Helokinestatin-7 peptides from the venoms of Heloderma lizards

Helokinestatins 1–6 constitute a family of bradykinin antagonist peptides originally isolated from the venoms of the Gila Monster, Heloderma suspectum and the Mexican beaded lizard, Heloderma horridum. Here we report the identification, isolation and preliminary pharmacological characterization of two novel tridecapeptides, named helokinestatin-7S (FDDDSTELILEPR – 1550 Da) and helokinestatin-7H (FDDDSRKLILEPR – 1604 Da), whose primary structures were predicted from cDNAs cloned from venom libraries of respective Heloderma lizards. Computed molecular masses of putative helokinestatin-7 peptides were used as tools to locate these peptides in archived LC/MS fractions from respective venoms and sequences were confirmed by MS/MS fragmentation. A synthetic replicate of helokinestatin-7H was found to antagonize the relaxation effect of bradykinin on rat arterial smooth muscle but to have no measurable effects alone. In contrast, synthetic helokinestatin-7S was found to directly contract this preparation. Studies on related natural peptides with subtle differences in primary structure can provide the tools for structure/activity studies in pharmacological investigations directed toward unraveling the molecular basis of venom toxicity and for the evaluation of potential therapeutic leads.

Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial

BACKGROUND:
Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE--an international, open-label, randomised controlled trial--uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A).
METHODS:
Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544.
FINDINGS:
2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·94 (95% CI 0·74-1·20). [corrected]. 2-year FFS was 51% (95% CI 46-56) in arm A and 51% (95% CI 43-58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20-27] patients in arm A and 64 [25%, 19-30] in arm D). The most common grade 3-5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee.
INTERPRETATION:
Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival.

Technology Assessment for a Complex Aircraft System using Technology Scenarios

Military decision makers need to understand and assess the benefits and consequences of their decisions in order to make cost efficient, timely, and successful choices. Technology selection is one such critical decision, especially when considering the design or retrofit of a complex system, such as an aircraft. An integrated and systematic methodology that will support decision-making between technology alternatives and options while assessing the consequences of such decisions is a key enabler. This paper presents and demonstrates, through application to a notional medium range short takeoff and landing (STOL) aircraft, one such enabler: the Technology Impact Forecasting (TIF) method. The goal of the TIF process is to explore both generic, undefined areas of technology, as well as specific technologies, and assess their potential impacts. This is actualized through the development and use of technology scenarios, and allows the designer to determine where to allocate resources for further technology definition and refinement, as well as provide useful design information. The paper particularly discusses the use of technology scenarios and demonstrates their use in the exploration of seven technologies of varying technology readiness levels.

Detection of undiagnosed coeliac disease with atypical features using antireticulin and antigliadin antibodies

Eighteen patients with a variety of non-gastrointestinal symptoms were incidentally found to have circulating antireticulin antibody and on subsequent testing were also positive for antigliadin antibody. They prospectively underwent jejunal biopsy to determine whether or not they had coeliac disease. Their age range was 21-79 years (mean 42 years). Enteropathy was present in 13 (72 per cent) and was always associated with circulating IgA antigliadin antibody. Enteropathy was not present in the five cases who had only IgG antibody. Clinical improvement occurred in eight of 11 patients who complied with a gluten-free diet and was paralleled by an improvement in the mucosal histology in seven of eight who were re-biopsied. The most remarkable cases were two patients who presented with severe debility and no apparent haematological or biochemical abnormalities, and who subsequently made a dramatic recovery on a gluten-free diet. It is concluded that antireticulin antibody detected by routine autoantibody screening and confirmed to have IgA antigliadin antibody specificity is a useful indicator of an otherwise undiagnosed enteropathy. This serves to emphasize that the condition can sometimes be associated with atypical features and significant morbidity.

Developing Approaches for Solving a Telecommunications Feature Subscription Problem

Call control features (e.g., call-divert, voice-mail) are primitive options to which users can subscribe off-line to personalise their service. The configuration of a feature subscription involves choosing and sequencing features from a catalogue and is subject to constraints that prevent undesirable feature interactions at run-time. When the subscription requested by a user is inconsistent, one problem is to find an optimal relaxation, which is a generalisation of the feedback vertex set problem on directed graphs, and thus it is an NP-hard task. We present several constraint programming formulations of the problem. We also present formulations using partial weighted maximum Boolean satisfiability and mixed integer linear programming. We study all these formulations by experimentally comparing them on a variety of randomly generated instances of the feature subscription problem.

Comparison of the acute renal and peripheral vascular responses to frusemide and bumetanide at low and high dose

1. The effects of equipotent doses of frusemide (10 mg and 100 mg) and bumetanide (250 micrograms and 2.5 mg) upon renal and peripheral vascular responses, urinary prostaglandin excretion, plasma renin activity, angiotensin II and noradrenaline were compared in nine healthy volunteers. 2. Frusemide (10 mg and 100 mg) and bumetanide (2.5 mg) increased renal blood flow acutely compared with placebo but bumetanide (250 micrograms) had no effect. The changes in peripheral vascular responses were not significantly different from placebo. 3. Urinary prostaglandin metabolite excretion was acutely increased by all treatments, with no inter-treatment difference. Plasma renin activity was increased acutely by both doses of frusemide and by bumetanide (2.5 mg) compared with placebo and to bumetanide (250 micrograms). There were no differences between the latter two treatments. Angiotensin II was increased significantly 30 min after frusemide 100 mg and bumetanide 2.5 mg, and by all four treatments at 50 min when compared with placebo. There were no significant differences between either of the low doses or the higher doses. Plasma noradrenaline was unchanged by all treatments. 4. Frusemide 100 mg and bumetanide 2.5 mg have the same effects on the renal vasculature and the renin-angiotensin-prostaglandin system. Under the conditions of this study, frusemide 10 mg had different effects on plasma renin activity than bumetanide 250 micrograms.

Minimal Hilbert series for quadratic algebras and the Anick conjecture

We study the question on whether the famous Golod–Shafarevich estimate, which gives a lower bound for the Hilbert series of a (noncommutative) algebra, is attained. This question was considered by Anick in his 1983 paper ‘Generic algebras and CW-complexes’, Princeton Univ. Press, where he proved that the estimate is attained for the number of quadratic relations $d\leq n^2/4$
and $d\geq n^2/2$, and conjectured that it is the case for any number of quadratic relations. The particular point where the number of relations is equal to $n(n-1)/2$ was addressed by Vershik. He conjectured that a generic algebra with this number of relations is finite dimensional. We announce here the result that over any infinite field, the Anick conjecture holds for $d \geq 4(n2+n)/9$ and an arbitrary number of generators. We also discuss the result that confirms the Vershik conjecture over any field of characteristic 0, and a series of related
asymptotic results.

Hypercyclic tuples of operators on $C^n$ and $R^n$

A tuple $(T_1,\dots,T_n)$ of continuous linear operators on a topological vector space $X$ is called hypercyclic if there is $x\in X$ such that the the orbit of $x$ under the action of the semigroup generated by $T_1,\dots,T_n$ is dense in $X$. This concept was introduced by N.~Feldman, who have raised 7 questions on hypercyclic tuples. We answer those 4 of them, which can be dealt with on the level of operators on finite dimensional spaces. In
particular, we prove that the minimal cardinality of a hypercyclic tuple of operators on $\C^n$ (respectively, on $\R^n$) is $n+1$ (respectively, $\frac n2+\frac{5+(-1)^n}{4}$), that there are non-diagonalizable tuples of operators on $\R^2$ which possess an orbit being neither dense nor nowhere dense and construct a hypercyclic 6-tuple of operators on $\C^3$ such that every operator commuting with each member of the tuple is non-cyclic.

Emergency slaughter of casualty cattle increases the prevalence of anthelmintic drug residues in muscle

The ProSafeBeef project studied the prevalence of residues of anthelmintic drugs used to control parasitic worms and fluke in beef cattle in Ireland. Injured (casualty) cattle may enter the human food chain under certain conditions, verified by an attending veterinarian and the livestock keeper. An analytical survey was conducted to determine if muscle from casualty cattle contained a higher prevalence of anthelmintic drug residues than healthy (full slaughter weight) cattle as a result of possible non-observance of complete drug withdrawal periods. A validated analytical method based on matrix solid-phase dispersive extraction (QuEChERS) and ultra-performance liquid chromatography-tandem mass spectrometry was used to quantify 37 anthelmintic drugs and metabolites in muscle (assay decision limits, CCa, 0.15-10.2 µg kg -1). Of 199 control samples of beef purchased in Irish shops, 7% contained detectable anthelmintic drug residues but all were compliant with European Union Maximum Residue Limits (MRL). Of 305 muscle samples from injured cattle submitted to abattoirs in Northern Ireland, 17% contained detectable residues and 2% were non-compliant (containing either residues at concentrations above the MRL or residues of a compound unlicensed for use in cattle). Closantel and ivermectin were the most common residues, but a wider range of drugs was detected in muscle of casualty cattle than in retail beef. These data suggest that specific targeting of casualty cattle for testing for anthelmintic residues may be warranted in a manner similar to the targeted testing for antimicrobial compounds often applied in European National Residues Surveillance Schemes. © 2012 Copyright Taylor and Francis Group, LLC.