Search

At the 2019 International Aspirin Foundation Scientific Conference ‘Benefits and Risks of Antithrombotic Therapy for Cardiovascular Disease Prevention', held in Rome, Italy, international experts sought to discuss and debate the optimal antithrombotic strategy for the secondary prevention of cardiovascular disease (CVD) and to seek agreement around dosing and target populations for aspirin use in primary disease prevention. Getting the best evidence to support real-life decisions in the clinic can be complex, and individualising management in order to balance both the risks and benefits of different disease prevention strategies appears to be the best approach. It is hoped that future decision-making tools and biomarkers will help direct treatments at those most likely to benefit.

This systematic review and meta-analysis is the first to evaluate the evidence for an association between metformin use and cancer outcomes in patients undergoing treatment with curative intent for individual cancer types. Our findings suggest that adjuvant metformin could have beneficial effects, particularly on cancer outcomes in colorectal and prostate cancer. Randomised trials are warranted., Background Metformin use has been associated with a reduced risk of developing cancer and an improvement in overall cancer survival rates in meta-analyses, but, to date, evidence to support the use of metformin as an adjuvant therapy in individual cancer types has not been presented. Patients and methods We systematically searched research databases, conference abstracts and trial registries for any studies reporting cancer outcomes for individual tumour types in metformin users compared with non-users, and extracted data on patients with early-stage cancer. Studies were assessed for design and quality, and a meta-analysis was conducted to quantify the adjuvant effect of metformin on recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS), to inform future trial design. Results Of 7670 articles screened, 27 eligible studies were identified comprising 24 178 participants, all enrolled in observational studies. In those with early-stage colorectal cancer, metformin use was associated with a significant benefit in all outcomes [RFS hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.47–0.85; OS HR 0.69, CI 0.58–0.83; CSS HR 0.58, CI 0.39–0.86]. For men with early-stage prostate cancer, metformin was associated with significant, or borderline significant, benefits in all outcomes (RFS HR 0.83, CI 0.69–1.00; OS HR 0.82, CI 0.73–0.93; CSS HR 0.58, CI 0.37–0.93); however, there was significant heterogeneity between studies. The data suggest that prostate cancer patients treated with radical radiotherapy may benefit more from metformin (RFS HR 0.45, CI 0.29–0.70). In breast and urothelial cancer, no significant benefits were identified. Sufficient data were not available to conduct analyses on the impact of metformin dose and duration. Conclusions Our findings suggest that metformin could be a useful adjuvant agent, with the greatest benefits seen in colorectal and prostate cancer, particularly in those receiving radical radiotherapy, and randomised, controlled trials which investigate dose and duration, alongside efficacy, are advocated.

BACKGROUND Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P

Novel arrangements of active frequency selective surfaces (AFSSs) with integrated voltage control wiring are proposed for bi-state (transparency/reflectance) operation at specified frequencies. The AFSSs are comprised of passive arrays of intertwined patterns of slots in a conductor screen and an active dipole array with pin diodes placed either on the same or opposite sides of a thin dielectric substrate. Simulation and measurement results show that such AFSSs exhibit good isolation (~ 15 dB) between the translucency and reflection states at normal incidence that slightly decreases at oblique incidence. The proposed AFSSs maintain the high angular and polarisation stability over broad fractional bandwidths (FBWs) inherent to the constituent periodic arrays of intertwined conductor patterns with substantially subwavelength unit cells. The merits of these AFSS arrangements also include resilience to parasitic effects of real switches, whose insertion loss in the on-state only enhances the AFSS on/off isolation. Such AFSSs are essential elements for reconfiguring and controlling the electromagnetic architecture of buildings.

Background: It is believed that hypoalbuminaemia confounds interpretation of the anion gap (AG) unless corrected for serum albumin in critically ill children with shock. Aim: To compare the ability of the AG and the albumin corrected anion gap (CAG) to detect the presence of occult tissue anions. Methods: Prospective observational study in children with shock in a 22 bed multidisciplinary paediatric intensive care unit of a university childrenrsquo;s hospital. Blood was sampled at admission and at 24 hours, for acid-base parameters, serum albumin, and electrolytes. Occult tissue anions (lactate + truly “unmeasured” anions) were calculated from the strong ion gap. The anion gap ((Na + K) − (Cl + bicarbonate)) was corrected for serum albumin using the equation of Figge: AG + (0.25 × (44 − albumin)). Occult tissue anions (TA) predicted by the anion gap were calculated by (anion gap − 15 mEq/l). Optimal cut off values of anion gap were compared by means of receiver operating characteristic (ROC) curves. Ninety three sets of data from 55 children (median age 7 months, median weight 4.9 kg) were analysed. Data are expressed as mean (SD), and mean bias (limits of agreement). Results: The incidence of hypoalbuminaemia was 76% (n = 42/55). Mean serum albumin was 25 g/l (SD 8). Mean AG was 15.0 mEq/l (SD 6.1), compared to the CAG of 19.9 mEq/l (SD 6.6). Mean TA was 10.2 mmol/l (SD 6.3). The AG underestimated TA with mean bias 10.2 mmol/l (4.1–16.1), compared to the CAG, mean bias 5.3 mmol/l (0.4–10.2). A clinically significant increase of TA >5 mmol/l was present in 83% (n = 77/93) of samples, of which the AG detected 48% (n = 36/77), and the CAG 87% (n = 67/77). Post hoc ROC analysis revealed optimal cut off values for detection of TA >5 mmol/l to be AG >10 mEq/l, and CAG >15.5 mEq/l. Conclusion: Hypoalbuminaemia is common in critically ill children with shock, and is associated with a low observed anion gap that may fail to detect clinically significant amounts of lactate and other occult tissue anions. We suggest that the albumin corrected anion gap should be calculated to screen for occult tissue anions in these children.

Einleitung: Secukinumab (SEC), ein vollständig humaner monoklonaler anti-IL-17A Antikörper, zeigte in Phase III Studien bei der Behandlung von Plaque-Psoriasis Wirksamkeit. Hier wird über die Wirksamkeit und Sicherheit von SEC gegenüber Placebo (PBO) und Etanercept (ETN) bei Patienten[for full text, please go to the a.m. URL], 42. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 28. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 24. wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), potent inflammatory cytokines, are released by macrophages during endotoxin shock. However, the contribution of these cytokines to endotoxin-induced inflammation has not been defined. The expression of E-selectin, measured using the dual radiolabeled monoclonal antibody (mAb) technique, was monitored in different tissues of endotoxin-challenged wild-type and IFN-gamma-deficient mice receiving a mAb to TNF-alpha (TN3). A significant elevation in E-selectin expression occurred in all tissues of wild-type mice challenged with endotoxin. Injection of TN3 in wild-type mice significantly attenuated the endotoxin-induced up-regulation of E-selectin in all tissues (p < .05) except the pancreas. The level of reduction in endotoxin-induced E-selectin expression ranged between 30% in the stomach to 60% in the small intestine. E-selectin expression in endotoxin-challenged, IFN-gamma-deficient mice was significantly reduced in the small and large intestines, when compared with endotoxin-challenged wild-type mice. Although IFN-gamma deficiency had no effect on E-selectin expression in other tissues, administration of TN3 to endotoxin-challenged, IFN-gamma-deficient mice significantly reduced E-selectin expression to levels observed in endotoxin-challenged, wild-type mice that received TN3. These findings indicate that TNF-alpha is essential for achievement of maximal E-selectin expression in most vascular beds during endotoxemia, whereas the contribution of IFN-gamma is largely confined to the small intestine.

Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features, and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would die differed markedly from those who would survive. The different profiles of proteins and metabolites clustered into fatty acid transport and β-oxidation, gluconeogenesis and the citric acid cycle. They differed consistently among several sets of patients, and diverged more as death approached. In contrast, the metabolomes and proteomes of surviving patients with mild sepsis did not differ from survivors with severe sepsis or septic shock. An algorithm derived from clinical features together with measurements of seven metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined = 4.09 × 10−9; odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13–1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined = 2.74 × 10−10; OR = 1.14, 95% CI = 1.10–1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

A large and complex evaluation of a Can$1.3 billion energy R&D program was recently carried out for the Canadian government. The challenges included a controversial and complex program, multiple stakeholders with very diverse interests, a large investment, an atmosphere of suspicion and mistrust and very tight deadlines. The methods used in the management of the study and which led to its successful completion are applicable to similar large-scale evaluation situations. Copyright , Beech Tree Publishing.

The kinetics of iron release from C-terminal monoferric transferrin (Fe C Tf) to pyrophosphate (PP) under pseudo-first-order conditions show an apparent saturation linear dependence of k obs on [PP]. The variation of k obs with [PP] was studied under conditions of variable temperature and added anion (X) concentration (Cl - , ClO 4 - , NO 3 - , SO 4 2- , HPO 4 2- )

The CASSIOPE Enhanced Polar Outflow Probe (e-POP) is a Canadian small-satellite mission dedicated to the study of polar ion outflows and related magnetosphere-ionosphere coupling processes in the topside ionosphere. Scheduled for launch in 2009, it will carry eight scientific instruments, including imaging plasma and neutral particle sensors, magnetometers, dual-frequency GPS receivers, CCD cameras, a radio wave receiver and a beacon transmitter, for in-situ particle, field, and current measurements and auroral imaging and radio measurements. We present an overview of the e-POP mission, its current status and plan of observations and data distribution during the operation phase of the mission.

BACKGROUND: Biologic therapies such as adalimumab, a tumour necrosis factor antagonist, are safe and effective in the treatment of moderate to severe chronic plaque psoriasis. OBJECTIVES: To compare a biologic agent with methotrexate, a traditional systemic agent, to define clearly the role of biologics in psoriasis. METHODS: Patients with moderate to severe plaque psoriasis were randomized to adalimumab (80 mg subcutaneously at week 0, then 40 mg every other week, n=108), methotrexate (7.5 mg orally, increased as needed and as tolerated to 25 mg weekly; n=110) or placebo (n=53) for 16 weeks. The primary efficacy endpoint was the proportion of patients achieving at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) after 16 weeks. Safety was assessed at all visits through week 16. RESULTS: After 16 weeks, 79.6% of adalimumab-treated patients achieved PASI 75, compared with 35.5% for methotrexate (P

Background/Aims: Infliximab has been approved for the treatment of chronic plaque psoriasis for only a few years. As physicians gain confidence in initiating and maintaining this therapy, guidance on the management of patients beyond several months or years is needed. To date, there is little or no information about the long-term management in clinical trials or guidelines. Methods: Here we report on the key aspects related to the use of infliximab for the treatment of psoriasis. The data presented here were derived using a modified Delphi survey to obtain a consensus opinion of 11 dermatologists from Europe and Canada experienced in long-term therapy with infliximab. Results/Conclusion: The Delphi participants reviewed several important topics related to biological therapy and infliximab. This paper is not intended to provide a recommendation on all practical aspects related to biological therapy; it has rather been written to provide useful and practical information on the 'best practice' use of infliximab. Copyright © 2008 S. Karger AG.

A novel, compact and low profile internal antenna capable of operating in multiple bands is proposed. It consists of a long monopole ring, which is top-loaded by a helical element in order to produce two main resonances of wide bandwidth. Its compact size of length 10 mm, width 28 mm and height of 6 mm and small volume of 1.68 cm3, makes it possible to be used internally, inside the mobile phone. With the help of a small matching circuit a VSWR < 3 is achieved covering the bands of GSM900 (880-960 MHz), DCS (1710-1880 MHz) and PCS (1850-1990 MHz). The efficiency is above 50% in all bands. The Specific Absorption Rate (SAR) is also measured, presented and discussed in this article.

Mortality in children with shock is more closely related to the nature, rather than the magnitude (base deficit/excess), of a metabolic acidosis. To examine the relationship between base excess (BE), hyperlactataemia, hyperchloraemia, 'unmeasured' strong anions, and mortality. Prospective observational study set in a multi-disciplinary Paediatric Intensive Care Unit (PICU). Forty-six children, median age 6 months (1.5–14.4), median weight 5 kg (3.2–8.8), admitted to PICU with shock. Predicted mortality was calculated from the paediatric index of mortality (PIM) score. The pH, base excess, serum lactate, corrected chloride, and 'unmeasured' strong anions (Strong Ion Gap) were measured or calculated at admission and 24 h. Observed mortality (n=16) was 35%, with a standardised mortality ratio (SMR) of 1.03 (95% CI 0.71–1.35). There was no significant difference in admission pH or BE between survivors and nonsurvivors. There was no association between elevation of 'unmeasured' anions and mortality, although there was a trend towards hyperchloraemia in survivors (P=0.08). Admission lactate was higher in nonsurvivors (median 11.6 vs 3.3 mmol/l; P=0.0003). Area under the mortality receiver operating characteristic curve for lactate was 0.83 (955 CI 0.70–0.95), compared to 0.71 (95% CI 0.53–0.88) for the PIM score. Admission lactate level >5 mmol/l had maximum diagnostic efficiency for mortality, with a likelihood ratio of 2.0. There is no association between the magnitude of metabolic acidosis, quantified by the base excess, and mortality in children with shock. Hyperlactataemia, but not elevation of 'unmeasured' anions, is predictive of a poor outcome.

The safety of balanced electrolyte polyethylene glycol (PEG) solutions has been documented in children.1, 2 We describe a previously well child who developed fulminant pulmonary oedema after treatment with Golytely (Braintree Laboratories, Braintree, USA). The 5 year old boy was electively admitted for treatment of constipation. A nasogastric tube (NGT) was passed for …

We attempted to explore the possible differential involvement of beta-adrenoceptor subtypes in the dilator response of the human dorsal hand vein to isoprenaline by examining the ability of bisoprolol, a selective beta1-adrenoceptor antagonist, and nadolol, a nonselective beta1/beta2-adrenoceptor antagonist, to antagonize the response.Twelve healthy male volunteers participated in four weekly sessions. In the preliminary session a dose-response curve to the vasoconstrictor effect of phenylephrine was constructed and the dose producing 50-75% maximal response was determined for each individual. In each of the remaining three (treatment) sessions, nadolol (40 mg), bisoprolol (5 mg) or placebo was ingested, and isoprenaline hydrochloride (3.33-1000 ng min(-1)) was infused locally into the dorsal hand vein along with a constant dose of phenylephrine hydrochloride (to preconstrict the vein) 2 h after the ingestion of the drugs. Changes in vein diameter were monitored with the dorsal hand vein compliance technique. Subjects were allocated to treatment session according to a double-blind balanced cross-over design. Systolic and diastolic blood pressure, and heart rate were also measured.Isoprenaline produced dose-dependent venodilatation which was antagonized by nadolol but remained unaffected by bisoprolol (ANOVA with repeated measures: P0.025; Dunnett's test: placebo vs nadolol, P0.01; placebo vs bisoprolol, P = NS). Mean log ED50 (ng min-1) was significantly increased in the presence of nadolol and remained unchanged in the presence of bisoprolol (ANOVA, P0.025; Dunnett's test: placebo vs nadolol, P0.005; placebo vs bisoprolol, P = NS; differences between mean log ED50 [95% CI]: placebo vs bisoprolol -0.11 [-0.38, 0.16], placebo vs nadolol 0.32[0.09, 0.72], bisoprolol vs nadolol -0.43 [-0.71, -0.15]). Mean Emax did not differ in the three treatment conditions.The failure of bisoprolol to attenuate isoprenaline-evoked venodilatation in the human dorsal hand vein argues against the involvement of a beta1-adrenoceptor-mediated component in the isoprenaline-evoked venodilatory responses. The possibility cannot be excluded that the consequences of beta1-adrenoceptor blockade by bisoprolol might have been obscured by a possible venodilator effect of bisoprolol.

To examine the effects of high ambient temperature ('heat stressor') on parasympathetically mediated cardiovascular reflexes (power of respiratory sinus dysrhythmia; change in heart rate elicited by change in posture from lying to standing ['30 : 15 ratio']).Twelve healthy male volunteers participated in four weekly sessions, each of which was associated with one treatment condition (placebo at an ambient temperature of 22 degrees C; propranolol 40 mg at 22 degrees C; placebo at 40 degrees C; propranolol 40 mg at 40 degrees C), according to a balanced double-blind design. Heart rate was recorded by ECG, finger tremor (7-12 Hz) with an accelerometer strapped to the middle finger of the nondominant hand, and sublingual temperature by a mercury thermometer. Power of finger tremor and the variations of the R-R intervals of the ECG were obtained from Fourier transformations of the data. Data were analysed by analysis of variance, with repeated measures using a significance criterion of P0.05; individual comparisons of active treatment with placebo and of data obtained at 40 degrees C with those obtained at 22 degrees C were made with Fisher's Least Significant Difference test.Heart rate was increased by the heat stressor, and this increase was abolished by propranolol. The heat stressor reduced the power of respiratory sinus dysrhythmia and the 30 : 15 ratio, and increased the power of physiological finger tremor. Propranolol did not affect heat stressor-induced changes in the parasympathetic cardiac reflexes, but reduced the heat stressor-induced enhancement of finger tremor.The increase in the power of physiological finger tremor at high ambient temperature is consistent with sympathetic activation, whereas the reduction in the power of respiratory sinus dysrhythmia and 30 : 15 ratio indicates a decrease in parasympathetic activity. These results demonstrate that high ambient temperature may induce vagal withdrawal in the heart.

The estimates of the zenith wet delay resulting from the analysis of data from space techniques, such as GPS and VLBI, have a strong potential in climate modeling and weather forecast applications. In order to be useful to meteorology, these estimates have to be converted to precipitable water vapor, a process that requires the knowledge of the weighted mean temperature of the atmosphere, which varies both in space and time. In recent years, several models have been proposed to predict this quantity. Using a database of mean temperature values obtained by ray-tracing radiosonde profiles of more than 100 stations covering the globe, and about 2.5 year’s worth of data, we have analyzed several of these models. Based on data from the European region, we have concluded that the models provide identical levels of precision, but different levels of accuracy. Our results indicate that regionally-optimized models do not provide superior performance compared to the global models.

This paper develops a modelling technique for equipment load panels which directly produces (adequate) models of the underlying dynamics on which to base robust controller design/evaluations. This technique is based on the use of the Lagrange's equations of motion and the resulting models are verified against those produced by a finite Element Method Model

Acetylcholinesterase (AChE) molecular isoforms from aganglionic and adjacent unaffected (control) colonic tissue in patients with Hirschsprung's disease (HD) were analysed by density gradient centrifugation in order to determine the major AChE isoforms and the effect of a reported MgCl 2 inactivation assay method upon them, with a view to improving the AChE assay used in the diagnosis of Hirschsprung's disease. The total AChE level was greater in the HD-affected colonic tissue than the control tissue (HD: 9.0 vs. control: 7.3 units/g tissue) and this was due to a consistently greater elevation of the globular tetrameric form, G4 (HD: 48.8% vs. control: 35.5% of total AChE). The inactivation of whole tissue homogenates by brief exposure to 4 mol/l MgCl 2 followed the same pattern (HD: 48.4% vs. control: 28.7% inactivation). The detergent-extractable G4 is inhibited to a greater extent than the low salt-soluble G4 by exposure to 4 mol/l MgCl 2 (83.8% vs. 51.1%). These results imply that the elevated AChE levels in HD are mainly due to increases of the hydrophobic globular tetrameric form of AChE of the same type that is found in differentiating nervous tissue before synapse formation. The monomeric globular isoform G1 is not inhibited but the asymmetric A4, A8 and A12 isoforms are completely inhibited by exposure to 4 mol/l MgCl 2 . All isoforms of Torpedo (electric ray) electroplax and human erythrocyte AChE, mainly amphiphilic G2, are almost completely inhibited. The inhibition by 4 mol/l MgCl 2 of the main G4 isoform in HD-affected intestine accentuates the difference between aganglionic and unaffected intestine in fractionated samples, but does not provide a sufficiently specific G4 isoform assay. The use of 2–4 mol/l MgCl 2 in histochemical AChE staining reduces the activity slightly but does not differentiate the tetrameric AChE isoform that is increased in Hirschsprung's disease but does reduce contaminating erythrocyte AChE levels that can obscure the result in blood-stained biopsies. A specific immunochemical stain for hydrophobic AChE tetramers or the associated 20 kDa membrane associated subunit is therefore needed to provide specificity.

PAV protease is able to cleave between the crosslinked sites of the gamma-chain of fibrin and fibrin-derived D-dimer. The rate of digestion can be increased fourfold to tenfold by the addition of zinc ions. Although the PAV protease is a zinc-containing metalloenzyme, the enhanced rate of cleavage can be shown to be due to histidine-specific zinc binding by D-dimer. It is proposed that zinc ions cause a distortion of the inter-crosslink peptide chain, creating a novel protease-susceptible site. The physiologic relevance is uncertain due to the relatively low measured zinc binding constant Kd = 10(-3.88) M. Zinc binding could, nevertheless, create a useful fibrin-specific neoepitope for antibody recognition in vitro.

The role of calcium in the stabilization of fibrinogen and fibrin plasmin digestion products, D-monomer and D-dimer has been studied. The largest D fragment, D1 ∗ , and D-dimer are both stable to further plasmin degradation in the presence of calcium ions. Chelation of calcium leads to further plasmin digestion due to sequential cleavage of peptides from the C-terminal end of the γ-chain. This stabilization is due to calcium ions and not to occupation of the cross-link site. All the digestion products of D-dimer were also found to be stabilized by the re-addition of calcium ions.

The oceanographic and meteorological data bases presently available at the Canadian Climate Centre, Environment Canada are used to produce plots for the coefficient of variation of annual and monthly environmental loads due to winds and waves. This parameter is extremely important for the calculation of design risks and is linked to the selection of the environmental load factors in design codes. Extreme wind loads and wave loads induced by both drag and inertia are examined for the East Coast, the West Coast and the Beaufort Sea areas of Canada.

Simple mixing of acid purified histones H3 and H4 in equimolar quantities at low ionic strength near pH 7 does not yield the tetramer but rather a high Mr aggregate. Dialysis of acid extracted total or core histones into 2 M NaCl 150 mM phosphate (pH 7.4) followed by fractionation of the histone complexes at lower ionic strength (150 mM NaCl) results in an H3H4 tetramer of a structure identical to that derived from salt-extracted histones. Dialysis of acid extracted total or core histones directly into the lower ionic strength buffer with subsequent fractionation, results in H3H4 tetramer of closely similar structure.

The distribution and quantitation of the iron-binding proteins of rat small intestinal mucosa was studied, in iron-deficient and replete animals, to explore their role in the absorption of iron. Adsorption (mucosal uptake) of iron in in situ ligated loops of small intestinal mucosa was found to be uniform throughout the length of the small intestine whereas absorption (carcass uptake) showed a steep decreasing gradient from the duodenum to the ileum. The disrupted, in vivo labeled mucosal cells were fractionated by isopycnic centrifugation and transferrin and ferritin were quantitated by radioimmunoassay. Transferrin derived from mucosal cells was shown to have a higher affinity for the antibody than transferrin in serum. Of the transferrin present in the mucosal extract, only a portion could be accounted for by contamination from the serum; the proteolysis resistant and intrinsic transferrin may be mucosal cell specific. Transferrin was found in similar amounts in all regions of the small intestine, was not affected by iron loading but doubled in response to iron deficiency. Mucosal ferritin was found in greater amounts in the iron-absorbing areas of the intestine, increased in the duodenum of iron-loaded animals, and decreased in iron-deficient animals. The incorporation of newly absorbed radioiron into ferritin was only found in iron absorbing regions and was completely inhibited by colchicine and cytochalasin-B, suggesting that ferritin was loaded with iron at the point of iron absorption and that the process is associated with vesicle movement and not simple diffusion. Transferrin and ferritin-specific immunoabsorption and also gel filtration established that no other soluble iron binding proteins were involved in absorption.

The engineering feasibility of several potential methods for inducing the large scale fracture of icebergs has been investigated. These methods included conventional explosives and incendiaries, thermal fracture of ice, various sorts of directed beams (radiation, fluid or particles), injected pressurised fluid (both confined and unconfined) and cutting with an electrically heated wire. All methods required large quantities of materials and/or energy. Some methods, while technically and perhaps economically feasible, were unacceptable from an environmental viewpoint. It has been determined that the cutting of an iceberg with an electrically heated small diameter tube stands out as the most practical approach. The tube is heated with a DC current of several hundred amperes and simultaneously moderated with a flow of fluid to prevent burnout. The electric power requirements are manageable in the marine context (a few hundreds of kilowatts) and the equipment is fairly conventional; hence not overly difficult to obtain and configure. A field program carried out within the context of the present study has demonstrated the functionality of the hot wire cutting method. Based on the results of this program, the design for a fully operational full scale version of an iceberg cutting system has been outlined and is judged appropriate for serious consideration in developing iceberg management strategies for Canada's East Coast oilfields.

Surveys in the Middle Estuary of the St Lawrence have yielded a data base consisting of more than 15,000 T‐S pairs distributed over 62 13‐h profiling stations. Although the T‐S curves at each station are remarkably linear, the variability of the slopes and intercepts of the lines is considerable. The means and standard deviations of the temperature and salinity at each individual station are not explicable in terms of linear combinations of the parameters for location in the Estuary, the upstream water properties, the phase of the spring‐neap cycle and the tidal energies. It is shown that the tidally‐averaged density structure is separable into horizontal and vertical components and that its vertical variation over the whole Estuary may be explained by any one of three different functional forms. However, its horizontal variation is not explicable in terms of linear combinations of the parameters mentioned in the paragraph above. Plots of the horizontal variations in temperature, salinity or dens...

Over the past two decades there has been a great deal of interest in calculating design waves for offshore structures. This paper reviews the data limitations, statistical assumptions, distributions, fitting methods, and statistical tests used to determine confidence intervals and goodness of fit. Use is made of an illustrative example from the Grand Banks of Canada to indicate how a design wave could be calculated. It is concluded that no single method will be entirely suitable for all data sets.

Modern structural analysis techniques are heavily dependent upon statistical methods. The determination of design loads involves the calculation of long‐return period environmental parameters such as the 100‐year wind speed or the 100‐year wave height. One way in which to do this is to use the theory of compound distributions rather than the usual extreme value theory. Of critical importance, however, is the determination of which probability distributions to use. It is shown in this paper that the arrival rate of storms on Canada's East Coast is Poisson distributed and, therefore, that compound distributions may be used to calculate long return‐period environmental parameters.

Previous studies are in conflict over the effect of infusing mixed fibrinogen-fibrin degradation products on fibrinogen synthesis, as determined by changes in fibrinogen concentration or by incorporation of labeled amino acids into fibrinogen. We have injected purified homologous fragments D1 and E into rats and measured their fibrinogen and albumin synthetic rates by the [14C]carbonate technique, a method that provides quantitative estimates of hepatic secretory protein synthesis. Fibrinogen fractional synthetic rates were increased 2.5 times in animals injected with fragment D1, compared with saline-injected controls. No increase were observed in fragment E-injected animals. Neither fragment produced changes in albumin synthesis. Fragment D increased plasma fibrinogen concentration, but did not raise plasma haptoglobin levels. These results suggest that fragment D is a regulator of fibrinogen synthesis.

SUMMARY The use of alpha-fetoprotein (AFP) in the diagnosis of liver cell cancer is invaluable; most cases can be accurately diagnosed or justification can be provided to pursue the diagnosis by other means. Whether or not the measurement of AFP is justified as an epidemiological tool is doubtful since there is a normal AFP level (the effects of subclinical hepatitis altering this normal level) and since liver cell cancer is, in general, not responsive to treatment. As a model system to demonstrate the possibilities of an early cancer detection system, the AFP test has exposed some interesting problems. Do all cancers grow to the clinical or sub-clinical stage as rapidly as liver cell cancer in southern Africa appears to do? Is the promotion of tumour growth really so dramatically triggered and is the initial transformation perhaps less significant in the time scale? Further prospective surveys using the quantitation which radioimmunoassay can provide are required, hopefully, to answer some of these questions before we can hope to intervene in the development of the early stages of the evolving cancer to the benefit of the patient.

Publisher Summary This chapter reviews one-dimensional numerical modeling of unsteady flow in networks of canals, rivers, and estuaries. The model allows the computation of water elevation and velocity in any network of open channels to which many assumptions are applicable, such as appropriate boundary conditions are available. Flow in open channels can be described by two equations, one, expressing the conservation of mass (the continuity equation) and second, expressing the conservation of momentum in the longitudinal direction (the momentum equation). This chapter develops all of the theory necessary to construct a numerical model for simulating unsteady flow conditions in networks of open channels. It presents a form1 method for describing the flow relationships in any network. The implicit finite difference method is then described and extended for use in networks. The equations of motion are given, with a description of a generalized equation solver, and the properties of the finite difference scheme are discussed.

Observations of tidal currents are traditionally analysed by means of spectral analysis, to ensure that only tidal frequencies are present and by harmonic analysis, to obtain the amplitude and phases of the tidal constituents and to allow the prediction of future currents. When this was done for a series of records obtained in the St. Lawrence it was found that 95% of the energy was at the tidal frequencies, and that the calculated “tidal constituents” allowed hindcasting the tidal currents with great accuracy. However, neither the amplitudes nor the phases of the “tidal constituents” could be interpreted as standing or progressive waves over the whole Estuary and these amplitudes and phases seemed to be entirely uncorrelated, even though the observations were separated by re1 atively short distances when compared to the expected wave lengths of the barotropic waves. The topography and density field of the Estuary allow the The topography and density field of the Estuary allow the generation and propagation of internal gravity waves at the same frequencies as the barotropic tides but with much shorter wave lengths. These internal tides may interfere linearly with the barotropic tidal currents, causing phase and ampitude variations, depending upon the location in the Estuary and the density field in the Estuary. By means of admittance calculations on very short portions of the observed currents records, it is possible to show that the amplitudes and phases of the “tidal constituents” obtained from the harmonic analyses vary in a way that would be expected if both barotropic and internal tides were present in the Estuary.

Rat fibrinogen plasmic fragment E was found to contain one oligosaccharide chain per gamma-chain attached by a glycosylamine linkage. The oligosaccharide was composed of 1 sialic acid, 1 galactose, 2 mannose and 2 glucosamine residues. The probable sequence from the nonreducing end was sialic acid leads to galactose beta leads to mannose alpha leads to mannose alpha leads to glucosamine leads to glucosamine. No difference in the rate of clearance from the rat circulation could be detected between native and desialated fragment E. A non-denaturing method for the purification of fragment E is described.

An established and validated method using loops of intestine in vivo in rats was used to study the effects of cytoskeletal inhibitors on iron absorption. Radioactive iron instilled into the loop of intestine pretreated with test substance was monitored in the blood and, after death, ferritin loading radioactive iron was measured on density gradients of mucosal cell homogenates and absorbed iron in the carcass was determined. Colchicine, vincristine and cytochalasin B all caused dose- and time-dependent inhibition of iron absorption, and the effects of cytochalasin B were reversible within 1 h. It is not known which cellular component is the vehicle for the transcellular movement of iron from the intestinal lumen onto plasma transferrin; however, this study showed that the uptake of iron by ferritin in an iron-absorbing loop of intestine paralleled the actual absorption of iron into the carcass. This phenomenon did not occur in non-iron-absorbing intestinal and was inhibited by the action of the cytoskeletal inhibitors in the iron-absorbing region. Previously we had shown that iron uptake into cells and onto cellular transferrin was virtually the same throughout the small intestine, irrespective of the iron-absorbing capacity of the region. The results of this study therefore suggest that iron absorption depends on an intact cytoskeletal system and that ferritin in the iron-absorbing cell is able to load from the pool of iron committed to transcellular movement onto plasma transferrin.

Histone octamers have been reconstituted from acid-extracted chicken erythrocyte histones. By the criteria of molecular size on exclusion chromatography as well as sedimentation velocity and conformational properties established by circular dichroism, fluorescence spectroscopy and imido-ester cross-linking, the reconstituted octamers have a structure identical to that of salt-extracted octamers.

This Thesis investigates the methods which are currently avail- able for the dynamic analysis of Offshore Mooring Terminals, particular regard being paid to Single Point Mooring (SPM) Terminals. Various aspects of the problem are considered in turn, these being the random vibration of non-linear systems, the analysis of catenary mooring lines, buoy dynamics, ship motions, second order (or slow drift) forces and motions, and low frequency motions caused by instabilities. These various aspects are then applied to the dynamic analysis of a Single Buoy Storage (SBS) System and the effect of the method of analysis employed, the system dimensions and the environmental conditions on the computed response is investigated. A Time Domain investigation of the stability of the SBS System in the presence of wind and current alone reveals that the system is only unstable for combinations of wind and current which are unlikely to occur in practise. A static offset position is then assumed and the calculation of the three-dimensional first and second order response to random waves is performed in the Frequency Domain, linear wave theory being used. The first order wave forces are calculated by using strip theory for the tanker and Morison's equation for the buoy. The second order response in surge, sway and yaw is calculated by a reflection coefficient method, these coefficients being obtained from published literature. The non-linear mooring system and the drag forces acting on the buoy are linearised using the equivalent linearisation method, due account being taken of the coupling between the first and second order response. The model developed for the first order response of the system allows the use of a spreading function in the incident wave spectrum. The accuracy of linearisation techniques and the statistics of the second order force and response are also investigated.

We have examined the plasmic digestion products of fibrin formed in the presence of dansylcadaverine, the fluorescent D dimer, to determine whether they are held together not only by the cross-link region on the gamma chain but also by other interactions on the D domain. Antibodies to the D dimer reacted 8X more strongly with sites on the D dimer (purified or in the presence of E) than with sites on fibrinogen or plasmin-digested fibrinogen. The reactivity of this surface site was lost when the gamma chain was cleaved by plasmin after the molecule had been destabilized by the removal of calcium ions, thus breaking the covalent linkage of the homodimer. The noncovalent D dimer retained its dimeric structure by the criteria of molar volume, measured by fluorescence polarization, and molecular sieving. The noncovalently attached, cross-link-containing peptide bound tightly to the parent molecules at higher temperatures but rotated more freely below 15 degrees C, and could be lost from the parent molecules without destroying the dimeric structure. We therefore propose that the forces maintaining the dimeric structure of the noncovalently joined molecule are not solely located at the gamma-chain cross-link region. These other sites on the D domain are therefore candidates for the initial fibrinogen polymerization site and may also have a role in fibrinogen half-molecule assembly.

Puff adder venom contains a protease capable of cleaving the gamma-chain of cross-linked D-dimer, derived from the plasmin digestion of fibrin, into apparently symmetrical monomers. The cross-linked gamma-chains are separated in the process without apparent loss of mass and without loss of the substituent at the glutamine cross-link site, if fluorescent D-dimer (the lysine analogue dansylcadaverine used as substituent) is used as substrate [Purves, L. R., Purves, M., Lindsey, G. G., & Linton, N. J. (1986) S. Afr. J. Sci. 82, 30]. The gamma-chain from puff adder venom digested D-monomer was isolated and cleaved by cyanogen bromide, and the carboxy-terminal peptide was isolated and sequenced. The carboxy-terminal peptide composition indicated a lower content of histidine, leucine, and glycine than expected. Manual microsequencing by gas-phase Edman degradation demonstrated that two amino-terminal ends were present. By use of the known sequence of the human fibrinogen gamma-chain, the sequencing data could be resolved into a dipeptide cross-linked between lysine-406 and either glutamine-398 or -399 (residues 6 and 13 or 14 from the carboxy-terminal end of the gamma-chain) with the loss of residues 401-404 that occur between the cross-link sites of both antiparallel cross-linked gamma-chains. D-dimer is therefore separated into monomers by cleavage of the gamma-chain between the cross-link sites. Two symmetrical fragments are produced consisting of a cross-linked dipeptide with the loss of four amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)