Chemical and physical strategies promoting nanoparticle permeation through intestinal mucus barrier

Orally administered therapeutic agents need to cross the mucosal epithelial membrane in the intestine to reach the systemic circulation. This intestinal epithelial membrane is covered by a biopolymer barrier, namely, mucus which protects the underlying layer through trapping or degrading of foreign particles and macromolecules. Thus, mucus can restrict the systemic absorption of some therapeutic agents such as peptides by enzymatic degradation. Nanoparticles (NPs) could serve as a carrier for these peptides to protect them from environmental conditions in the mucus and to increase their bioavailability. However, these NPs can be trapped themselves by the mucus, hence, a proper nano-strategy should be selected to deliver these peptides orally. NPs delivery through intestinal mucus barrier has been studied extensively, where various in vitro tests and mucus models were investigated to mimic the in vivo test. In this thesis, two mucus models were assessed for their suitability as intestinal mucus barrier through which NPs diffusion can be studied. Also, multiple particle tracking (MPT) technique was exploited to study the diffusion and interaction of nanoparticles through pig intestinal mucus barrier. This technique (MPT) was used to understand the factors affecting the diffusion through mucus of NPs representing various nano-strategies such as PEGylated NPs and mucolytic NPs. Based on data obtained for the diffusion of NPs, we adopted a nano-strategy mimicking the capsid shell virus in which the NPs surfaces are densely covered with oppositely charged groups but with overall neutral charge. To do so, polyelectrolyte (PEC) NPs based on the self-assembly of (+) chitosan and (-) polyacrylic acid (PAA) were synthesized and the diffusion of these densely charged NPs was studied. After proving the concept, RAFT technique was used to synthesize zwitterionic densely charged NPs in which butyl methcrylate (BMA) was used as the lipophilic core and sulfobetaine as the shell of NPs. Native mucus prepared by our group was found to be a proper model to study NPs diffusion through it by the MPT technique. Study of diffusion of NPs representing various nano-strategies through mucus revealed the impact of various properties of these NPs on their diffusion. For example, particle size, zeta potential, type and molecular weight of the polymer, type and concentration of the diffusion enhancer and method of synthesis of NPs were detected to affect the diffusion of these NPs. For PEC NPs, the data obtained showed a relation between the zeta potential of NPs and their diffusivities through the mucus, where the highest diffusivity was obtained for the neutrally charged PEC NPs. Accordingly, sulfobetaine NPs were highly efficient NPs in term of their stability, charge density, particle size and importantly their diffusivities through the mucus barrier which was significantly higher as compared with all other tested NPs and related to the ratio of the sulfobetaine polymer in the NPs. This indicates that densely charged viral like NPs can be promising carriers to improve the mucus permeation of some therapeutic agents

Chemical and physical strategies promoting nanoparticle permeation through intestinal mucus barrier

Orally administered therapeutic agents need to cross the mucosal epithelial membrane in the intestine to reach the systemic circulation. This intestinal epithelial membrane is covered by a biopolymer barrier, namely, mucus which protects the underlying layer through trapping or degrading of foreign particles and macromolecules. Thus, mucus can restrict the systemic absorption of some therapeutic agents such as peptides by enzymatic degradation. Nanoparticles (NPs) could serve as a carrier for these peptides to protect them from environmental conditions in the mucus and to increase their bioavailability. However, these NPs can be trapped themselves by the mucus, hence, a proper nano-strategy should be selected to deliver these peptides orally. NPs delivery through intestinal mucus barrier has been studied extensively, where various in vitro tests and mucus models were investigated to mimic the in vivo test. In this thesis, two mucus models were assessed for their suitability as intestinal mucus barrier through which NPs diffusion can be studied. Also, multiple particle tracking (MPT) technique was exploited to study the diffusion and interaction of nanoparticles through pig intestinal mucus barrier. This technique (MPT) was used to understand the factors affecting the diffusion through mucus of NPs representing various nano-strategies such as PEGylated NPs and mucolytic NPs. Based on data obtained for the diffusion of NPs, we adopted a nano-strategy mimicking the capsid shell virus in which the NPs surfaces are densely covered with oppositely charged groups but with overall neutral charge. To do so, polyelectrolyte (PEC) NPs based on the self-assembly of (+) chitosan and (-) polyacrylic acid (PAA) were synthesized and the diffusion of these densely charged NPs was studied. After proving the concept, RAFT technique was used to synthesize zwitterionic densely charged NPs in which butyl methcrylate (BMA) was used as the lipophilic core and sulfobetaine as the shell of NPs. Native mucus prepared by our group was found to be a proper model to study NPs diffusion through it by the MPT technique. Study of diffusion of NPs representing various nano-strategies through mucus revealed the impact of various properties of these NPs on their diffusion. For example, particle size, zeta potential, type and molecular weight of the polymer, type and concentration of the diffusion enhancer and method of synthesis of NPs were detected to affect the diffusion of these NPs. For PEC NPs, the data obtained showed a relation between the zeta potential of NPs and their diffusivities through the mucus, where the highest diffusivity was obtained for the neutrally charged PEC NPs. Accordingly, sulfobetaine NPs were highly efficient NPs in term of their stability, charge density, particle size and importantly their diffusivities through the mucus barrier which was significantly higher as compared with all other tested NPs and related to the ratio of the sulfobetaine polymer in the NPs. This indicates that densely charged viral like NPs can be promising carriers to improve the mucus permeation of some therapeutic agents

Bone mineral density in patients with lithium-associated hyperparathyroidism

Background: Lithium is the most effective long-term treatment for bipolar disease. It has, however,been associated with hypercalcemia and hyperparathyroidism. The aim of the study is to research howlithium associated hyperparathyroidism(LHPT)affects bone mineral density. Method: A sub-analysis was performed on an ongoing randomized prospective study evaluating the operation results from parathyroidectomy versus watchful waiting in 22patients with LHPT. The patients were followed-up for 2 years and their blood samples, bone mineral density (BMD) and FRAX assessment were analysed. The data from LHPT patients was also compared to a separate group of patients with primary hyperparathyroidism (PHPT) corresponding in age.Results: In comparing LHPT patients with PHPT apparent differences in the biochemical profile were detected, including elevated values of ionized Ca in PHPT (p=0.001), lower excretion of 24h urinary calcium in LHPT (p=0.003) and significantly higher values of PTH excretion in PHPT. LHPT showed tendencies to having better BMD (p=0.176). At 2-year follow-up of 8 LHPT patients, biochemicalvalues improved, suggesting cure, including lower risks of skeletal fractures. Discussion: The biochemical features in LHPT are distinctive from PHPT. However, each case is unique, and thebiochemicalvariety issimilar to PHPT. Confounding factors include age, sex, renal function and stability of the bipolar condition. Conclusions:The present study illustratesthat LHPT differs biochemically from PHPT. In comparison to PHPT, LHPT patients tend to have reduced BMD and the present study could not confirm the previous postulation that lithium could be protective of the skeleton. In conclusion, casesof LHPT should be assessed individually, since the clinical course is diverse. In patients risking fracture, parathyroidectomy should be considered

Design of Overhead Crane Runway

Kranlaster som verkar på kranbanor varierar med tiden och kan inte behandlas som statiska laster, detta gör att en statisk beräkning inte är tillräckligt säker, därför bör kranbalkar utformas på så sett att den klarar av statiska såväl som dynamiska kranlaster. Arbetet valdes efter förstudier som gjordes på internet för att få grundläggande kunskap om ämnet. Informationen söktes på svenska, engelska och tyska för att kunna hitta relevanta och pålitliga källor som behandlar traverskranbanor enligt eurokod. Tack vare råd från Björn Åsted från Stålbyggnadsinstitutet (SBI), kunde en bok på tyska hittas. För att kunna jämföra resultaten används ett svenskt program CraneGirder EC3 under arbetet. Rapporten innehåller en beräkningsmodell för en valsad profil balk, beräkningar baserades på eurokod ekvationer och föreskrifter vilket var som dimensionerings underlag för arbetet. I denna rapport hänvisas hur en kranbana skall dimensioneras med hög utnyttjandegrad, ett antal kontroller gjordes för att säkerställa att balken och dess detaljer, såsom räl och svets är säkert utformade mot utmattning och deformation. Dimensioneringen utgick ifrån lastberäkningar för traverskranen. Handberäkningar visade hur olika kranlaster kan kombineras i lastgrupper för att åstadkomma högsta inverkan på balken, handberäknings resultat visade att HEB 280 och dimensioneringen dominerades enbart av lastgrupp 1 och 5. Med hjälp av beräkningsprogram stämde resultaten i hög grad överens med programmet men med några avvikelser. För den avgränsningen som antogs i arbetet verkade utmattningen inte ha en dominerande inverkan.Crane Loads acts on runways which varies with time and cannot be treated as static loads, this allows that the static estimation is not secure enough, therefore the crane runways should be designed in such terms that it can handle static as well as dynamic crane loads. The work was chosen after feasibility studies which were made on the internet to get basic knowledge on the subject. The information was sought in Swedish, English and German in order to find relevant and reliable sources which deal with overhead crane runway according to Eurocode. Thanks to advice from Björn Åsted from the Steel Construction Institute (SBI), a book in German was found. In order to compare the results, a Swedish software CraneGirder EC3 was used during the project. The report contains a calculation method for a rolled section girder, calculations were based on Eurocode equations and regulations which were the design basis for the project. The report refer to how a crane runway must be designed with a high utilization level, a number of controls were made to ensure that the beam and its details, such as rail and welding are surely designed to fatigue and deformation. The design was based on load calculations for the overhead crane. Traditional calculations showed how different crane loads can be combined in load groups to achieve the highest impact on the beam, calculations showed that HEB 280 and dimensioning dominated only by load group 1 and 5. With the help of calculation software the results were largely consistent with the program but with some differences. For the delimitation that was assumed in the project the fatigue seemed to have an effect especially on some small details like weld

Apology as a Performative Speech Act: A Pragmatic Study of Implicit Apology Strategies in the Quranic Discourse

     لمّا لم نجد من اعتنى بدراسة موضوعية تداولية تطبيقية للاعتذار فعلًا انجازيًا بحسب أوستن في الخطاب القرآني ولاسيما الضمني منه عمدنا إلى عقد هذه الدراسة؛ للكشف عن فلسفة لغة الخطاب الاعتذاري الضمني في هذا الكتاب المقدس، وتوصل البحث إلى أنّ الاعتذار الضمني يتحقق بتراكيب ثلاثة؛ استفهامية، وأمريّة، وخبريّة، ويدخل في هذه التراكيب استراتيجيات عدة، منها استراتيجية التبرير، واستراتيجية تقديم الحجة، واستراتيجية طلب التسامح عن الخطأ، واستراتيجية تحمل المسؤولية... وتوصل البحث أيضًا إلى أنّنا إذا أردنا إدراج الاعتذار أسلوبًا من الأساليب الإنشائية عند العرب، يمكننا اختيار (أعتذر) وما ماثلها كـ(أنا آسف) هيئة للاعتذار الصريح، كما اختاروا للنداء هيئات مخصوصة، ويمكن عدّ (سامحني) اعتذارًا ضمنيًا لخروجه عن صيغة الاعتذار الصريح وعدم احتماله الصدق والكذب.    Since we did not find anyone who took care of an objective, pragmatic and applied study of the apology, according to Austin, in the Qur’anic discourse, and we did not forget about it, we decided to conduct this study; In order to reveal the  philosophy of the language of the implicit apologetic discourse in this Bible, the research concluded that the implicit apology is achieved by three combinations; Interrogative, imperative, and declarative, and several strategies are included in these structures, including the strategy of justification, the strategy of presenting the argument, the strategy of asking for forgiveness for error, and the strategy of taking responsibility... The research also concluded that if we wanted to include apology as one of the structural methods among Arabs, we could Choosing (I apologize) and the like as (I am sorry) a body for express apology, as they chose specific bodies for the appeal, and (Forgive me) can be considered an implicit apology for deviating from the formula of explicit apology and intolerance of truth and lies

Effectiveness of antioxidants in preventing oxidation of palm oil enriched with heme iron: A model for iron fortification in baked products

Bakery products such as biscuits, cookies, and pastries represent a good medium for iron fortification in food products, since they are consumed by a large proportion of the population at risk of developing iron deficiency anemia, mainly children. The drawback, however, is that iron fortification can promote oxidation. To assess the extent of this, palm oil added with heme iron and different antioxidants was used as a model for evaluating the oxidative stability of some bakery products, such as baked goods containing chocolate. The palm oil samples were heated at 220°C for 10 min to mimic the conditions found during a typical baking processing. The selected antioxidants were a free radical scavenger (tocopherol extract (TE), 0 and 500 mg/kg), an oxygen scavenger (ascorbyl palmitate (AP), 0 and 500 mg/kg), and a chelating agent (citric acid (CA), 0 and 300 mg/kg). These antioxidants were combined using a factorial design and were compared to a control sample, which was not supplemented with antioxidants. Primary (peroxide value and lipid hydroperoxide content) and secondary oxidation parameters (p-anisidine value, p-AnV) were monitored over a period of 200 days in storage at room temperature. The combination of AP and CA was the most effective treatment in delaying the onset of oxidation. TE was not effective in preventing oxidation. The p-AnV did not increase during the storage period, indicating that this oxidation marker was not suitable for monitoring oxidation in this model