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Background The purpose of this study was to show the similarity between the pericardial constraint over the right and left ventricles of humans at various levels of central venous pressure (CVP) using flat Silastic balloons in the pericardial space during elective cardiac surgery. Methods Six subjects (aged 19-76 years) were instrumented with flat, liquid-containing Silastic balloons in the pericardial space during elective cardiac surgery. No subject had valvular disease or right ventricular (RV) hypertrophy. These balloons were positioned to lie over the RV and left ventricular (LV) free walls to measure RV and LV pericardial pressure (P prv and P plv , respectively). Volume loading was achieved by an intravenous infusion of 1 to 2 L of Ringer's lactate or normal saline. Depending on the patient's status during the operative procedure, the mean CVP was increased by 5-10 mm Hg from the baseline postinduction levels. RV and LV pericardial pressures were measured continuously throughout the volume loading. Results The pooled data from all subjects demonstrate that RV pericardial pressure is equal to LV pericardial pressure over central venous pressures ranging from 4 to 18 mm Hg and that the RV late-diastolic (pre–a-wave) cavitary pressure (P rv ) correlates with LV pericardial pressure. Conclusions Changes in LV pericardial pressure are approximately equal to changes in RV pericardial pressure and RV late-diastolic (pre–a-wave) cavitary pressure is a good predictor of LV pericardial pressure.

Production of the blue-pigmented antibiotic actinorhodin is greatly enhanced in Streptomyces lividans and Streptomyces coelicolor by transformation with a 2.7-kb DNA fragment from the S. coelicolor chromosome cloned on a multicopy plasmid. Southern analysis, restriction map comparisons, and map locations of the cloned genes revealed that these genes were different from other known S. coelicolor genes concerned with actinorhodin biosynthesis or its pleiotropic regulation. Computer analysis of the DNA sequence showed five putative open reading frames (ORFs), which were named ORFA, ORFB, and ORFC (transcribed in one direction) and ORFD and ORFE (transcribed in the opposite direction). Subcloning experiments revealed that ORFB together with 137 bp downstream of it is responsible for antibiotic overproduction in S. lividans. Insertion of a phi C31 prophage into ORFB by homologous recombination gave rise to a mutant phenotype in which the production of actinorhodin, undecylprodigiosin, and the calcium-dependent antibiotic (but not methylenomycin) was reduced or abolished. The nonproducing mutants were not affected in the timing or vigor or sporulation. A possible involvement of ORFA in antibiotic production in S. coelicolor is not excluded. abaA constitutes a new locus which, like the afs and abs genes previously described, pleiotropically regulates antibiotic production. DNA sequences that hybridize with the cloned DNA are present in several different Streptomyces species.

Objective: This study was undertaken to evaluate transit-time flow (TTF) as a tool to detect technical errors in arterial bypass grafts intraoperatively and predict outcomes. Methods: TTF's three parameters, pulsatility index (PI, index of resistance), flow (cc min -1 ) and diastolic filling (DF, proportion of diastole with coronary flow), were measured in 990/1000 (99%) of arterial grafts in 336 consecutive patients, prospectively enrolled in a database. Grafts were revised when TTF findings supported the otherwise suspected graft malfunction. If no other signs/suspicion of graft malfunction existed (normal electrocardiogram (EKG), stable haemodynamics and unchanged ventricular function on trans-oesophageal echocardiography (TEE)), and the PI was >5, grafts were not revised. Major adverse cardiac events (MACEs: recurrent angina, perioperative myocardial infarction, postoperative angioplasty, re-operation and/or perioperative death) were related to TTF measurements. Results: The average number of grafts per patient was 3.02, of which 99% were arterial. Satisfactory grafts were achieved in 916/990 (93%) of the grafts, with flows from 34 to 61 cc min 1 , PI ≤5 and DF of 62-85%. Fourteen conduits, 20 grafts (2%) suspected to be problematic, were revised. Patients were divided into two groups: 277 (82%) with at least one graft with PI ≤5 and 59 (18%) with a PI >5. MACE occurred in 25 (7.4%) patients -15/277 patients with a PI ≤5 (5.4%) and 10/59 with a PI >5 (17%, p = 0.005). Mortality following non-emergent surgery was significantly higher in patients with a PI >5 (5/54, 9%) than in patients with a PI

RECONSTRUCT OR NOT— LESSONS FROM THE STICH TRIAL To the Editor: Recently at the 89th Annual Meeting of The American Association for Thoracic Surgery in Boston, May 9–13, 2009, there was a very clarifying debate on the STICH trial (Surgical Treatment for Ischemic Heart Failure) between Dr Robert H. Jones (pro) and Dr Gerald D. Buckberg (con), moderated by Dr Andrew S. Wechsler, which sparked the following thoughts. Clearly, surgeons involved in the STICH trial had a difficult job: they were instructed to include patients in the trial if they honestly believed they could undergo coronary artery bypass grafting (CABG) either alone or in combination with surgical ventricular reconstruction (SVR) with safety. It would seem likely that, ethically, patients with either global hypokinesis (no clear-cut aneurysm) or those with large aneurysms would be hard to include in this trial. Also, results of the two patient groups (CABG alone vs CABGþSVR) are uncannily similar: identical improvements in congestive heart failure and angina class for both groups (1.7 and 1.0, respectively), increase in distance on the 6-minute walk test (48 vs 52 m), death or hospital readmission for cardiac cause (59% vs 58%), death from any cause (28% vs 28%), hospitalization for cardiac cause (42% vs 41%), and operative mortality astreated (5% vs 6%) or as intentionto-treat (5% vs 5%). These results are practically identical as if coming from a single patient population divided in half..because they are. They were selected by ethical surgeons aware of the extensive current literature by many expert surgeonscientists working on hibernating myocardium (no aneurysm, poor ventricles) and overgrown ventricles resulting from infarction (aneurysm causing poor function). Perhaps during the conception of STICH such knowledge was not available, but perhaps the performance of SVR (or not) has reached the level of the ‘‘randomized controlled study of the parachute.’’ The real message of the STICH trial is this: if one is pondering treatment of patients with poor ventricular function and mild aneurysmal dilatation, do not perform the SVR surgery, because if you do not send the patient to heaven, you will only prolong his or her and your own suffering (increased crossclamp, operative, and intensive care unit times and total length of stay) with no clinical benefit in ensuing years. The STICH investigators and surgeons are to be congratulated for their ethical dealing with this controversial topic. However, the message that CABG surgery alone is enough for patients with coronary artery disease and left ventricular aneurysms should not be interpreted from the STICH trial, as many patients with disabling left ventricular aneurysms would be at risk for the wrong treatment.

Implantable defibrillators reduce the risk of sudden death in patients with malignant ventricular arrhythmias, but significant restriction in quality of life can occur as a result of frequent device activation. To determine if a device that provides both antitachy-cardia pacing and shock therapy can safely reduce the frequency of shocks after implantation, 46 consecutive patients undergoing initial implantation of a defibrillator were studied. In all patients, the implanted device provided antitachycardia pacing and shock therapy. Detected tachycardia characteristics and the results of therapy were stored in the device's memory.There were 42 men and 4 women, aged 26 to 71 years (mean 58.7 ± 13.5). Left ventricular ejection fraction ranged from 13% to 67% (mean 32.2 ± 13.4%) and 31 patients had experienced one or more episodes of cardiac arrest. Induced arrhythmias included sustained monomorphic ventricular tachycardia in 38 patients, nonsustained polymorphic ventricular tachycardia in 2 and ventricular fibrillation in 4.Over a total follow-up period of 255 patient-months (range 1 to 13, mean 6.1), 25 patients experienced spontaneous arrhythmic events. In 22 patients, 909 episodes of tachycardia were treated by antitachycardia pacing, which was successful on 840 occasions (92.4%). Acceleration of ventricular tachycardia by pacing therapy was estimated to have occurred 39 times. Syncope occurred once during pacing-induced acceleration of ventricular tachycardia. Forty-four episodes of tachycardia in seven patients were treated directly by shocks because of short tachycardia cycle length; 88% of all detected tachycardias were treated without the need for shocks. Four patients died from cardiorespiratory failure and one patient died suddenly without any detected tachyarrhythmia.These initial results demonstrate that a device that provides graded therapy with antitachycardia pacing for ventricular arrhythmias reduces the need for high energy shocks and rarely results in detrimental delays in the treatment of ventricular tachycardia.

Background Surgery is of increasing importance in the treatment and outcome of diseases of the pancreas worldwide. The incidence of pancreatic cancer (7—11/ 100,000 per year) has risen over the last years and surgical resection remains the only option for definite cure. Twenty-five percent of all resections are left of the superior mesenteric vein (distal pancreatectomy) and the appropriate closure technique for the pancreatic remnant remains unclear. Pancreatic fistulas are the most common (0—40%) and relevant postoperative complication. The optimal surgical strategy for pancreatic resection needs to be identified from the large number of surgical procedures available today.Purpose To evaluate the effectiveness of the two most common surgical techniques for distal pancreatectomy: stapler versus hand-sewn closure of the pancreatic remnant.Methods In order to account for the uncertainty and clinical heterogeneity in the management of the pancreatic remnant following distal pancreatectomy, a study protocol is developed on the basis of a retrospective survey of patients in a center of excellence for pancreatic surgery and a systematic review with meta-analysis.Results The DISPACT trial is a multicentered, randomized, controlled and patient-and observer-blinded trial using a two-group parallel group-sequential superiority design to compare the two techniques mentioned above. It will include approximately 336 randomized patients at up to 20 centers of excellence in pancreatic surgery, who are undergoing elective distal pancreatectomy for resectable benign, malign, and neuroendocrine tumors, chronic pancreatitis and pseudocysts of the pancreatic body and tail. The combination of the rate of postoperative pancreatic fistula and mortality will be evaluated as the primary endpoint. In addition, a set of general and surgical parameters will be analyzed. Pre-specified treatment manuals and continuous intra-operative (photo-documentation of surgical procedures and blinded evaluation thereafter) and on-site monitoring will assure that the treatment of the study patients conforms to protocol and will minimize clinical heterogeneity. Due to uncertainties about the effect sizes of the primary endpoint, an a priori planned interim analysis of the primary endpoint will be conducted after 224 evaluable patients are selected in order to reassess the initially planned sample size. Limitations Since pre-existing evidence was limited our initial sample size calculation is based on uncertain assumptions and may need to be modified in a planned interim analysis. Moreover, since surgical experience remains a potential confounder in surgical trials, learning curve bias has to be taken into account when analyzing the results. Given the participating trial sites, standardization of peri-and postoperative treatment represents a major issue of trial conduct.Conclusions A group-sequential study design accounts for the uncertainty of pre-existing evidence. Also, standardization of surgical and postoperative care and blinded outcome assessment as well as adjustment for varying surgical expertise will contribute to a high validity and generalizability of the results. Clinical Trials 2008; 5: 534—545. http://ctj.sagepub.com

Based on the original data from two double-blind, randomized, placebo-controlled clinical trials and the acute phase of a long-term study that investigated the antidepressant efficacy of St. John’s wort extract WS® 5570, we present a re-analysis of a subset of patients suffering from an acute episode of mild depression according to DSM criteria. Out of a total of more than 1,200 patients included into these trials 217 had a pre-treatment total score ≤20 points on the 17-item Hamilton Rating Scale for Depression (HAMD) and were eligible for our re-analysis. They received 600, 900, or 1,200 mg/day WS® 5570 or placebo for 6 weeks. In patients treated with WS® 5570 the HAMD total score decreased by averages of 10.8 (600 mg/day), 9.6 (900 mg/day), and 10.7 (1,200 mg/day) points between the pre-treatment baseline value and the end of acute treatment, compared to 6.8 points in the placebo group (p < 0.01 for all pairwise comparisons of WS® 5570 against placebo). This corresponded to average relative decreases by 49–57% for WS® 5570 and by 36% for placebo. The rates of responders (i.e., patients with a HAMD total score decrease ≥50%) were 73%, 64%, 71%, and 37% for WS® 5570 600 mg/day, 900 mg/day and 1,200 mg/day, and placebo, respectively. At the end of acute treatment 57% of the patients treated with WS® 5570 600 mg/day, 33% in the 900 mg/day group and 62% in the 1,200 mg/day group, as well as 25% in the placebo group were in remission (HAMD total score ≤7 points). The analysis shows that St. John’s wort extract WS® 5570 has a meaningful beneficial effect during acute treatment of patients suffering from mild depression and leads to a substantial increase in the probability of remission.

Objective: To evaluate the efficacy and safety of the natural platelet-activating factor receptor antagonist, BN 52021 (ginkgolide B) in the treatment of patients with severe sepsis related to Gram-negative and mixed bacterial infection. Design and setting: Prospective, randomised, double-blind, placebo-controlled, multicentre study carried out in 13 academic medical intensive care centres in Germany with up to 14 patients per centre. Patients: 88 patients with severe sepsis under standard medical and surgical care: nine patients with pure Gram-positive infection, 79 patients with Gram-negative or mixed bacterial infections (subgroup for which efficacy was to be established). Interventions: Patients were randomised to receive either placebo or BN 52021 1.25 mg/kg body weight intravenously every 12h over a 4-day period in addition to their standard medical and surgical care. Main outcome measures and results: The primary efficacy variable was the 28-day all-cause mortality rate. The treatment groups were similar with respect to demographic data and prognostic factors influencing the outcome except for bodyweight and adequacy of antibiotic therapy. Analysis of patients with Gram-negative or mixed bacterial infection, for which efficacy was to be established, resulted in a 28-day all-cause mortality of 42.5% in the placebo group (n = 40; 17 deaths) versus 38.5% in the BN 52021 group (n = 39; 15 deaths). Among all randomised patients, the 28-day all-cause mortality rate was 40.9% in the placebo group (n = 44; 18 deaths) and 38.6% in the BN 52021 group (n = 44; 17 deaths). There were no differences in frequency and severity of adverse events between the two treatment groups. Conclusions: Four-day administration of BN 52021 failed to demonstrate a statistically significant reduction in mortality in patients with severe sepsis suspected or confirmed to be related to infections other than Gram-positive bacterial infection.

BACKGROUND: The CORONARY trial (NCT00463294, N1⁄44752 patients randomly assigned to offor on-pump CABG) demonstrated similar results between off-pump CABG compared with on-pump CABG at 1 year. As CABG aims to restore adequate blood supply to the ischemic heart, the success of the operation depends mainly on the patency of the grafts. The long-term patency, especially vein grafts, is limited and graft failure has consequences similar to those of native coronary artery disease: recurrent angina, myocardial infarct (MI), additional revascularization procedures, or death. It is still debated whether off-pump CABG surgery is associated with worse graft patency when performed by skilled surgeons in higher risk patients. The purpose of this study was to determine whether off-pump compared to on-pump is associated with lower CABG patency, and if there is an association between graft failure and clinical outcomes. METHODS: PATENCY-CORONARY (NCT01414049) is a multicenter trial of a consecutive subset of patients from the CORONARY trial undergoing graft patency assessment using non-invasive ECG-gated computed tomography angiography (CTA). All CORONARY patients from 3 high volume offpump CABG Canadian Centers reaching one-year follow-up (window of eligibility 9 months-24 months) were systematically approached to be included in the study. RESULTS: From the 335 patients eligible to participate in PATENCY-CORONARY (no kidney failure, no atrial fibrillation, NYHA

Information about adverse drug reactions plays an important role when assessing the benefit/risk profile of a drug. Identifying rare adverse drug reactions, however, is a difficult task. This paper illustrates the advantages of using a prescription database for this purpose.The mediplus database used in our analysis covered data from 320,644 outpatients observed between July 1999 and June 2002. The example of bleeding complications during intake of antidementia drugs is used to illustrate this approach. The comparison of cohorts and subgroups is nearly always a problem in surveys. For our analyses we considered a set of patients who had taken a selected medication for a certain period of time and compared the frequency of adverse events with those occurring when the same patients did not take this medication. Hence, the comparison with versus without a certain medication is based on the same set of patients as in a cross-over study.Our evaluations indicate that the rate of bleeding complications is low when taking any of the widely used antidementia drugs, glutamate modulators, cholinesterase inhibitors, calcium antagonists or the phytomedicine Ginkgo biloba.Basing the comparison of the rates of complications during periods with and without intake of a certain drug on the same set of patients may be a useful tool for assessing adverse drug reactions from data reported in prescription databases.

ContextAtrial tachyarrhythmias after cardiac surgery are associated with adverse outcomes and increased costs. Previous trials of amiodarone prophylaxis, while promising, were relatively small and yielded conflicting results.ObjectiveTo determine whether a brief perioperative course of oral amiodarone is an effective and safe prophylaxis for atrial tachyarrhythmias after cardiac surgery overall and in important subgroups.Design, Setting, and PatientsDouble-blind randomized controlled trial of 601 patients listed for nonemergent coronary artery bypass graft (CABG) surgery and/or valve replacement/repair surgery between February 1, 1999, and September 26, 2003, at a tertiary care hospital. The patients were followed up for 1 year.InterventionOral amiodarone (10 mg/kg daily) or placebo administered 6 days prior to surgery through 6 days after surgery (13 days). Randomization was stratified for subgroups defined by age, type of surgery, and use of preoperative β-blockers.Main Outcome MeasureIncidence of atrial tachyarrhythmias lasting 5 minutes or longer that prompted therapy by the sixth postoperative day.ResultsAtrial tachyarrhythmias occurred in fewer amiodarone patients (48/299; 16.1%) than in placebo patients (89/302; 29.5%) overall (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.34-0.69; P

The sequencing of the entire genetic complement of Streptomyces coelicolor A3(2) has been completed with the determination of the 365,023 bp sequence of the linear plasmid SCP1. Remarkably, the functional distribution of SCP1 genes somewhat resembles that of the chromosome: predicted gene products/functions include ECF sigma factors, antibiotic biosynthesis, a gamma-butyrolactone signalling system, members of the actinomycete-specific Wbl class of regulatory proteins and 14 secreted proteins. Some of these genes are among the 18 that contain a TTA codon, making them targets for the developmentally important tRNA encoded by the bldA gene. RNA analysis and gene fusions showed that one of the TTA-containing genes is part of a large bldA-dependent operon, the gene products of which include three proteins isolated from the spore surface by detergent washing (SapC, D and E), and several probable metabolic enzymes. SCP1 shows much evidence of recombinational interactions with other replicons and transposable elements during its history. For example, it has two sets of partitioning genes (which may explain why an integrated copy of SCP1 partially suppressed the defective partitioning of a parAB-deleted chromosome during sporulation). SCP1 carries a cluster of probable transfer determinants and genes encoding likely DNA polymerase III subunits, but it lacks an obvious candidate gene for the terminal protein associated with its ends. This may be related to atypical features of its end sequences.

The degree to which the lungs and other mediastinal structures constrain the heart during cardiac surgery is uncertain.To assess the degree of constraint to left ventricular (LV) filling that is present during cardiac surgery.Central venous (CVP) and pulmonary capillary wedge pressures (PCWP), and an index of LV end-diastolic volume (LVEDV) - LV area, transesophageal echocardiography - were measured before and after sternotomy, after volume loading, after pericardiotomy, and before and after sternal closure following the clinically indicated procedure in 12 patients undergoing cardiac surgery. PCWP and estimated transmural LVEDP (PCWP-CVP) were plotted against the LV area.In all patients, the difference between PCWP and estimated transmural LVEDP-LV area relations over the full range of LV areas was substantial, indicating the presence of important constraint to filling. Even at small LV areas, when transmural LVEDP approached zero, PCWP was almost always greater than 10 mmHg. Because transmural LVEDP approached zero when areas were smallest, transmural LVEDP-LV area relations were judged to be more plausible than the corresponding PCWP-LV area relations.Considerable constraint to cardiac filling is effected by the lungs and other mediastinal structures. This constraint must be considered when assessing LV filling pressure - PCWP is not a reliable measure of LV preload in these circumstances.

The aim of the study was to carry out an economic evaluation of the therapeutic effects achievable with ginkgo special extract Egb 761 in dementia in Austria. The care-cost savings that could be achieved with ginkgo special extract Egb 761 therapy were estimated on the basis of the extent to which it delayed growing dependency and an increasing need for care--this being ascertained from the active treatment/placebo differences on GERRI after 6 months of treatment with Egb 761 and evaluated using the rates of the Austrian Federal Care Allowance Law--and compared with the cost of this therapy. The duration of illness, the start and duration of treatment, and the Egb 761 dose were varied in a series of scenarios in a sensitivity analysis. In all the scenarios the care-cost savings exceed the costs of the ginkgo special extract Egb 761 therapy. The cost/savings ratio is most favourable when the treatment is started early and when it is used in patients with dementia of the Alzheimer type. For every month by which the transition from the stage requiring a small to moderate amount of care to the stage requiring considerable or very considerable care can be delayed, one can save 812 [symbol: see text]. Prescribing ginkgo special extract Egb 761 for dementia makes sense from the national economic viewpoint because the product can yield care-cost savings that exceed the cost of the treatment itself.

Streptomyces coelicolor is a representative of the group of soil-dwelling, filamentous bacteria responsible for producing most natural antibiotics used in human and veterinary medicine. Here we report the 8,667,507 base pair linear chromosome of this organism, containing the largest number of genes so far discovered in a bacterium. The 7,825 predicted genes include more than 20 clusters coding for known or predicted secondary metabolites. The genome contains an unprecedented proportion of regulatory genes, predominantly those likely to be involved in responses to external stimuli and stresses, and many duplicated gene sets that may represent 'tissue-specific' isoforms operating in different phases of colonial development, a unique situation for a bacterium. An ancient synteny was revealed between the central 'core' of the chromosome and the whole chromosome of pathogens Mycobacterium tuberculosis and Corynebacterium diphtheriae. The genome sequence will greatly increase our understanding of microbial life in the soil as well as aiding the generation of new drug candidates by genetic engineering.

To explore the treatment effect of EGb 761((R)) (EGb) in Alzheimer's disease depending on baseline severity.We applied stratification to the intent-to-treat data set collected during a 52-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study with 120 mg of EGb, using cutoff points of 23 and 14 for the Mini-Mental State Examination (MMSE) score. Outcome measures used were the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) and the Geriatric Evaluation by Relative's Rating Instrument (GERRI).In the severity stratum 1 (MMSE23), the placebo group did not show significant changes, while the EGb group improved significantly by 1.7 points on the ADAS-Cog and by 0.09 points on the GERRI. In the severity stratum 2 (MMSE24), the placebo group worsened by 4.1 points on the ADAS-Cog and 0.18 points on the GERRI, whereas the EGb group showed 60% less decline on the ADAS-Cog (treatment difference of 2.5 points) and no change on the GERRI (treatment difference of 0.25 points). The most severely impaired subgroup (MMSE15) showed slightly more pronounced worsening for both treatment groups. However, in comparison to placebo, EGb induced virtually the same magnitude of effect as was observed in the entire stratum 2.The results of this retrospective analysis indicated that a treatment effect favorable to EGb could be observed with respect to cognitive performance (p = 0.02) and social functioning (p = 0.001) regardless of the stage of dementia, whether mild or moderately severe. However, the relative changes from baseline measured at endpoint depended heavily on the severity at baseline. Improvement was observed in the group of patients with very mild to mild cognitive impairment, while in more severe dementia, the mean EGb effect should be considered more in terms of stabilization or slowing down of worsening, as compared to the greater deterioration observed with placebo.

Objectives: Diminished production of nitric oxide has been linked to saphenous vein endothelial dysfunction. Tetrahydrobiopterin is an obligate cofactor for the oxidation of L -arginine by nitric oxide synthase in the production of nitric oxide by endothelial cells. The objective of the present study was to examine whether the exogenous addition of tetrahydrobiopterin improves endothelial function in saphenous veins from patients undergoing coronary artery bypass graft operations. Methods: Vascular segments of saphenous veins were obtained from 17 patients undergoing elective coronary artery bypass grafting, and in vitro endothelium-dependent and endothelium-independent responses to acetylcholine and sodium nitroprusside were assessed. Isometric dose-response curves were constructed in precontracted rings in the presence and absence of tetrahydrobiopterin (0.1 mmol/L) with the use of the organ bath apparatus. The percentages of maximum relaxation and sensitivity were compared between interventions. Results: Acetylcholine caused dose-dependent endothelium-mediated relaxation in saphenous veins. In the presence of tetrahydrobiopterin, acetylcholine-induced relaxation was significantly augmented (percentage maximum relaxation, 16.8% ± 2.9% vs control 7.5% ± 1.8%; P = .003) without an effect on agonist sensitivity. These effects were endothelium-specific because endothelium-independent responses to sodium nitroprusside were preserved. Conclusions: These data uncover beneficial effects of acute tetrahydrobiopterin addition on endothelial function in human vessels. Because endothelial dysfunction has been implicated in the development of graft failure, studies aimed at chronic delivery of tetrahydrobiopterin would be useful in determining the contribution of this cofactor toward saphenous vein atherosclerosis. (J Thorac Cardiovasc Surg 2000;120:668-71)

This intent-to-treat (ITT) analysis was performed to provide a realistic image of the efficacy that could be expected after 26 weeks treatment with a 120-mg dose (40 mg t.i.d.) of EGb 761 (EGb). The data were collected during a 52-week, double-blind, placebo-controlled, fixed dose, parallel-group, multicenter study. Patients were mildly to severely impaired and diagnosed with uncomplicated Alzheimer's disease or multi-infarct dementia according to ICD-10 and DSM-III-R criteria. The primary outcome measures included the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Geriatric Evaluation by Relative's Rating Instrument (GERRI) and Clinical Global Impression of Change. From 309 patients included in the ITT analysis, 244 patients (76% for placebo and 73% for EGb) actually reached the 26th week visit. In comparison to the baseline values, the placebo group showed a statistically significant worsening in all domains of assessment, while the group receiving EGb was considered slightly improved on the cognitive assessment and the daily living and social behavior. Mean treatment differences favored EGb with 1.3 and 0.12 points, respectively, on the ADAS-Cog (p = 0.04) and the GERRI (p = 0.007). In the group receiving EGb, 26% of the patients achieved at least a 4-point improvement on the ADAS-Cog, compared to 17% with placebo (p = 0.04). On the GERRI, 30% of the EGb group improved and 17% worsened, while the placebo group showed an opposite trend with 37% of patients worsening for 25% improved (p = 0.006). Regarding safety, no differences between EGb and placebo were observed.

A region of the Streptomyces coelicolor A3(2) chromosome was identified and cloned by using as a probe the lipase gene from Streptomyces exfoliatus M11. The cloned region consisted of 6286 bp, and carried a complete lipase gene, lipA, as well as a gene encoding a transcriptional activator (lipR). The S. coelicolor A3(2) lipA gene encodes a functional extracellular lipase 82% identical to the S. exfoliatus M11 lipase; the partially purified S. coelicolor enzyme showed a preference for substrates of short to medium chain length. Transcription of lipA was completely dependent on the presence of lipR, and occurred from a single promoter similar to the lipA promoters of S. exfoliatus M11 and Streptomyces albus G. These three Streptomyces lipA promoters have well-conserved -10 and -35 regions, as well as additional conserved sequences upstream of the -35 region, which could function as targets for transcriptional activation by the cognate LipR regulators. The Streptomyces LipR activators are related to other bacterial regulators of a similar size, constituting a previously unidentified family of proteins that includes MalT, AcoK, AlkS, AfsR, five mycobacterial proteins of unknown function and some Streptomyces regulators in antibiotic synthesis clusters. A lipase-deficient strain of S. coelicolor was constructed and found to be slightly affected in production of the polyketide antibiotic actinorhodin.

Because the first stage of expiration or “postinspiration” is an active neurorespiratory event, we expect some persistence of diaphragm electromyogram (EMG) after the cessation of inspiratory airflow, as postinspiratory inspiratory activity (PIIA). The costal and crural segments of the mammalian diaphragm have different mechanical and proprioceptive characteristics, so postinspiratory activity of these two portions may be different. In six canines, we implanted chronically EMG electrodes and sonomicrometer transducers and then sampled EMG activity and length of costal and crural diaphragm segments at 4 kHz, 10.2 days after implantation during wakeful, resting breathing. Costal and crural EMG were reviewed on-screen, and duration of PIIA was calculated for each breath. Crural PIIA was present in nearly every breath, with mean duration 16% of expiratory time, compared with costal PIIA with duration −2.6% of expiratory time ( P < 0.002). A linear regression model of crural centroid frequency vs. length, which was computed during the active shortening of inspiration, did not accurately predict crural EMG centroid frequency values at equivalent length during the controlled relaxation of postinspiration. This difference in activation of crural diaphragm in inspiration and postinspiration is consistent with a different pattern of motor unit recruitment during PIIA.

Fine wire recordings of the respiratory muscle electromyogram are often employed to represent muscle activity, and recently ultrasound-sonomicrometry has become a common method of measuring length of respiratory muscles in both acute and chronic preparations. Although recording both EMG and sonomicrometry simultaneously has become standard practice, there has not been any consideration of the potential confounding influence of ultrasound noise upon the recorded EMG spectrum. Activation of the sonomicrometry-ultrasound tranducer introduces a high frequency, high amplitude voltage pulse plus harmonics, which can contaminate the EMG spectrum directly, as well as through aliasing when EMG is sampled directly digitally. We describe the use of a new, combined, wing stabilized sonomicrometry- and EMG measurement transducer to characterize exactly the influence of ultrasound upon the crural diaphragm EMG spectrum, and the development of digital filtering techniques which effectively eliminate the ultrasound interference. Two alternative methods of avoiding ultrasound-EMG interference are also considered. The isolation and elimination of ultrasound-sonomicrometry signal interference may be important in studies where EMG and length are measured together.

A multicentric, randomized, placebo-controlled double-blind study on ginkgo biloba special extract EGb 761 (Tebonin forte) in patients suffering from peripheral occlusive arterial disease (POAD) in Fontaine stage II b was carried out in order to prove its clinical efficacy in this indication according to guidelines of European Community authorities and the German Angiological Society and to confirm the results of former clinical studies with EGb 761.In total, 111 patients with angiographically proven POAD in Fontaine stage II b and intermittent claudication (pain-free walking distance150 m on the treadmill) were recruited in 5 centers and treated with either EGb 761 or placebo at a daily dose of 3 times 1 film-coated tablet over a duration of 24 weeks following a 2-week placebo run-in period. The primary response variable was the difference of the pain-free walking distance between the start of treatment and after 8, 16 and 24 weeks as measured on the treadmill (walking speed 3 km/h and slope of 12%) under standardized conditions.At the start of the treatment period, the mean pain-free walking distances were very similar with 108.5 m in the EGb 761 group and 105.2 m in the placebo group. At the end of the treatment period these values increased to 153.2 m and 126.6 m, respectively. The group differences were statistically significant at all three control visits with p = 0.017, p = 0.007, and p = 0.016. The differences for the maximum walking distance and the relative increases of the pain-free walking distance and the maximum distance were also significantly higher in the EGb 761 group with p-values0.05 each. In both groups Doppler indices remained nearly unchanged during therapy. The subjective assessment of the patients demonstrated an amelioration of complaints in both groups. Tolerability was very good with no adverse events under EGb 761 and one case of heartburn and gastric pain in the placebo group.It can be concluded from the results of this study that treatment with EGb 761 in POAD patients with Fontaine stage II b is very safe and causes a significant and therapeutically relevant prolongation of the patients' walking distance.

The efficacy and safety of the standardized herbal combination preparation of Enteroplant, consisting of peppermint oil (90 mg) and caraway (50 mg) in an enteric coated capsule, have been studied in a double-blind, placebo-controlled multicentre trial in patients with non-ulcer dyspepsia. A total of 45 patients were included in the trial after thorough physical and gastro-enterological examination. The primary outcome variables were the change in the intensity of pain and the global clinical impression (Clinical Global Impression [CGI], Item 2), which were evaluated for 39 patients (test preparation: 19, placebo: 20). After four weeks of treatment both target parameters were significantly improved for the group of patients treated with the peppermint oil/caraway oil combination compared to the placebo group (p = 0.015 and 0.008, respectively). Before the start of treatment all patients in the test preparation group reported moderate to severe pain, while by the end of the study 63.2% of these patients were free of pain. The pain symptoms had improved in a total of 89.5% of the patients in the active treatment group. After 4 weeks the Clinical Global Impressions were improved for 94.5% of the patients treated with the peppermint oil/caraway oil combination. The trial medication was also superior to placebo with respect to pain frequency, medical prognosis, the severity of the disorder and the efficacy index (CGI, Items 1 and 3), which were adopted as secondary end-points for evaluation of efficacy. There were similarly favourable findings for the herbal combination, compared with placebo, with respect to the reduction of other gastrointestinal symptoms. The combination preparation was found to be excellently tolerated. There was a total of 7 adverse events (test preparation: 4, placebo: 3), with a causal association with the treatment being ascribed in one case for the test preparation group and one case for the placebo group.

This monocenter, randomized, placebo-controlled double-blind study with parallel-group comparison was carried out in order to demonstrate the efficacy of Ginkgo biloba special extract EGb 761 on objective and subjective parameters of the walking performance in trained patients suffering from peripheral arterial occlusive disease in Fontaine stage IIb. In total 60 patients were recruited (42 men; aged 47-82 years) with angiographically proven peripheral arterial occlusive disease of the lower extremities and an intermittent claudication existing for at least 6 months. No improvement had been shown despite consistent walking training and a maximum pain-free walking distance on the treadmill of less than 150 m was recorded at the beginning of the study. The therapeutic groups were treated with either Ginkgo biloba special extract EGb 761 at a dose of 3 times 1 film-coated tablet of 40 mg per day by oral route or placebo over a duration of 24 weeks following a two-week placebo run-in phase. The main outcome measure was the difference of the walking distance between the start of treatment and after 8, 16 and 24 weeks of treatment as measured on the treadmill (walking speed 3 km/h and slope of 12%). As secondary parameters the corresponding differences for the maximum walking distance, the relative increase of the pain-free walking distance, the Doppler index and the subjective evaluation of the patients were analyzed. The absolute changes in the pain-free walking distance in treatment weeks 8, 16 and 24 as against the treatment beginning (median values with 95% confidence interval) led to the following values for the patients treated with Ginkgo biloba special extract EGb 761:19 m (14, 33), 34 m (18, 50) and 41 m (26, 64). The corresponding values in the placebo group were as follows: 7 m (-4, 12), 12 m (5, 22) and 8 m (-1, 21). The advantage of the EGb 761-treated group as compared to the placebo group could be verified statistically at the 3 time points with p0.0001, p = 0.0003 and p0.0001. The test for the presence of a clinically relevant difference of 20% between EGb 761 and placebo also produced a statistically significant result (p = 0.008). The Doppler index remained unchanged in both therapeutic groups: A corresponding statistically significant advantage for the EGb 761 group was observed on a descriptive level for the other parameters tested. The tolerance of the treatment was very good. The results of this placebo-controlled study show that treatment with Ginkgo biloba special extract EGb 761 produces a statistically highly significant and clinically relevant improvement of the walking performance in trained patients suffering from intermittent claudication with very good tolerance of the study preparation.

In the planning phase of a therapeutic equivalence trial, a range has to be specified that defines the parameter region within which the treatments to be compared are considered equal for practical purposes. It is current practice in equivalence assessment to fix some value for limiting the equivalence range and to test the corresponding null hypothesis in confirmatory analysis. This procedure is unsatisfactory, if, for example, the drug to be investigated is not only equivalent but turns out to be even superior to standard. In this situation it would be desirable to test not only for equivalence but also for superiority. The paper presents an alternative approach that allows for a flexible handling of the problem. If therapeutic equivalence can be established the method additionally allows, under maintenance of the multiple level, for testing all null hypotheses that correspond to acceptable equivalence ranges and even of superiority. Because of the special structure of the hypotheses no alpha-adjustment is needed for these additional confirmatory analyses.

The Provincial Advisory Committee on Cardiovascular Services was established in January of 1990 to advise concerning these services. One of the first tasks assigned was to monitor waiting times for cardiac surgery. Referring cardiologists categorized their patients into four priorities: emergency, urgent-inpatient, urgent-outpatient, and planned. Data of the southern Alberta centers for the past three years were analyzed for events while waiting for surgery. (Median time to event in days) M1=Myocardial Infarction EM=Emergency D=Day A hierarchy was used to assign the single most serious event for patients having more than one event: deathMIreadmission or change from urgent-inpatient to emergency. Events were frequent and unpredictable, particularly in outpatients. Categorization of patient suitable to wait at home for cardiac surgery is imperfect. The risk of having an event while on the waiting list is much greater for out-patients than in-patients: 12.8% (169/1323) versus 1.9% (19/1002). All adverse events for the in-patients occurred at four days--one day less than the proposed maximum waiting time. In the out-patient population, the median waiting time to experiencing adverse events ranged between 32 and 54 days. Target waiting times set by PACCS for these two categories is 14 and 56 days respectively. Total adverse events occurred to 8% of the patients on the waiting list. Median waiting time to experiencing an adverse event while on the list occurs much earlier than suspected: four days in urgent in-patients and 36 days for out-patients; well below the intended maximum of 56 days. This database proved invaluable for this important critical data collection. It is hoped it will serve as a model for similar future projects.

The ability of Tisseel fibrin sealant to control bleeding was evaluated in this retrospective study. A new cardiac surgical unit was opened at the Foothills Hospital in Calgary, Alberta, in September 1988. Bleeding problems associated with its development led to a policy, instituted in late February 1989, of using Tisseel on all open-heart patients. Three hundred patients were reviewed in this study: 100 consecutive patients prior to the use of Tisseel (group I), 100 consecutive patients immediately following the initial use of Tisseel (group II), and 100 consecutive patients 1 year later (group III). These groups allowed the evaluation of Tisseel’s effectiveness in light of possible learning curves as the surgical unit developed. No significant differences in age, sex, type of surgery performed, use of hypothermia, pump time, or cross-clamp time were found among the three groups. A significantly higher percentage of patients in group III, the late Tisseel group, underwent urgent or emergent surgery. The use of Tisseel, both initially (group II) and 1 year later (group III), was found to result in significant reductions in the number of units transfused during surgery, chest tube drainage within the first 24 h after surgery, and total chest tube drainage. The reoperation rate for bleeding was also significantly reduced when Tisseel was used, both initially (group II) and 1 year later (group III). Finally, the percentage of patients requiring no blood products during open-heart surgery increased dramatically with the use of Tisseel (groups II and III compared to group I). Comparison of blood product use in the two Tisseel groups yielded no significant differences. This suggests that Tisseel, rather than a learning curve, greatly benefited our patients with regards to bleeding in cardiac surgery.

Two Streptomyces coelicolor A3(2) groEL-like genes, groEL1 and groEL2, were cloned and characterized. Pulsed-field-gel electrophoresis located these genes, which were not adjacent, in the same segment of the chromosome. Nucleotide sequence analysis revealed that groEL1, but not groEL2, was preceded by a groES-like gene. Northern blots showed that heat shock induced the accumulation of transcripts corresponding to groES (0.7 kb), groES/EL1 (2.3 kb) and groEL2 (2.1 kb). Unique transcription start points and promoters were located for groES/EL1 and groEL2, having -10 and -35 hexamers similar to eubacterial vegetative promoters. Regions located 5' to the groES/EL1 or groEL2 structural genes contain 'GCACTCN9GAGTGC' motifs conserved upstream from the heat-shock genes of other bacteria.

Differences in acute and chronic pacing thresholds were compared in patients receiving either the Medtronic Model 4004 steroid-eluting lead or the Medtronic Model 4012 microporous platinum lead. Patients (n = 35) were randomized at the time of implant to receive either a steroid-eluting (n = 17) or a microporous (n = 18) lead. Pacing thresholds were determined within 24 hours and at 2, 4, 6, 12, 24, and 52 weeks postimplant. By 2 weeks postimplant, pacing thresholds measured at 0.8, 1.6, 2.5, 3.3, and 4.2 V were significantly lower in the steroid lead group compared to the microporous lead group (P < 0.05). At 24 weeks, the voltage threshold at 0.3 msec was 0.8 V in 88% of patients with a steroid lead whereas this threshold was only observed in 33% of patients with the microporous lead (P < 0.01). At 52 weeks the pacing energy measured at 1.6 V, twice pulse duration threshold, was significantly lower in the steroid lead group (0.81 +/- 0.59 microJ) compared to the microporous lead group (1.25 +/- 0.60 microJ, P < 0.05). Thirteen patients in the steroid lead group and 9 patients in the microporous lead group have been programmed at a pulse amplitude of 1.6 V since the 24-week follow-up visit. These patients have been followed for a minimum of 6 months without documented failure to capture. This study shows that pacemaker/lead systems with stable chronic low thresholds can be safely programmed to low pulse amplitude settings. This practice will prolong the longevity of pulse generators.

The SLP2 plasmid had previously been demonstrated genetically to exist in Streptomyces lividans by its ability to promote conjugation and to elicit 'pocks' on recipient (SLP2-) cultures, but it had not been physically detected. Using pulsed-field gel electrophoresis, a 50 kb linear DNA was isolated from SLP2+ but not SLP2- strains of S. lividans, and from Streptomyces coelicolor and Streptomyces parvulus strains to which SLP2 had been transferred by conjugation or transformation. We conclude that this linear DNA is SLP2. The terminal fragments of SLP2 were cloned. The determined sequences revealed a 44bp imperfect terminal inverted repeat. The terminal 12bp sequence of SLP2 was identical to those of two other Streptomyces linear plasmids, pSLA2 and pSCL, and similar to the terminal sequences of another Streptomyces linear plasmid, SCP1. The termini of SLP2 DNA were resistant to digestion by lambda exonuclease and ExoIII. A truncated (probably crippled) copy of Tn4811 is present on the plasmid. While the SLP2 plasmid exists as a free form in the host, a 15.7 kb sequence corresponding to the segment of SLP2 from Tn4811 to the right terminus is also present (at a copy number similar to the free form) elsewhere in the genome of S. lividans. Furthermore, SLP2 is partially homologous to a newly discovered 650 kb linear plasmid in S. parvulus.

A comparison of defibrillation thresholds was made using biphasic and monophasic shocks delivered by a nonthoracotomy lead system in 2 clinically distinct groups of patients. The first group were patients receiving an implantable cardioverter-defibrillator who were studied before surgery with their chests closed. The second group were patients undergoing coronary artery bypass grafting (CABG) who were studied before surgery with their chests open but reapproximated. Biphasic defibrillation thresholds (stored energy) were significantly (p0.001) less than monophasic ones in subjects with the implantable cardioverter-defibrillator (12.3 +/- 5.3 vs 21.1 +/- 9.3 J) or CABG (14.6 +/- 7.1 vs 24.2 +/- 12.6 J). These values are less than were previously reported with a similar nonthoracotomy lead configuration. There were no significant differences between the 2 groups in all measurements derived from corresponding shock waveforms, although impedance tended to be greater in patients with CABG. However, subjects with CABG had greater left ventricular ejection fractions and did not have history of potentially lethal ventricular arrhythmias. Despite these differences, the conclusion that biphasic shocks are more effective would have been made in a study of either group alone. It is concluded that patients with CABG who have not had preceding potentially lethal ventricular arrhythmias may be a potential source of surrogate subjects for defibrillation research such as epicardial mapping, which requires that the chest be open.

Blutungskomplikationen stellen nach Herzoperationen fur die bereits kritisch erkrankten Patienten ein erhebliches Risiko dar. Die Komplikationen im Rahmen einer postoperativen Blutung umfassen sowohl die erforderliche Nachoperation als auch die dabei haufig notwendige Gabe von Blut und Blutprodukten in groserem Umfang und die damit verbundene mogliche Ubertragung von Erkankungen (8).

A DNA fragment stimulating actinorhodin, undecylprodigiosin, and A-factor production in Streptomyces lividans 66 was cloned from Streptomyces coelicolor A3(2). Nucleotide sequencing revealed the presence of an open reading frame of 225 codons, named afsQ1, that showed great similarity in amino acid sequence to the response regulators of typical prokaryotic two-component regulatory systems responsible for adaptive responses. The termination codon, TGA, of afsQ1 overlapped the initiation codon, GTG, of a second open reading frame, afsQ2, of 535 codons. The afsQ2 gene product showed homology with the sensory histidine protein kinases of two-component systems. In agreement with the assumption that the AfsQ1 and AfsQ2 proteins comprise an aspartate-histidine phosphotransfer system, an amino acid replacement from Asp to Glu at residue 52 of AfsQ1, generated by site-directed mutagenesis, resulted in loss of the protein's ability to stimulate antibiotic production in S. lividans. Primer extension experiments indicated that transcription of the afsQ1 and afsQ2 genes initiates at the translational start codon (GTG) of the afsQ1 gene. The afsQ1 and afsQ2 genes were physically mapped at a chromosomal position near the actinorhodin biosynthetic gene cluster (act) by hybridization to Southern blots of restriction fragments separated by pulsed-field gel electrophoresis. Disruption of either afsQ1 or afsQ2 on the S. coelicolor chromosome by use of phage phi C31KC515 led to no detectable change in secondary metabolite formation or morphogenesis. The afsQ1 gene on pIJ922 suppressed the S. coelicolor absA mutation and caused actinorhodin production but did not suppress the absB mutation. Southern blot hybridization showed that sequences homologous to afsQ1 and afsQ2 are present in almost all of the actinomycetes examined.

The restriction enzymes AseI (ATTAAT), DraI (TTTAAA), and SspI (AATATT) cut the Streptomyces coelicolor A3(2) chromosome into 17, 8, and 25 fragments separable by pulsed-field gel electrophoresis (PFGE). The sums of their lengths indicated that the chromosome consists of about 8 Mb of DNA, some 75% more than that of Escherichia coli K-12. A physical map of the chromosome was constructed for AseI and DraI, using single and double digests, linking clones, cross-hybridization of restriction fragments, and locations of genetically mapped genes, insertion sequences, prophages, and the integrated SCP1 and SLP1 plasmids on the physical map. The physical map was aligned with the previously established genetic map, revealing that the two long opposite quadrants of the genetic map that are almost devoid of markers (the silent regions at 3 o'clock and 9 o'clock) are indeed physically long rather than being hot spots for genetic exchange. They must therefore contain long stretches of DNA different in function from the remainder of the genome. Consistent with this conclusion are the locations of significant deletions in both of the silent regions. Of these, a 40-kb deletion in the 9 o'clock region accompanied or followed integration of the SCP1 linear plasmid to produce the NF fertility state. PFGE analysis of Streptomyces lividans 66, a close relative of S. coelicolor A3(2), was hampered by the previously described susceptibility of its DNA to degradation during electrophoresis. However, ZX7, a mutant derivative of S. lividans lacking the DNA modification responsible for this degradation, yielded good PFGE preparations. Not more than 7 of the 17 S. coelicolor AseI fragments could be shared by the S. lividans strain.

Psychological data from 560 male survivors of acute myocardial infarction (AMI) were documented in the third week after onset of AMI. The psychodiagnostic assessment was designed to detect different forms of depression as well as hyperactive behaviour. A complete follow-up of these patients, which covers a period of 6 months, is available. Our findings indicate that affective disorders play an important role in the post-acute phase after AMI although the extent of myocardial infarction (as defined by an ECG score) and behaviour responses are not significantly related to one another. Different subforms of depression are not influenced by a history of angina pectoris, the degree and location of myocardial infarction, the occurrence of late potentials and age, whereas dyspnoea ( P < 0·001) and the recurrence of myocardial infarction ( P < 0·001) favour depressive mood states. Twelve cardiac deaths and 17 arrhythmic events occurred during the study period; they were significantly predicted by severe forms of post-AMI depression as revealed by univariate analysis. The evidence was stronger for predicting cardiac death ( P < 0·001) than for arrhythmic events ( P = < 0·035). The effect remains of borderline significance for cardiac death if all risk factors with a significant univariate influence are included in a multiple logistic regression model. The effect of depression is illustrated by Kaplan—Meier survival curves separated for patient groups with high as compared to low degrees of depression. Hyperactivity showed no impact on patient survival.