Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer's disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients. METHODS: We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer's disease aged 50-85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid β (Aβ)(1-40) between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759). FINDINGS: 89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aβ(1-40) was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (-18·0 [range -1347·0 to 1068·5] for 0·2 g/kg, -364·3 [-5834·5 to 1953·5] for 0·5 g/kg, and -351·8 [-1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs -116·3 [-1379·0 to 5266·0] for placebo; and -13·8 [-1729·0 to 307·0] for 0·1 g/kg, and -32·5 [-1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma Aβ(1-40) between the 0·4 g/kg every 2 weeks group (47·0 [range -341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group. INTERPRETATION: Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer's disease.

Canakinumab Relieves Symptoms of Acute Flares and Improves Health-Related Quality Of Life (HRQoL) in Difficult-To-Treat Gouty Arthritis Patients by Suppressing Inflammation: Results of a Randomized, Dose-Ranging Study

RATIONALE:We investigated the impact of canakinumab, a fully human anti-interleukin-1b monoclonal antibody on inflammation and HRQoL in gouty arthritis patients.METHODS: In this 8-week, single-blind, dose-ranging study, patients with acute gouty arthritis flares, unresponsive/intolerant or contraindicated to NSAIDs and/or colchicine were randomized to single subcutaneous canakinumab (10, 25, 50, 90, or 150mg, N5143) or single intramuscular triamcinolone acetonide (TA, 40mg, N557). Patients assessed pain (Likert scale), physicians assessed clinical signs of joint inflammation, and HRQoL was recorded using SF-36.RESULTS: At baseline, 98% patients had moderate-to-extreme pain, 85% had moderate/severe joint swelling, 64-79% had elevated inflammatory markers and HRQoL scores indicated impaired physical function. Percentage of patients with no/mild pain was numerically greater in most canakinumab groups vs. TA, 24-72h post-dose; difference significant for 150mg group at these time-points (P<0.05). Canakinumab 150mg was associated with significantly lower Likert scores for tenderness [OR, 3.2; 95% CI, 1.27-7.89; P50.014] and swelling (OR, 2.7; 95% CI, 1.09-6.50, P50.032) at 72h vs. TA; erythema was not different. Median CRP and SAA levels normalized by 7 days post-dose in most canakinumab groups, but remained elevated in TA. Physical function improved at 7 days postdose in all groups, highest improvement for canakinumab 150mg. SF-36 scores for physical functioning and bodily pain with canakinumab 150mg approached US general population scores by 7 days post-dose and exceeded normal values by 8 weeks post-dose.CONCLUSION: Canakinumab 150mg produced significantly greater and rapid pain-relief and improvements in HRQoL vs. TAin acute gouty arthritis patients.

Optimization of heterologous microsatellites in Piracanjuba

Abstract: The objective of this work was to evaluate 41 microsatellite markers for heterologous amplifications in piracanjuba (Brycon orbignyanus). Some markers were tested for the first time. Loci were optimized for PCR conditions and applied to a sample of 49 individuals. Thirty-one loci resulted in PCR product formation, whereas ten loci yielded intelligible polymorphic patterns in the evaluated sample and can be used for amplifications in this species. From the evaluated markers, four loci (BoM1, BoM13, Bh6, and Bh16) are valid to be applied in the study of piracanjuba.

Optimization of the ink removal in deinking plant

Diplomityön tarkoituksena oli parantaa Stora Enso Sachsenin siistausprosessissa tuotetun uusiomassan vaaleuden kehitystä ja tutkia siihen vaikuttavia tekijöitä. Työn kirjallisessa osassa käsiteltiin uusiomassan kuidutusta ja vaahdotussiistausprosessia, sekä keräyspaperin ominaisuuksia ja käyttöä paperiteollisuuden raaka-aineena. Kokeellisessa osassa keskityttiin modifioidun natriumsilikaatin annostuksenoptimointiin ja vaikutuksiin laboratorio- ja prosessioloissa, sekä kesäefektin vaikutuksen tutkimiseen kuidutuksessa ja flotaation eri vaiheissa. Natriumsilikaatin laboratoriotutkimuksessa havaittiin, että korkein vaaleus suhteellisesti pienimmällä laboratorioflotaation häviöllä saavutettiin korkeimmalla tutkitulla natriumsilikaatin annostuksella, joka oli 1,1 %. Korkea natriumsilikaattiannostus yhdistettyinä korkeisiin vetyperoksidiannostukseen, 0,5 %, sekä korkeaan kokonaisalkaliteettiin, 0.33 %, johti korkeimpaan massan vaaleuteen ja pienimpiin häviöihin. Laboratoriotutkimuksen pohjalta modifioidulla natriumsilikaatilla suoritettiin koeajoja prosessissa. Noin 1 % natriumsilikaatin annostuksella havaittiin parempi pH:n bufferointikyky, pienempi kalsiumkarbonaatin määrä flotaation primäärivaiheissa, sekä lievästi parempi massan vaaleus verrattuna prosessissa aiemmin käytettyyn standardinatriumsilikaattiin. Kesäefektitutkimuksessa havaittiin, että kesäefektillä on suurin vaikutus esiflotaation primäärivaiheeseen, sillä primäärivaiheessa kuitujen osuus on huomattavasti suurempi kuin sekundäärivaiheissa. Esiflotaation primäärivaiheen uusiomassojen laboratorioflotaatioiden avulla saavutettujen maksimivaaleuksien ero kesän ja talven välillä oli noin 1,5 %ISO. Kesäefektin ei havaittu suuresti vaikuttavan flotaation sekundäärivaiheisiin.

Optimization of energy consumption in wastewater pumping

Pumppauksessa arvioidaan olevan niin teknisesti kuin taloudellisestikin huomattavia mahdollisuuksia säästää energiaa. Maailmanlaajuisesti pumppaus kuluttaa lähes 22 % sähkö-moottorien energiantarpeesta. Tietyillä teollisuudenaloilla jopa yli 50 % moottorien käyttämästä sähköenergiasta voi kulua pumppaukseen. Jäteveden pumppauksessa pumppujen toiminta perustuu tyypillisesti on-off käyntiin, jolloin pumpun ollessa päällä se käy täydellä teholla. Monissa tapauksissa pumput ovat myös ylimitoitettuja. Yhdessä nämä seikat johtavat kasvaneeseen energian kulutukseen. Työn teoriaosassa esitellään perusteet jätevesihuollosta ja jäteveden käsittelystä sekä pumppaussysteemin pääkomponentit: pumppu, putkisto, moottori ja taajuusmuuttaja. Työn empiirisessä osassa esitellään työn aikana kehitetty laskuri, jonka avulla voidaan arvioida energiansäästöpotentiaalia jäteveden pumppaussysteemeissä. Laskurilla on mandollista laskea energiansäästöpotentiaali käytettäessä pumpun tuoton ohjaustapana pyörimisnopeuden säätöä taajuusmuuttajalla on-off säädön sijasta. Laskuri ilmoittaa optimaalisimmanpumpun pyörimisnopeuden sekä ominaisenergiankulutuksen. Perustuen laskuriin, kolme kunnallista jätevedenpumppaamoa tutkittiin. Myös laboratorio-testitsuoritettiin laskurin simuloimiseksi sekä energiansäästöpotentiaalin arvioimiseksi. Tutkimukset osoittavat, että jätevedenpumppauksessa on huomattavia mandollisuuksia säästää energiaa pumpun pyörimisnopeutta pienentämällä. Geodeettisen nostokorkeuden ollessa pieni, voidaan energiaa säästää jopa 50 % ja pitkällä aikavälillä säästö voi olla merkittävä. Tulokset vahvistavat myös tarpeen jätevedenpumppaussysteemien toiminnan optimoimiseksi.

Early high-dose treatment: SCT results from the European High Risk Neuroblastoma Study

Aims: The HR-NBL1 Study of the European SIOP Neuroblastoma Group (SIOPEN) randomised two high dose regimens to learn about potential superiority and toxicity profiles.Patients and Methods: At interim analysis 1483 high risk neuroblastoma patients (893 males) were included since 2002 with either INSS stage 4 disease (1383 pts) above 1 year, or as infants (59 pts) and stage 2&3 of any age (145 pts) with MYCN amplification. The median age at diagnosis was 2.9 years (1 month-19.9 years) with a median follow up of 3 years. Response eligibility criteria prior randomisation after Rapid Cojec Induction (J Clin Oncol, 2010) ± 2 courses of TVD (Cancer, 2003) included complete bone marrow remission and at least partial response at skeletal sites with no more than 3, but improved mIBG positive spots and a PBSC harvest of at least 3x10E6 CD34/kgBW. The randomised regimens were BuMel [busulfan oral till 2006, 4x150mg/m² in 4 ED; or intravenous use according to body weight as licenced thereafter; melphalan 140mg/m²/day) and CEM [carboplatinum ctn. infusion (4x AUC 4.1mg/ml.min/day, etoposid ctn. infusion (4x 338mg/m²/day or [4x 200mg/m²/day]*, melphalan (3x70mg/m²/day; 3x60mg/m²/day*;*reduced dosis if GFR< 100ml/min/1.73m²). Supportive care followed institutional guidelines. VOD prophylaxis included ursadiol, but randomised patients were not eligible for the prophylactic defibrotide trial. Local control included surgery and radiotherapy of 21Gy.Results: Of 1483 patients, 584 were being randomised for the high dose question at data lock. A significant difference in event free survival (3-year EFS 49% vs. 33%, p<0.001) and overall survival (3-year OS 61% vs. 48%, p=0.003) favouring the BuMel regimen over the CEM regimen was demonstrated. The relapse/progression rate was significantly higher after CEM (0.60±0.03) than after BuMel (0.48±0.03)(p<0.001). Toxicity data had reached 80% completeness at last analysis. The severe toxicity rate up to day 100 (ICU and toxic deaths) was below 10%, but was significantly higher for CEM (p= 0.014). The acute toxic death rate was 3% for BuMel and 5% for CEM (NS). The acute HDT toxicity profile favours the BuMel regimen in spite of a total VOD incidence of 18% (grade 3:5%).Conclusions: The Peto rule of P<0.001 at interim analysis on the primary endpoint, EFS was met. Hence randomization was stopped with BuMel as recommended standard treatment in the HR-NBl1/SIOPEN trial which is still accruing for the randomised immunotherapy question.

Optimization of the procedure for removing iron deposits on ceramic filter media

In this thesis, cleaning of ceramic filter media was studied. Mechanisms of fouling and dissolution of iron compounds, as well as methods for cleaning ceramic membranes fouled by iron deposits were studied in the literature part. Cleaning agents and different methods were closer examined in the experimental part of the thesis. Pyrite is found in the geologic strata. It is oxidized to form ferrous ions Fe(II) and ferric ions Fe(III). Fe(III) is further oxidized in the hydrolysis to form ferric hydroxide. Hematite and goethite, for instance, are naturally occurring iron oxidesand hydroxides. In contact with filter media, they can cause severe fouling, which common cleaning techniques competent enough to remove. Mechanisms for the dissolution of iron oxides include the ligand-promoted pathway and the proton-promoted pathway. The dissolution can also be reductive or non-reductive. The most efficient mechanism is the ligand-promoted reductive mechanism that comprises two stages: the induction period and the autocatalytic dissolution.Reducing agents(such as hydroquinone and hydroxylamine hydrochloride), chelating agents (such as EDTA) and organic acids are used for the removal of iron compounds. Oxalic acid is the most effective known cleaning agent for iron deposits. Since formulations are often more effective than organic acids, reducing agents or chelating agents alone, the citrate¿bicarbonate¿dithionite system among others is well studied in the literature. The cleaning is also enhanced with ultrasound and backpulsing.In the experimental part, oxalic acid and nitric acid were studied alone andin combinations. Also citric acid and ascorbic acid among other chemicals were tested. Soaking experiments, experiments with ultrasound and experiments for alternative methods to apply the cleaning solution on the filter samples were carried out. Permeability and ISO Brightness measurements were performed to examine the influence of the cleaning methods on the samples. Inductively coupled plasma optical emission spectroscopy (ICP-OES) analysis of the solutions was carried out to determine the dissolved metals.

Enhanced cytotoxicity and decreased CD8 dependence of human cancer-specific cytotoxic T lymphocytes after vaccination with low peptide dose.

In mice, vaccination with high peptide doses generates higher frequencies of specific CD8+ T cells, but with lower avidity compared to vaccination with lower peptide doses. To investigate the impact of peptide dose on CD8+ T cell responses in humans, melanoma patients were vaccinated with 0.1 or 0.5 mg Melan-A/MART-1 peptide, mixed with CpG 7909 and Incomplete Freund's adjuvant. Neither the kinetics nor the amplitude of the Melan-A-specific CD8+ T cell responses differed between the two vaccination groups. Also, CD8+ T cell differentiation and cytokine production ex vivo were similar in the two groups. Interestingly, after low peptide dose vaccination, Melan-A-specific CD8+ T cells showed enhanced degranulation upon peptide stimulation, as assessed by CD107a upregulation and perforin release ex vivo. In accordance, CD8+ T cell clones derived from low peptide dose-vaccinated patients showed significantly increased degranulation and stronger cytotoxicity. In parallel, Melan-A-specific CD8+ T cells and clones from low peptide dose-vaccinated patients expressed lower CD8 levels, despite similar or even stronger binding to tetramers. Furthermore, CD8+ T cell clones from low peptide dose-vaccinated patients bound CD8 binding-deficient tetramers more efficiently, suggesting that they may express higher affinity TCRs. We conclude that low peptide dose vaccination generated CD8+ T cell responses with stronger cytotoxicity and lower CD8 dependence.

Optimization of a protocol for the micropropagation of pineapple

The present work aimed at maximizing the number of plantlets obtained by the micropropagation of pineapple (Ananas comosus (L.) Merrill) cv. Pérola. Changes in benzylaminopurine (BAP) concentration, type of medium (liquid or solidified) and the type of explant in the proliferation phase were evaluated. Slips were used as the explant source, which consisted of axillary buds obtained after careful excision of the leaves. A Sterilization was done in the hood with ethanol (70%), for three minutes, followed by calcium hypochlorite (2%), for fifteen minutes, and three washes in sterile water. The explants were introduced in MS medium supplemented with 2mg L-1 BAP and maintained in a growth room at a 16h photoperiod (40 mmol.m-2.s-1), 27 ± 2ºC. After eight weeks, cultures were subcultured for multiplication in MS medium. The following treatments were tested: liquid x solidified medium with different BAP concentrations (0.0, 1.5 or 3.0 mg L-1), and the longitudinal cut, or not, of the shoot bud used as explant. The results showed that liquid medium supplemented with BAP at 1.5 mg L-1, associated with the longitudinal sectioning of the shoot bud used as explant presented the best results, maximizing shoot proliferation. On average, the best treatment would allow for an estimated production of 161,080 plantlets by the micropropagation of the axillary buds of one plant with eight slips and ten buds/slips, within a period of eight months.

Covariance Matrix Estimation and Mean-Variance Optimization in application to International Diversification

Tutkimus keskittyy kansainväliseen hajauttamiseen suomalaisen sijoittajan näkökulmasta. Tutkimuksen toinen tavoite on selvittää tehostavatko uudet kovarianssimatriisiestimaattorit minimivarianssiportfolion optimointiprosessia. Tavallisen otoskovarianssimatriisin lisäksi optimoinnissa käytetään kahta kutistusestimaattoria ja joustavaa monimuuttuja-GARCH(1,1)-mallia. Tutkimusaineisto koostuu Dow Jonesin toimialaindekseistä ja OMX-H:n portfolioindeksistä. Kansainvälinen hajautusstrategia on toteutettu käyttäen toimialalähestymistapaa ja portfoliota optimoidaan käyttäen kahtatoista komponenttia. Tutkimusaieisto kattaa vuodet 1996-2005 eli 120 kuukausittaista havaintoa. Muodostettujen portfolioiden suorituskykyä mitataan Sharpen indeksillä. Tutkimustulosten mukaan kansainvälisesti hajautettujen investointien ja kotimaisen portfolion riskikorjattujen tuottojen välillä ei ole tilastollisesti merkitsevää eroa. Myöskään uusien kovarianssimatriisiestimaattoreiden käytöstä ei synnytilastollisesti merkitsevää lisäarvoa verrattuna otoskovarianssimatrisiin perustuvaan portfolion optimointiin.

Efeitos de dose de nitrogênio, fósforo e potássio sobre os componentes da produção e a qualidade de bananas 'Prata Anã' no distrito agroindustrial de Jaíba

Com o objetivo de verificar os efeitos da adubação nitrogenada, fosfatada e potássica sobre os componentes da produção e a qualidade de bananas 'Prata Anã', no Distrito Agroindustrial de Jaíba, em Matias Cardoso-MG, foi conduzido um experimento com dez tratamentos constituídos pela combinação de doses (g/touceira) de N, P e K de acordo com uma matriz baconiana, sendo 1: 250-45-700, 2: 250-25-700, 3: 250-70-700, 4: 250-100-700, 5: 250-45-300, 6: 250-45-500, 7: 250-45-1000, 8: 150-45-700, 9: 400-45-700, 10: 600-45-700. O tratamento um é o de referência, correspondendo às doses adotadas pelos bananicultores da região. O delineamento foi de blocos ao acaso com quatro repetições. Avaliou-se a produção do primeiro ciclo. Os cachos foram colhidos, despencados e avaliados quanto ao número de pencas, número de frutos e massa do cacho, massa média das pencas e massa média, diâmetro e comprimentos total e comercial do fruto. Os resultados indicaram que as doses de nitrogênio ou fósforo utilizadas pelos produtores de banana do Distrito Agroindustrial de Jaíba podem ser reduzidas para 150 ou 25 g/touceira, respectivamente, sem prejuízo para a produção e qualidade dos frutos. Por outro lado, as doses de potássio até 1000 g/touceira, parceladas semanalmente, proporcionaram aumentos significativos na massa, comprimento total e comercial do fruto.