Variance reduction for fixed-source Monte Carlo calculations in multiplying systems by improving chain-length statistics

For a fixed-source calculation in a multiplying system, the variance in the neutron-chain length can create an unstable calculation and a neutron flux with high variance. In this paper an analytical frame is derived to calculate a priori the variance of the neutron flux in a simple model of a fixed-source calculation. This method is then used to find better variance reduction techniques not only for this simplified problem, but also for general cases.     

Muscle transformation of the sartorius muscle in a canine model: clinical impact for electrodynamic graciloplasty as a "neosphincter"

PURPOSE: Transformation of fast-twitching skeletal muscles to slow-twitching, slowly fatigable muscles has become of clinical interest in the recent past. Transposition and transformation of the gracilis muscle to use it as a substitute for a resected or defected anal sphincter (graciloplasty) have been reported as achieving promising results in the treatment of fecal incontinence caused by sphincter defects or following abdominoperineal anorectal excision for cancer. METHOD: This experimental study used a canine model and the sartorius muscle to evaluate the functional efficiency of two different configurations of the muscle loop to compare the presently applied transformation program (8 weeks) with a shorter (5 weeks) protocol. In six beagle dogs, both sartorius muscles were wrapped around two stomas, either in an alpha fashion or in the so-called split-sling technique. Muscle transformation was achieved by controlled neuromuscular stimulation either during eight (Program A) or five weeks (Program B). After completion of the transformation period, the function of the muscle slings was evaluated by manometry, and histomorphologic evaluation of the sartorius muscles was performed. RESULTS: It was shown that muscle transformation led to a slowly fatigable muscle that made it possible to perform continuos (tetanic) contraction, regardless of the configuration or the duration of the transformation. Median pressures created by these muscles also did not differ significantly. In accordance with these functional findings, the histologic evaluation showed the typical, significant increase of Type I fibers in both muscle slings and following both transformation protocols. Although the decrease of fast-twitching Type II fibers was more pronounced following the conventional (8 weeks) program, this finding did not influence the functional results. CONCLUSIONS: Results of our experiment indicate the possibility for using a shorter transformation protocol for transformation of the gracilis muscle during graciloplasty in the clinical setting. Furthermore, the efficacy and safety of the modified (split-sling) wrap technique was demonstrated.     

Discovery and evaluation of a series of 3-acylindole imidazopyridine platelet-activating factor antagonists

Studies conducted with the goal of discovering a second-generation platelet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solubility and long duration of action in animal models. The compounds arose from the combination of the lipophilic indole portion of Abbott's first-generation PAF antagonist ABT-299 (2) with the methylimidazopyridine heterocycle moiety of British Biotechnology's BB-882 (1) and possess the positive attributes of both of these clinical candidates. Structure-activity relationship (SAR) studies indicated that modification of the indole and benzoyl spacer of lead compound 7b gave analogues that were more potent, longer-lived, and bioavailable and resulted in the identification of 1-(N, N-dimethylcarbamoyl)-4-ethynyl-3-[3-fluoro-4-[(1H-2-methylimidazo[4,5-c] pyrid-1-yl)methyl]benzoyl]indole hydrochloride (ABT-491, 22 m.HCl) which has been evaluated extensively and is currently in clinical development.     

The effects of phosphorylation of cardiac troponin-I on its interactions with actin and cardiac troponin-C

It is known that the phosphorylation of two serine residues on the NH2-terminal extension specific to cardiac troponin-I (Tn-I) modulates the calcium-dependent activation of the myofilaments. The process by which this occurs remains an unsolved puzzle. We have applied a dissective approach to study the effect of this phosphorylation on the interactions between Tn-I and its partner proteins, actin and troponin-C (Tn-C). Using N-[14C]ethylmaleimide-labelled Tn-I in sedimentation assays with F-actin, we found that the dephosphorylated Tn-I binds to F-actin with pronounced positive cooperativity, both in the absence and the presence of tropomyosin. Phosphorylation of the protein slightly weakens the interaction in the absence of tropomyosin, but the cooperativity remained. In the presence of tropomyosin, phosphorylation of the Tn-I also appeared to slightly weaken the interaction as well but, more significantly, the cooperativity was eliminated. These data can only be explained simply by a cooperative interaction between the monomer units in the actin filament. The interactions between cardiac Tn-I and Tn-C were studied by labelling the Tn-C with the fluorescent probe dansyl aziridine. As expected, the binding of the dephosphorylated Tn-I to Tn-C was strengthened by over 20-fold upon the addition of calcium to the assay. Phosphorylation of the protein, however, had a dramatic effect on the interaction in that it appeared to desensitise the complex to the effect of calcium: the Ka values obtained for both interactions (+/- Ca2+) were almost identical. These results clearly indicate that the phosphorylation of Tn-I in the cardiac system has dramatic effects on the isolated inter-protein interactions. We also discuss the possible significance of such an effect on the interactions of the isolated proteins in their roles within the intact cardiac regulatory complex.     

Risks and benefits of diagnostic angiography after aneurysm surgery: a retrospective analysis of 597 studies

INTRODUCTION: Cerebral angiography performed after aneurysm surgery can identify causes of morbidity and mortality that may be corrected. The risks and benefits of angiography that is performed after aneurysm surgery, however, have not been clearly defined. We therefore reviewed our experience with postoperative angiography to determine its dangers and benefits. METHODS: During 10 years, 543 consecutive patients received treatment for cerebral aneurysms. A retrospective analysis of 597 diagnostic angiograms obtained after aneurysm surgery for 494 of these patients was performed. RESULTS: Catheter-induced vessel spasm and dissection, occurring most frequently in the internal carotid artery, were observed in seven (1.2%) and six (1%) studies, respectively. No angiography-associated strokes were identified. No association between age, smoking, hypertension, blood pressure, atherosclerosis, or severe vasospasm and angiographic complications was observed. Aneurysm remnants were identified in 36 (5.7%) of the 637 aneurysms that were surgically treated. Atherosclerosis (P < 0.01) or multiple clip applications (P < 0.01) were significantly associated with aneurysm remnants. Angiographic vessel occlusion was observed in 28 (5.7%) patients and resulted in stroke in 14 of these patients. Vessel occlusion was significantly associated with increasing aneurysm size (P < 0.001), atherosclerosis (P < 0.001), temporary clips (P < 0.001), multiple clips (P=0.03), multiple clip applications (P=0.001), and a new postoperative neurological deficit (P=0.002). Severe vasospasm and newly identified aneurysms were observed in 51 and 16 patients, respectively. CONCLUSION: Angiography after aneurysm surgery is safe and can be routinely performed. Angiography after aneurysm surgery should be particularly considered for patients with large aneurysms or cerebrovascular atherosclerosis and for those who develop new postoperative neurological deficits.     

Clinical experience with the percutaneous hemopump during high-risk coronary angioplasty

The percutaneous Hemopump showed beneficial effects during coronary angioplasty in 32 high-risk patients with unloading of the left ventricle during ischemia and maintaining cardiac output with mean aortic pressures of 50 mm Hg in case of cardiac arrest (3 patients). High procedure-related morbidity (occlusion of femoral artery in 2 patients; bleeding with need of transfusion in 4 patients) and mortality (4 of 32 patients) rates demonstrate the need for a very careful selection of patients.     

Feasibility of estimating glomerular filtration rate in children using single-sample adult technique

This work was undertaken to verify whether a single-sample adult technique, when applied using body surface-corrected plasma concentration, can be used in place of specific pediatric method to estimate 51Cr-EDTA renal clearance in children. METHODS: In a series of 90 children (aged 0.1 to 15 yr). 51Cr-EDTA renal clearance was calculated using for different approaches. The first approach used specific pediatric single-sample methods; three techniques were chosen and they all used 120-min plasma concentration. The second approach used the same three specific pediatric methods, but they were applied using 120-min plasma concentration prescaled for 1.73 m2 body surface area. The third approach used single-sample methods designed for adults; three methods were again chosen. They all used 240-min plasma concentration. The fourth approach used the same adults algorithms, but they were applied using 240-min plasma concentration prescaled for 1.73 m2 body surface area. RESULTS: Clearances calculated using the three specific pediatric methods were all closely cross-correlated regardless of whether or not the plasma concentration was prescaled. The use of classical adult methods produced in some cases obviously erroneous clearance values. Improvements were observed when the same adult methods were applied using prescaled plasma concentration. Nonetheless, the clearance values obtained only fairly correlated with those obtained using specific pediatric methods. CONCLUSION: The single-sample adult technique using plasma concentration prescaled for 1.73 m2 body surface area cannot be used in place of a specific pediatric single-sample method to estimate 51Cr-EDTA renal clearance in children.     

Simplified appendectomy without stump embedding. Experiences of 20 years conventional and 5 years laparoscopic application

Since 1975, the Department of Surgery in the Grevenbroich Community Hospital (Germany) has applied a simplified technique of open appendectomy. The inhouse modified procedure without stump embedding has been performed in 3,448 cases to date. The same approach has been used in 1,463 laparoscopic appendectomies since 1991. In the laparoscopic procedure the stump is ligated solely with Roeder's loop. None of the 4,911 patients who have undergone either open or laparoscopic appendectomy have developed stump inadequacy or stercoral fistulae. According to the special literature, the complication rate after appendectomies without stump embedding is lower than that after standard procedures. In retrospect, laparoscopic appendectomy with simple ligation has confirmed the results achieved with simple ligation in open appendectomies. The technique should therefore become more common practice in open appendectomies, as well.     

2-Azetidinone cholesterol absorption inhibitors: structure-activity relationships on the heterocyclic nucleus

A series of azetidinone cholesterol absorption inhibitors related to SCH 48461 ((-)-6) has been prepared, and compounds were evaluated for their ability to inhibit hepatic cholesteryl ester formation in a cholesterol-fed hamster model. Although originally designed as acyl CoA: cholesterol acyltransferase (ACAT) inhibitors, comparison of in vivo potency with in vitro activity in a microsomal ACAT assay indicates no correlation between activity in these two models. The molecular mechanism by which these compounds inhibit cholesterol absorption is unknown. Despite this limitation, examination of the in vivo activity of a range of compounds has revealed clear structure-activity relationships consistent with a well-defined molecular target. The details of these structure-activity relationships and their implications on the nature of the putative pharmacophore are discussed.