Intolerant

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Distribution within Medical Sciences

Terms modified by Intolerant

  • intolerant species

  • Selected Abstracts


    Three novel thiopurine S-methyltransferase allelic variants (TPMT*20, *21, *22) , association with decreased enzyme function,,

    HUMAN MUTATION, Issue 9 2006
    Elke Schaeffeler
    Abstract The genetic polymorphism of the thiopurine S-methyltransferase, TPMT, comprises at least 21 alleles causing three distinct drug metabolism phenotypes termed normal/high, intermediate, and deficient methylators. In consequence, adverse drug reactions may occur if standard doses of thiopurines are applied routinely. Genetic prediction of the methylator phenotype as a basis for dose selection requires the extensive knowledge of single nucleotide polymorphisms occurring naturally in the population. Here we describe three novel missense variants in the TPMT gene which were associated with an intermediate red blood cell TPMT activity in three Caucasians. The following alleles were designated: TPMT*20 (c.712A>G), *21 (c.205C>G), and *22 (c.488G>C). No further genetic variations in remaining coding regions as well as the 5,flanking region of TPMT were identified. These sequence variants are present in highly conserved nucleotide positions of the TPMT gene throughout various mammalian species and in zebra fish, and are predicted to be intolerant when the functional consequences of variations were analyzed using SIFT (Sorting Intolerant From Tolerant) algorithm. In Caucasians the occurrence of these genetic variants appears to be extremely rare since none of these alleles were identified in a randomly selected control population of 1048 individuals. © 2006 Wiley-Liss, Inc. [source]


    A longitudinal observational study of a cohort of patients with relapsing,remitting multiple sclerosis treated with glatiramer acetate

    EUROPEAN JOURNAL OF NEUROLOGY, Issue 11 2007
    M. Debouverie
    Immunomodulatory treatments for relapsing,remitting multiple sclerosis (RRMS) are not efficacious or tolerated in all patients. It is important to evaluate alternative classes of treatment in patients failing first-line therapy. The objective of this prospective observational study was to evaluate the efficacy and safety of glatiramer acetate in patients, to whom , -interferons could not be administered. The study included patients with RRMS who were intolerant to or had contraindications to , -interferon. After initiation of glatiramer acetate treatment, follow-up visits were made every 3 months, when data on neurologist-ascertained relapses and disability [Expanded Disability Status Scale (EDSS) score] were collected. Tolerability was evaluated by spontaneous adverse event reporting. Overall, 205 patients were studied and 113 (55.1%) treated for at least 4 years. The proportion of patients presenting over three relapses per year decreased from 51.2% to 8.4% in the 2 years following treatment initiation. Over 5 years of treatment, mean annualized relapse rates and mean EDSS scores remained stable (0.4,0.6 relapses/year and 3.6 ± 1.8,3.3 ± 2.1 respectively). Adverse events were reported by 179 patients, leading to discontinuation of treatment in 10 patients. Patients with RRMS to whom , -interferons cannot be prescribed can benefit from treatment with glatiramer acetate. [source]


    Assessing biotic integrity in a Mediterranean watershed: development and evaluation of a fish-based index

    FISHERIES MANAGEMENT & ECOLOGY, Issue 4 2008
    M. F. MAGALHÃES
    Abstract, Biological indicators for Mediterranean rivers are poorly developed. This study evaluates the effectiveness of the Index of Biotic Integrity approach (IBI) with fish assemblages in the Guadiana catchment, a typical Mediterranean watershed in Southern Portugal. Reference sites were selected from a set of 95 sites, using a multivariate approach. Fifty-five candidate metrics were screened for range, responsiveness, precision and redundancy. Final metrics included: proportion of native fish, number of intolerant and intermediate species, number of invertivore native fish, number of phyto-lithophilic and polyphilic species, and catches of exotics. The IBI scores correlated with composite gradients of human impact and differed significantly between reference and non-reference sites. Application of the IBI to an independent validation set with 123 sites produced results congruent with the development set and repeatable assessments at 22 sites showed concordance in IBI scoring. This application highlights the effectiveness of the IBI approach even with fish assemblages of limited diversity and ecological specialisation as in Mediterranean streams. [source]


    Clofarabine in the treatment of poor risk acute myeloid leukaemia

    HEMATOLOGICAL ONCOLOGY, Issue 3 2010
    Janusz Krawczyk
    Abstract Clofarabine is a second generation nucleoside analogue. It inhibits DNA repair and activates the mitochondrial apoptotic pathway leading to cell death. In vitro clofarabine has demonstrated synergy with daunorubicin and Ara-C and in phase II clinical trials has shown promising activity in poor risk Acute myeloid leukaemia (AML) patients. In our institution over a 24 month period 22 AML patients (11 M, 11 F) with poor risk features, deemed unsuitable for standard therapy, were treated with clofarabine, alone (eight patients) or in combination (14 patients) for up to three cycles of treatment. The median age was 67.5 years (24,76) with 16 patients > 60 years. At the time of treatment 18 patients had active AML. Four patients intolerant of standard induction received clofarabine as consolidation. The overall response rate (ORR) for the 18 patients with active AML was 61%, nine patients (50%) achieving a complete response (CR). Induction and consolidation were well tolerated with no unexpected toxicities. Predictably, all patients developed grade 4 neutropenia but the median duration was only 20 days (17,120). Induction mortality was acceptable at 17%. In conclusion, clofarabine (alone or in combination) is active in poor risk AML with an acceptable safety profile and should be considered a potential option in poor risk AML patients. Copyright © 2009 John Wiley & Sons, Ltd. [source]


    Three novel thiopurine S-methyltransferase allelic variants (TPMT*20, *21, *22) , association with decreased enzyme function,,

    HUMAN MUTATION, Issue 9 2006
    Elke Schaeffeler
    Abstract The genetic polymorphism of the thiopurine S-methyltransferase, TPMT, comprises at least 21 alleles causing three distinct drug metabolism phenotypes termed normal/high, intermediate, and deficient methylators. In consequence, adverse drug reactions may occur if standard doses of thiopurines are applied routinely. Genetic prediction of the methylator phenotype as a basis for dose selection requires the extensive knowledge of single nucleotide polymorphisms occurring naturally in the population. Here we describe three novel missense variants in the TPMT gene which were associated with an intermediate red blood cell TPMT activity in three Caucasians. The following alleles were designated: TPMT*20 (c.712A>G), *21 (c.205C>G), and *22 (c.488G>C). No further genetic variations in remaining coding regions as well as the 5,flanking region of TPMT were identified. These sequence variants are present in highly conserved nucleotide positions of the TPMT gene throughout various mammalian species and in zebra fish, and are predicted to be intolerant when the functional consequences of variations were analyzed using SIFT (Sorting Intolerant From Tolerant) algorithm. In Caucasians the occurrence of these genetic variants appears to be extremely rare since none of these alleles were identified in a randomly selected control population of 1048 individuals. © 2006 Wiley-Liss, Inc. [source]


    Diagnostic and therapeutic value of apomorphine in Parkinsonian patients

    INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 11 2004
    J.C. Sharma
    Summary Apomorphine is a dopamine agonist administered subcutaneously for the management of motor symptoms of Parkinson's disease (PD). Patients with Parkinsonian syndrome underwent an apomorphine challenge for therapeutic efficacy, a positive response being a reduction of >15% score on motor unified PD rating scale. Of the 42 patients, aged 37,81, disease duration 12 months to 20 years, 36 had a positive response. Six non-responders were later diagnosed as non-PD as compared with only two of the 36 responders. Tremor-predominant patients obtained higher motor response. Few patients demonstrated a delayed positive response. Seven (three idiopathic PD (iPD), four non-PD) suffered adverse reactions of nausea, vomiting or ill-sustained symptomatic fall in BP. Majority of the patients who continued with apomorphine therapy were able to reduce levodopa and achieved an improvement in dyskinesia and motor symptoms. Thirteen responding patients were managed by increasing dopamine agonists. Five patients, intolerant of oral dopamine agonists, were able to beneficially tolerate apomorphine. Age and disease duration did not influence tolerability or efficacy. The patients treated with apomorphine were able to significantly reduce the dose of levodopa, and there was a reduction in dyskinesia, hallucinations and fluctuations (all p < 0.05). In some patients, apomorphine prevented admission to institutions. We also describe the use of apomorphine in acutely ill patients unable to ingest oral medication. Apomorphine seems to have a diagnostic element for iPD. Its use leads to a reduction in dyskinesia, improvement in motor symptoms and prevention of institutional care. Apomorphine test also identifies patients likely to benefit with an increase in oral medication. Age and disease duration should not prevent the use of this valuable drug. Apomorphine also has a role in acutely ill PD patients. [source]


    Effects of Interactions of Moisture Regime and Nutrient Addition on Nodulation and Carbon Partitioning in Two Cultivars of Bean (Phaseolus vulgaris L.)

    JOURNAL OF AGRONOMY AND CROP SCIENCE, Issue 4 2001
    T. Boutraa
    Major limitations of bean (Phaseolus vulgaris L.) production in arid and semiarid regions are lack of moisture and low soil fertility. An experiment was conducted to determine the effects of soil moisture and N : P : K (20 : 10 : 10) fertilizer on root and shoot growth of two cultivars of bean: cv. Carioca, an indeterminate Brazilian landrace, and cv. Prince, a determinate cultivar grown in Europe. Carioca appears generally stress-tolerant while Prince is intolerant. Seedlings were grown in pots of non-sterile soil at 30, 60 or 90 % field capacity (FC), and given 0, 0.1 or 1 g (kg soil),1 of compound fertilizer. The soil contained a population of effective Rhizobium. Growth of both cultivars was greatest in the high moisture and high nutrient treatments. Root fractions were highest at low nutrient supply; the effect of water was not significant. Leaf fraction decreased as root fraction increased. Numbers of nodules were highest at high and intermediate moisture when no fertilizer was applied. Numbers were lowest at 30 % FC and at the highest fertilizer rate. Masses of nodules and fractions followed the same pattern. Decreasing water regime reduced the relative growth rate (RGR) of Prince, while Carioca maintained high RGR at unfavourable conditions of water and nutrients. Net assimilation rates (NAR) were unaffected by nutrient addition, and reduced by low moisture regime. Water use efficiencies (WUEs) were reduced by water stress but increased by nutrient deficiency. The water utilization for dry matter production was optimal at 60 % FC. Einflüsse der Interaktionen von Bodendenfeuchte und Düngung auf die Knöllchenbildung und Kohlenstoff verteilung bei zwei Bohnenkultivaren (Phaseolus vulgaris L.) Der begrenzende Hauptfaktor der Bohnenproduktion in ariden und semiariden Regionen sind der Feuchtigkeitsmangel und die Bodenfruchbarkeit. Es wurde ein Experiment durchgeführt, um die Wirkungen des Bodenwassers und von N : P : K (20 : 10 : 10) Dünger auf das Wurzel- und Sproßwachstum an zwei Kultivaren von Bohnen (Phaseolus vulgaris L. cv. Carioca, eine brasilianischen, indeterminierte Landsorte und cv. Prince, eine determinierter in Europa angebauter Kultivar) zu untersuchen. Carioca erscheint grundsätzlich streßtoleranter im Vergleich zu Prince. Die Sämlinge wurden in Gefäßen mit nichtsterilisiertem Boden unter Feldkapazitäten von 30,60 oder 90 % mit 0, 0,1 oder 1 g eines Volldüngers angezogen. Der Boden enthielt eine Population von wirksamem Rhizobium. Das stärkste Wachstum wurde bei beiden Kultivaren unter dem Einfluß des höchsten Feuchtigkeitsgehaltes und der höchsten Düngermenge gefunden. Der Wurzelanteil war bei der geringen Düngermenge am niedrigsten. Der Einfluß der Bodenfeuchtigkeit war nicht signifikant. Der Blattanteil nahm mit zunehmendem Wurzelanteil ab. Die Anzahl der Knötchen war bei hoher und mittlerer Bodenfeuchte und ohne Düngeranwendung am höchsten. Die Anzahl war am geringsten bei 30 % FC und der höchsten Düngermenge. Die Knötchenmasse und ihr Anteil reagierte entsprechend. Abnehmende Bodenfeuchte reduzierte die relative Wachtumsrate (RGR) von Prince, während Carioca einen hohen RGR auch bei ungünstigen Bedingungen bezüglich Wasser und Düngung behielt. Die Nettoassimilationsraten wurden durch die Düngung nicht beeinflußt; sie gingen bei geringer Bodenfeuchte zurück. Die Wassernutzungseffiziens (WUE) wurde bei Wasserstreß reduziert, nahm aber bei Düngermangel zu. Die Wassernutzung für die Trockenmasseproduktion war bei 60 % Feldkapazität am höchsten. [source]


    Regular or "Super-Aspirins"?

    JOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 4 2001
    A Review of Thienopyridines or Aspirin to Prevent Stroke
    PURPOSE: To review the evidence for the effectiveness and safety of the thienopyridines (ticlopidine and clopidogrel) compared with aspirin for the prevention of vascular events among patients at high risk of vascular disease. BACKGROUND: Atherosclerosis and resultant cardiovascular disease are important causes of morbidity and mortality in older people. In particular, atherosclerosis of the cerebral arteries can lead to transient ischemic attacks (TIAs) and stroke. Stroke ranks as the third-leading cause of death in the United States and in 1997 was responsible for over 150,000 fatalities.1 In addition to the mortality associated with this disease, stroke is also a leading source of long-term disability in survivors. Nearly 4.5 million stroke survivors are alive today,1 highlighting the fact that primary, but also secondary, prevention are extremely important for minimizing the complications of this illness. DATA SOURCES: Specialized trial registers of the Cochrane Stroke Group and the Antithrombotic Trialist's Collaboration, MEDLINE, and Embase were searched. Additional unpublished information and data were sought from Sanofi, the pharmaceutical company that developed and manufactures ticlopidine and clopidogrel, as well as the principal investigators of the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial,7 the largest of the trials identified. STUDY SELECTION CRITERIA: All unconfounded randomized trials comparing either ticlopidine or clopidogrel with aspirin among patients at high risk of vascular disease (those with symptoms of ischemia of the cerebral, coronary, or peripheral circulations) who were followed for at least 1 month for the recurrence of vascular events were included. DATA EXTRACTION: Data were extracted from four completed randomized trials completed in the past 20 years, which included 22,656 patients.7,10 Two authors independently extracted the data from these trials for the following information: the types of patients enrolled; the entry and exclusion criteria; the randomization method; the number of patients originally allocated to the treatment and control groups; the method and duration of follow-up; the number of patients in each group lost to follow-up; information on compliance with the treatment allocated; the definitions of outcome events; the number of outcome events in each treatment group; and any method used for blinding patients, treating clinicians, and outcome assessors to treatment allocation. MAIN RESULTS: Four completed trials involving a total of 22,656 patients were identified. Aspirin was compared with ticlopidine in three trials (3,471 patients)8,10 and with clopidogrel in one trial (19,185 patients).7 A recent TIA or ischemic stroke was the qualifying event in 9,840 patients, a recent myocardial infarction in 6,302 patients, and symptomatic peripheral arterial disease in 6,514 patients. The average age of the patients was approximately 63, with approximately two-thirds of the patients being male and white. The duration of follow-up ranged from 12 to 40 months. CONCLUSIONS: This systematic review demonstrates that, compared with aspirin, thienopyridines are only modestly more effective in preventing serious vascular events in high-risk patients. For patients who are intolerant of, or allergic to aspirin, the available safety and efficacy data suggest that clopidogrel is an appropriate, but more-expensive, alternative antiplatelet drug. It appears safer than ticlopidine and as safe as aspirin but it should not replace aspirin as the first-choice antiplatelet agent for all patients. Further studies are necessary to determine which, if any, particular types of patients would benefit most and least from clopidogrel instead of aspirin. [source]


    Biogeography of Iberian freshwater fishes revisited: the roles of historical versus contemporary constraints

    JOURNAL OF BIOGEOGRAPHY, Issue 11 2009
    Ana F. Filipe
    Abstract Aim, The question of how much of the shared geographical distribution of biota is due to environmental vs. historical constraints remains unanswered. The aim of this paper is to disentangle the contribution of historical vs. contemporary factors to the distribution of freshwater fish species. In addition, it illustrates how quantifying the contribution of each type of factor improves the classification of biogeographical provinces. Location, Iberian Peninsula, south-western Europe (c. 581,000 km2). Methods, We used the most comprehensive data on native fish distributions for the Iberian Peninsula, compiled from Portuguese and Spanish sources on a 20-km grid-cell resolution. Overall, 58 species were analysed after being categorized into three groups according to their ability to disperse through saltwater: (1) species strictly intolerant of saltwater (primary species); (2) species partially tolerant of saltwater, making limited incursions into saltwaters (secondary species); and (3) saltwater-tolerant species that migrate back and forth from sea to freshwaters or have invaded freshwaters recently (peripheral species). Distance-based multivariate analyses were used to test the role of historical (basin formation) vs. contemporary environmental (climate) conditions in explaining current patterns of native fish assemblage composition. Cluster analyses were performed to explore species co-occurrence patterns and redefine biogeographical provinces based on the distributions of fishes. Results, River basin boundaries were better at segregating species composition for all species groups than contemporary climate variables. This historical signal was especially evident for primary and secondary freshwater fishes. Eleven biogeographical provinces were delineated. Basins flowing to the Atlantic Ocean north of the Tagus Basin and those flowing to the Mediterranean Sea north of the Mijares Basin were the most dissimilar group. Primary and secondary freshwater species had higher province fidelity than peripheral species. Main conclusions, The results support the hypothesis that historical factors exert greater constraints on native freshwater fish assemblages in the Iberian Peninsula than do current environmental factors. After examining patterns of assemblage variation across space, as evidenced by the biogeographical provinces, we discuss the likely dispersal and speciation events that underlie these patterns. [source]


    Pollution status of a tropical forest river using aquatic insects as indicators

    AFRICAN JOURNAL OF ECOLOGY, Issue 1 2010
    Tunde Ohiokhioya Thadeus Imoobe
    Abstract Aquatic insects inhabiting Okhuo River, in a tropical forest near Benin City, Southern Nigerian, were studied between January and December 2006 to determine the taxa composition, diversity, EPT index, relative proportions of the various groups and hence the pollution level of the waterbody. Three stations were selected and sampled monthly using the kick sampling technique. A total of 3235 individual aquatic insects belonging to 24 taxa distributed among 23 genera in six orders were collected. The insect orders occurred in the following order of dominance: Ephemeroptera > Odonata > Coleoptera > Diptera > Plecoptera > Tricoptera. Based on the diverse composition of the community dominated by organisms intolerant of organic enrichment, and the high diversity and EPT index, water quality in Okhuo River is not significantly degraded. Community composition varies seasonally, with a trend toward a declining proportion during the rainy season and increasing proportions during the dry season. Aquatic insect composition in Okhuo River compares favourably with those in similar, relatively undisturbed forest streams and rivers in Nigeria, but the diversity and proportional distribution of taxa vary considerably between streams. Résumé Les insectes aquatiques qui vivent dans la rivière Okhuo près de la ville de Benin, au sud du Nigeria, ont étéétudiés entre janvier et décembre 2006 afin de déterminer la composition des taxons, leur diversité, l'indice EPT, les proportions relatives des différents groupes et, de là, le taux de pollution de la rivière. On a sélectionné trois stations qui ont étééchantillonnées chaque mois en utilisant la technique d'échantillonnage par coups de pied. On a collecté un total de 3 235 insectes aquatiques appartenant à 24 taxons répartis entre 23 genres de six ordres. Les ordres des insectes se plaçaient dans l'ordre de dominance suivant : Ephéméroptères > Odonates > Coléoptères > Diptères > Plécoptères > Trichoptères. Si l'on se base sur la composition diversifiée de la communauté où dominent des organismes intolérants aux enrichissements organiques, et sur la grande diversité et l'indice EPT, on peut dire que la qualité de l'eau de la rivière Okhuo n'est pas significativement dégradée. La composition de la communauté varie avec les saisons, avec une tendance à la diminution au cours de la saison des pluies et à une augmentation au cours de la saison sèche. La composition des insectes aquatiques de la rivière Okhuo se compare avantageusement avec celles des cours d'eau semblables des forêts intactes du Nigeria, mais la diversité et la distribution proportionnelle des différents taxons varient considérablement entre les cours d'eau. [source]


    Wind-throw mortality in the southern boreal forest: effects of species, diameter and stand age

    JOURNAL OF ECOLOGY, Issue 6 2007
    ROY L. RICH
    Summary 1Patterns of tree mortality as influenced by species, diameter and stand age were assessed across a gradient in wind disturbance intensity in a southern boreal forest in Minnesota, USA. Few previous studies have addressed how wind impacts boreal forests where fire was historically the dominant type of disturbance. 2We surveyed 29 334 trees of nine species within a 236 000 ha blowdown in the Boundary Waters Canoe Area Wilderness (BWCAW), in forests that have never been logged and were not salvaged after the windstorm. Within the disturbed area, a range of disturbance severity from zero to complete canopy mortality was present, overlaying an existing mosaic of fire origin stands. For this study, we derived an index of wind disturbance intensity by standardizing the observed disturbance severity using common species with similar diameter at breast height (d.b.h.) distributions. We then used multiple logistic regression to assess patterns of tree mortality across gradients in tree size and wind intensity index, and for three stand ages. 3Probability of mortality was higher with increasing ln d.b.h. for all nine species, with two species (Abies balsamea and Picea mariana) showing much more dramatic shifts in mortality with d.b.h. than the others. As hypothesized, the species most susceptible to windthrow at all d.b.h. classes were early successional and shade intolerant (Pinus banksiana, Pinus resinosa, Populus tremuloides) and those least susceptible were generally shade tolerant (e.g. Thuja occidentalis, Acer rubrum), although the intolerant species Betula papyrifera also had low mortality. 4Mortality rates were higher in mature (c. 90 years old) stands than for old and very old (c. 126,200 years old) stands, probably because old stands had already gone through transition to a multi-aged stage of development. 5Synthesis. Quantification of canopy mortality patterns generally supports disturbance-mediated accelerated succession following wind disturbance in the southern boreal forest. This wind-induced weeding of the forest favoured Thuja occidentalis, Betula papyrifera and Acer rubrum trees of all sizes, along with small Abies balsamea and Picea mariana trees. Overall, the net impact of wind disturbance must concurrently consider species mortality probability, abundance and diameter distributions. [source]


    New approaches to parenteral nutrition in infants and children

    JOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 5 2002
    RG Heine
    Abstract: Parenteral nutrition (PN) has become a mainstay in the treatment of children with intestinal failure or conditions that preclude enteral feeding. Estimated energy and protein requirements can usually be met, unless the patient is fluid volume restricted or glucose intolerant. Although PN is generally well tolerated, in some patients it is still associated with a significant morbidity. Complications include metabolic disturbances, venous access device infection or dysfunction, venous thrombosis and cholestatic liver disease. Patients need to be carefully monitored for evidence of micronutrient deficiencies or excesses. There is a close relationship between line sepsis and thrombosis. Strict aseptic technique is the key to preventing line infections. Recurrent sepsis and thrombosis may eventually lead to loss of venous access and may jeopardize the long-term delivery of PN. Chronic cholestatic liver disease is common in premature infants with gastrointestinal problems, recurrent sepsis and lack of enteral feeding. The aetiology is multifactorial. Early enteral feeding is the most effective strategy in preventing PN-associated liver disease. New specialized nutrient solutions and lipid emulsions promise improved clinical outcomes. However, long-term clinical data are not yet available in children. In recent years, nutrition support teams have improved clinical and economic outcomes by encouraging the appropriate use and monitoring of PN therapy. In patients with intestinal failure, parent-administered home PN has become an alternative to long-term hospitalization. Apart from a positive effect on the quality of life of patient and family, home PN is cost-effective and reduces the risk of nosocomial infections and catheter-related complications. [source]


    Potential roles of melatonin and chronotherapy among the new trends in hypertension treatment

    JOURNAL OF PINEAL RESEARCH, Issue 2 2009
    Fedor Simko
    Abstract:, The number of well-controlled hypertensives is unacceptably low worldwide. Respecting the circadian variation of blood pressure, nontraditional antihypertensives, and treatment in early stages of hypertension are potential ways to improve hypertension therapy. First, prominent variations in circadian rhythm are characteristic for blood pressure. The revolutionary MAPEC (Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study, in 3000 adult hypertensives investigates, whether chronotherapy influences the cardiovascular prognosis beyond blood pressure reduction per se. Second, melatonin, statins and aliskiren are hopeful drugs for hypertension treatment. Melatonin, through its scavenging and antioxidant effects, preservation of NO availability, sympatholytic effect or specific melatonin receptor activation exerts antihypertensive and anti-remodeling effects and may be useful especially in patients with nondipping nighttime blood pressure pattern or with nocturnal hypertension and in hypertensives with left ventricular hypertrophy (LVH). Owing to its multifunctional physiological actions, this indolamine may offer cardiovascular protection far beyond its hemodynamic benefit. Statins exert several pleiotropic effects through inhibition of small guanosine triphosphate-binding proteins such as Ras and Rho. Remarkably, statins reduce blood pressure in hypertensive patients and more importantly they attenuate LVH. Addition of statins should be considered for high-risk hypertensives, for hypertensives with LVH, and possibly for high-risk prehypertensive patients. The direct renin inhibitor, aliskiren, inhibits catalytic activity of renin molecules in circulation and in the kidney, thus lowering angiotensin II levels. Furthermore, aliskiren by modifying the prorenin conformation may prevent prorenin activation. At present, aliskiren should be considered in hypertensive patients not sufficiently controlled or intolerant to other inhibitors of renin,angiotensin system. Third, TROPHY (Trial of Preventing Hypertension) is the first pharmacological intervention for prehypertensive patients revealing that treatment with angiotensin II type 1 receptor blocker attenuates hypertension development and thus decreases the risk of cardiovascular events. [source]


    Methotrexate in paediatric ulcerative colitis: a retrospective survey at a single tertiary referral centre

    ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2010
    M. Aloi
    Aliment Pharmacol Ther 2010; 32: 1017,1022 Summary Background, Patients with ulcerative colitis often receive thiopurines as immunomodulators (IMs) to maintain remission and avoid corticosteroids. If unresponsive or intolerant to these agents, patients are treated with methotrexate, an antimetabolite never assessed in paediatric ulcerative colitis. Aim, To describe the experience with methotrexate in children with ulcerative colitis. Methods, Thirty-two patients (median age 13.9 years) received methotrexate. Pediatric Ulcerative Colitis Activity Index (PUCAI) and use of corticosteroids were the main outcomes evaluated at baseline and at 3, 6 and 12 months. Results, Indications to methotrexate were azathioprine unresponsiveness in 18 patients, azathioprine intolerance/toxicity in 10 and spondyloarthropathy in four. Response or remission was achieved in 72%, 63% and 50% of patients at 3, 6 and 12 months respectively. Mean PUCAI were 49.5 ± 23.3 at baseline and 32.9 ± 21.9, 29.5 ± 21.8 and 29.4 ± 19.9 at 3, 6 and 12 months respectively (P: 0.03). At the beginning of methotrexate, 16 patients (50%) received corticosteroids that were discontinued in 13 of them (81%) by 6 months. At the end of the study, 11 patients (33%) needed short courses of corticosteroids for disease relapse. Conclusions, Methotrexate may be useful in treating children with ulcerative colitis, although large, controlled trials are warranted to define better its effectiveness. [source]


    Systematic review: the short-term and long-term efficacy of adalimumab following discontinuation of infliximab

    ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2009
    C. MA
    Summary Background, Therapy with adalimumab has been shown to be effective in Crohn's disease (CD) patients who have lost response or are intolerant to infliximab. Aim, To determine the efficacy of adalimumab in CD patients who discontinued infliximab through a systematic review. Methods, Electronic searches of EMBASE and MEDLINE databases up to May 1, 2009, as well as abstracts from the AGA (2006,2008), ACG (2006,2007), UEGW (2006,2008) and CDDW (2006,2009) identified randomized-controlled trials (RCT) or open-labelled cohorts (OLC) evaluating the short-term and/or long-term efficacy of adalimumab in infliximab failures. The response rates for short-term (clinical response and remission at 4 weeks) and long-term (remission at 6 and 12 months) efficacy were considered. Results, A total of 1810 CD patients were identified among the 15 studies (2 RCT and 13 OLC). The majority of studies evaluated CD patients who either lost response or were intolerable to infliximab, although five OLCs permitted patients refractory to infliximab. Short-term clinical response (n = 9 articles) ranged from 41% to 83%. Long-term clinical remission at 12 months (n = 8 articles) ranged from 19% to 68%. The occurrence of severe adverse events ranged from 0% to 19% and four patients died. Conclusions, Current RCT and OLC evidence suggest that adalimumab is an efficacious therapy for CD patients who discontinue infliximab. [source]


    Efficacy of methotrexate in Crohn's disease and ulcerative colitis patients unresponsive or intolerant to azathioprine,/mercaptopurine

    ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2009
    M. WAHED
    Summary Background, Despite the wide use of azathioprine/mercaptopurine (AZA/MP) therapy in the management of both Crohn's disease (CD) and ulcerative colitis (UC), approximately 20% of patients cannot tolerate the drugs and 30% do not respond. Aim, To examine the efficacy and safety profile of methotrexate (MTX) in patients with CD or UC who are either intolerant or non-responsive to AZA/MP. Methods, A total of 131 patients with IBD treated with MTX were identified. Retrospective data were obtained by case note review. Clinical response (defined as steroid withdrawal, normalization of previously raised CRP or physician's clinical assessment of improvement) was assessed at 6 months. Results, Clinical response in Crohn's disease occurred in 18 of 29 patients (62%) refractory to AZA/MP and 42 of 70 patients (60%) intolerant to AZA/MP, with no difference between the groups (P = 1.0). In UC, clinical response was seen in 7 of 9 (78%) patients refractory to AZA/MP and 15 of 23 (65%) intolerant to thiopurines. MTX was well tolerated in a majority of individuals. Conclusions, Methotrexate appears effective in both CD and UC patients who fail to respond to or are intolerant to AZA/MP therapy. [source]


    Relationships between soil hydrology and forest structure and composition in the southern Brazilian Amazon

    JOURNAL OF VEGETATION SCIENCE, Issue 2 2007
    Stefan Jirka
    Abstract Question: Is soil hydrology an important niche-based driver of biodiversity in tropical forests? More specifically, we asked whether seasonal dynamics in soil water regime contributed to vegetation partitioning into distinct forest types. Location: Tropical rain forest in northwestern Mato Grosso, Brazil. Methods: We investigated the distribution of trees and lianas , 1 cm DBH in ten transects that crossed distinct hydrological transitions. Soil water content and depth to water table were measured regularly over a 13-month period. Results: A detrended correspondence analysis (DCA) of 20 dominant species and structural attributes in 10 × 10 m subplots segregated three major forest types: (1) high-statured upland forest with intermediate stem density, (2) medium-statured forest dominated by palms, and (3) low-statured campinarana forest with high stem density. During the rainy season and transition into the dry season, distinct characteristics of the soil water regime (i.e. hydro-indicators) were closely associated with each vegetation community. Stand structural attributes and hydro-indicators were statistically different among forest types. Conclusions: Some upland species appeared intolerant of anaerobic conditions as they were not present in palm and campinarana sites, which experienced prolonged periods of saturation at the soil surface. A shallow impermeable layer restricted rooting depth in the campinarana community, which could heighten drought stress during the dry season. The only vegetation able to persist in campinarana sites were short-statured trees that appear to be well-adapted to the dual extremes of inundation and drought. [source]


    Adalimumab for Crohn's disease with intolerance or lost response to infliximab: a 3-year single-centre experience

    ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2009
    A. OUSSALAH
    Summary Background, Adalimumab is effective in inducing clinical remission in patients with Crohn's disease who lost response or became intolerant to infliximab. Aim, To evaluate long-term efficacy and safety of adalimumab as a second line therapy in luminal and fistulizing Crohn's disease. Methods, We report our single-centre experience in 53 patients. We evaluated maintenance of clinical response defined as the absence of adverse events leading to drug withdrawal, no major abdominal surgery and no loss of clinical response in initial responders. Major abdominal surgery, steroid sparing, complete fistula closure and safety were also assessed. Results, The probability of maintaining clinical response was 77.2%, 67.8% and 50.8% at 26, 52 and 130 weeks respectively. The probability of remaining major abdominal surgery-free was 82.3% at 26, 52 and 130 weeks. Complete fistula closure occurred in six of 10 patients, and eight of 10 patients were able to taper steroid therapy. Adverse events occurred in 31 patients (58.5%) leading to adalimumab withdrawal in nine patients (17%). Conclusion, Adalimumab therapy may be effective in the long term in both luminal and fistulizing Crohn's disease in infliximab-failure patients, half of patients maintaining clinical response and potentially avoiding major abdominal surgery in 80% of cases. [source]


    Constitutional responses to extremist political associations ,ETA, Batasuna and democratic norms

    LEGAL STUDIES, Issue 1 2008
    Ian Cram
    Systems of representative democracy require that the electorate be given at regular intervals the opportunity to replace the party in government with a rival political association. In this context, the right of individuals to freedom of association permits the formation of competitor parties and prevents forms of state intervention that might otherwise privilege existing office holders and their political programmes. It follows then that restrictions on the right to political association are deserving of particularly close scrutiny. At the same time, liberal democratic constitutions usually insist that participants in electoral process manifest a level of commitment to core liberal democratic norms (such as the rule of law, toleration, the equal worth of each individual and the peaceful resolution of grievances). In the case of intolerant, extremist parties that would reject some/most of these norms, the state may invoke a range of defensive measures up to and including proscription in order to safeguard democracy. This paper takes as its focus the constitutional issues raised by the banning in Spain of Batasuna , the political wing of ETA. A legal challenge to the ban is currently before the European Court of Human Rights. Making reference to work of John Rawls, this paper considers whether the ban on Batasuna is justifiable in terms of liberal political theory, before analysing the extent to which proscription conforms to international human rights law and European Court of Human Rights jurisprudence. [source]


    Azathioprine or methotrexate in the treatment of patients with steroid-dependent or steroid-resistant ulcerative colitis: results of an open-label study on efficacy and tolerability in inducing and maintaining remission

    ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2002
    O. A. Paoluzi
    Summary Background : The role of azathioprine and methotrexate in inducing and maintaining remission in patients with ulcerative colitis is still controversial. Aim : To evaluate the efficacy and tolerability of these two drugs in a series of patients with steroid-dependent or steroid-resistant active ulcerative colitis. Methods : Forty-two patients were treated with a daily dose of azathioprine (2 mg/kg) and, if intolerant or not responding, with methotrexate (12.5 mg/week intramuscularly), and their efficacy was established by clinical, endoscopic and histological examinations at 6 months. Patients achieving clinical remission continued with treatment and were followed up. Results : Of the 42 patients on azathioprine, 10 experienced early side-effects requiring withdrawal from treatment, 22 (69%) achieved complete remission, six (19%) achieved improvement and four (12%) obtained no substantial benefit. Methotrexate, administered to eight patients intolerant to and two patients resistant to azathioprine, induced complete remission in six patients (60%) and improvement in four (40%). During follow-up, a larger number of patients on azathioprine relapsed in comparison with patients on methotrexate [16/28 (57%) vs. 2/10 (20%), respectively; P < 0.05]. Only minor side-effects wereobserved on both treatments. Conclusions : Azathioprine is effective in patients with steroid-dependent or steroid-resistant ulcerative colitis. Methotrexate seems to be a good alternative in patients intolerant to or not responding to azathioprine. [source]


    Lipoxin A4 generation is decreased in aspirin-sensitive patients in lysine-aspirin nasal challenge in vivo model

    ALLERGY, Issue 12 2009
    M. Kupczyk
    Background:, Lipoxins represent a group of lipoxygenase derived eicosanoids which, in contrast to leukotrienes, are potent anti-inflammatory mediators. The aim of our study was to determine lipoxin A4 (LXA4) and leukotriene C4 (LTC4) levels in nasal lavages after intranasal challenge with aspirin in aspirin intolerant (AIA) in comparison to aspirin tolerant (ATA) asthmatics and after allergen challenge in patients suffering from allergic rhinitis. Methods:, Twelve AIA, 8 ATA and 20 allergic patients were challenged with placebo, 16 mg of lysine-aspirin (Lys-ASA) or allergen (grasses). Nasal lavages were collected and eicosanoids' levels were determined using ELISA. Results:, Clinically positive Lys-ASA challenge in AIA resulted in influx of leukocytes (eosinophils and basophils) to nasal secretions and increase of LTC4 to 106.82 pg/ml (P < 0.05 vs baseline (26.58 pg/ml)) on first hour after the challenge. We did not observe any differences in LTC4 level before and after ASA challenge in ATA. In AIA group the mean level of LXA4 was 43 ± 21.5 pg/ml after placebo and decreased in 2 h after Lys-ASA challenge (29 ± 17 pg/ml, P = 0.015). We found an increase in LXA4 in ATA after ASA provocation as compared to placebo (33 ± 16 pg/ml vs 52 ± 31 pg/ml, P = 0.046). In atopic patients baseline level of LXA4 was 33.49 ± 16.95 pg/ml with no difference after the clinically positive allergen challenge (36.22 ± 13.26 pg/ml, P = 0.23). Conclusions:, Results of our study confirm that AIA have diminished LXs' biosynthesis capacities in vivo after ASA challenge. Taking into consideration anti-inflammatory properties of lipoxins this phenomenon may be partially responsible for the development of chronic inflammation in AIA patients. [source]


    Assay of gliadin by real-time immunopolymerase chain reaction

    MOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 5 2003
    Nadine Henterich
    Abstract Patients with coeliac disease (gluten-sensitive enteropathy) are intolerant against gliadins from wheat and the respective proteins from related cereals and have to keep a lifelong gluten-free diet. For control of gliadin in gluten-free food sensitive assay techniques are necessary. We developed an immunopolymerase chain reaction (iPCR) assay for gliadin. In this technique immunological detection of gliadin by a monoclonal antibody R5 conjugated with an oligonucleotide is amplified by PCR. For quantification, iPCR was performed as real-time PCR (real-time iPCR) in one step. By means of real-time iPCR, the sensitivity of gliadin analysis was increased more than 30-fold above the level reached by enzyme immunoassay. Real time-iPCR using R5 directly conjugated with oligonucleotide was clearly more sensitive than real time-iPCR applying sequentially biotinylated R5, streptavidin, and biotinylated oligonucleotide. With directly conjugated R5 gliadin was detected at a concentration as low as 0.16 ng/mL corresponding to 16 ,g gliadin/100 g food or 0.16 ppm (corresponding to 0.25 g of food extracted in 10 mL of solvent and 25-fold dilution of the extract prior to analysis). This is the first report applying the highly sensitive technique of iPCR for gliadin analysis. Furthermore, this is the first approach to perform real-time iPCR in one step without changing the reaction vessels after enzyme immunoassay for subsequent PCR analysis thus minimizing risks of contamination and loss of sensitivity. [source]


    Methadone for refractory restless legs syndrome

    MOVEMENT DISORDERS, Issue 3 2005
    William G. Ondo MD
    Abstract Most cases of restless legs syndrome (RLS) initially respond well to dopaminergic agonists. However, an unknown percentage of patients is intolerant of dopaminergic adverse events, initially or subsequently refractory, or develops limiting augmentation. We administered methadone 5 to 40 mg/day (final dose, 15.6 ± 7.7) to 29 RLS patients who failed dopaminergics. They were currently taking or had previously tried 5.9 ± 1.7 (range, 3,9) different medications for RLS and 2.9 ± 0.8 (range, 2,4) different dopaminergics. Of the 27 patients who met inclusion criteria, 17 have remained on methadone for 23 ± 12 months (range, 4,44 months) at a dose of 15.5 ± 7.7 mg/day; 2 dialysis RLS patients died while on methadone, and 8 stopped the treatment (5 for adverse events, 2 for lack of efficacy, and 1 for logistical reasons). All patients who remain on methadone report at least a 75% reduction in symptoms, and none have developed augmentation. Methadone should be considered in RLS patients with an unsatisfactory dopaminergic response. © 2004 Movement Disorder Society [source]


    Pharmacological properties and clinical efficacy of a recently licensed systemic antifungal, caspofungin

    MYCOSES, Issue 4 2005
    Georg Maschmeyer
    Summary Caspofungin, a semisynthetic derivative of the pneumocandin B0, is the first licensed compound of a new class of antifungal agents, the echinocandins. It attacks the fungal cell by selective inhibition of the beta-(1,3)- d -glucan synthase, which is not present in mammalian cells. In vitro studies have indicated a potent fungicidal effect on Candida species, and in vivo studies in immunocompromised animals with invasive candidiasis demonstrated a favourable outcome. In randomized clinical trials in patients with oropharyngeal/oesophageal and invasive candidiasis, caspofungin was at least as effective as amphotericin B deoxycholate, yet showed a significantly superior safety profile. Of patients with invasive aspergillosis refractory to or intolerant of other antifungal agents, 45% showed a partial or complete response to caspofungin given as a salvage treatment. Also, it demonstrated comparable clinical efficacy but superior tolerability in the empirical antifungal therapy in neutropenic patients compared with liposomal amphothericin B. Caspofungin has an excellent tolerability and a low potential for drug interactions. Thus, caspofungin represents an interesting and clinically valuable new antifungal drug that broadens the available therapeutic armamentarium for the treatment of invasive fungal infections. [source]


    Byron to D'Annunzio: from liberalism to fascism in national poetry, 1815,1920

    NATIONS AND NATIONALISM, Issue 3 2008
    DAVID ABERBACH
    ABSTRACT. From Byron's death at Missolonghi in 1824 to D'Annunzio's capture of Fiume for Italy in 1919, the nationalism of universal liberalism and independence struggles changed, in literature as in politics, to cruel dictatorial fascism. Byron was followed by a series of idealistic fighter-poets and poet-martyrs for national freedom, but international tensions culminating in World War I exposed fully the intolerant, brutal side of nationalism. D'Annunzio, like Byron, both a major poet and charismatic war leader, was a key figure in transforming nineteenth-century democratic nationalism into twentieth-century dictatorial fascism. The poet's ,lyrical dictatorship' at Fiume (1919,20) inspired Mussolini's seizure of power in 1922, with far-reaching political consequences. The poet became the dangerous example of a Nietzschean Übermensch, above common morality, predatory and morally irresponsible. This article shows how the meaning of nationalism was partly determined and transformed by poets, illustrating their role as ,unacknowledged legislators of the world'. [source]


    Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: Results from a phase 3 study,,

    AMERICAN JOURNAL OF HEMATOLOGY, Issue 3 2010
    Michael B. Lilly
    Dasatinib 70 mg twice daily is indicated for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) intolerant or resistant to imatinib. In patients with chronic-phase chronic myelogenous leukemia, once-daily dosing has similar efficacy with improved safety, compared with twice-daily dosing. A phase 3 study (n = 611) assessed the efficacy and safety of dasatinib 140 mg once daily versus 70 mg twice-daily in patients with advanced phase chronic myelogenous leukemia or Ph+ ALL resistant or intolerant to imatinib. Here, results from the Ph+ ALL subset (n = 84) with a 2-year follow-up are reported. Patients were randomly assigned to receive dasatinib either 140 mg once daily (n = 40) or 70 mg twice daily (n = 44). The rate of confirmed major hematologic response with once-daily dosing (38%) was similar to that with twice-daily dosing (32%). The rate of major cytogenetic response with once-daily dosing (70%) was higher than that with twice-daily dosing (52%). Compared with the twice-daily schedule, the once-daily schedule had longer progression-free survival (median, 3.0 months versus 4.0 months, respectively) and shorter overall survival (median, 9.1 months versus 6.5 months, respectively). Overall safety profiles were similar between two groups, with nonhematologic adverse events being mostly grade 1 or 2. Pleural effusion was less frequent with once-daily dosing than with twice-daily dosing (all grades, 18% versus 32%). Notably, none of the differences between the two schedules was statistically significant. Compared with the 70 mg twice daily, dasatinib 140 mg once daily had similar overall efficacy and safety in patients with imatinib-resistant or intolerant Ph+ ALL. (clinicaltrials.gov identifier: NCT00123487). Am. J. Hematol. 2010. © 2009 Wiley-Liss, Inc. [source]


    Successful treatment of pure red cell aplasia with autologous stem cell transplantation

    AMERICAN JOURNAL OF HEMATOLOGY, Issue 9 2007
    Jae H. Park
    We report a case of 64-year-old patient with pure red cell aplasia (PRCA) who was intolerant of conventional immunosuppressive therapies but achieved a complete long-term remission following autologous hematologic stem cell transplant (HSCT). The patient was initially treated with high-dose prednisone, cyclophosphamide, cyclosporine, antithymocyte globulin, and then rituximab. With the exception of rituximab, all of the above regimens achieved a transient response. However, because of the persistent requirement for red blood cell transfusions and intolerance to the multiple immunosuppressive therapies, autologous HSCT was eventually performed. The patient remains in complete remission and on no other therapy for 36 months following the autologous HSCT. Am. J. Hematol., 2007. © 2007 Wiley-Liss, Inc. [source]


    The mechanism of boron tolerance for maintenance of root growth in barley (Hordeum vulgare L.)

    PLANT CELL & ENVIRONMENT, Issue 8 2007
    EUN-YOUNG CHOI
    ABSTRACT Cultivar differences in root elongation under B toxic conditions were observed in barley (Hordeum vulgare L.). A significant increase in the length and width of the root meristematic zone (RMZ) was observed in Sahara 3771 (B tolerant) when it was grown under excessive B concentration, compared to when grown at adequate B supply. This coincided with an increase in cell width and cell numbers in the meristematic zone (MZ), whereas a significant decrease in the length and no significant effect on the width of the MZ was observed in Clipper (B intolerant) when it was grown under excessive B supply. This was accompanied by a decrease in cell numbers, but an increase in the length and width of individual cells present along the MZ. Excessive B concentrations led to a significantly lower osmotic potential within the cell sap of the root tip in SloopVic (B tolerant) and Sahara 3771, while the opposite was observed in Clipper. Enhanced sugar levels in the root tips of SloopVic were observed between 48 and 96 h after excess B was applied. This coincided with an increase in the root elongation rate and with a 2.7-fold increase in sucrose level within mature leaf tissue. A significant decrease in reducing sugar levels was observed in the root tips of Clipper under excessive B concentrations. This coincided with significantly lower root elongation rates and lower sucrose levels in leaf tissues. Results indicate a B tolerance mechanism associated with a complex control of sucrose levels between leaf and root tip that assist in maintaining root growth under B toxicity. [source]


    Ecological distribution and phenology of an invasive species, Cardamine hirsuta L., and its native counterpart, Cardamine flexuosa With., in central Japan

    PLANT SPECIES BIOLOGY, Issue 1 2003
    YOSHINORI YATSU
    Abstract Cardamine hirsuta is a European species that was recently introduced into Japan and its wide distribution has been confirmed in the Kanto district. To understand mechanisms of the recent spread of C. hirsuta in Japan, a comparative study of the alien species and its native congeneric species, C. flexuosa, was conducted. Habitat preferences, phenology and seed germination were examined. Cardamine hirsuta and C. flexuosa showed distinctive habitat-preferences; the former was most common in open habitats created by recent man-made constructions, and the latter was common in rice paddy fields and surrounding areas. The results indicate that C. flexuosa is a year-long annual, with a mixed phenology of summer and winter germination and growth. Seed dormancy during summer was relatively weak for C. flexuosa, and some plants that germinated early in summer reproduced during the same summer,autumn period. Plants that germinated in late summer and autumn behaved as winter annuals. In rice paddy fields, C. flexuosa is a winter annual because germination is prevented by submergence during summer. Plants flower during the following spring and complete their life cycle before the fields are flooded for rice cultivation. Cardamine hirsuta showed strong seed dormancy during summer and behaved as a typical winter annual. Seeds of C. hirsuta were intolerant to submergence in water, a condition that breaks seed dormancy of C. flexuosa. The results explain the absence of C. hirsuta from rice paddy fields. It was concluded that the spread of C. hirsuta is attributable to the recent expansion of urban habitats created by human activity and has occurred without direct competition with C. flexuosa. Considering recent urbanization in many areas, it is suggested that C. hirsuta has been spreading rapidly in Japan. [source]


    Low free energy cost of very long loop insertions in proteins

    PROTEIN SCIENCE, Issue 2 2003
    Michelle Scalley-Kim
    Abstract Long insertions into a loop of a folded host protein are expected to have destabilizing effects because of the entropic cost associated with loop closure unless the inserted sequence adopts a folded structure with amino- and carboxy-termini in close proximity. A loop entropy reduction screen based on this concept was used in an attempt to retrieve folded sequences from random sequence libraries. A library of long random sequences was inserted into a loop of the SH2 domain, displayed on the surface of M13 phage, and the inserted sequences that did not disrupt SH2 function were retrieved by panning using beads coated with a phosphotyrosine containing SH2 peptide ligand. Two sequences of a library of 2 × 108 sequences were isolated after multiple rounds of panning, and were found to have recovery levels similar to the wild-type SH2 domain and to be relatively intolerant to further mutation in PCR mutagenesis experiments. Surprisingly, although these inserted sequences exhibited little nonrandom structure, they do not significantly destabilize the host SH2 domain. Additional insertion variants recovered at lower levels in the panning experiments were also found to have a minimal effect on the stability and peptide-binding function of the SH2 domain. The additional level of selection present in the panning experiments is likely to involve in vivo folding and assembly, as there was a rough correlation between recovery levels in the phage-panning experiments and protein solubility. The finding that loop insertions of 60,80 amino acids have minimal effects on SH2 domain stability suggests that the free energy cost of inserting long loops may be considerably less than polymer theory estimates based on the entropic cost of loop closure, and, hence, that loop insertion may have provided an evolutionary route to multidomain protein structures. [source]