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Extended hepatic resection: a 6-year retrospective study of risk factors for perioperative mortality.

BACKGROUND: Extended hepatic resection (more than four liver segments) is a major operative procedure that is associated with significant risk. The purpose of this study was to assess the impact of perioperative variables on in-hospital mortality after extended hepatectomy. STUDY DESIGN: Consecutive patients who underwent extended hepatic resection were studied. The prognostic value of 29 perioperative variables was evaluated using in-hospital mortality as the endpoint. For each variable, the odds ratio (95% confidence interval) for in-hospital mortality was calculated. Those variables with a lower confidence limit > 1 were considered important risk factors. The population was stratified into categories of patients having the same number of risk factors, and mortality was estimated for each group. These data were used to develop a risk assessment algorithm. RESULTS: There were 14 deaths (6%) in 226 patients. Three preoperative variables (cholangitis, creatinine > 1.3 mg/dL, and total bilirubin > 6 mg/dL) and two operative variables (blood loss > 3 L and vena caval resection) appear to be important factors for in-hospital mortality. The mortality associated with the presence of any two of the five factors was 100% (5 of 5), and the mortality associated with the absence of these factors was 3% (6 of 191). CONCLUSIONS: Perioperative evaluation of patients undergoing extended hepatic resection should include the quantitation of mortality risk factors. The combination of any two factors among preoperative cholangitis, elevated serum creatinine, elevated serum bilirubin, high operative blood loss, and vena cava resection may carry a high mortality risk. These results require prospective validation.

Adolescent↗

Comparative study of extended release albuterol sulfate and long-acting inhaled salmeterol xinafoate in the treatment of nocturnal asthma.

BACKGROUND: Nocturnal worsening of asthma is a common problem in asthma and is associated with increased morbidity and mortality. Long acting beta-2 agonists are considered long-term symptom control medications, especially for nocturnal symptoms. OBJECTIVE: To compare efficacy of an extended release oral beta-2 agonist, albuterol sulfate (Volmax), to a long-acting inhaled agent, salmeterol (Serevent) in the treatment of nocturnal asthma. METHODS: This was a multicenter double-blind, double-dummy, randomized, crossover design with a 1-week baseline period and two 3-week treatment periods separated by a 7 to 9-day washout. An optional 2-week, open-label phase was conducted to evaluate patient preference. RESULTS: A total of 46 patients were included in the efficacy analysis. For the primary outcome variable of morning peak expiratory flow, there were similar and significant improvements over the 3-week treatment period for both medications compared with baseline (P < .001). Similar improvements were seen in the overnight change in PEF values (P < .001). The morning and overnight changes in FEV1 were not significantly different between treatment arms (P > .05). There were significant improvements in both treatment periods in regard to the percentage of nights without awakenings (baseline 53.6+/-5.3%), extended release albuterol 83.3+/-3.0% (P < .001), and salmeterol 88.8+/-2.4%. The percentage of patients who had no awakenings during treatment did not differ significantly for the two medications. Both treatments also resulted in a decrease in the use of rescue albuterol (extended release 2.66+/-0.35 puffs per day, salmeterol 1.85+/-0.29) from baseline (4.57+/-0.41, P < .001). There was a significant difference between groups (P = .001). The reasons why patients preferred one medication over the other varied. CONCLUSION: Both extended release albuterol tablets and inhaled salmeterol resulted in similar bronchodilation and good control of nocturnal asthma symptoms.

Administration, Inhalation↗

Extended-release albuterol in the treatment of 6- to 12-year-old asthmatic children.

BACKGROUND: Albuterol sulfate, in the syrup and tablet form for oral administration, has been an effective treatment for adults and children with bronchial asthma. Extended-release albuterol sulfate tablets (Proventil Repetabs, Schering Corp.) provide a convenient, twice-daily dosing regimen, but are indicated only for patients > or = 12 years of age. OBJECTIVE: This study was undertaken to determine whether patients 6 to 12 years of age could be effectively and safely treated with extended-release albuterol tablets. METHODS: This was a randomized, double-blind, placebo-controlled, parallel group study of 157 patients in five centers. Patients were randomized to 4 weeks' treatment with extended-release albuterol tablets, 4 mg twice daily (q 12h), increasing up to 12 mg q 12h, or placebo. Efficacy was evaluated based on pulmonary function tests (PFTs), physician and patient evaluations, and data collected from patients' diaries on PEFR, asthma symptoms, number of nighttime awakenings, and number of tablets taken. The primary efficacy parameter was area under the curve (AUC) for FEV1, evaluated for 8 to 12 hours post-dosing. Safety was evaluated based on vital signs, electrocardiograms, and adverse events. RESULTS: Mean AUCs for FEV1 were significantly greater in the albuterol group at days 1 and 8 (P < or = .03). The albuterol group showed consistently lower severity scores for asthma symptoms. Physicians' and patients' global evaluations favored the albuterol group over the placebo group. No serious, treatment-related adverse events were reported. There were no clinically meaningful changes from baseline in either treatment group for vital signs or electrocardiograms. CONCLUSIONS: Extended-release albuterol tablets (4 mg), administered to children 6 to 12 years old in divided doses of up to 24 mg/day, improved pulmonary function and asthmatic symptoms and were well tolerated.

Adolescent↗

Genomic plasticity, energy allocations, and the extended longevity phenotypes of Drosophila.

The antagonistic pleiotropy theory of the evolution of aging is shown to be too simple to fully apply to the situation in which Drosophila are selected directly for delayed female fecundity and indirectly for extended longevity. We re-evaluated our own previously reported selection experiments using previously unreported data, as well as new data from the literature. The facts that led to this re-evaluation were: (1) the recognition that there are at least three different extended longevity phenotypes; (2) the existence of metabolic and mitochondrial differences between normal- and long-lived organisms; and most importantly; (3) the observation that animals selected for extended longevity are both more fecund and longer-lived than their progenitor control animals. This latter observation appears to contradict the theory. A revised interpretation of the events underlying the selection process indicates that there is a two-step change in energy allocations leading to a complex phenotype. Initial selection first allows the up-regulation of the antioxidant defense system genes and a shift to the use of the pentose shunt. This is later followed by alterations in mitochondrial fatty acid composition and other changes necessary to reduce the leakage of H(2)O(2) from the mitochondria into the cytosol. The recaptured energy available from the latter step is diverted from somatic maintenance back into reproduction, resulting in animals that are both long-lived and fecund. Literature review suggests the involvement of mitochondrial and antioxidant changes are likely universal in the Type 1 extended longevity phenotype.

Aging↗

Streptokinase binds preferentially to the extended conformation of plasminogen through lysine binding site and catalytic domain interactions.

Binding of streptokinase (SK) to plasminogen (Pg) activates the zymogen conformationally and initiates its conversion into the fibrinolytic proteinase, plasmin (Pm). Equilibrium binding studies of SK interactions with a homologous series of catalytic site-labeled fluorescent Pg and Pm analogues were performed to resolve the contributions of lysine binding site interactions, associated changes between extended and compact conformations of Pg, and activation of the proteinase domain to the affinity for SK. SK bound to fluorescein-labeled [Glu]Pg(1) and [Lys]Pg(1) with dissociation constants of 624 +/- 112 and 38 +/- 5 nM, respectively, whereas labeled [Lys]Pm(1) bound with a 57000-fold tighter dissociation constant of 11 +/- 2 pM. Saturation of lysine binding sites with 6-aminohexanoic acid had no effect on SK binding to labeled [Glu]Pg(1), but weakened binding to labeled [Lys]Pg(1) and [Lys]Pm(1) 31- and 20-fold, respectively. At low Cl(-) concentrations, where [Glu]Pg assumes the extended conformation without occupation of lysine binding sites, a 23-fold increase in the affinity of SK for labeled [Glu]Pg(1) was observed, which was quantitatively accounted for by expression of new lysine binding site interactions. The results support the conclusion that the SK affinity for the fluorescent Pg and Pm analogues is enhanced 13-16-fold by conversion of labeled [Glu]Pg to the extended conformation of the [Lys]Pg derivative as a result of lysine binding site interactions, and is enhanced 3100-3500-fold further by the increased affinity of SK for the activated proteinase domain. The results imply that binding of SK to [Glu]Pg results in transition of [Glu]Pg to an extended conformation in an early event in the SK activation mechanism.

Amino Acid Chloromethyl Ketones↗

Calmodulin remains extended upon binding to smooth muscle caldesmon: a combined small-angle scattering and fourier transform infrared spectroscopy study.

We show that calmodulin (CaM) has an extended conformation in its complexes with sequences from the smooth muscle thin filament protein caldesmon (CaD) by using small-angle X-ray and neutron scattering with contrast variation. The CaD sequences used in these experiments were a C-terminal fragment, 22kCaD, and a smaller peptide sequence within this fragment, MG56C. Each of these sequences contains the CaM-binding sites A and B previously shown to interact with the C- and N-terminal lobes of CaM, respectively [Wang et al. (1997) Biochemistry 36, 15026]. By modeling the scattering data, we show that the majority of the MG56C sequence binds to the N-terminal domain of CaM. FTIR data on CaM complexed with 22kCaD or with MG56C peptide show the 22kCaD sequence contains unordered, helix, and extended structures, and that the extended structures reside primarily in the MG56C portion of the sequence. There are small changes in secondary structure, involving approximately 12 residues, induced by CaM binding to CaD. These changes involve a net decrease in extended structures accompanied by an increase in alpha-helix, and they occur within the CaM and/or in the MG56C sequence.

Animals↗

Extended glucuronidation is another major path of cyanidin 3-O-beta-D-glucopyranoside metabolism in rats.

We previously determined that five rather hydrophobic metabolites appeared in blood plasma after oral administration of cyanidin 3-O-beta-D-glucopyranoside, but a group of hydrophilic metabolites still remained unidentified. In the present study, 12 hydrophilic metabolites found were collected from urine and plasma samples by high-performance liquid chromatography (HPLC) and then analyzed by tandem MS spectrometry. From the MS spectra, four metabolites out of 12 were assigned as glucuronides of cyanidin 3-O-beta-D-glucopyranoside and six out of 12 were glucuronides of the primary metabolites of cyanidin 3-O-beta-D-glucopyranoside (O-methyl cyanidin 3-O-beta-D-glucopyranoside). Extended glucuronides of cyanidin 3-O-beta-D-glucopyranoside and O-methyl cyanidin 3-O-beta-D-glucopyranoside showed their maximum plasma concentrations at 15 and 60 min (or 30 min) after oral administration, respectively. Their maximum plasma concentrations ranged from 15 to 70 nM. From the profile of urinary-excreted anthocyanins after intravenous administration, it was deduced that extended glucuronides of cyanidin 3-O-beta-D-glucopyranoside and O-methyl cyanidin 3-O-beta-D-glucopyranoside were mainly produced in the liver rather than by intestinal flora. The area under the plasma concentration curve was 0.25 micromol min/L for extended glucuronides of cyanidin 3-O-beta-D-glucopyranoside and 0.14 micromol min/L for O-methyl cyanidin 3-O-beta-D-glucopyranoside, respectively, when evaluated as cyanidin 3-O-beta-D-glucopyranoside equivalent, indicating that extended glucuronidation is a critical pathway in cyanidin 3-O-beta-D-glucopyranoside metabolism in rats.

Animals↗

New chain-extended analogues of salacinol and blintol and their glycosidase inhibitory activities. Mapping the active-site requirements of human maltase glucoamylase.

The synthesis of new chain-extended sulfonium and selenonium salts of 1,4-anhydro-4-thio-(or 4-seleno)-d-arabinitol, analogues of the naturally occurring glycosidase inhibitor salacinol, is described. Nucleophilic attack at the least hindered carbon atom of 4,6-O-benzylidene-2,5-di-O-p-methoxybenzyl-d-mannitol-1,3-cyclic sulfate by 2,3,5-tri-O-p-methoxybenzyl-1,4-anhydro-4-thio-(or 4-seleno)-d-arabinitol gave the sulfonium and selenonium sulfates, respectively. Subsequent deprotection with trifluoroacetic acid yielded the target compounds. In these analogues, an extended polyhydroxylated aliphatic side chain has been incorporated while maintaining the stereochemistry of C-2' and C-3' of salacinol or blintol. These compounds were designed to probe the premise that they would bind with higher affinity to glucosidases than salacinol because the extra hydroxyl groups in the acyclic chain would make favorable polar contacts within the active site. Both target compounds inhibited recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with Ki values in the low micromolar range. Comparison of these values to those of related compounds synthesized in previous studies has provided a better understanding of structure-activity relationships and the optimal stereochemistry at the different stereogenic centers required of an inhibitor of this enzyme. With respect to chain extension, the configurations at C-2' and C-4' are critical for activity, the configuration at C-3', bearing the sulfate moiety, being unimportant. The desired configuration at C-5' is also specified. However, comparison of the activities of the chain-extended analogues with those of salacinol and blintol indicates that there is no particular advantage of the chain-extension relative to salacinol or blintol. These results are similar to those reported earlier for kotalanol, a 7-carbon-extended derivative, versus salacinol against rat intestinal maltase, sucrase, and isomaltase.

Binding Sites↗

Extended photon counting histogram and fluorescence intensity distribution analysis approaches for optically biased photon counting statistics.

A gradient potential induced by a strongly focused laser beam can perturb the diffusion dynamics of particles in solutions and result in biased photon counting statistics in fluorescence fluctuation spectroscopy (FFS). In this paper, the theories of the photon counting histogram (PCH) and fluorescence intensity distribution analysis (FIDA) approaches are extended independently to fit the biased experimental data and retrieve the unbiased parameters, i.e., the average number of the sample particles in the focal volume N, their brightness epsilon, and polarizability alpha. The extended theories are tested using Monte Carlo simulations for single- and double-component systems. It is also proved numerically and analytically that the extended PCH and FIDA approaches are completely equivalent. Practical implementations and possible applications of extended PCH and FIDA are discussed.

Journal Article↗

Similar risk reduction of death of extended-release metoprolol once daily and immediate-release metoprolol twice daily during 5 years after myocardial infarction.

The pooled results from five placebo-controlled postinfarction studies with metoprolol have shown a significant reduction in total mortality. All five studies used immediate-release metoprolol twice daily. An extended-release formulation of metoprolol for once-daily use has since been developed. The aim of the present study was to compare the two different forms of metoprolol with regard to the risk reduction of death for 5 years postinfarction and to analyze whether treatment with the beta-blocker metoprolol is associated with a reduced mortality after the introduction of modern therapies such as thrombolysis, aspirin, and ACE inhibitors. All patients discharged after an acute myocardial infarction (AMI) from Sahlgrenska University Hospital (SU) during 1986-1987 (n = 740, Period I) and during 1990-1991 (n = 1446, Period II) from both SU and Ostra Hospital, Göteborg, Sweden, were included in the study. During Period I, 56% were prescribed immediate-release metoprolol compared with 61% prescribed extended-release metoprolol during Period II. Immediate-release metoprolol was not available for outpatient use during Period II. In a multivariate analysis, all variables significantly associated with either increased or decreased postinfarction mortality during Periods I and II (univariate analysis of patient characteristics, medical history, complications during the AMI medication at discharge) studied were with Cox's proportional hazards model. Treatment with immediate-release metoprolol was significantly associated with reduced mortality over 5 years during Period I (relative risk reduction for total mortality, -34%, P = 0.003; 95% CI for RR, 0.51-0.87), and treatment with extended-release metoprolol was significantly associated with reduced mortality during Period II (-34%, P < 0.0001; 95% CI for RR, 0.53-0.82). Thrombolysis and the use of aspirin and ACE inhibitors were more frequently used during Period II. The results showed that postinfarction treatment with extended-release metoprolol given once daily was associated with a similar risk reduction of death over 5 years as immediate-release metoprolol given twice daily. The data, furthermore, indicate that the beta-blocker metoprolol is associated with a reduced risk of death after the introduction of modern therapy such as thrombolysis, aspirin, and ACE inhibitors.

Adrenergic beta-Antagonists↗

Optimizing a hydroxyapatite/tricalcium-phosphate ceramic as a bone graft extender for impaction grafting.

The mechanical properties of morsellized bone allografts and synthetic hydroxapatite/tricalcium-phosphate (HA/TCP) ceramic extender materials for the use in impaction grafting revision hip surgery were investigated using two test methods: a basic compression test and an endurance test in an in-vitro model of an impaction grafted femur. Formalin fixed ovine bone graft was identified as mechanically similar to fresh human bone and thus suitable as an experimental material for in-vitro testing. For 1 : 1 volumetric mixes of bone allograft and synthetic extender, the granular ceramic's properties were varied in porosity, chemical composition, sintering temperature and particle size. Initial mechanical stability, a crucial prerequisite for clinical success in impaction grafting, was increased for all bone/extender mixes. A high porosity, tricalcium-phosphate rich ceramic of medium particle size and sintered at high temperatures was recognized as an optimized extender material for impaction grafting balancing the mechanical and biological demands. Using the extender without bone graft as a pure replacement is not recommended.

Journal Article↗

Modeling of hepatic elimination and organ distribution kinetics with the extended convection-dispersion model.

The conventional convection-dispersion (also called axial dispersion) model is widely used to interrelate hepatic availability (F) and clearance (Cl) with the morphology and physiology of the liver and to predict effects such as changes in liver blood flow on F and Cl. An extended form of the convection-dispersion model has been developed to adequately describe the outflow concentration-time profiles for vascular markers at both short and long times after bolus injections into perfused livers. The model, based on flux concentration and a convolution of catheters and large vessels, assumes that solute elimination in hepatocytes follows either fast distribution into or radial diffusion in hepatocytes. The model includes a secondary vascular compartment, postulated to be interconnecting sinusoids. Analysis of the mean hepatic transit time (MTT) and normalized variance (CV2) of solutes with extraction showed that the discrepancy between the predictions of MTT and CV2 for the extended and unweighted conventional convection-dispersion models decreases as hepatic extraction increases. A correspondence of more than 95% in F and Cl exists for all solute extractions. In addition, the analysis showed that the outflow concentration-time profiles for both the extended and conventional models are essentially identical irrespective of the magnitude of rate constants representing permeability, volume, and clearance parameters, providing that there is significant hepatic extraction. In conclusion, the application of a newly developed extended convection-dispersion model has shown that the unweighted conventional convection-dispersion model can be used to describe the disposition of extracted solutes and, in particular, to estimate hepatic availability and clearance in both experimental and clinical situations.

Humans↗

Long-term safety of extended-release oxybutynin chloride in a community-dwelling population of participants with overactive bladder: a one-year study.

In this multicenter, open-label study of extended- and immediate-release oxybutynin chloride, community-dwelling participants were studied for up to 12 months to evaluate the long-term safety profile of extended-release oxybutynin. Quality-of-life assessments designed to measure the impact of incontinence and evaluate treatment outcome were used to study subjective improvement. A total of 904 women and 163 men (mean age 64 years, range 29-91 years) were enrolled. The majority of discontinuations were in the first 3 months (25.5%); of those who continued after 3 months, 62% remained on extended-release oxybutynin chloride for one year. The majority of discontinuations were for adverse events; dry mouth was the most frequently cited event leading to discontinuation (8.4%). Significant improvements were seen in QOL measures. Long-term therapy with extended-release oxybutynin chloride was generally well tolerated and effective, improving quality of life significantly in participants with overactive bladder over 3-12 months of therapy.

Adult↗

Human vascular endothelial cells with extended life spans: in vitro cell response, protein expression, and angiogenesis.

An in vitro angiogenesis system was designed for screening angiogenic agonists and antagonists. In order to obtain large quantities of cells and reproducibility, human endothelial cells with extended life spans were developed by retroviral transfection. The resulting cells grown in a serum-free medium containing endothelial cell growth supplement (ECGS) have a telomerase activity, extended life spans of at least 21 passages, and an endothelial cell phenotype (diI-acetylated-LDL upake, factor VIII-related antigen, VEGFR-1 and R-2, and tissue-type plasminogen activator (tPA)) that resembled that of unaltered primary endothelial cells. Exceptions were (i) a higher expression of tPA, and (ii) a non-significant growth response to FGF-2 or VEGF stimulation. Within three-dimensional fibrin gels, specific cell clones rapidly formed tubular structures in a more reproducible manner than those observed with low-passage primary cells. Tube formation by primary endothelial cells and those with extended life spans was dependent upon FGF-2 and ECGS, respectively. Both cell types produced FGF-2 and VEGF cytokines. Increasing doses of suramin significantly decreased the size of microvessels formed by both cell lines. These functional results indicate that a vascular matrix system containing human cells with extended life spans can be successfully utilized as an in vitro assay for antiangiogenic compounds.

Angiogenesis Inhibitors↗

Pre-social benefits of extended parental care.

The evolution of helping, in which some individuals forfeit their own reproduction and help others to reproduce, is a central problem in evolutionary biology. Recently proposed insurance-based mechanisms rely on a pre-existing life history with a long period of offspring dependency relative to the short life expectancies of adult carers: a lone mother's offspring are doomed if she dies young, whereas after a helper dies, other group members can finish rearing the offspring. A critical question, however, is how this life history could evolve in ancestral non-social populations, as offspring survival would then depend on a single, short-lived carer. Here, we resolve this paradox by focusing on the extended parental care inherent in prolonged dependency. We show experimentally that in non-social wasps, extended care can significantly reduce the impact of interspecific parasites. Under extended care, offspring are less vulnerable by the time they are exposed to parasites, and costs of parasitism are reduced because mothers have the option to terminate investment in failing offspring. By experimentally simulating aspects of extended care in a species where it is lacking, we demonstrate that neither benefit requires specialized behaviour. Such benefits could therefore offset the disadvantage of prolonged dependency in non-social species, thereby facilitating the evolution of helping.

Animals↗

Dpo4 is hindered in extending a G.T mismatch by a reverse wobble.

The ability or inability of a DNA polymerase to extend a mispair directly affects the establishment of genomic mutations. We report here kinetic analyses of the ability of Dpo4, a Y-family polymerase from Sulfolobus solfataricus, to extend from all mispairs opposite a template G or T. Dpo4 is equally inefficient at extending these mispairs, which include, surprisingly, a G.T mispair expected to conform closely to Watson-Crick geometry. To elucidate the basis of this, we solved the structure of Dpo4 bound to G.T-mispaired primer template in the presence of an incoming nucleotide. As a control, we also determined the structure of Dpo4 bound to a matched A-T base pair at the primer terminus. The structures offer a basis for the low efficiency of Dpo4 in extending a G.T mispair: a reverse wobble that deflects the primer 3'-OH away from the incoming nucleotide.

Bacterial Proteins↗

Extended polyglutamine selectively interacts with caspase-8 and -10 in nuclear aggregates.

A growing number of inherited neurodegenerative disorders, including Huntington's disease, have been shown to be caused by the expansion of CAG/polyglutamine repeats. The molecular mechanism underlying these disorders, however, has yet to be clarified. We and others previously demonstrated that caspase-8 was activated by proteolysis in association with the expression of extended polyglutamine. Here, we further analyzed the selectivity of caspases in the process mediated by extended polyglutamine. Among upstream caspases, caspase-10, a close homolog of caspase-8, was also proteolytically activated, but caspase-9 was not. Caspase-8 and -10 were recruited into nuclear aggregates of extended polyglutamine, where at least a fraction of these caspases was converted to the activated forms. Caspase-8 and -10 were co-immunoprecipitated with polyglutamine only when the polyglutamine was pathologically extended, whereas caspase-2, -3, -6, -7 and -9 were not co-immunoprecipitated with polyglutamine regardless of its size. A dominant-negative form of caspase-8 with a mutation at the catalytic cysteine residue inhibited polyglutamine-mediated nuclear apoptotic phenotype. These results suggest that caspase-8 and -10 are autoactivated as a result of close proximity of the proforms of these molecules that occurs due to aggregate formation, which reveals a novel toxic gain-of-function mechanism for the pathogenesis of CAG-repeat disorders.

Apoptosis↗

Temperature-dependence of open-complex formation at two Escherichia coli promoters with extended -10 sequences.

We have studied the formation of open complexes between purified RNA polymerase from Escherichia coli and DNA fragments carrying the galP1 promoter, a promoter with an extended -10 region. Unusually, these complexes are formed readily at low temperatures. This low-temperature opening is unaffected by deletions of either upstream or downstream promoter sequences. We conclude that low-temperature open-complex formation is due to specific base sequences in and just upstream of the extended -10 region. In contrast, open complexes are not formed at low temperatures with DNA fragments carrying the E. coli cysG promoter, which also has an extended -10 region. This demonstrates that an extended -10 sequence alone is not sufficient for low-temperature opening. Additionally, we report the temperature dependence of a hybrid galP1-cysG promoter, the related galP2 and galP3 promoters and a derivative of galP1 with an improved -10 hexamer sequence.

Base Sequence↗