Cyclosporine population pharmacokinetics in pediatric renal transplant recipients

Cyclosporine is an immunosuppressant drug with a narrow therapeutic index and large variability in pharmacokinetics. To improve cyclosporine dose individualization in children, we used population pharmacokinetic modeling to study the effects of developmental, clinical, and genetic factors on cyclosporine pharmacokinetics in altogether 176 subjects (age range: 0.36–20.2 years) before and up to 16 years after renal transplantation. Pre-transplantation test doses of cyclosporine were given intravenously (3 mg/kg) and orally (10 mg/kg), on separate occasions, followed by blood sampling for 24 hours (n=175). After transplantation, in a total of 137 patients, cyclosporine concentration was quantified at trough, two hours post-dose, or with dose-interval curves. One-hundred-four of the studied patients were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. Pharmacokinetic modeling was performed with the nonlinear mixed effects modeling computer program, NONMEM. A 3-compartment population pharmacokinetic model with first order absorption without lag-time was used to describe the data. The most important covariate affecting systemic clearance and distribution volume was allometrically scaled body weight i.e. body weight**3/4 for clearance and absolute body weight for volume of distribution. The clearance adjusted by absolute body weight declined with age and pre-pubertal children (< 8 years) had an approximately 25% higher clearance/body weight (L/h/kg) than did older children. Adjustment of clearance for allometric body weight removed its relationship to age after the first year of life. This finding is consistent with a gradual reduction in relative liver size towards adult values, and a relatively constant CYP3A content in the liver from about 6–12 months of age to adulthood. The other significant covariates affecting cyclosporine clearance and volume of distribution were hematocrit, plasma cholesterol, and serum creatinine, explaining up to 20%–30% of inter-individual differences before transplantation. After transplantation, their predictive role was smaller, as the variations in hematocrit, plasma cholesterol, and serum creatinine were also smaller. Before transplantation, no clinical or demographic covariates were found to affect oral bioavailability, and no systematic age-related changes in oral bioavailability were observed. After transplantation, older children receiving cyclosporine twice daily as the gelatine capsule microemulsion formulation had an about 1.25–1.3 times higher bioavailability than did the younger children receiving the liquid microemulsion formulation thrice daily. Moreover, cyclosporine oral bioavailability increased over 1.5-fold in the first month after transplantation, returning thereafter gradually to its initial value in 1–1.5 years. The largest cyclosporine doses were administered in the first 3–6 months after transplantation, and thereafter the single doses of cyclosporine were often smaller than 3 mg/kg. Thus, the results suggest that cyclosporine displays dose-dependent, saturable pre-systemic metabolism even at low single doses, whereas complete saturation of CYP3A4 and MDR1 (P-glycoprotein) renders cyclosporine pharmacokinetics dose-linear at higher doses. No significant associations were found between genetic polymorphisms and cyclosporine pharmacokinetics before transplantation in the whole population for which genetic data was available (n=104). However, in children older than eight years (n=22), heterozygous and homozygous carriers of the ABCB1 c.2677T or c.1236T alleles had an about 1.3 times or 1.6 times higher oral bioavailability, respectively, than did non-carriers. After transplantation, none of the ABCB1 SNPs or any other SNPs were found to be associated with cyclosporine clearance or oral bioavailability in the whole population, in the patients older than eight years, or in the patients younger than eight years. In the whole population, in those patients carrying the NR1I2 g.-25385C–g.-24381A–g.-205_-200GAGAAG–g.7635G–g.8055C haplotype, however, the bioavailability of cyclosporine was about one tenth lower, per allele, than in non-carriers. This effect was significant also in a subgroup of patients older than eight years. Furthermore, in patients carrying the NR1I2 g.-25385C–g.-24381A–g.-205_-200GAGAAG–g.7635G–g.8055T haplotype, the bioavailability was almost one fifth higher, per allele, than in non-carriers. It may be possible to improve individualization of cyclosporine dosing in children by accounting for the effects of developmental factors (body weight, liver size), time after transplantation, and cyclosporine dosing frequency/formulation. Further studies are required on the predictive value of genotyping for individualization of cyclosporine dosing in children.

Slim P‐E hysteresis loop and anomalous dielectric response in sol-gel derived antiferroelectric PbZrO3 thin films

Sol-gel derived PbZrO3 (PZ) thin films have been deposited on Pt(111)/Ti/SiO2/Si substrate and according to the pseudotetragonal symmetry of PZ, the relatively preferred (110)t oriented phase formation has been noticed. The room temperature P‐E hysteresis loops have been observed to be slim by nature. The slim hysteresis loops are attributed to the [110]t directional antiparallel lattice motion of Pb ions and by the directionality of the applied electric field. Pure PZ formation has been characterized by the dielectric phase transition at 235 °C and antiferroelectric P‐E hysteresis loops at room temperature. Dielectric response has been characterized within a frequency domain of 100 Hz–1 MHz at various temperatures ranging from 40 to 350 °C. Though frequency dispersion of dielectric behaves like a Maxwell–Wagner type of relaxation, ω2 dependency of ac conductivity indicates that there must be G‐C equivalent circuit dominance at high frequency. The presence of trap charges in PZ has been determined by Arrhenius plots of ac conductivity. The temperature dependent n (calculated from the universal power law of ac conductivity) values indicate an anomalous behavior of the trapped charges. This anomaly has been explained by strongly and weakly correlated potential wells of trapped charges and their behavior on thermal activation. The dominance of circuit∕circuits resembling Maxwell–Wagner type has been investigated by logarithmic Nyquist plots at various temperatures and it has been justified that the dielectric dispersion is not from the actual Maxwell–Wagner-type response.

The Exeter Contemporary flanged cemented acetabular component in primary total hip arthroplasty

Aims: We report on the outcome of the Exeter Contemporary flanged cemented all-polyethylene acetabular component with a mean follow-up of 12 years (10 to 13.9). This study reviewed 203 hips in 194 patients. 129 hips in 122 patients are still in situ; 66 hips in 64 patients were in patients who died before ten years, and eight hips (eight patients) were revised. Clinical outcome scores were available for 108 hips (104 patients) and radiographs for 103 hips (100 patients). Patients and Methods: A retrospective review was undertaken of a consecutive series of 203 routine primary cemented total hip arthroplasties (THA) in 194 patients. Results: There were no acetabular component revisions for aseptic loosening. Acetabular revision was undertaken in eight hips. In four hips revision was necessitated by periprosthetic femoral fractures, in two hips by recurrent dislocation, in one hip for infection and in one hip for unexplained ongoing pain. Oxford and Harris hip scores demonstrated significant clinical improvement (all p < 0.001). Radiolucent lines were present in 37 (36%) of the 103 acetabular components available for radiological evaluation. In 27 of these, the line was confined to zone 1. No component had migrated. Conclusion: Kaplan–Meier survivorship, with revision for aseptic loosening as the endpoint, was 100% at 12.5 years and for all causes was 97.8% (95% confidence interval 95.6 to 100) when 40 components remained at risk. The Exeter Contemporary flanged cemented acetabular component demonstrates excellent survivorship at 12.5 years. Take home message: The Exeter Contemporary flanged cemented acetabular component has excellent clinical outcomes and survivorship when used with the Exeter stem in total hip arthroplasty.

Prediction of fatigue strength in plain and reinforced concrete beams

A fatigue crack propagation model for concrete is proposed based on the concepts of fracture mechanics. This model takes into account the loading history, frequency of applied load, and size, effect parameters. Using this model, a method is described based on linear elastic fracture mechanics to assess the residual strength of cracked plain and reinforced concrete (RC) beams. This could be used to predict the residual strength (load carrying capacity) of cracked or damaged plain and reinforced concrete beams at a given level of damage. It has been seen that the fatigue crack propagation rate increases as. the size of plain concrete, beam increases indicating an increase in brittleness. In reinforced concrete (RC) beams, the fracture process becomes stable only when the beam is sufficiently reinforced.

Cystine peptides Antiparallel β-sheet conformation of the cyclic biscystine peptide [Boc-Cys-Ala-Cys-NHCH3]2

The crystal structure analysis of the cyclic biscystine peptide [Boc-Cys1-Ala2-Cys3-NHCH3]2 with two disulfide bridges confirms the antiparallel ?-sheet conformation for the molecule as proposed for the conformation in solution. The molecule has exact twofold rotation symmetry. The 22-membered ring contains two transannular NH ? OC hydrogen bonds and two additional NH ? OC bonds are formed at both ends of the molecule between the terminal (CH3)3COCO and NHCH3 groups. The antiparallel peptide strands are distorted from a regularly pleated sheet, caused mainly by the L-Ala residue in which ?=� 155° and ?= 162°. In the disulfide bridge C? (1)-C? (1)-S(1)-(3')-C?(3')-C?(3'), S�S = 2.030 Å, angles C? SS = 107° and 105°, and the torsional angles are �49, �104, +99, �81, �61°, respectively. The biscystine peptide crystallizes in space group C2 with a = 14.555(2) Ã…, b = 10.854(2) Ã…, c = 16.512(2)Ã…, and ?= 101.34(1) with one-half formula unit of C30H52N8O10S4· 2(CH3)2SO per asymmetric unit. Least-squares refinement of 1375 reflections observed with |F| > 3?(F) yielded an R factor of 7.2%.

Tytöt, pojat ja sukupuolinen häirintä

In this research I ask what is interpreted as sex-based harassment by 15-16-year old girls and boys. By sex-based harassment I refer to one-sided, unwanted attention that is based on gender and that makes the target feel embarrassed, frightened, hurt or angry. My focus is not on the most overt cases of harassment but rather on everyday encounters. While young people differentiate between harassing and non-harassing attention, at the same time they define, assign value to and construct differences and power relations on the basis of gender, age and ethnicity, for example. My main data consists of essays (N 104, 54 girls, 54 boys) and thematic interviews (N 14; 20 girls, 3 boys) of ninth graders of a secondary school in Helsinki. In the essays and interviews, students construe the border between pleasant and unpleasant, tolerable and intolerable attention as clear in principle, but, they suggest that in practice this border is ambivalent, negotiable and contextual. The interpretations of incidents are justified by referring to features of the target, the scene or the perpetrator. Targets of harassment are most often construed as being girls who are characterized as thin-skinned, but at the same time they are expected to be understanding toward any sex-based attention they may get, particularly when it is not physical. On the other hand, girls are regarded as equal and even active participants in incidents of harassment. Such statements include considerations of how girls either reject or invite particular kinds of attention by their actions and outward appearance. Forms of harassment, ways of understanding it as well as overcoming it vary according to spatial context. By situating incidents in different spaces and places, young people contrast their experiences with ordinary and predictable non-harassment that takes place e.g. in discos and unusual and unexpected harassment that takes place e.g. in the city streets in the daytime. The behaviour of boys harassing a girls is naturalized by appealing to young masculinity and the childishness but also strong sexual drive which is seen as characteristic of teenage boys. On the other hand, sex-based harassment is racialized and pathologized in ways that separate the phenomenon from young, Finnish, normal masculinity. Both the material experiences of the young people and the definitions of the parties involved in harassing incidents are gendered. Girls encounter and deal with sexualized commenting and unwanted approaches much more often and in a more intensive way than boys. Furthermore, there is a vast cultural repertoire of acceptable accounts that can be mobilised in order to excuse male harassers, to critically evaluate the appearance or action of the female targets and to divide the responsibility between the female target and the male perpetrator.

Unfolding studies on soybean agglutinin and concanavalin a tetramers: A comparative account

The unfolding pathway of two very similar tetrameric legume lectins soybean agglutinin (SBA) and Concanavalin A ( ConA) were determined using GdnCl-induced denaturation. Both proteins displayed a reversible two-state unfolding mechanism. The analysis of isothermal denaturation data provided values for conformational stability of the two proteins. It was found that the DeltaG of unfolding of SBA was much higher than ConA at all the temperatures at which the experiments were done. ConA had a T-g 18 degreesC less than SBA. The higher conformational stability of SBA in comparison to ConA is largely due to substantial differences in their degrees of subunit interactions. Ionic interactions at the interface of the two proteins especially at the noncanonical interface seem to play a significant role in the observed stability differences between these two proteins. Furthermore, SBA is a glycoprotein with a GlcNac(2)Man(9) chain attached to Asn-75 of each subunit. The sugar chain in SBA lies at the noncanonical interface of the protein, and it is found to interact with the amino acid residues in the adjacent noncanonical interface. These interactions further stabilize SBA with respect to ConA, which is not glycosylated.

N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yI)colcemid, a probe for different classes of colchincine-binding site on tubulin

The nature of binding of 7-nitrobenz-2-oxa-1,3-diazol-4-yl-colcemid (NBD-colcemid), an environment-sensitive fluorescent analogue of colchicine, to tubulin was tested. This article reports the first fluorometric study where two types of binding site of colchincine analogue on tubulin were detected. Binding of NBD-colcemid to one of these sites equilibrates slsowly. NBD-colcemid competes with colchicine for this site. Binding of NBD-colcemid to this site also causes inhibition of tubulin self-assembly. In contrast, NBD-colcemid binding to the other site is characterised by rapid equilibration and lack of competition with colchicine. Nevertheless, binding to this site is highly specific for the cholchicine nucleus, as alkyl-NBD analogues have no significant binding activity. Fast-reaction-kinetic studies gave 1.76 × 105 M–1 s–1 for the association and 0.79 s–1 for the dissociation rate constants for the binding of NBD-colcemid to the fast site of tubulin. The association rate constants for the two phases of the slow site are 0.016 × 10–4 M–1 s–1 and 3.5 × 10–4 M–1 respectively. These two sites may be related to the two sites of colchicine reported earlier, with binding characteristics altered by the increased hydrophobic nature of NBD-colcemid.

Tammen alueellisen levinneisyyden rajoitteet : Tapaustutkimus Länsi-Turunmaalla

Elinympäristön vaikutusta eliölajien esiintymiseen voidaan tutkia habitaattimallinnuksen keinoin. Havainnot lajin esiintymisestä ja puuttumisesta eri kohdissa maisemaa suhteutetaan tilastollisen mallin avulla ympäristötekijöihin, jolloin saadaan kuva lajin elinympäristövaatimuksista. Tällöin oletetaan, että laji esiintyy kaikkialla siellä, missä sen elinympäristövaatimukset täyttyvät. Metapopulaatioteorian valossa näin ei kuitenkaan aina ole: maisemassa voi olla runsaasti lajille soveltuvia mutta asuttamattomia kasvupaikkoja, koska uusien yksilöiden leviäminen ja vanhojen häviäminen eivät välttämättä ole yksittäisten kasvupaikkojen tasolla tasapainossa. Siten myös lajin leviämiskyky vaikuttaa siihen, millaiseksi sen levinneisyyskuvio maisematasolla muodostuu. Tässä työssä keskityn tammen (Quercus robur) alueellisen levinneisyyden mallintamiseen. Tammen suhteellinen harvinaisuus Suomessa sekä sen rooli luonnon monimuotoisuuden merkittävänä tukipilarina tekevät siitä mielenkiintoisen kohdelajin ekologiselle tutkimukselle. Tutkimuskohteekseni valitsin Wattkastin saaren, n. 5 km2:n alueen Länsi-Turunmaalta. Wattkastissa on tutkittu kahdeksan vuoden ajan tammella elävien hyönteisyhteisöjen rakennetta ja kannanvaihteluita, ja saaressa kasvaa yli 1800 luonnonvaraista tammea, joiden tarkat sijainnit tiedetään. Tässä ympäristössä tutkin, rajoittaako tammen alueellista levinneisyyttä ensisijaisesti sopivien elinympäristöjen tilajakauma vai pikemminkin sen leviämiskyky. Yhdistin tammen esiintymiskuviota kuvaavaan habitaattimalliin kokeellisen aineiston, jonka avulla arvioin tammen paikallisen esiintymiskuvion ja tammelle soveltuvien elinympäristöjen tilajakauman vastaavuutta. Kokeellisen aineiston muodostivat 104 Wattkastiin vuonna 2004 istutettua pikkutammea, joiden selviytymisen ja kasvupaikkaolot kartoitin syksyllä 2009. Tutkin yleistetyillä lineaarisilla malleilla puiden menestymiseen siis selviytymiseen ja kuntoon vaikuttavia tekijöitä. Etsin potentiaalisia selittäjiä tammen menestymiselle kasvupaikan ympäristötekijöistä sekä istutetun puun sijainnista suhteessa luontaisiin tammikasvustoihin. Lisäksi tutkin habitaattimallin avulla, selittävätkö ympäristötekijät tammen nykyisen esiintymiskuvion Wattkastissa. Havaitsin, että istutetut puut olivat selviytyneet keskimäärin hyvin ja ettei niiden menestyminen riippunut sijainnista suhteessa luontaisiin tammikasvustoihin. Habitaattimallin selitysaste oli vain 19 %, eli kasvupaikkatekijät selittivät heikosti tammen nykyisen esiintymiskuvion Wattkastissa. Tulosten perusteella tammen paikallinen esiintymiskuvio ei vastaa sille soveltuvien elinympäristöjen jakaumaa maisemassa, joten tammen levinneisyyttä Wattkastissa rajoittaa ilmeisesti sen leviämiskyky. Tulokseni viittaavat siihen, ettei tammen elinympäristön laadussa ole suuria vaihteluita Wattkastin sisällä, koska sopivia kasvupaikkoja on tarjolla tammen nykyesiintymiseen nähden runsaasti. Tämä on tammihyönteistutkimusten kannalta kiinnostava tulos, koska se tarkoittaa, että aiemmat havainnot isäntäpuun sijainnin ja hyönteisten kannanvaihteluiden välisestä yhteydestä edustavat todellisia, tilaan sidottuja populaatioprosesseja eivätkä isäntäpuun välittämiä eroja elinympäristön laadussa. Lisäksi tutkimukseni osoittaa, että yhdistämällä habitaattimallinnukseen kokeellinen lähestymistapa saadaan realistisempi kuva lajin levinneisyyttä rajoittavista tekijöistä kuin tutkimalla pelkästään ympäristötekijöiden vaikutusta lajin esiintymiseen. Jos lajin rajoittunut leviämiskyky on vaikuttanut sen esiintymiskuvion syntyyn, pelkästään ympäristötekijöihin perustuva levinneisyysmalli liioittelee levinneisyyttä. Kokeellisen tutkimuksen avulla on tällaisessa tapauksessa mahdollista paljastaa myös leviämiskyvyn rooli esiintymiskuvion taustalla.

Combination of Tevatron Searches for the Standard Model Higgs Boson in the W+W- Decay Mode

We combine searches by the CDF and D0 collaborations for a Higgs boson decaying to W+W-. The data correspond to an integrated total luminosity of 4.8 (CDF) and 5.4 (D0) fb-1 of p-pbar collisions at sqrt{s}=1.96 TeV at the Fermilab Tevatron collider. No excess is observed above background expectation, and resulting limits on Higgs boson production exclude a standard-model Higgs boson in the mass range 162-166 GeV at the 95% C.L.

Inclusive Search for Standard Model Higgs Boson Production in the WW Decay Channel using the CDF II Detector

We present a search for standard model (SM) Higgs boson production using ppbar collision data at sqrt(s) = 1.96 TeV, collected with the CDF II detector and corresponding to an integrated luminosity of 4.8 fb-1. We search for Higgs bosons produced in all processes with a significant production rate and decaying to two W bosons. We find no evidence for SM Higgs boson production and place upper limits at the 95% confidence level on the SM production cross section (sigma(H)) for values of the Higgs boson mass (m_H) in the range from 110 to 200 GeV. These limits are the most stringent for m_H > 130 GeV and are 1.29 above the predicted value of sigma(H) for mH = 165 GeV.

First Measurement of the b-Jet Cross Section in Events with a W Boson in pp̅ Collisions at √s=1.96 TeV

The cross section for jets from b quarks produced with a W boson has been measured in ppbar collision data from 1.9/fb of integrated luminosity recorded by the CDF II detector at the Tevatron. The W+b-jets process poses a significant background in measurements of top quark production and prominent searches for the Higgs boson. We measure a b-jet cross section of 2.74 +- 0.27(stat.) +- 0.42(syst.) pb in association with a single flavor of leptonic W boson decay over a limited kinematic phase space. This measured result cannot be accommodated in several available theoretical predictions.

Measurement of the WW+WZ Production Cross Section Using the lepton+jets Final State at CDF II

We report two complementary measurements of the WW+WZ cross section in the final state consisting of an electron or muon, missing transverse energy, and jets, performed using p\bar{p} collision data at sqrt{s} = 1.96 TeV collected by the CDF II detector. The first method uses the dijet invariant mass distribution while the second more sensitive method uses matrix-element calculations. The result from the second method has a signal significance of 5.4 sigma and is the first observation of WW+WZ production using this signature. Combining the results gives sigma_{WW+WZ} = 16.0 +/- 3.3 pb, in agreement with the standard model prediction.

Measurement of the Λb0 Lifetime in Λb0→Λc+π- Decays in pp̅ Collisions at √s=1.96 TeV

We report a measurement of the lifetime of the Lambda_b baryon in decays to the Lambda_C+ pi- final state in a sample corresponding to 1.1 fb^-1 collected in p-pbar collisions at sqrt(s) = 1.96 TeV by the CDF II detector at the Tevatron collider. Using a sample of about 3000 fully reconstructed Lambda_b events we measure tau(Lambda_b) = 1.401 +- 0.046 (stat) +- 0.035 (syst) ps (corresponding to c.tau(Lambda_b) = 420.1 +- 13.7 (stat) +- 10.6 (syst) um, where c is the speed of light). The ratio of this result and the world average B^0 lifetime yields tau(Lambda_b)/tau(B^0) = 0.918 +- 0.038 (stat and syst), in good agreement with recent theoretical predictions.

Search for Pair Production of Supersymmetric Top Quarks in Dilepton Events from pp̅ Collisions at √s=1.96 TeV

We present the results of a search for pair production of the supersymmetric partner of the top quark (the stop quark $\tilde{t}_{1}$) decaying to a $b$-quark and a chargino $\chargino$ with a subsequent $\chargino$ decay into a neutralino $\neutralino$, lepton $\ell$, and neutrino $\nu$. Using a data sample corresponding to 2.7 fb$^{-1}$ of integrated luminosity of $p\bar{p}$ collisions at $\sqrt{s} = 1.96$ TeV collected by the CDF II detector, we reconstruct the mass of candidate stop events and fit the observed mass spectrum to a combination of standard model processes and stop quark signal. We find no evidence for $\pairstop$ production and set 95% C.L. limits on the masses of the stop quark and the neutralino for several values of the chargino mass and the branching ratio ${\cal B}(\chargino\to\neutralino\ell^{\pm}\nu)$.