O objetivo desta dissertação é propor um modelo estendido para operacionalização do Business Process Management (BPM), observando fatores culturais e interpessoais. Para atingir o objetivo, foram desenvolvidos três artigos. No primeiro artigo, foi realizada uma revisão da literatura explorando a relação entre os pressupostos culturais básicos das organizações e as novas tecnologias de gestão. Como resultado, a pesquisa apresenta um quadro que relaciona as novas tecnologias de gestão em função dos pressupostos culturais básicos, identificando as tecnologias de gestão que mais afetam ou são afetadas pela cultura organizacional, dando um novo panorama aos conceitos subjacentes às tecnologias de gestão, no qual BPM se enquadra. No segundo artigo, buscou-se identificar os Fatores Críticos de Sucesso (FCS) em uma iniciativa BPM através da revisão da literatura e observação participante em um estudo de caso. Entre os principais resultados deste artigo destaca-se: a identificação de novos FCS, antes não mencionados na literatura. No terceiro artigo, foi proposto um modelo estendido para operacionalização do BPM baseado nos novos FCS apresentados no artigo anterior, dentre eles está: a falta de uma estrutura de trabalho entre a área de TI e Equipe de Processos; através do estudo de diversas metodologias de implantação e as relações entre as áreas foi proposto um modelo estendido para solucionar o problema em questão. Além disso, verificou-se que as poucas soluções propostas pela literatura raramente são relacionadas à operacionalização e às adversidades na inter-relação entre as áreas em uma organização. Por fim, os resultados encontrados devem possibilitar pesquisas futuras na área de BPM. / The aim of this work is to propose an extended model for operating Business Process Management (BPM), observing cultural and interpersonal factors. To achieve the goal, it was developed three articles. In the first article, a literature review exploring the relationship between the basic cultural assumptions of organizations and new management technologies was held. As a result, the research presents a framework that relates the new management according to the basic cultural assumptions, identifying the management technologies that most affect or are affected by organizational culture, giving a new perspective to the concepts underlying management technologies, in which BPM fits. In the second article, we sought to identify the Critical Success Factors (CSF) in a BPM initiative through literature review and participant observation in a case study. The main results of this article stands out: the identification of new CSF, not previously mentioned in the literature. In the third article, we propose an extended model for implementation of BPM based on the new CSF presented in the previous article, among them are: the lack of a framework between the area of IT and Process Team; through the study of various implementation methodologies and the relationship between areas was proposed an extended model to solve the problem at hand. In addition, it was found that the few solutions proposed in the literature are rarely related to the implementation and the adversities in the interrelationship between the areas in an organization. Finally, the results should enable future research in the BPM area.

Cancer är idag en vanlig sjukdom som uppstår på grund av okontrollerad celltillväxt och kan visa sig som cirka 200 olika sjukdomar beroende på vilken celltyp som drabbas. Trots dagens standardterapier med kirurgi, strålning och kemoterapi så dör årligen runt 23 000 människor av cancer i Sverige. Dödsfallen beror ofta på svåråtkomliga metastaser som bildats från ursprungstumören och sedan spridits med blod och lymfa ut i kroppen. En långt gången cancer kan även visa upp resistens mot vissa terapier, vilket försvårar behandling ytterligare.  Det är därför viktigt att nya effektiva läkemedel och behandlingsmetoder utvecklas. Ett alternativ är onkolytisk virusterapi. Onkolytiska adenovirus är modifierade till att selektivt replikera i och lysera tumörceller, samtidigt som friska celler lämnas opåverkade. Genom att armera det onkolytiska adenoviruset med cytokinet granulocyt makrofag-kolonistimulerande faktor (GM-CSF) kan den terapeutiska effektiviteten ökas ytterligare. GM-CSF kommer då uttryckas i infekterade tumörceller och stimulera kroppens immunförsvar till ökad antitumoral immunrespons. Syftet med detta arbete var att undersöka om behandling med onkolytiskt adenovirus armerat med GM-CSF kan fungera som behandling mot cancer. För att svara på frågeställningen analyserades fem vetenskapliga studier som rörde frågeställningen. Två av dessa var av fas I-typ och hade därför som främsta syfte att undersöka säkerheten hos olika doser. Den antitumorala effekten studerades dock också och därför inkluderades de i arbetet. Antitumorala effekter sågs hos vissa patienter i form av minskning av tumörstorlek, densitet och tumörmarkörer i blodet. I studier där CD8+ T-celler mättes sågs ofta en ökning av nivån vilket kan tyda på ökad immunrespons.  Patientgrupperna var små i samtliga studier vilket gör det svårt att dra några slutsatser om behandlingens effektivitet. I tre av fem studier hade patienterna även olika cancersjukdomar, vilket försvårar analysen ytterligare. Resultaten från behandlingen ser lovande ut med milda biverkningar, men för att med säkerhet kunna säga att det finns en antitumoral effektivitet hos onkolytiskt adenovirus armerat med GM-CSF krävs större studier på mer specifika patientgrupper.

Stěžejní částí práce je specifikace zavedení a nadefinování hlavních CSF zavedení e-learningového systému. Práce reaguje na chybný trend chápat úspěšné zavedení e-learningového systému jako úspěšnou instalaci systému LMS. Teoretická část práce definuje termíny a souvislosti důležité pro pochopení principu elektronické formy vzdělávání, aktuální e-learningové trendy a standardy IMS a SCORM. V praktické části jsou diskutovány požadavky na e-learningové systémy, role rozhodující o zavedení, analýza vzdělávacích potřeb, umístění systému, integrace s ostatními systémy a pilotní nasazení. Hlavním přínosem práce je definice CSF zavedení systému, konkrétně definice cílů, motivace uživatelů, funkčnost a dostupnost, komunikace, kontrola výuky a zpětná vazba během vzdělávacího procesu.

Encephalitis is a matter for serious public health concern because of the high morbidity and mortality associated with many cases. Epidemiological studies have shown that viral encephalitis (VE) is more common than the sum of encephalitis caused by all other pathogens. However, more than 95% of cases have no known cause. Thus, there is a significant need to develop a sensitive method for the diagnosis of these unknown cases. Previous sequence independent amplification (SIA) assays have proved successful in detecting new viruses in many biological samples but not in CSF samples. This may be due to the relatively low sensitivity of most available methods as CSF usually contains lower concentrations of pathogen than most other samples. A known problem with these types of assays is the annealing of the random primers to human DNA which facilitates preferential amplification of background human DNA. Thus, large scale sequencing is usually required to detect a virus, which in turn reduces the detection sensitivity to more than 1000 viral copies/µl, a CSF concentration that is rarely seen in cases of VE.This project was designed to develop a highly sensitive SIA assay for novel nucleic acid identification that could be used in testing CSF samples obtained from patients with neurological diseases of unknown cause. The study started with evaluation of two existing SIA assays commonly used for virus discovery; whole genome amplification (WGA) and random PCR (r-PCR). Sequential modification and adaptation of these methods was carried out to increase their sensitivity. Ultimately, a novel primer (Sa primer) that showed no binding to most human DNA sequences in GenBank was designed and synthesised. Its 3' end was tagged with 6 and 7 random nucleotides generating 2 r-primers; Sa-6 and Sa-7. The sensitivity of the r-primers was checked in a novel assay developed during this project and named Sa-SIA using known concentrations of HCMV and HSV-1. CSF samples from Malawian children were then tested using the developed assay. Results showed that adaptation of the existing WGA and r-PCR assays allowed detection of up to 1300 viral copies/µl. When the novel primers developed in this project were used in a random PCR assay (Sa-r-PCR), it was found that using Sa-6 primer 130, 13, and 1.3 HCMV copies/µl could be detected with 100, 60, and 50% efficiency respectively. When using Sa-7 primer, the same concentrations of virus were detected with 100, 42, and 28.6% efficiency. DNase-1 treatment of the samples pre-extraction resulted in an improvement in viral detection sensitivity in samples with a high background of host DNA. Starting with template concentrations of 11000, 110, 11, and 1.1 HSV-1 copies/µl, viral detection efficiency was increased from 33.3, 10, 0, and 0% to 92, 55.6, 16.7, and 0% respectively when pre-extraction DNase-1 treatment preceded Sa-r-PCR using Sa-6 primer. The final developed assay (Sa-SIA) consisted of centrifugation, DNase-1 treatment, DNA extraction, Sa-r-PCR using Sa-6 and Sa primers, gel electrophoresis, band excision, cloning, small scale sequencing (sequencing of ≤ 20 positive clones from one constructed DNA library), and bioinformatics. It had a detection sensitivity of 1.3-11 viral copies/µl. When this assay was applied to stored CSF samples, one 448bp sequence was identified which gave 96% coverage with 81% identity to Torque teno midi virus-1 and 93% coverage with 81% identity to small anellovirus-2. A 236bp sequence from another CSF sample showed 66% coverage with 97% homology to an unclassified sequence previously identified in a viral genomic survey of stool sample in an earlier published study. In conclusion, the standardised method had been shown to detect 1.3 to 11 viral copies/µl of two viruses; HCMV and HSV-1. The detection of these viruses was achieved with only small scale sequencing. Application of this method to CSF samples has shown promising results. However, this method could be followed by more advanced post amplification analyses such as next generation sequencing.

Indiana University-Purdue University Indianapolis (IUPUI) / Hydrocephalus is a medical condition characterized by a buildup of cerebrospinal fluid which causes hydrostatic pressure to increase resulting neuronal destruction and can ultimately cause death. Hydrocephalus is seen in both the pediatric population and adults. Treatment of hydrocephalus usually involves surgical placement of a relocation system to drain the fluid into the abdominal cavity. Hydrocephalus may be caused by mechanical obstruction of the outflow of CSF from the ventricles or by faulty reabsorption. It can be also caused by CSF overproduction by the choroid plexus found in the lateral, third, and fourth ventricles of the brain. The choroid plexus is composed of a high resistance monolayer epithelium which surrounds a network of capillaries. Its primary function is to regulate transport of ions and water that control the production and movement of CSF. Therefore it is important to understand the mechanism of CSF production by the choroid plexus. Recently, a stable porcine choroid plexus (PCP-R) epithelial cell line with a high transepithelial resistance (TER) was developed that provides an important model to study regulation of CSF production. Ussing style electrophysiology was used to measure short circuit current (SCC) to characterize stimulated transepithelial ion transport in confluent PCP-R cells. GSK1016790, a TRPV4 agonist, was used to understand the role of TRPV4 in CSF production by the choroid plexus using PCP-R cell model. TRPV4 activation produces a sustained ion transport response that is consistent with an increase in cation secretion and/or anion absorption which is accompanied by a reversible decrease in TER. The effect of the agonist on both SCC and TER was blocked by HC067047, a TRPV4 antagonist, showing that the sustained ion transport and TER change is TRPV4 specific. TRPV4 mediated ion flux was inhibited by CFTR inhibitor II GlyH-101, a cell permeable inhibitor of the cAMP activated chloride channel CFTR, when added on either side of the membrane and was not accompanied by a TER reversal which showed that CFTR is activated by TRPV4 mediated ion flux. TMEM16A, a calcium activated chloride channel, was speculated to be located in that basal membrane as T16Ainh-AO1, a membrane permeable TMEM16A inhibitor, reversed the TRPV4 mediated ion flux when added on either side of the membrane. Slight reversal in TER was observed when T16Ainh-AO1 was added on the apical side. Apamin, a differential inhibitor of calcium activated small conductance potassium channel 1, 2 and 3 (SK1, SK2 and SK3) had no effect on the TRPV4 mediated ion flux. Whereas, fluoxetine, a membrane permeable inhibitor of SK1, SK2 and SK3 channel, inhibited the TRPV4 mediated ion flux and TER change. Bumetanide, an inhibitor of the sodium-potassium-chloride cotransporter reversed TRPV4 mediated ion flux when added on the apical membrane but not on the basal membrane indicating a possible K+ secretion via SK1 and/or SK4/IK channels and Cl- absorption through CFTR and TMEM16A channels. Acetazolamide, a carbonic anhydrase inhibitor and a compound used to treat hydrocephalus had no effect on the TRPV4 mediated ion flux. cAMP is an intracellular mediator involved in neuromodulator effects, inflammatory responses and other regulatory mechanisms and is constitutively activated by forskolin. In PCP-R cells, forskolin stimulated an increase in transepithelial ion flux that is consistent with an increase in cation absorption and/or anion secretion. Forskolin mediated ion transport was inhibited by CFTR inhibitor II GlyH-101 when added on either side of the membrane. No change in TER was observed. No effect on forskolin mediated ion flux was observed when T16Ainh-A01, apamin or fluoxetine were added. Forskolin stimulated transport is partially inhibited by 1 mM BaCl2. Barium chloride is a general inhibitor of K+ channels. No change in TER was observed.

<p>  </p> <p>The choroid plexus (CP) in brain ventricles secrete cerebrospinal fluid (CSF) that bathes the adjacent subventricular zone (SVZ); the latter is the largest neurogenic region in adult brain harboring neural stem/progenitor cells (NSPCs) and supplies newborn neurons to the olfactory bulb (OB) for normal olfaction. We discovered the presence of a CP-SVZ regulatory (CSR) axis in which the CP, by secreting small extracellular vesicles (sEVs), regulated adult neurogenesis in the SVZ and maintained olfaction. The proposed CSR axis was supported by 1) differential neurogenesis outcomes in the OB when animals treated with intracerebroventricular (ICV) infusion of sEVs collected from the CP of normal or manganese (Mn)-poisoned mice, 2) progressively diminished SVZ adult neurogenesis in mice following CP-targeted knockdown of SMPD3 to suppress CP sEV secretion, and 3) compromised olfactory performance in these CP-SMPD3-knockdown mice. Collectively, our findings demonstrate the biological and physiological presence of this sEV-dependent CSR axis in adult brains.</p>

Preeclampsia is an important disease during pregnancy and causes significant maternal and fetal mortality and morbidity. Despite intense research efforts, the etiology and pathogenesis of the disease remain largely unknown. Since placentas from preeclamptic patients are smaller than normal, and cytokine growth factors are suggested to be important in placental growth, the effects of macrophage-colony stimulating factor (M-CSF) on human trophoblast cells were examined. While term trophoblast cells did not respond to M-CSF, those from early trimester and choriocarcinoma cells showed enhanced growth after treatment. In addition, the serum level of M-CSF in hypertensive pregnant women at the second trimester were significantly lower than those of normal pregnant women. These data suggest possible roles of M-CSF in preeclampsia. When M-CSF was administered to pregnant rats on days 8-11, rats had smaller placentas at day 12 and increased fetal resorption rate at day 20. The effects of interleukin-12 (IL-12) was also examined on days 8-11. While placental development was normal at both days 12 and 20, fetuses were significantly smaller at day 20. To remedy the difficulties and dangers associated with obtaining human placentas, I characterized endovascular trophoblast cell behavior in pregnant rats. In normal pregnancy, rat trophoblast cells simulated all features of human endovascular trophoblast behavior including selective invasion into the spiral arteries, retrograde migration, embedding, and secretion of PAS-positive materials as well as IIphysiological changes," In pregnancy terminated with a certain type of spontaneous fetal resorption, defective endovascular trophoblast cell behavior was observed, which was similar to that reported in preeclamptic pregnancy. Finally, the roles of cytoskeleton on trophoblast cell locomotion were investigated in vivo with a cytoskeleton-disrupting agent, cytochalasin B. This treatment impaired trophoblast cell invasion at day 12 and induced smaller fetuses at day 20, suggesting the importance of cytoskeleton in trophoblast movement. In conclusion, the results suggest the importance of the use of appropriate specimens and endpoints in the study of pregnancy, and rats may serve as a suitable animal model for the study of endovascular trophoblast cell behavior with clinical relevance to preeclampsia. / Ph. D.

Alzheimer's Disease (AD) is a neurodegenerative disorder affecting over 35 million people. Early diagnosis and intervention are crucial for improving outcomes. Digital Cognitive Biomarkers (DCBs) offer a promising approach for early detection and disease management, quantifying cognitive processes of encoding and retrieval through a hierarchical Bayesian cognitive processing model using wordlist memory tests. We hypothesize that DCBs will correlate with classic AD cerebrospinal fluid (CSF) biomarkers (Aβ42, T-tau, p-tau) in patients with varying cognitive decline levels compared to healthy elderly controls. Using Alzheimer's Disease Neuroimaging Initiative (ADNI) data and paired Pearson correlation coefficient analysis, our results support the hypothesis, indicating that DCBs correlate with CSF biomarkers and demonstrating their potential as a noninvasive diagnostic tool for AD. Furthermore, DCBs exhibited improved diagnostic accuracy compared to classic AD CSF biomarkers, as indicated by the area under the Receiver Operating Characteristic curve analysis. DCBs hold promise for monitoring disease progression, response to therapeutics, and identifying patients at earlier disease stages. Future research should validate these findings in diverse populations and conduct longitudinal studies to assess DCBs' potential in tracking disease progression and treatment response. Integrating DCBs with other diagnostic approaches, such as neuroimaging, could enhance overall AD diagnosis accuracy and provide a comprehensive understanding of an individual's cognitive health. In conclusion, DCBs may offer a valuable, noninvasive tool for early diagnosis and management of Alzheimer's Disease, supporting the initial hypothesis.

The purpose of these studies was to determine if an immunomodulator was present in caprine serum. Controlled studies demonstrated that CSF-I, material fractionated from caprine serum possessed an immunomodulatory compound. Caprine serum was further fractionated into it?s peptidic components and a small contaminant of immunoglobulin G and albumin (Caprine serum fraction - immunomodulator 2, or CSF-I2). This was refined to a three peptidic isolate collectively identified as tri-peptidic immunostimulant or TPI. CSF-I2 does not possess antibacterial capabilities (as typically characteristic of a cationic peptide or defensin), does not contain a level of endotoxin sufficient to promote a pyrogenic response, and its functional ability to improve animal survival after an infectious challenge does not reside with molecular weight components greater than 10 kilodaltons, effectively excluding the immunoglobins, albumin, cytokines, and collectins. CSF-I2 was able to significantly reduce the mortality observed in chickens (from 80% to 13%) infected with Pasteurella multocida (Willeford et al., 2000), in mice (from 83% to 13.3%) infected with Salmonella typhimurium, and in canines (from 50% to 9.8%) diagnosed with parvovirus. CSF-I2 may well prove to provide prophylactic and therapeutic health benefits to humans. CSF-I2 may effectively combat pathogenesis when used as either an adjunct with conventional therapy (e.g., antibiotics) or when provided as the primary medicant.

No description available.