome was analysed according to stent diameter (3.0 mm or less, or 3.5 mm or more) and by angina status (stable or unstable). In patients in whom at least one stent was 3.0 mm diameter, four of 86 patients suffered acute stent occlusion, whereas in the 132 patients in whom all stents were at least 3.5 mm diameter there were no cases of stent occlusion (p = 0.02). In the unstable angina group two of 55 patients suffered acute stent occlusion compared to two of 163 patients in the stable angina group (NS). In patients with unstable angina and at least one stent of 3.0 mm diameter, the acute occlusion rate was 7.1% (two of 28 patients). Three of the four patients with stent occlusion had undergone complex procedures. Twenty eight patients were restudied for recurrent symptoms during the follow up period. Of these, eight patients had restenosis within their stent. In seven of these patients the stent size was 3.0 mm diameter, and in the remaining patient the stent size was 4.0 mm diameter. Three of the 28 patients restudied had developed new disease remote from the stented site, and 17 had patent stents and no significant other coronary lesion. Conclusions—This study suggests that coronary intervention using the Multi-link stent is safe and effective using aspirin alone, without IVUS or QCA, when stent diameter is greater than 3.0 mm. All cases of stent occlusion in this series occurred in patients in whom at least one stent was 3.0 mm diameter, with stent occlusion being higher in patients with unstable angina compared to those with stable angina. Additional antiplatelet therapy may be beneficial in those patients in whom Multi-link stent diameter is less than 3.5 mm, particularly in those with unstable angina, but is not necessary for patients receiving Multi-link stents of 3.5 mm diameter or greater. Keywords: intracoronary Multi-link stents; aspirin; stent occlusion

Recent work by Shi et al. on the mechanism of high-temperature antigen retrieval has claimed that the antigen retrieval process is pH-dependent, with different antigens benefitting at high or low pH values of antigen retrieval solutions. It has previously been claimed that chelation of Ca2+ at high temperature is an essential feature of the antigen retrieval process. In order to resolve this apparent dichotomy, the relative antigen retrieval effects were analysed using the buffers employed by Shi et al. in both a facilitating and an inhibitory mode. The results show that calcium-related effects are optimal at high pH values and do not operate at very low pH. The relative antigen retrieval effectiveness of hydrochloric acid and its metal halide solutions were also investigated in relation to pH. The results of these experiments showed that whilst HCl alone produced antigen retrieval (AR), it also produced severe tissue damage, which was reduced by the inclusion of inorganic salts. These results suggest that antigen retrieval at low pH may be achieved through the dissociation of Ca2+ complexes by high concentrations of H+ ions and/or the breaking up of cross-links from formalin fixation. Results are also presented to show that chaotropic denaturants such as urea and guanidine hydrochloride also function principally through calcium chelation, whilst detergents have no role to play in high-temperature retrieval.

Objective Valsartan is an oral antagonist of angiotensin II that competes with angiotensin II for the AT1-receptor and is being developed as an antihypertensive agent. This study assessed the ability of 80 mg valsartan to inhibit the pressor effect of exogenous angiotensin II in healthy normotensive men, first after a single dose and then after multiple doses once daily for 7 days. Methods This was a single-center, double-blind, placebo-controlled, randomized crossover study. Six healthy men underwent angiotensin II challenges to determine a suitable dose required to increase their systolic blood pressure by approximately 30 mm Hg. Each subject then received an 80 mg dose of valsartan or matching placebo. The inhibition of the angiotensin II pressor effect was determined by the systolic blood pressure response to repeated angiotensin II challenges at multiple time points. Results Systolic blood pressure responses to angiotensin II challenges after single and multiple doses of valsartan were significantly lower than placebo, indicating that valsartan blocked the blood pressure response to angiotensin II. The maximum blocking effect was observed within 2 to 3 hours. Mean data suggested that differences in effect between valsartan and placebo were similar after both single and multiple doses and persisted up to 24 hours after administration. The angiotensin II blocking effect was maintained up to this time, despite low plasma valsartan levels and minimal accumulation after multiple doses. Conclusion Valsartan, 80 mg, is a potent angiotensin II antagonist with a rapid onset of action and persistent angiotensin II inhibition up to 24 hours. There is no attenuation of this effect after multiple doses. Clinical Pharmacology & Therapeutics (1997) 61, 35–44; doi

Introduction The ability to predict arrhythmia risk in patients with LVSD is important, as the clinical and cost-effectiveness of implantable cardioverter defibrillator (ICD) therapy depends on its use in appropriately selected patient populations. Individual biomarkers can be powerful predictors of prognosis, but studies are limited to small marker panels, chosen a priori. Mass spectroscopy based proteomic techniques can powerfully and simultaneously demonstrate differential candidate proteins in an unbiased fashion but resolving power can be limited by high serum abundant proteins. Depletion methods can overcome this, but often result in coremoval of potential biomarkers too. The aim of the study was to utilise a novel wide spectrum technique to identify candidate biomarkers from the whole proteome associated with arrhythmia outcomes. Methods Consecutive patients attending device follow up clinic were recruited to the study. Serum was collected and stored at −80°C. The occurrence of prespecified arrhythmia end points and death was recorded. Sera were then pooled according to clinical categories occurring during follow up. Grouped sera underwent stable isotope iTRAC labelling, and following protein fractionation and immunodepletion, samples underwent simultaneous tandem mass spectroscopy followed by data processing and identification of differentially expressed protein peaks p Results 243 patients (54% male, age 71±6) were included in the analysis. During follow up of 40 months, there were eight cardiovascular deaths. 25 experienced VT>182 bpm or VF, whilst 48 never experienced VT at any rate/VF (controls). 634 proteins were identified by this method. When compared to the control group, proteins had significant differential expression if twofold up- or down-regulated. Overall, 94 proteins were differentially expressed in those who died or experienced VT>182 or VF. 15 proteins were associated with the arrhythmia endpoint but not death (table 1). BNP was detected by both MS and ELISA, and had greater up-regulation in patients who died, but was not discriminative for arrhythmia occurrence. Conclusions This study provides proof of principle that proteomic techniques can identify candidate proteins for use as biomarkers of arrhythmia risk. Further investigation is needed to select proteins with potential for clinical application before testing in a prospective setting.

Introduction Myocardial scar burden, quantified by MRI, predicts ventricular arrhythmogenesis. MRI use is resource and cost limited in contrast to conventional 12 lead ECG. Manual assessment of ECG time domain features lacks specificity for scar. We hypothesise that frequency and phase domain ECG analysis could yield data indicative of myocardial scar burden. A supervised learning method (support vector machine, SVM) was used to develop a novel computerised algorithm capable of screening ECGs for the presence of myocardial scar, so allowing large data volumes to be processed. Methods 153 consecutive adult patients (age 63±12, male 65%), attending for cardiac MRI with scar analysis for clinical reasons were recruited, and underwent digital ECG acquisition (500Hz, 18bit) at the time of scanning. Semi automated quantification of late gadolinium contrast enhancement was used to identify myocardial scar. The ECGs from those with no scar were used to construct a median template beat for each of the standard 12 leads. ECGs from 35 patients with scar and 35 with no scar were used to train the SVM by feature comparison with the median beat. The algorithm was then tested on the remaining 83 ECGs. Results 16 comparative parameters were included: cross correlation, covariance, magnitude and phase of wavelet coherence, mean value, median value, variance, SD, inter-quartile range, skewness, kurtosis, mobility and complexity of the power spectrum, Hurst exponent slope, detrended fluctuation factor, and differential entropy. Clinical and ECG characteristics in those with scar (age 64±11, LVEF 56±17%, QRS width 115±22 ms) and no scar (age 61±13, LVEF 60±19, QRS width 110±18 ms) were similar (p=NS). The test set consisted of ECGs from 72 patients with scar and 11 patients with no scar. SVM was able to classify the test ECGs with 80.6% sensitivity and 72.7% specificity. Conclusions Digital ECG analysis of frequency and phase signals, using a newly developed SVM, characterises features which classify myocardial scar, but our observations require confirmation in larger prospective studies. The sensitivity and specificity of this approach could make it valuable in population screening for more costly complex investigations such as MRI scanning.

The epidermal growth factor receptor (EGFr) family has been increasingly recognized as an important component in the control of normal cell proliferation and the pathogenesis of cancer. We have studied EGFr expression in 104 cases of hyperparathyroidism by immunocytochemistry (ICC) and by in situ hybridization (ISH). Using two different monoclonal antibodies, ICC for EGFr was performed on 66 cryostat sections and 38 wax-embedded parathyroid glands. ISH was performed on 49 of these glands using a cocktail of three anti-sense probes to EGFr mRNA and a nonspecific control probe to human HPV-18 virus. Breast and prostate tumors were employed as positive controls for both ICC and ISH. Controls demonstrated positive EGFr staining. None of the 104 parathyroid glands showed any ICC positivity. ISH displayed positive staining for EGFr mRNA in five of six carcinomas and eight of nine nonrenal hyperplastic glands. Only 3 of 15 adenomas and 3 of 19 renal hyperplastic glands showed positive staining. This difference was statistically significant between adenoma and carcinoma (p0.05) and between adenoma and nonrenal hyperplasia (p0.01) (Tukey's multiple comparison test). This study demonstrates that EGFr mRNA is present in parathyroid tumors. Expression in carcinoma and nonrenal hyperplasia is significantly different from adenoma and renal hyperplastic glands. In contrast, ICC failed to demonstrate EGFr protein expression. These findings suggest that either receptor numbers are too low to detect by ICC or there is a failure of mRNA translation. More studies are needed to establish whether the EGFr plays a role in the development of parathyroid cancer or hyperplasia.

Background The present study was designed to determine the efficacy and safety of Niaspan (Kos Pharmaceuticals, Inc, Hollywood, FL), a new controlled-release formulation of niacin, in the treatment of primary hyperlipidemia, the occurrence and severity of flushing events, and potential adverse effects, particularly hepatotoxicity. Methods and Results The study was conducted as a multicenter, randomized, double-blind, placebo-controlled, parallel comparison of Niaspan in doses of 1000 mg/day and 2000 mg/day, administered once a day at bedtime. One hundred twenty-two patients with low-density lipoprotein cholesterol levels > 4.14 mM/L (160 mg/dL) with dietary intervention and high-density lipoprotein cholesterol ≤ 1.81 mM/L (70 mg/dL) were randomized to one of three treatment groups: placebo, and 1000 mg/day or 2000 mg/day of Niaspan. Safety and efficacy measures included 12-hour serum fasting lipid and lipoprotein concentrations, serum analyte levels for major organ function, flushing diaries, and adverse event records. The placebo group demonstrated no significant changes in serum lipoprotein concentrations over the treatment period of 12 weeks, except for a slight 4% increase in high-density lipoprotein cholesterol. Niaspan significantly lowered low-density lipoprotein cholesterol levels by 6% and 14% for the 1000 mg/day and 2000 mg/day doses, respectively. High-density lipoprotein cholesterol levels rose significantly, with a 17% increase occurring at the 1000 mg/day dose and a 23% increase occurring at the 2000 mg/day dose. Niaspan (2000 mg/day) produced significant decreases of 27% and 29%, respectively, for serum lipoprotein(a) and triglyceride concentration. Although the incidence of flushing was significant, these episodes were generally well tolerated. Conclusion Niaspan administered in doses of 1000 mg/day and 2000 mg/day at bedtime were well tolerated with few side effects and produced favorable effects on the major circulating lipoproteins of patients with primary dyslipidemias as specified by the enrollment criteria.

High-temperature preheating of sections in the presence of a salt (e.g., citrate) or a protein denaturant (e.g., urea) solution has been shown recently to provide a reliable alternative to tissue proteolysis for antigen retrieval from formaldehyde-fixed, paraffin-embedded tissues. However, the underlying mechanism of action of this form of pretreatment remains highly speculative. In this study, we show that calcium chelating agents such EDTA and EGTA are more effective than citrate in the retrieval of a citrate-sensitive nuclear antigen, Ki-67. Also, sodium carbonate and another calcium precipitating agent are both able to effect antigen retrieval at high temperatures. The overall data therefore suggest that either the chelation or the precipitation of tissue-bound calcium ions, and perhaps also other divalent metal cations, is a critical step in salt-mediated antigen retrieval. As a corollary, it is suggested that tight complexing of calcium ions or other divalent metal cations with proteins during formaldehyde tissue fixation is responsible for the masking of certain antigens.

The effect of intravenous (i.v.) libenzapril was studied in six healthy males by administering i.v. angiotensin I (AI) administered in stepwise increments of 20 ng/kg/5 min until the subjects' systolic blood pressure (SBP) had increased 20-30 mm Hg above baseline. The mean baseline infusion of 63 ng/kg/5 min resulted in a significant (P < 0.05) increase in the ratio of AII to AI plasma levels from 0.52 +/- 0.46 to 7.92 +/- 4.48 and a SBP increase of 120 +/- 7.1 to 147 +/- 5.6. Within 15 minutes of starting the 1-mg infusion of libenzapril over 1.5 hours, the AII/AI ratio decreased to baseline values, and the SBP had returned to baseline in 1 hour. Repeat AI challenges at 3.5 and 5 hours postdose did not increase SBP significantly. Even the 6.5-hour challenge demonstrated only a slight increase in SBP, with an AII/AI ratio of 0.26. At 24 hours, SBP was only 40% of the baseline response, demonstrating that libenzapril is a potent long-acting ACE inhibitor.

A bioequivalency study of an experimental transdermal nitroglycerin system relative to the commercial Transderm-Nitro 0.4 mg/h system was performed on eight healthy volunteers by using an innovative stable isotope technique. Plasma clearance changes for nitroglycerin (NTG) during patch application were corrected with simultaneously administered intravenous infusion of (15)N-labeled nitroglycerin ((15)N-NTG) solution. The total amount of NTG transdermally absorbed (AUC x CL) during a 22-h application for the experimental system was not statistically different from that for the commercial system (9.7 plus minus 3.3 versus 8.1 plus minus 2.6 mg; p = 0.41). The analysis of residual drug content in the used system revealed that the difference in amounts of NTG delivered from the experimental and commercial systems were not significant (12.2 plus minus 3.1 versus 10.8 plus minus 3.1 mg; p = 0.29). With the isotope-labeled method, the absorption rate was evaluated at each time interval during the system application. The peak concentration values were 0.52 plus minus 0.21 mg h(minus sign1) at 1 h for the experimental system and 0.41 plus minus 0.15 mg h(minus sign1) at 2 h for commercial systems. After the peak concentrations, the absorption rates remained constant for both systems over the 16-h period. There was no statistical difference in absorption between the two systems at any sampling time. In this study, substantial fluctuations in the plasma concentrations of both NTG and (15)N-NTG were observed within and between subjects. In addition, the variability in plasma concentrations of NTG correlated well with that of (15)N-NTG for all participating subjects. The momentary changes of clearance, estimated from (15)N-NTG plasma data, were found to be responsible for the fluctuation of NTG in plasma.

3-Methyl-2-(3-pyridyl)-1-indoleoctanoic acid (CGS-12970) is a reversible thromboxane synthase inhibitor that was noted to lower serum uric acid during preliminary trials in humans. Our clinical research unit studied 20 healthy male volunteers who received two doses of CGS-12970 12 hours apart (100, 200, 300, or 400 mg twice a day). Four subjects received placebo as a control. Serum uric acid concentrations decreased between 34% and 47%. Urinary excretion of uric acid increased between 28% and 134% within 12 hours of the first dose. Urinary excretion of uric acid returned to baseline within 24 hours after the last dose. In vitro study of bovine-creme xanthine oxidase inhibitor activity revealed minimal inhibition of xanthine oxidase by either CGS-12970 or its metabolite, CGS-12961. CGS-12970 appears to be a potent reversible uricosuric agent. We hypothesize that the uricosuric effect may be attributable to the acidic properties of CGS-12970 rather than to its inhibition of thromboxane synthase. Clinical Pharmacology and Therapeutics (1993) 54, 65–69; doi:10.1038/clpt.1993.112

Recombinant human insulin-like growth factor-I (rhIGF-I) produced by expression in a yeast vector was evaluated in seven normal men to determine effects on plasma glucose and insulin levels. Each subject received an initial intravenous infusion of normal saline and on the following day, rhIGF-I at a rate of 21.4 micrograms/kg/hour. Each infusion lasted for 7 hours. The subjects' fasting baseline glucose and insulin levels were not statistically different (P > .05) from their pre-dose levels. Compared with the saline (control) infusion, serum glucose levels were statistically lower (P < .05) 2 hours into the rhIGF-I infusion. These lower glucose levels were maintained until the subjects consumed a standard lunch (4 hours into the infusion). Insulin levels demonstrated a similar response to rhIGF-I, but decreases in insulin levels occurred after the rhIGF-I hypoglycemic effect. This observation suggests that suppression of insulin levels may be due to secondary hypoglycemia rather than to a direct rhIGF-I effect. This study demonstrated the desired rhIGF-I effect of lowering subjects' glucose levels without clinically significant hypoglycemia. This finding suggests that rhIGF-I may have potential clinical utility in hyperglycemic states.

This study was designed to investigate the predictive value of the event-related potentials (ERPs) preceding the initiation of a difficult perceptual-memory task and to investigate whether these ERPs require a motor movement on the part of the subject for their occurrence. Across 4 conditions the DC-potential shifts were recorded from 23 right-handed subjects using DC amplifiers. Although the start of each trial began with a ready signal, the conditions differed in that the subjects initiated the task by a button press in 2 conditions and the computer initiated it in 2 others without a press. The results showed that, especially in the frontocentral electrode sites, the DC-potential shifts which began those trials ending in correct performance were more negative relative to those trials ending in an incorrect response. Those conditions which required the subjects to self-initiate the trial and those which were initiated by the computer showed similar results indicating that the negative DC-potential shifts preceding correct performance are neither produced by nor depend on a task initiating motor movement. The onset of the DC-potential shifts preceded task initiation by up to 4.1 sec indicating that they were more than the Bereitschaftspotential.

The National Cholesterol Education Program (NCEP) guidelines recommend dietary restriction of fat and cholesterol to reduce high circulating cholesterol concentrations in adult Americans. Thus, diet counselors recommend consumption of fewer than four egg yolks per week. The present protocol was designed to determine whether the efficacy of an NCEP diet would be reduced by the incorporation of 12 modified eggs per week, and whether the resulting low fat, high cholesterol diet would increase serum lipid concentrations in adults with initial undesirably high (5.17-7.76 mmol/L) concentrations of serum total cholesterol. Feeding a controlled ration to laying hens produced modified eggs that consistently contained more vitamin E and iodine, and more unsaturated fat, than generic eggs. Subjects were randomly assigned to and NCEP diet including either no whole eggs or 12 whole study eggs a week. Ninety-eight subjects completed the parallel study. Subjects in both groups significantly reduced their serum total, LDL and HDL cholesterol (P < 0.001 for total and LDL cholesterol, P < 0.02 for HDL cholesterol) over the 6 wk of study. No significant differences were found between diet groups. We conclude that the study eggs did not adversely affect measured lipid concentrations when added to a low fat diet that favorably alters lipid profiles in hypercholesterolemic subjects.

Abnormal dispersion of repolarization may contribute to the arrhythmogenic physiologic substrate of ventricular arrhythmia. Geographic dispersion of monophasic action potential duration was determined in steady state (drive cycle lengths 600 and 430 ms) between widely spaced right ventricular endocardial sites (geographic dispersion) in 10 control patients with right ventricular disease and complicating ventricular tachycardia (n = 9), 6 patients with right and left ventricular disease and complicating ventricular tachycardia and 7 patients with ischemic heart disease and complicating ventricular tachycardia. No significant difference in geographic dispersion could be demonstrated among the groups. Difference of monophasic action potential duration at adjacent right ventricular endocardial sites (adjacent dispersion) was determined after ventricular extrastimulation during construction of simultaneous electrical restitution curves in the same patient groups. Maximal adjacent dispersion over the electrical restitution curve was compared between disease and control groups. There was a significant difference in observations of maximal adjacent dispersion in patients with right ventricular disease and complicating ventricular tachycardia (range 5 to 85 ms, median 22.5; 14 pairs of sites; p less than 0.05) and patients with right and left ventricular disease and complicating ventricular tachycardia (range 5 to 50 ms, median 17.5; 14 pairs of sites; p less than 0.05) compared with control patients (range 5 to 20 ms, median 10; 15 pairs of sites). This difference was not evident when patients with ischemic heart disease and complicating ventricular tachycardia (range 5 to 25 ms, median 12.5; 12 pairs of sites) were compared with control patients. Maximal percent monophasic action potential shortening from steady state was significantly greater (p less than 0.001) in both groups with greater adjacent dispersions, and prolongation of activation time at monophasic action potential recording sites after premature extrastimulation tended to be greater in patients with right or right and left ventricular disease and complicating ventricular tachycardia. It is concluded that in disease, exaggeration of monophasic action potential shortening after premature ventricular extrastimulation may contribute to the electrophysiologic arrhythmogenic substrate.

OBJECTIVE--To characterise electrical restitution in the intact human heart. PATIENTS AND METHODS--A series of monophasic action potential electrical restitution curves were constructed from a single right ventricular endocardial site in eight patients (three men) without structural heart disease aged 52-68 (mean 55 years). A combination pacing/monophasic action potential electrode was used to pace and record monophasic action potentials at drive cycle lengths of from 350 ms to 1500 ms. Ventricular extrastimuli were delivered at 20 cycle intervals and decreased from the longest coupling interval attainable without escape beats. RESULTS--Restitution curves shifted downward and towards the left; steady state action potential duration shifted from the restitution plateau and descended the curve, the amount of shift being linearly related to drive cycle length in two patients in whom the relation could be assessed; the amount of monophasic action potential shortening was a function of the degree of prematurity and that relation was unaffected by drive rate; the magnitude of restitution and the time constant of the restitution curve were not changed significantly by altered drive cycle length. CONCLUSION--In the intact heart in vivo, electrical restitution (of the monophasic action potential) has similar characteristics to those (of the transmembrane action potential) in cellular preparations in vitro. Thus the alteration of action potential plateau currents by instantaneous rate change or drug effects, which can be directly observed by techniques available to the cellular electrophysiologist, may be indirectly assessed in vivo by characterisation of the effect of these on electrical restitution.

Background: Recent innovations in HER2 testing include the development of novel chromogenic in situ hybridisation tests. Most countries use FISH or ISH based testing for HER2 gene amplification in equivocal (IHC 2+) cases. Data on the reproducibility and portability of novel and even established HER2 ISH methods is sparse. We report initial results from the multicentre evaluation of intra and inter-observer/site variation in scoring HER2 results from 30 breast cancers measured in 5 laboratories using the Ventana Dual colour ISH assay.Methods: A commercially available tissue micro-array (TMA; Stretton Scientific UK) containing 2 replicate cores from 30 breast cancers was circulated to 5 UK NEQAS reference laboratories (numbered 1-5). All laboratories performed chromogenic ISH using a 60 core TMA and reported results for all assessable cores. For all cases 20 cells were scored and a further 20 cells scored on a separate occasion to check intra-observer variation. Results were collated centrally and compared with FISH peformed in a single laboratory. Concordance between FISH and CISH is reported on a core by core and case by case analysis. Intra and inter-observer variation between laboratories is also assessed. Finally regression analysis comparing results was performed. Results from a single laboratory are presented here and full results will be available for the meeting.Results: 93% of cores were successfully analysed by the Ventana dual colour ISH assay. 87% of cores were successfully analysed by PathyVision® FISH CISH was concordant with FISH in 96.4% of cores evaluated. In one sample FISH results were 2.05 & 1.93 vs CISH of 2.03 and 2.14. In a second sample FISH results were 1.60 & 1.53 versus CISH results of 2.00 & 1.65. When mean results were calculated (2 cores per case) concordance between FISH and CISH results for this laboratories was 96.7% (1 discordant case – mean FISH – 1.99, mean CISH 2.09). 48 cores were scored twice (20 cells x 2) by a single observer. Mean intra-observer variation (for HER2 ratio) was 1.72% (Range 0.0-7.42%). No difference in scores was observed for the first vs second 20 cells. Scoring 40 cells produced no advantage. For results from a single observer for 2 cores (intra-site variation) from 42 core pairs (each core counted twice) variation was 7.5%.Conclusions: Preliminary evidence from the current study suggest that the Ventana INFORM™ HER2 dual colour single slide ISH assay can be robustly evaluated using conventional scoring approaches (20 cells per case). Concordance with FISH was excellent in the single laboratory reporting results to date. Further evidence will be reported from the other 4 participating laboratories. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6011.

The American Society of Clinical Oncology/College of American Pathologists guidelines highlighted the critical importance of quality assurance in diagnostic testing for HER2.Unstained formalin-fixed, paraffin-embedded human breast carcinoma cell line sections were circulated to scheme participants on 15 occasions over 5 years. “Reference laboratories” reported results for the HER2/chromosome 17 ratio and HER2 copy number for 5 years for each cell line. Results from the 5th years participants (3 runs 13, 14, 15) were assessed for the pass rate in UK versus rest of the world (EU, US, Asia, etc). The number of participants was 76-78 laboratories/run (UK 30-35, ROW 43-46).Results: The percentage of laboratories achieving “appropriate” results ranged from 78-82% overall. Significantly higher performance was observed over 3 runs for UK laboratories (91-97%, “appropriate” results) versus ROW laboratories (67-74% “appropriate” results), p = 0.004. All methods used by scheme participants in UK Laboratories had excellent performance rates (Pathvysion, PharmDx, Ventana SISH/Inform, Kreatech Posieden). However in the ROW there was evidence of poor performance, which may be related to the assay format, although numbers of comparisons are relatively small.Participation in external quality assurance schemes is a valuable mechanism for evaluation and benchmarking of performance between laboratories. It also serves to improve consistency of HER2 testing by in situ hybridization. Using data from the UK NEQAS scheme we identified that laboratories whose performance is monitored and linked to an intergrated corrective action component(UK laboratories) perform consistently better than laboratories where performance data alone is provided (ROW). In the UK both participation and adequate performance in a national EQA scheme is required for laboratory accreditation. Whilst, in the context of robust EQA there is no evidence that different methods affect performance, in the ROW implementation of some assays appears sub-optimal. This poor performance does not, however, identify fundamental flaws with these methods, which are currently very well controlled amongst UK users but suggests greater attention to EQA results and change to improve laboratory performance is required in the rest of the world. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6010.

Reduction of pulmonary vascular resistance by a high inspired oxygen concentration is a common, but not universal phenomenon in patients with pulmonary vascular disease of varying etiology that may determine their response to long-term domiciliary oxygen therapy. We therefore determined changes in PVR during oxygen therapy in two patient populations not previously studied: systemic sclerosis (n = 8, mean age +/- SEM, 44.5 +/- 5.4 years) and primary pulmonary hypertension (n = 7, mean age +/- SEM 38 +/- 7.8 years). All patients were hypoxemic (arterial oxygen tension, on air 9.5 +/- 1.2 kPa for SSc and 8.3 +/- 0.6 kPa for PPH, p greater than 0.05). Right atrial pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, systemic arterial pressure, PaO2 and cardiac output by thermodilution were measured at three, 20-min intervals while inspiring air and again after inspiring 60 percent oxygen for 30 min. The PVR fell significantly with oxygen in patients with SSc from 797.6 +/- 179.2 to 610 +/- 151.6 dynes/s/cm-5 (p less than 0.01), and this fall correlated with baseline PAP and PaO2 prior to oxygen therapy (r = 0.86, p less than 0.025; r = 0.77, p less than 0.05, respectively). In patients with PPH, there was no significant fall in PVR with oxygen (from 969 +/- 80.2 to 851.9 +/- 91.2 dynes/s/cm-5, p greater than 0.05) and no predictor of a vasodilator response in individual patients. In SSc, hypoxic pulmonary vasoconstriction contributes more consistently to elevated PVR than in patients with PPH.

Adaptation of effective refractory period (ERP) and monophasic action potential (MAP) shortening after a step increase in drive frequency was determined at adjacent endocardial sites in the right ventricle of six patients without myocardial disease. ERP and MAP shortening occurred simultaneously. ERP shortening and MAP shortening were similar in time course in individuals, although the degree of shortening varied between individuals as the size of the step increase in pacing frequency varied. Shortening of both ERP and MAP was complete after a mean of 67 +/- 7.5 seconds. To allow group analysis, the percent change from baseline of action potential duration and ERP was calculated for each patient at intervals during adaptation and mean percent change for the group plotted against time from the beginning of the step rate increase. A mean step increase in pacing frequency of 49.3% of baseline for the group caused the ERP to shorten by a mean of 18.12%, and MAP90 by 17.43% of baseline. There was no significant difference (P = 0.05) between the action potential and ERP adaptation curves of the group. We conclude that in normal myocardium, there is a close relationship between shortening of ventricular ERP and action potential duration after a change in rate.

Coronary arterial occlusion may occur experimentally during acute myocarditis but has not been documented in man. We report the case of a young female with severe myocarditis who later required cardiac transplantation and in whom coronary occlusion was demonstrated arteriographically before transplantation and by pathological examination of the heart after explantation.

Using appropriate dietary modification, many studies have shown a beneficial impact of serum cholesterol lowering on the risk of coronary heart disease (CHD). In addition, an association between certain types of food, specifically the consumption of nuts, has been associated with reduced cardiovascular risks. Two small studies carried out in volunteers in a controlled environment provided suggestive evidence for a cholesterol lowering effect attributable to walnut ingestion. The purpose of this study was to determine whether the consumption of walnuts by hypercholesterolemic, free living men and women had a favorable effect on their serum lipid levels [total cholesterol (TC), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TG)] when consumed as part of a NCEP Step I diet. A total of 67 subjects with total cholesterol levels >200 mg/dl enrolled in an open-label, randomized, crossover design trial. Subjects received diet instruction by a registered dietitian on the NCEP Step I diet and maintained 3-day diet records between visits. Subjects completed a 6-week dietary lead-in period during which lipid response to this diet was established. Subjects were then randomly assigned to one of two treatment groups for a 6 week period: continuation of Step I diet (reference diet group) or to a diet group wherein subjects consumed 2.25 ounces/day of walnuts as part of the NCEP Step I diet (the Walnut diet). After 6 weeks, all patients were switched to the alternate diet for an additional 6-week period. Results of the study showed that TC, LDL-C, and TG levels remained stable when subjects were randomized to the reference diet. However, while consuming the Walnut diet, subjects demonstrated a reduction in TC by 3%, LDL-C by 4% and TG by 12%. These changes in lipid levels demonstrated a beneficial trend of the Walnut diet (p= 0.10, NS) and no adverse changes in serum lipoprotein regulation. The results suggest that consumption of walnuts favorably affect serum lipid levels, and can be used as a flavorflil snack while adhering to the NCEP Step I diet.

During 1970-87 43 patients with unexplained pulmonary hypertension (mean pulmonary arterial pressure greater than 25 mm Hg) were admitted to the Brompton Hospital and classified by angiographic criteria as having either symmetrical peripheral pulmonary artery pruning (thought to represent primary plexogenic pulmonary arteriopathy), n = 21, or asymmetrical pulmonary arterial occlusions (thought to represent chronic thromboembolic disease), n = 22. Patients with symmetrical pulmonary arteriopathy had significantly higher mean pulmonary arterial pressures (67 mm Hg) at the time of presentation than those with asymmetrical pulmonary arteriopathy (49 mm Hg). Clinical distinction between these two groups was impossible. Survival from the time of diagnosis was similarly poor in the two groups (26 weeks and 38 weeks) and did not correlate with any of the haemodynamic measurements. The difficulties in making distinctions between these conditions are discussed.

If retrograde arterial catheterization of the left ventricle fails because of a stenosed native or tissue valve or is contraindicated because of the presence of a mechanical aortic prosthesis, then alternative routes of access to the left ventricle are either transseptal or direct (transapical) left ventricular puncture. The transseptal approach is contraindicated in the presence of a mechanical mitral valve prosthesis. Under these circumstances we have used direct transapical left ventricular puncture in the treatment of 112 patients and have found this technique to be successful with little associated risk. A major complication occurred in 3% of the patients, but the study provided the required data in 95%, and these figures compare favorably with the reported results of transseptal catheterization.

This article describes three applications of the Universal Soil Loss Equation for further defining differences between natural environments in terms of their suitabilities for recreation use. Physical capacity limits based upon vulnerability to erosion and loss of soil productivity are discussed. Examples include: (a) applications to site planning and comparison of existing campsites; (b) use of the methodology for setting limits of acceptable change; and (c) characterization of third-order or larger watersheds that compare ecological land type interpretations with those based upon application of the equation.

Utilizing an adaptation of the Universal Soil Loss Equation, this article discusses a method for approximating the physical carrying capacity of natural areas for outdoor recreation. Classification of forested woodland and field environments is based upon the conversion of ground cover coefficients to the percentage of ground cover required to maintain soil productivity over time. Four canopy types, three canopy densities, and two general types of ground cover are recognized in the equation as well as soil characteristics, topographical variations, and rainfall velocities and intensities. The method requires that the areal distribution of soils occurring within natural areas be mapped. Approximations will vary according to the intensity of the planning desired, and may range from a general classification of large land areas to highly site-specific evaluations. Data generated from over 40 years of cooperative research form the basis for classifying natural areas according to their relative physical capacities to accommodate outdoor recreation.

Between 1964 and 1986 a total of 71 pulmonary embolectomies were performed for acute massive pulmonary embolism. All patients were severely compromised haemodynamically. Sixteen (64%) of 25 patients who had sustained significant periods of cardiac arrest before operation died. The principal cause of death in this group was severe neurological damage. Five (11%) of the 46 who had not had a cardiac arrest died. The 50 (70%) patients who survived did so largely without morbidity during their hospital admission and in the follow up period. Most were not treated with long term anticoagulants and only two had another embolism. When a patient with acute massive pulmonary embolism is too ill to be given thrombolytic treatment, or when thrombolysis is either contraindicated or too slow in producing benefit, pulmonary embolectomy remains an effective alternative treatment with an acceptable mortality.

The treatment of ameloblastoma is briefly presented. A case, which may represent the largest ameloblastoma successfully removed, has been presented. An unusually good cosmetic result was obtained without prosthesis or bone graft. Certain advances in the management of such cases are suggested.

A young man with Takayasu's disease had severe right and left coronary ostial stenoses. Severe angina was relieved by operation at which the right coronary ostium was enlarged by a pericardial patch extending across the stenosis from aorta to coronary artery; the aortic end of a vein graft to the left coronary artery was attached to this patch. This technique may reduce the risk of recurrence of ostial stenosis or of stenosis at graft origins.