Procjena varijabli stanja sustava s gorivnim člankom i uzlaznim pretvaračem metodom brzog uzorkovanja signala

Estimation of state variables of a peak current mode (PCM) controlled DC-DC boost converter supplied by a PEM fuel cell is described in this paper. Since this system is highly nonlinear and non-minimum phase, its state variables are estimated by using fast output sampling method. Estimated state variables are the converter output voltage and its first derivative, and they are suitable for model reference adaptive control or sliding mode based control techniques. The estimator has been designed in a way that it gives a good estimate of the state variables in the continuous and in the discontinuous conduction mode of the converter, and in the presence of measurement and process noise caused by converter switching-mode operation. Experimental results of estimating the state variables on a 450 W boost converter supplied by the emulator of the PEM fuel cell BCS 64-32 show good results of the estimation, regardless of the conduction mode of the converter, i.e. the operating point determined by its output current.U ovom radu obrađena je procjena varijabli stanja sustava s istomjernim uzlaznim pretvaračem u vršnom strujnom načinu upravljanja napajanim PEM gorivnim člankom. Budući da je taj sustav izrazito nelinearan te neminimalno-fazan, za procjenu njegovih varijabli stanja upotrebljena je metoda brzog uzorkovanja izlaznog signala. Procjenjene varijable stanja su izlazni napon uzlaznog pretvarača te njegova prva derivacija, te su pogodne za adaptivno upravljanje s referentnim modelom i upravljanje temeljeno na kliznim režimima. Procjenitelj je projektiran na način da daje dobru procjenu varijabli stanja u kontinuiranom i diskontinuiranom režimu rada pretvarača, te u uvjetima mjernog i procesnog šuma uzrokovanog sklopnim načinom rada pretvarača. Eksperimentalni rezultati procjene varijabli stanja na uzlaznom pretvaraču snage 450 W napajanim emulatorom gorivnog članka BCS 64-32 pokazuju dobre rezultate procjene, neovisno o režimu rada pretvarača, odnosno radnoj točki određenoj njegovom izlaznom strujom

The neonicotinoid insecticide Imidacloprid repels pollinating flies and beetles at field-realistic concentrations

Neonicotinoids are widely used systemic insecticides which, when applied to flowering crops, are translocated to the nectar and pollen where they may impact upon pollinators. Given global concerns over pollinator declines, this potential impact has recently received much attention. Field exposure of pollinators to neonicotinoids depends on the concentrations present in flowering crops and the degree to which pollinators choose to feed upon them. Here we describe a simple experiment using paired yellow pan traps with or without insecticide to assess whether the commonly used neonicotinoid imidacloprid repels or attracts flying insects. Both Diptera and Coleoptera exhibited marked avoidance of traps containing imidacloprid at a field-realistic dose of 1 μg L-1, with Diptera avoiding concentrations as low as 0.01 μg L-1. This is to our knowledge the first evidence for any biological activity at such low concentrations, which are below the limits of laboratory detection using most commonly available techniques. Catch of spiders in pan traps was also slightly reduced by the highest concentrations of imidacloprid used (1 μg L-1), but catch was increased by lower concentrations. It remains to be seen if the repellent effect on insects occurs when neonicotinoids are present in real flowers, but if so then this could have implications for exposure of pollinators to neonicotinoids and for crop pollination. © 2013 Easton, Goulson

Mehanizam toksičnosti i detoksikacije organofosfornih spojeva s naglaskom na istraživanja u Hrvatskoj

This review comprises studies on the mechanisms of toxicity and detoxication of organophosphorus (OP) compounds done in Croatia in different research areas. One area is the synthesis of antidotes against OP poisoning and their in vivo testing in experimental animals. In vitro studies included in this review focus on the mechanisms of reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), protection of cholinesterases from inhibition by OPs, and reactivation of phosphylated cholinesterases. The third area comprises distribution profiles of BChE and paraoxonase (PON) phenotypes in selected population groups and the detection of OPs and metabolites in humans. Finally, methods are described for the detection of OP compounds in human blood and other media by means of cholinesterase inhibitionPrikazana su istraživanja vođena u Hrvatskoj na različitim područjima mehanizma toksičnosti i detoksikacije organofosfornih (OP) spojeva. Jedno je područje sinteza antidota protiv otrovanja OP spojevima i testiranje in vivo antidota na eksperimentalnim životinjama. Istraživanja in vitro odnose se na mehanizam reverzibilne inhibicije acetilkolinesteraze (AChE) i buturilkolinesteraze (BChE), zaštitu kolinesteraza od inhibicije OP spojevima te reaktivaciju fosfiliranih kolinesteraza. Treće je područje distribucija fenotipova BChE i paraoksonaze (PON) u odabranim populacijama te detekcija OP spojeva i njihovih metabolita u ljudima. Na kraju su opisane metode detekcije OP spojeva u ljudskoj krvi i drugim medijima koje se osnivaju na inhibiciji kolinesteraza

Odnos strukture i aktivnosti u reaktivaciji tabunom fosforilirane ljudske acetilkolinesteraze bispiridinijevim para-aldoksimima

We investigated interactions of bispyridinium para-aldoximes N,N’-(propano)bis(4-hydroxyiminomethyl) pyridinium bromide (TMB-4), N,N’-(ethano)bis(4-hydroxyiminomethyl)pyridinium methanosulphonate (DMB-4), and N,N’-(methano)bis(4-hydroxyiminomethyl)pyridinium chloride (MMB-4) with human erythrocyte acetylcholinesterase phosphorylated by tabun. We analysed aldoxime conformations to determine the flexibility of aldoxime as an important feature for binding to the acetylcholinesterase active site. Tabun-inhibited human erythrocyte acetylcholinesterase was completely reactivated only by the most flexible bispyridinium aldoxime - TMB-4 with a propylene chain between two rings. Shorter linkers than propylene (methylene or ethylene) as in MMB-4 and DMB-4 did not allow appropriate orientation in the active site, and MMB-4 and DMB-4 were not efficient reactivators of tabun-phosphorylated acetylcholinesterase. Since aldoximes are also reversible inhibitors of native acetylcholinesterase, we determined dissociation constants and their protective index against acetylcholinesterase inactivation by tabun.Proučavali smo interakcije bispiridinijevih para-oksima N,N’-(propano)bis(4-hidroksiiminometil)piridinijeva bromida (TMB-4), N,N’-(etanano)bis(4-hidroksiiminometil)piridinijeva metanosulfonata (DMB-4) i N,N’- (metano)bis(4-hidroksiiminometil)piridinijeva klorida (MMB-4) s ljudskom eritrocitnom acetilkolinesterazom fosforiliranom tabunom. Da bismo odredili fleksibilnosti aldoksima, što je važna osobina kod njihova vezanja u aktivno mjesto acetilkolinesteraze, analizirali smo i konformacijske odlike aldoksima. Ljudska acetilkolinesteraza inhibirana tabunom bila je potpuno reaktivirana samo najfleksibilnijim bispiridinijevim aldoksimom – TMB-4. Aldoksimi MMB-4 i DMB-4 nisu bili efikasni reaktivatori acetilkolinesteraze fosforilirane tabunom jer je kod tih spojeva lanac koji povezuje dva prstena kraći od propilena (metilen u MMB-4 i etilen u DMB-4), što ne dopušta povoljnu orijentaciju tih aldoksima unutar aktivnog mjesta enzima. S obzirom na to da su aldoksimi i reverzibilni inhibitori nativne acetilkolinesteraze, odredili smo njihove disocijacijske konstante, kao i zaštitu acetilkolinesteraze od inhibiranja tabunom reverzibilnim vezanjem aldoksima

Microneedle Array Design Determines the Induction of Protective Memory CD8+ T Cell Responses Induced by a Recombinant Live Malaria Vaccine in Mice

BACKGROUND: Vaccine delivery into the skin has received renewed interest due to ease of access to the immune system and microvasculature, however the stratum corneum (SC), must be breached for successful vaccination. This has been achieved by removing the SC by abrasion or scarification or by delivering the vaccine intradermally (ID) with traditional needle-and-syringes or with long microneedle devices. Microneedle patch-based transdermal vaccine studies have predominantly focused on antibody induction by inactivated or subunit vaccines. Here, our principal aim is to determine if the design of a microneedle patch affects the CD8(+) T cell responses to a malaria antigen induced by a live vaccine. METHODOLOGY AND FINDINGS: Recombinant modified vaccinia virus Ankara (MVA) expressing a malaria antigen was percutaneously administered to mice using a range of silicon microneedle patches, termed ImmuPatch, that differed in microneedle height, density, patch area and total pore volume. We demonstrate that microneedle arrays that have small total pore volumes induce a significantly greater proportion of central memory T cells that vigorously expand to secondary immunization. Microneedle-mediated vaccine priming induced significantly greater T cell immunity post-boost and equivalent protection against malaria challenge compared to ID vaccination. Notably, unlike ID administration, ImmuPatch-mediated vaccination did not induce inflammatory responses at the site of immunization or in draining lymph nodes. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that the design of microneedle patches significantly influences the magnitude and memory of vaccine-induced CD8(+) T cell responses and can be optimised for the induction of desired immune responses. Furthermore, ImmuPatch-mediated delivery may be of benefit to reducing unwanted vaccine reactogenicity. In addition to the advantages of low cost and lack of pain, the development of optimised microneedle array designs for the induction of T cell responses by live vaccines aids the development of solutions to current obstacles of immunization programmes

Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer

BACKGROUND: The randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone (hazard ratio [HR]=0.75, 95% confidence interval [CI] 0.61-0.93). We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety. RESULTS: Of the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR=0.79, 95% CI 0.59-1.06), combined second- and third-line PFS (HR=0.85, 95% CI 0.68-1.05) or OS (HR=0.96, 95% CI 0.76-1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected. CONCLUSION: In this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS but no improvement in longer-term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life. CLINICALTRIALSGOV: NCT01250379

Microneedles: A New Frontier in Nanomedicine Delivery

This review aims to concisely chart the development of two individual research fields, namely nanomedicines, with specific emphasis on nanoparticles (NP) and microparticles (MP), and microneedle (MN) technologies, which have, in the recent past, been exploited in combinatorial approaches for the efficient delivery of a variety of medicinal agents across the skin. This is an emerging and exciting area of pharmaceutical sciences research within the remit of transdermal drug delivery and as such will undoubtedly continue to grow with the emergence of new formulation and fabrication methodologies for particles and MN. Firstly, the fundamental aspects of skin architecture and structure are outlined, with particular reference to their influence on NP and MP penetration. Following on from this, a variety of different particles are described, as are the diverse range of MN modalities currently under development. The review concludes by highlighting some of the novel delivery systems which have been described in the literature exploiting these two approaches and directs the reader towards emerging uses for nanomedicines in combination with MN