Human alveolar macrophages infected by virulent bacteria expressing SipB are a major source of active interleukin-18.

Recent publications have demonstrated that the protease caspase-1 is responsible for the processing of pro-interleukin 18 (IL-18) into the active form. Studies on cell lines and murine macrophages have shown that the bacterial invasion factor SipB activates caspase-1, triggering cell death. Thus, we investigated the role of SipB in the activation and release of IL-18 in human alveolar macrophages (AM), which are the first line of defense against inhaled pathogens. Under steady-state conditions, AM are a more important source of IL-18 than are dendritic cells (DC) and monocytes. Cytokine production by AM and DC was compared after both types of cells had been infected with a virulent strain of Salmonella enterica serovar Typhimurium and an isogenic sipB mutant, which were used as an infection model. Infection with virulent Salmonella led to marked cell death with features of apoptosis while both intracellular activation and release of IL-18 were demonstrated. In contrast, the sipB mutant did not induce such cell death or the release of active IL-18. The specific caspase-1 inhibitor Ac-YVAD-CMK blocked the early IL-18 release in AM infected with the virulent strain. However, the type of Salmonella infection did not differentially regulate IL-18 gene expression. We concluded that the bacterial virulence factor SipB plays an essential posttranslational role in the intracellular activation of IL-18 and the release of the cytokine in human AM.

Antigen presentation in the lung: dendritic cells and macrophages.

Antigen presentation is a required prime event before T-cell activation can occur. Cells which constitutively express major histocompatibility antigen class I or II are responsible for presenting antigens. These are essentially alveolar macrophages (AM) residing mostly in the air spaces, and dendritic cells (DC), which create a tight surveillance network just below the epithelial cells of the airways and in the loose connective tissue around the vessels or in the pleura. AM are poor antigen presenting cells compared to DC. AM when encountering foreign particles or organisms may, however, influence the degree of activity or maturation of neighbouring DC, by releasing cytokines. Thus, we will describe how the innate immune processes may influence specific immunity and perhaps Th1 and Th2 differentiation. Following the description of the differences in phenotype and functions of AM and DC, we will provide data showing that in some pathological conditions, such as sarcoidosis, AM can acquire some specificities of DC.

Diffusive transport properties in monovalent and divalent metal-ion halide melts: A computer simulation study

Self- and cross-velocity correlation functions and related transport coefficients of molten salts are studied by molecular-dynamics simulation. Six representative systems are considered, i.e., NaCl and KCl alkali halides, CuCl and CuBr noble-metal halides, and SrCl2 and ZnCl2 divalent metal-ion halides. Computer simulation results are compared with experimental self-diffusion coefficients and electrical conductivities. Special attention is paid to dynamic cross correlations and their dependence on the Coulomb interactions as well as on the size and mass differences between anions and cations.

Idarubicin-loaded ONCOZENE drug-eluting embolic agents for chemoembolization of hepatocellular carcinoma: in vitro loading and release and in vivo pharmacokinetics.

PURPOSE: To present in vitro loading and release characteristics of idarubicin with ONCOZENE (CeloNova BioSciences, Inc, San Antonio, Texas) drug-eluting embolic (DEE) agents and in vivo pharmacokinetics data after transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents in patients with hepatocellular carcinoma. MATERIALS AND METHODS: Loading efficacy of idarubicin with ONCOZENE DEE agents 100 µm and DC Bead (Biocompatibles UK Ltd, Farnham, United Kingdom) DEE agents 100-300 µm was monitored at 10, 20, and 30 minutes loading time by high-pressure liquid chromatography. A T-apparatus was used to monitor the release of idarubicin from the two types of DEE agents over 12 hours. Clinical and 24-hour pharmacokinetics data were recorded after transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents in four patients with unresectable hepatocellular carcinoma. RESULTS: Idarubicin loading in ONCOZENE DEE agents was > 99% at 10 minutes. Time to reach 75% of the release plateau level was 37 minutes ± 6 for DC Bead DEE agents and 170 minutes ± 19 for ONCOZENE DEE agents both loaded with idarubicin 10 mg/mL. After transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents, three partial responses and one complete response were observed with only two asymptomatic grade 3 biologic adverse events. Median time to maximum concentration for idarubicin in patients was 10 minutes, and mean maximum concentration was 4.9 µg/L ± 1.7. Mean area under the concentration-time curve from 0-24 hours was equal to 29.5 µg.h/L ± 20.5. CONCLUSIONS: ONCOZENE DEE agents show promising results with very fast loading ability, a favorable in vivo pharmacokinetics profile with a sustained release of idarubicin during the first 24 hours, and encouraging safety and responses. Histopathologic and clinical studies are needed to evaluate idarubicin release around the DEE agents in tumor tissue and to confirm safety and efficacy.

Integration of local-scale hydrological and regional-scale geophysical based on a nonlinear Bayesian sequential simulation approach

Significant progress has been made with regard to the quantitative integration of geophysical and hydrological data at the local scale. However, extending the corresponding approaches to the regional scale represents a major, and as-of-yet largely unresolved, challenge. To address this problem, we have developed a downscaling procedure based on a non-linear Bayesian sequential simulation approach. The basic objective of this algorithm is to estimate the value of the sparsely sampled hydraulic conductivity at non-sampled locations based on its relation to the electrical conductivity, which is available throughout the model space. The in situ relationship between the hydraulic and electrical conductivities is described through a non-parametric multivariate kernel density function. This method is then applied to the stochastic integration of low-resolution, re- gional-scale electrical resistivity tomography (ERT) data in combination with high-resolution, local-scale downhole measurements of the hydraulic and electrical conductivities. Finally, the overall viability of this downscaling approach is tested and verified by performing and comparing flow and transport simulation through the original and the downscaled hydraulic conductivity fields. Our results indicate that the proposed procedure does indeed allow for obtaining remarkably faithful estimates of the regional-scale hydraulic conductivity structure and correspondingly reliable predictions of the transport characteristics over relatively long distances.

Concurrent use of cisplatin or cetuximab with definitive radiotherapy for locally advanced head and neck squamous cell carcinomas. Strahlentherapie in Kombination mit platinbasierter Chemotherapie oder Cetuximab zur Behandlung von lokal fortgeschrittenen Plattenepithelkarzinomen im Kopf-Hals-Bereich.

AIM: The goal of the present work was to compare outcomes of definitive concurrent cisplatin-based chemoradiotherapy (CRT) with cetuximab-based bioradiotherapy (BRT) in locally advanced head-and-neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Between 2006 and 2012, 265 patients with locally advanced HNSCC were treated at our institution with CRT (n = 194; 73 %) with three cycles of cisplatin (100 mg/m(2), every 3 weeks) or BRT (n = 71; 27 %) with weekly cetuximab. Patients receiving BRT had more pre-existing conditions (Charlson index ≥ 2) than the CRT group (p = 0.005). RESULTS: Median follow-up was 29 months. In all, 56 % of patients treated with CRT received the planned three cycles (92 % at least two cycles) and 79 % patients treated with BRT received six cycles or more. The 2-year actuarial overall survival (OS) and progression-free survival (PFS) were 72 % and 61 %, respectively. In the multivariate analysis (MVA), T4 stage, N2-3 stage, smoking status (current smoker as compared with never smoker), and non-oropharyngeal locations predicted for OS, whereas BRT association with OS was of borderline significance (p = 0.054). The 2-year actuarial locoregional control (LRC) and distant control (DC) rates were 73 and 79 %, respectively. CRT was independently associated with an improved LRC (2-year LRC: 76 % for CRT vs. 61 % for BRT) and DC (2-year LRC: 81 % for CRT vs. 68 % for BRT) in comparison with BRT (p < 0.001 and p = 0.01 in the MVA). Subgroup analyses showed that T4 patients benefited significantly from CRT (vs. BRT) in LRC, while T1-3 did not. BRT patients had more G3-4 skin complications (p < 0.001) and CRT patients had higher rates of feeding tube placement (p = 0.006) and G3-4 gastrointestinal toxicities (p < 0.001). CONCLUSION: This retrospective analysis showed a better LRC in locally advanced HNSCC treated by cisplatin-based CRT than cetuximab-based BRT, and a nonsignificant trend towards an improved OS.

Lvpercal: Nota a livio 1, 5, 1

In Livius 1,5,1 the reading Lupercal hoc ludicrum has been interpreted with the meaning of Lupercal game or festivity; however, this interpretation goes against the use in Latin of the singular form Lupercal, wich is used to refer to the cavern and not to the games, wich are always referred to with theplural form Lupercalia. Lexical reasons suggest that Lupercal should also be interpreted here in its usual local sense.

Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy.

BACKGROUND & AIMS: Vitamin D is an important immune modulator and preliminary data indicated an association between vitamin D deficiency and sustained virologic response (SVR) rates in hepatitis C virus (HCV) genotype 1 patients. We, therefore, performed a comprehensive analysis on the impact of vitamin D serum levels and of genetic polymorphisms with functional relevance within the vitamin D cascade on chronic hepatitis C and its treatment. METHODS: Vitamin D serum levels, genetic polymorphisms within the vitamin D receptor and 1α-hydroxylase were determined in a cohort of 468 HCV genotype 1, 2, and 3 infected patients who were treated with interferon-alfa based regimens. RESULTS: Chronic hepatitis C was associated with a high incidence of severe vitamin D deficiency compared to controls (25(OH)D(3)<10 ng/ml in 25% versus 12%, p<0.00001). 25(OH)D(3) deficiency correlated with SVR in HCV genotype 2 and 3 patients (50% and 81% SVR for patients with and without severe vitamin D deficiency, respectively, p<0.0001). In addition, the CYP27B1-1260 promoter polymorphism rs10877012 had substantial impact on 1,25-dihydroxyvitamin D serum levels (72, 61, and 60 pmol/ml for rs10877012 AA, AC, and CC, respectively, p=0.04) and on SVR rates in HCV genotype 1, 2, and 3 infected patients (77% and 65% versus 42% for rs10877012 AA, AC, and CC, respectively, p=0.02). CONCLUSIONS: Chronic hepatitis C virus infection is associated with vitamin D deficiency. Reduced 25-hydroxyvitamin D levels and CYP27B1-1260 promoter polymorphism leading to reduced 1,25-dihydroxyvitamin D levels are associated with failure to achieve SVR in HCV genotype 1, 2, and 3 infected patients.

A non-linear Bayesian approach for upscaling local-scale hydraulic conductivity measurements based on local- and regional-scale geophysical data

Significant progress has been made with regard to the quantitative integration of geophysical and hydrological data at the local scale. However, extending the corresponding approaches to the regional scale represents a major, and as-of-yet largely unresolved, challenge. To address this problem, we have developed an upscaling procedure based on a Bayesian sequential simulation approach. This method is then applied to the stochastic integration of low-resolution, regional-scale electrical resistivity tomography (ERT) data in combination with high-resolution, local-scale downhole measurements of the hydraulic and electrical conductivities. Finally, the overall viability of this upscaling approach is tested and verified by performing and comparing flow and transport simulation through the original and the upscaled hydraulic conductivity fields. Our results indicate that the proposed procedure does indeed allow for obtaining remarkably faithful estimates of the regional-scale hydraulic conductivity structure and correspondingly reliable predictions of the transport characteristics over relatively long distances.

Differentiation towards regulatory DC is maintained during RSV infection in airway epithelial cells

Airway epithelial cells have been shown to drive differentiation of monocytes into dendritic cells (DC) with suppressive phenotype. In this study we investigated the impact of virus-induced inflammatory mediator production on DC development. Monocyte differentiation into functional DC, as reflected by the expression of CD11c, CD123, BDCA-4 and DC-SIGN and the capacity to activate T cells, was similar for respiratory syncytial virus (RSV)- and mock-infected BEAS-2B and A549 cells. RSV-conditioned culture media resulted in a partially mature DC phenotype, but failed to upregulate CD80, CD83, CD86 and CCR7 and failed to release pro-inflammatory mediators upon TLR triggering. Nevertheless, these DCs were able to maintain an antiviral response by the release of type I IFN. Collectively, these data indicate that the airway epithelium maintains an important suppressive DC phenotype under inflammatory conditions induced by RSV infection.

Converter-flux-based current control of voltage source PWM rectifiers - analysis and implementation

Pulsewidth-modulated (PWM) rectifier technology is increasingly used in industrial applications like variable-speed motor drives, since it offers several desired features such as sinusoidal input currents, controllable power factor, bidirectional power flow and high quality DC output voltage. To achieve these features,however, an effective control system with fast and accurate current and DC voltage responses is required. From various control strategies proposed to meet these control objectives, in most cases the commonly known principle of the synchronous-frame current vector control along with some space-vector PWM scheme have been applied. Recently, however, new control approaches analogous to the well-established direct torque control (DTC) method for electrical machines have also emerged to implement a high-performance PWM rectifier. In this thesis the concepts of classical synchronous-frame current control and DTC-based PWM rectifier control are combined and a new converter-flux-based current control (CFCC) scheme is introduced. To achieve sufficient dynamic performance and to ensure a stable operation, the proposed control system is thoroughly analysed and simple rules for the controller design are suggested. Special attention is paid to the estimationof the converter flux, which is the key element of converter-flux-based control. Discrete-time implementation is also discussed. Line-voltage-sensorless reactive reactive power control methods for the L- and LCL-type line filters are presented. For the L-filter an open-loop control law for the d-axis current referenceis proposed. In the case of the LCL-filter the combined open-loop control and feedback control is proposed. The influence of the erroneous filter parameter estimates on the accuracy of the developed control schemes is also discussed. A newzero vector selection rule for suppressing the zero-sequence current in parallel-connected PWM rectifiers is proposed. With this method a truly standalone and independent control of the converter units is allowed and traditional transformer isolation and synchronised-control-based solutions are avoided. The implementation requires only one additional current sensor. The proposed schemes are evaluated by the simulations and laboratory experiments. A satisfactory performance and good agreement between the theory and practice are demonstrated.

Vaihtosuuntauksen ja suodatuksen toteuttaminen tasasähkönjakeluverkossa

Pienjännitejakeluverkko Suomessa on toteutettu 400 V:n kolmivaiheisella vaihtosähköllä. Pienestä jännitteestä johtuen 20/0.4 kV:n muuntajat täytyy sijoittaa lähelle kuluttajaa, jotta siirtohäviöt eivät nouse liian suuriksi. Suuremman vaihto- tai tasajännitteen käyttö pienjännitejakelussa kasvattaisi verkon tehonsiirtokapasiteettia ja mahdollistaisi pidempien siirtomatkojen käytön. Käynnissä olevassa tutkimushankkeessa käsitellään vaihtoehtoa, jossa tasajännitettä käytettäisiin 20 kV:n verkon ja kuluttajan välisessä tehonsiirrossa ja kuluttajalla sijaitseva vaihtosuuntaaja muodostaisi tasasähköstä standardien mukaista yksi- tai kolmivaiheista vaihtosähköä. Tässä diplomityössä käsitellään tehoelektroniikan soveltamista kuluttajalle sijoitetussa vaihtosuuntaajassa. Työssä tarkastellaan yksivaiheisia invertteritopologioita, niiden ohjausta ja soveltamista erilaisissa vaihtosuuntaajaratkaisuissa sekä LC- ja LCL-suotimien soveltuvuutta invertterin lähtöjännitteen suodatukseen. Lisäksi esitellään erilaisia rakenneratkaisuja vaihtosuuntauksen toteutukseen ja tarkastellaan näiden järjestelmien vikatilanteita ja sähköturvallisuutta. Lopuksi käsitellään koko järjestelmän häviöitä ja hyötysuhdetta eri suodinkomponenteilla sekä kytkentätaajuuksilla ja esitellään laboratorioprototyyppi. Työssä saatiin selville, että puolisiltainvertteri ei sovellu suurten kondensaattorien vuoksi syöttämään verkkotaajuista kuormaa, vaan joudutaan käyttämään kokosiltainvertteriä. Kokosiltainvertterin ja LC- tai LCL-suotimen käsittävää kokonaisuutta tarkasteltaessa havaittiin, että pienimmät häviöt saavutetaan LC-suotimella 5 %:n ja LCL-suotimella 1 %:n särövaatimuksella. Hyötysuhdekäyrää tarkasteltaessa saatiin sama tulos läpi koko invertterin tehoalueen. Suotimen häviöiden tarkka laskenta on kuitenkin erittäin haasteellista, joten tulokset ovat suuntaa-antavia.

Moottorimalliton skalaarisäätö

Työssä tutkitaan nopeusanturittoman vaihtovirtakäytön skalaarisia ohjaus- ja säätömenetelmiä. Työn alussa esitetään perusteoriat taajuusmuuttajista ja oikosulkumoottoreista. Tämän jälkeen esitellään yleisimmin kirjallisuudessa esiintyneet skalaariohjaukset ja –säädöt. Vektorisäätöä ja erityisesti moottoriparametrien vaikutusta säädön toimivuuteen esitellään lyhyesti. Työn tavoitteena on ACS800 taajuusmuuttajan skalaarisäädön tutkiminen. ACS800:n nykyinen skalaarisäätö on liian sidoksissa vektorisäätöön, joten simulointien ja kirjallisuustutkimuksen tarkoituksena on täysin vektorisäädöstä eriytetyn skalaarisäädön kehitysmahdollisuuksien tutkiminen. Kirjallisuudessa esiintyneiden säätöjen avulla muodostetaan diskreettiaikainen toteutus skalaarisäädölle vaihtovirtakäytössä, jossa on käytössä virran ja välipiirijännitteen takaisinkytkentä. Säädettävää moottoria mallinnetaan jatkuvaaikaisella L-sijaiskytkennällä. Välipiirin mallinnus toimii myös jatkuva-aikaisena lukuun ottamatta välipiirin tasavirtakomponenttia, joka muodostetaan virran takaisinkytkennän ja PWM-modulaattorin kytkinasentojen avulla. Simuloinnin tarkoituksena on mallintaa skalaarisäädön suurimpia ongelmia, kuten virta- ja välijännitesäätöä. Tuloksista voidaan päätellä, että perussäädöt toimivat moitteettomasti, mutta erityisesti virtasäätöä tulisi kehittää.

Uuden sukupolven sähköturvamittalaitteen prosessorikortin suunnittelu

Suomessa tuotetaan sähköä eri energialähteistä sekä menetelmistä. Pääosa sähköstä tuotetaan ydinenergian-, vesivoiman-, ja maakaasun avulla. Sähköä hyödynnetään niin kuluttaja- ja ammattilaiskäytössä erilaisten sähkölaitteiden muodossa. Useat sähkölaitteista toimivat joko AC- tai DC-virralla, tietyllä jännitealueella. Mikäli sähkölaitteiden valmistajat haluavat markkinoida tuotteitansa CE-hyväksytysti, tulee niiden täyttää tietyt vaatimukset. Eräs toteutettava direktiivi on pienjännitedirektiivi, minkä toteuttamalla sähkölaitetta voidaan markkinoida Euroopan Talousalueella, tällöin sähkölaite täyttää CE-merkinnän vaatimukset. Valmistettavista sähkölaitteista on kyettävä suorittamaan sähköturvamittauksia, sähköturvamittalaitteilla, jotka myös kehittyvät ja hyödyntävät nykyaikaista teknologiaa. Nykyaikaisen teknologian ansiosta sähköturvamittalaitteita voidaan soveltaa myös muunlaiseen sähköisiin mittauksiin,kuten jännite- ja virtamittauksin.Diplomityössä esitellään, kuinka modernin optisen tiedonsiirron omaavan sähköturvamittalaitteen prosessorikortti oheiskomponentteineen on suunniteltu ja toteutettu valmiiksi prototyypiksi.

Galactosaminoglycans from normal myometrium and leiomyoma

In many tumors, the amount of chondroitin sulfate in the extracellular matrix has been shown to be elevated when compared to the corresponding normal tissue. Nevertheless, the degree of chondroitin sulfate increase varies widely. In order to investigate a possible correlation between the amount of chondroitin sulfate and tumor size, several individual specimens of human leiomyoma, a benign uterine tumor, were analyzed. The glycosaminoglycans from eight tumors were extracted and compared with those from the respective adjacent normal myometrium. The main glycosaminoglycan found in normal myometrium was dermatan sulfate, with small amounts of chondroitin sulfate and heparan sulfate. In leiomyoma, both dermatan sulfate and chondroitin sulfate were detected and the total amounts of the two galactosaminoglycans was increased in all tumors when compared to normal tissue. In contrast, the heparan sulfate concentration decreased in the tumor. To assess the disaccharide composition of galactosaminoglycans, these compounds were incubated with bacterial chondroitinases AC and ABC. The amounts of L-iduronic acid-containing disaccharides remained constant, whereas the concentration of D-glucuronic acid-containing disaccharides increased from 2 to 10 times in the tumor, indicating that D-glucuronic acid-containing disaccharides are responsible for the elevation in galactosaminoglycan concentration. This increase is positively correlated with tumor size.