Disintegration of magnetic tablets in human stomach evaluated by alternate current biosusceptometry

Oral administration is the most convenient route for drug therapy. The knowledge of the gastrointestinal transit and specific site for drug delivery is a prerequisite for development of dosage forms. The aim of this work was to demonstrate that is possible to monitor the disintegration process of film-coated magnetic tablets by multi-sensor alternate current Biosusceptometry (ACB) in vivo and in vitro. This method is based on the recording of signals produced by the magnetic tablet using a seven sensors array and signal-processing techniques. The disintegration was confirmed by signals analysis in healthy human volunteers' measurements and in vitro experiments. Results showed that ACB is efficient to characterize the disintegration of dosage forms in the stomach, being a research tool for the development of new pharmaceutical dosage forms.

Alternate current biosusceptometry for the assessment of gastric motility after proximal gastrectomy in rats: a feasibility study

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Historical Observations of Humpback And Blue Whales in the North Atlantic Ocean: Clues to Migratory Routes and Possibly Additional Feeding Grounds

The seasonal distributions of humpback and blue whales (Megaptera novaeangliae and Balaenoptera musculus, respectively) in the North Atlantic Ocean are not fully understood. Although humpbacks have been studied intensively in nearshore or coastal feeding and breeding areas, their migratory movements between these areas have been largely inferred. Blue whales have only been studied intensively along the north shore of the Gulf of St. Lawrence, and their seasonal occurrence and movements elsewhere in the North Atlantic are poorly known. We investigated the historical seasonal distributions of these two species using sighting and catch data extracted from American 18th and 19th century whaling logbooks. These data suggest that humpback whales migrated seasonally from low-latitude calving/ breeding grounds over a protracted period, and that some of them traveled far offshore rather than following coastal routes. Also, at least some humpbacks apparently fed early in the summer west of the Mid-Atlantic Ridge, well south of their known present-day feeding grounds. In assessing the present status of the North Atlantic humpback population, it will be important to determine whether such offshore feeding does in fact occur. Blue whales were present across the southern half of the North Atlantic during the autumn and winter months, and farther north in spring and summer, but we had too few data points to support inferences about these whales’ migratory timing and routes.

Efficacy of Oral and Parenteral Routes of Mycobacterium bovis Bacille Calmette-Guerin Vaccination Against Experimental Bovine Tuberculosis in White-Tailed Deer (Odocoileus virginianus): A Feasibility Study

We investigated the efficacy of oral and parenteral Mycobacterium bovis bacille Calmette-Guerin Danish strain 1331 (BCG) in its ability to protect white-tailed deer (Odocoileus virginianus) against disease caused by M. bovis infection. Twenty-two white-tailed deer were divided into four groups. One group (n=5) received 109 colony-forming units (cfu) BCG via a lipid-formulated oral bait; one group (n=5) received 109 cfu BCG in culture directly to the oropharynx, one group (n=6) was vaccinated with 106 cfu BCG subcutaneously, and one group served as a control and received culture media directly to the oropharynx (n=6). All animals were challenged 3 mo after vaccination. Five months postchallenge the animals were examined for lesions. Results indicate that both oral forms of BCG and parenterally administerd BCG offered significant protection against M. bovis challenge as compared to controls. This study suggests that oral BCG vaccination may be a feasible means of controlling bovine tuberculosis in wild white-tailed deer populations.

The dual pathway in action: decoupling parallel routes for CO2 production during the oscillatory electro-oxidation of methanol

As in the case of most small organic molecules, the electro-oxidation of methanol to CO2 is believed to proceed through a so-called dual pathway mechanism. The direct pathway proceeds via reactive intermediates such as formaldehyde or formic acid, whereas the indirect pathway occurs in parallel, and proceeds via the formation of adsorbed carbon monoxide (COad). Despite the extensive literature on the electro-oxidation of methanol, no study to date distinguished the production of CO2 from direct and indirect pathways. Working under, far-from-equilibrium, oscillatory conditions, we were able to decouple, for the first time, the direct and indirect pathways that lead to CO2 during the oscillatory electro-oxidation of methanol on platinum. The CO2 production was followed by differential electrochemical mass spectrometry and the individual contributions of parallel pathways were identified by a combination of experiments and numerical simulations. We believe that our report opens some perspectives, particularly as a methodology to be used to identify the role played by surface modifiers in the relative weight of both pathways-a key issue to the effective development of catalysts for low temperature fuel cells.

New routes to enantioenriched substances through small organic molecules

In this thesis we will disclose the results obtained from the diastereoisomeric salt formation (n salt, p salt and p1,n1 salt) between non-racemic trans-chrysanthemic acid (trans-ChA) and pure enantiomers of threo-2-dimethylamino-1-phenyl-1,3-propanediol (DMPP). The occurrence of p1,n1 salt formation can have profound effects on enantiomer separation of scalemic (non-racemic) mixtures. This phenomenon when accompanied by substrate self-association impedes the complete recovery of the major enantiomer through formation of an inescapable racemate cage. A synthetic sequence for the asymmetric synthesis of bicyclo[3.2.0]heptanones and bicyclo[3.2.0]hept-3-en-6-ones through a cycloaddition strategy is reported. The fundamental step is a [2+2]-cycloaddition of an enantiopure amide derived from the reaction between a set of acids and an oxazolidinone as the chiral auxiliary. The inter- and intramolecular cycloaddition of in situ-generated keteniminium salts gives bicycles with a good enantioselection. A key intermediate of Iloprost, a chemically stable and biologically active mimic of prostacyclin PGI2 is synthesized following a ‘green approach’. An example of simple optical resolution of this racemic intermediate involving the diastereoisomeric salt formation is described.

Transformations of bridging ligands in diiron complexes: unconventional routes to new functionalized multisite bound organic frames

The main scope of this Ph.D. thesis has concerned the possible transformations of bridging ligands in diiron complexes, in order to explore unconventional routes to the synthesis of new functionalized multisite bound organic frames. The results achieved during the Ph.D. can be summarized in the following points: 1) We have extended the assembling between small unsaturated molecules and bridging carbyne ligands in diiron complexes to other species. In particular, we have investigated the coupling between olefins and thiocarbyne, leading to the synthesis of thioallylidene bridging diiron complexes. Then, we have extended the study to the coupling between olefins and aminocarbyne. This result shows that the coupling between activated olefins and heteroatom substituted bridging carbynes has a general character. 2) As we have shown, the coupling of bridging alkylidyne ligands with alkynes and alkenes provides excellent routes to the synthesis of bridging C3 hydrocarbyl ligands. As a possible extension of these results we have examined the synthesis of C4 bridging frames through the combination of bridging alkylidynes with allenes. Also in this case the reaction has a general character. 3) Diiron complexes bearing bridging functionalized C3 organic frames display the presence of donor atoms, such as N and S, potentially able to coordinate unsaturated metal fragments. Thus, we have studied the possibility for these systems to act as ‘organometallic ligands’, in particular towards Pd and Rh. 4) The possibility of releasing the organic frame from the bridging coordination appears particularly appealing in the direction of a metal-assisted organic synthesis. Within this field, we have investigated the possibility of involving the C3 bridging ligand in cycloaddition reactions with alkynes, with the aim of generating variously functionalized five-membered cycles. The [3+2] cyclization does not lead to the complete release of the organic fragment but rather it produces its transformation into a cyclopentadienyl ring, which remains coordinated to one Fe atom. This result introduces a new approach to the formation of polyfunctionalised ferrocenes. 5) Furthermore, I have spent a research period of about six months at the Department of Inorganic Chemistry of the Barcelona University, under the supervision of Prof. Concepción López, with the aim of studying the chemistry of polydentate ferrocenyl ligands and their use in organometallic synthesis.

Calix[4]arenes in the 1,3-alternate conformation

Calix[4]arenes fixed in the 1,3-alternate conformation offer an interesting platform for the attachment of further functionalities which has been less frequently used than the cone conformer. Several synthetic strategies were developed to attach four amino functions to the narrow rim, to the wide rim and to both rims of the calix[4]arene fixed in the 1,3-alternate conformation. Using different precursor groups (nitrile/phthalimide or nitro/phthalimide) which can be independently converted into amino functions opens the possibility to attach further groups selectively to the amino functions. Here the groups which is newly attached will determine the reaction sequence.

Food safety and zoonotic enteric pathogens: sources, risk factors and transmission routes of human salmonellosis and campylobacteriosis

Salmonella and Campylobacter are common causes of human gastroenteritis. Their epidemiology is complex and a multi-tiered approach to control is needed, taking into account the different reservoirs, pathways and risk factors. In this thesis, trends in human gastroenteritis and food-borne outbreak notifications in Italy were explored. Moreover, the improved sensitivity of two recently-implemented regional surveillance systems in Lombardy and Piedmont was evidenced, providing a basis for improving notification at the national level. Trends in human Salmonella serovars were explored: serovars Enteritidis and Infantis decreased, Typhimurium remained stable and 4,[5],12:i:-, Derby and Napoli increased, suggesting that sources of infection have changed over time. Attribution analysis identified pigs as the main source of human salmonellosis in Italy, accounting for 43–60% of infections, followed by Gallus gallus (18–34%). Attributions to pigs and Gallus gallus showed increasing and decreasing trends, respectively. Potential bias and sampling issues related to the use of non-local/non-recent multilocus sequence typing (MLST) data in Campylobacter jejuni/coli source attribution using the Asymmetric Island (AI) model were investigated. As MLST data become increasingly dissimilar with increasing geographical/temporal distance, attributions to sources not sampled close to human cases can be underestimated. A combined case-control and source attribution analysis was developed to investigate risk factors for human Campylobacter jejuni/coli infection of chicken, ruminant, environmental, pet and exotic origin in The Netherlands. Most infections (~87%) were attributed to chicken and cattle. Individuals infected from different reservoirs had different associated risk factors: chicken consumption increased the risk for chicken-attributed infections; animal contact, barbecuing, tripe consumption, and never/seldom chicken consumption increased that for ruminant-attributed infections; game consumption and attending swimming pools increased that for environment-attributed infections; and dog ownership increased that for environment- and pet-attributed infections. Person-to-person contacts around holiday periods were risk factors for infections with exotic strains, putatively introduced by returning travellers.

A study of new and more sustainable catalytic routes for the synthesis of adipic acid

The aim of my PhD research project was to investigate new and more sustainable routes, compared to those currently used, for the production of adipic acid (AA). AA is a very important chemical intermediate. The main use of AA is the production of Nylon-6,6 fibers, resins, polyesters, plasticizers. My project was divided into two parts: 1. The two-step oxidation of cyclohexene, where the latter is first oxidized into trans-1,2-cyclohexanediol (CHD) with aqueous hydrogen peroxide, and then the glycol is transformed into AA by reaction with molecular oxygen. Various catalysts were investigated in this process, both heterogeneous (alumina-supported Ru(OH)x and Au nanoparticles supported on TiO2, MgO and Mg(OH)2) and homogeneous (polyoxometalates). We also studied the mechanism of CHD oxidation with oxygen in the presence of these catalysts. 2. Baeyer-Villiger oxidation of cyclohexanone with aqueous hydrogen peroxide into ɛ-caprolactone, as a first step on the way to produce AA. Study on the mechanism of the uncatalyzed (thermal) oxidation of cyclohexanone were also carried out. Investigation on how the different heterogeneous catalysts affect the formation of the reaction products and their distribution was done.

Synthetic routes toward functional block copolymers and bioconjugates via RAFT polymerization

Synthetic Routes toward Functional Block Copolymers and Bioconjugates via RAFT PolymerizationrnSynthesewege für funktionelle Blockcopolymere und Biohybride über RAFT PolymerisationrnDissertation von Dipl.-Chem. Kerstin T. WissrnIm Rahmen dieser Arbeit wurden effiziente Methoden für die Funktionalisierung beider Polymerkettenenden für Polymer- und Bioanbindung von Polymeren entwickelt, die mittels „Reversible Addition-Fragmentation Chain Transfer“ (RAFT) Polymerisation hergestellt wurden. Zu diesem Zweck wurde ein Dithioester-basiertes Kettentransferagens (CTA) mit einer Aktivestereinheit in der R-Gruppe (Pentafluorphenyl-4-phenylthiocarbonylthio-4-cyanovaleriansäureester, kurz PFP-CTA) synthetisiert und seine Anwendung als universelles Werkzeug für die Funktionalisierung der -Endgruppe demonstriert. Zum Einen wurde gezeigt, wie dieser PFP-CTA als Vorläufer für die Synthese anderer funktioneller CTAs durch einfache Aminolyse des Aktivesters genutzt werden kann und somit den synthetischen Aufwand, der üblicherweise mit der Entwicklung neuer CTAs verbunden ist, reduzieren kann. Zum Anderen konnte der PFP-CTA für die Synthese verschiedener Poly(methacrylate) mit enger Molekulargewichtsverteilung und wohl definierter reaktiver -Endgruppe verwendet werden. Dieses Kettenende konnte dann erfolgreich mit verschiedenen primären Aminen wie Propargylamin, 1-Azido-3-aminopropan und Ethylendiamin oder direkt mit den Amin-Endgruppen verschiedener Peptide umgesetzt werden.rnAus der Reaktion des PFP-CTAs mit Propargylamin wurde ein Alkin-CTA erhalten, der sich als effizientes Werkzeug für die RAFT Polymerisation verschiedener Methacrylate erwiesen hat. Der Einbau der Alkin-Funktion am -Kettenende wurde mittels 1H und 13C NMR Spektroskopie sowie MALDI TOF Massenspektroskopie bestätigt. Als Modelreaktion wurde die Kopplung eines solchen alkin-terminierten Poly(di(ethylenglykol)methylethermethacrylates) (PDEGMEMA) mit azid-terminiertem Poly(tert-butylmethacrylat), das mittels Umsetzung einer Aktivester-Endgruppe erhalten wurde, als kupferkatalysierte Azid-Alkin-Cycloaddition (CuAAC) durchgeführt. Die Aufarbeitung des resultierenden Diblockcopolymers durch Fällen ermöglichte die vollständige Abtrennung des Polymerblocks 1, der im Überschuss eingesetzt wurde. Darüber hinaus blieb nur ein sehr kleiner Anteil (< 2 Gew.-%) nicht umgesetzten Polymerblocks 2, was eine erfolgreiche Polymeranbindung und die Effizienz der Endgruppen-Funktionalisierung ausgehend von der Aktivester--Endgruppe belegt.rnDie direkte Reaktion von stimuli-responsiven Polymeren mit Pentafluorphenyl(PFP)ester-Endgruppen, namentlich PDEGMEMA und Poly(oligo(ethylenglykol)methylethermethacrylat), mit kollagen-ähnlichen Peptiden ergab wohl definierte Polymer-Peptid-Diblockcopolymere und Polymer-Peptid-Polymer-Triblockcopolymer unter nahezu quantitativer Umsetzung der Endgruppen. Alle Produkte konnten vollständig von nicht umgesetztem Überschuss des Homopolymers befreit werden. In Analogie zu natürlichem Kollagen und dem nicht funktionalisierten kollagen-ähnlichen Peptid bilden die PDEGMEMA-basierten, entschützten Hybridcopolymere Trimere mit kollagen-ähnlichen Triple-Helices in kalter wässriger Lösung, was mittels Zirkular-Dichroismus-Spektroskopie (CD) nachgewiesen werden konnte. Temperaturabhängige CD-Spektroskopie, Trübungsmessungen und dynamische Lichtstreuung deuteten darauf hin, dass sie bei höheren Temperaturen doppelt stimuli-responsive Überstrukturen bilden, die mindestens zwei konformative Übergänge beim Aufheizen durchlaufen. Einer dieser Übergänge wird durch den hydrophoben Kollaps des Polymerblocks induziert, der andere durch Entfalten der kollagen-ähnlichen Triple-Helices.rnAls Ausweitung dieser synthetischen Strategie wurde homotelecheles PDEGMEMA mit zwei PFP-Esterendgruppen dargestellt, wozu der PFP-CTA für die Funktionalisierung der -Endgruppe und die radikalische Substitution des Dithioesters durch Behandlung mit einem Überschuss eines funktionellen AIBN-Derivates für die Funktionalisierung der -Endgruppe ausgenutzt wurde. Die Umsetzung der beiden reaktiven Kettenenden mit dem N-Terminus eines Peptidblocks ergab ein Peptid-Polymer-Peptid Triblockcopolymer.rnSchließlich konnten die anorganisch-organischen Hybridmaterialien PMSSQ-Poly(2,2-diethoxyethylacrylat) (PMSSQ-PDEEA) und PMSSQ-Poly(1,3-dioxolan-2-ylmethylacrylat) (PMSSQ-PDMA) für die Herstellung robuster, peptid-reaktiver Oberflächen durch Spin Coaten und thermisch induziertes Vernetzen angewendet werden. Nach saurem Entschützen der Acetalgruppen in diesen Filmen konnten die resultierenden Aldehydgruppen durch einfaches Eintauchen in eine Lösung mit einer Auswahl von Aminen und Hydroxylaminen umgesetzt werden, wodurch die Oberflächenhydrophilie modifiziert werden konnte. Darüber hinaus konnten auf Basis der unterschiedlichen Stabilität der zwei hier verglichenen Acetalgruppen Entschützungsprotokolle für die exklusive Entschützung der Diethylacetale in PMSSQ-PDEEA und deren Umsetzung ohne Entschützung der zyklischen Ethylenacetale in PMSSQ-PDMA entwickelt werden, die die Herstellung multifunktioneller Oberflächenbeschichtungen z.B. für die Proteinimmobilisierung ermöglichen.

'Alternate-goal bias' in antisaccades and the influence of expectation

Saccadic performance depends on the requirements of the current trial, but also may be influenced by other trials in the same experiment. This effect of trial context has been investigated most for saccadic error rate and reaction time but seldom for the positional accuracy of saccadic landing points. We investigated whether the direction of saccades towards one goal is affected by the location of a second goal used in other trials in the same experimental block. In our first experiment, landing points ('endpoints') of antisaccades but not prosaccades were shifted towards the location of the alternate goal. This spatial bias decreased with increasing angular separation between the current and alternative goals. In a second experiment, we explored whether expectancy about the goal location was responsible for the biasing of the saccadic endpoint. For this, we used a condition where the saccadic goal randomly changed from one trial to the next between locations on, above or below the horizontal meridian. We modulated the prior probability of the alternate-goal location by showing cues prior to stimulus onset. The results showed that expectation about the possible positions of the saccadic goal is sufficient to bias saccadic endpoints and can account for at least part of this phenomenon of 'alternate-goal bias'.

Clinical outcome and predictors for adverse events after transcatheter aortic valve implantation with the use of different devices and access routes

Background Transcatheter aortic valve implantation (TAVI) is a treatment option for high-risk patients with severe aortic stenosis. Previous reports focused on a single device or access site, whereas little is known of the combined use of different devices and access sites as selected by the heart team. The purpose of this study is to investigate clinical outcomes of TAVI using different devices and access sites. Methods A consecutive cohort of 200 patients underwent TAVI with the Medtronic CoreValve Revalving system (Medtronic Core Valve LLC, Irvine, CA; n = 130) or the Edwards SAPIEN valve (Edwards Lifesciences LLC, Irvine, CA; n = 70) implanted by either the transfemoral or transapical access route. Results Device success and procedure success were 99% and 95%, respectively, without differences between devices and access site. All-cause mortality was 7.5% at 30 days, with no differences between valve types or access sites. Using multivariable analysis, low body mass index (<20 kg/m2) (odds ratio [OR] 6.6, 95% CI 1.5-29.5) and previous stroke (OR 4.4, 95% CI 1.2-16.8) were independent risk factors for short-term mortality. The VARC-defined combined safety end point occurred in 18% of patients and was driven by major access site complications (8.0%), life-threatening bleeding (8.5%) or severe renal failure (4.5%). Transapical access emerged as independent predictor of adverse outcome for the Valve Academic Research Consortium–combined safety end point (OR 3.3, 95% CI 1.5-7.1). Conclusion A heart team–based selection of devices and access site among patients undergoing TAVI resulted in high device and procedural success. Low body mass index and history of previous stroke were independent predictors of mortality. Transapical access emerged as a risk factor for the Valve Academic Research Consortium–combined safety end point.