A study of prospective surveillance for inhibitors among persons with haemophilia in the United States

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106128/1/hae12302.pd

Osmoregulation in zebrafish: ion transport mechanisms and functional regulation

Fish, like mammals, have to maintain their body fluid ionic and osmotic homeostasis through sophisticated iono-/osmoregulation mechanisms, which are conducted mainly by ionocytes of the gill (the skin in embryonic stages), instead of the renal tubular cells in mammals. Given the advantages in terms of genetic database availability and manipulation, zebrafish is an emerging model for research into regulatory and integrative physiology. At least five types of ionocytes, HR, NaR, NCC, SLC26, and KS cells, have been identified to carry out Na+ uptake/H+ secretion/NH4+ excretion, Ca2+ uptake, Na+/Cl- uptake, K+ secretion, and Cl- uptake/HCO3- secretion, respectively, through distinct sets of transporters. Several hormones, namely isotocin, prolactin, cortisol, stanniocalcin-1, calcitonin, endothelin-1, vitamin D, parathyorid hormone 1, catecholamines, and the renin-angiotensin-system, have been demonstrated to positively or negatively regulate ion transport through specific receptors at different ionocytes stages, at either the transcriptional/translational or posttranslational level. The knowledge obtained using zebrafish answered many long-term contentious or unknown issues in the field of fish iono-/osmoregulation. The homology of ion transport pathways and hormone systems also means that the zebrafish model informs studies on mammals or other animal species, thereby providing insights into related fields

Three essays on intra-household resource allocation, the cost of illness measure, and immunization policy

The dissertation comprises three chapters, ranging from health economics to immunization policy analysis. In the first and second chapters I focus mainly on establishing theoretically correct measures of welfare benefit, while in the third chapter I aim to determine which kind of immunization program is best by using better measures of both benefits and costs associated with one episode of typhoid fever. The objective of the first chapter is to separately derive a mother's versus a father's willingness to spend money and time to save her child from one day of sickness. In order to accomplish this goal, I extend the existing theories of household decision-making by integrating Chiappori (1988)'s household decision-making model and Grossman (1972)'s health production model. All illnesses have financial and time consequences. When a child is sick, the mother and the father may respond differently to the health shock. They may have different preferences toward risk and they may not fully pool their income. They may thus want to allocate different amounts of money and time for improving their children's health. I take account of these differences using an interdisciplinary approach. The novelty of my approach, thus, is in its departure from the unitary household framework on which health valuation studies have relied until now. Finally, I find that maternal/paternal willingness to pay for the child's health is determined by six factors: the income share, the non-labor income, the price of medical care, an individual time value (i.e., wage), and the household's and individual technology for producing the child's health. In the second chapter, I compare measures estimating the benefits of reduced morbidity in order to answer several questions: what would be the theoretically correct benefit measure for reduced morbidity? How much would the true measure differ from others? What are the determinants of the differences between the true measure and others? In order to answer these basic questions, I begin with Bockstael and McConnell (2007)'s model, which derives welfare measures for non-marginal changes of morbidity, and then incorporate insurance into it, based on the proposition that insurance may have a significant effect on the magnitude of the discrepancies between the cost-of-illness (COI) and willingness-to-pay measures. Next, I incorporate uncertainty into the model, since an individual does not know what her health will be with certainty (Berger et al., 1987). In doing so, I derive ex ante COI and ex ante compensating variation measures. Theoretically they are unlikely to be the same. Based on the findings of this study, the COI estimates are not reliable and do not give clear guidance as to the lower bound on the theoretically true estimates in measuring the benefits of reduced morbidity. Therefore, the value of COI estimates in decision-making may be limited. The third chapter examines school-based immunization against typhoid fever in North Jakarta in order to assess the merits of such a program. Decisions about optimal vaccination programs involve tensions between efficiency and equity (Levy et al., 2007), especially in the developing world. Most vaccination policy analysis, however, mainly takes efficiency into account in order to find the lowest-cost program or the one providing maximum net benefits. Equality in the distribution of benefits is often overlooked (Yitzhaki, 2003) because of lack of data or interest. The absence of a systematic framework to consider both efficiency and equity results in a one-sided immunization policy that disregards or, at worst, enlarges the gap of inequality in children's immunization rate. In order to address this limitation, I incorporate efficiency measures and equity indicators within one framework. I believe that using quantitative indicators of inequality based on parents' level of education will help avoid immunization options that are dominated by efficiency at the expense of equity. The results of the analysis suggest that to strike a fair balance between efficiency and equity, policy makers would be best advised to adopt a school-based typhoid fever immunization program, partially funded by donors (and with plans for sustaining it in the future), in which the typhoid vaccine was simultaneously delivered with the TT booster vaccines. Even this solution, however, leaves unsolved the equity problem of immunizations for children not in school and the question of how such programs would be sustained after the end of the donor funding period (typically five years)

Retrospective study of necrotizing fasciitis and characterization of its associated Methicillin-resistant Staphylococcus aureus in Taiwan

<p>Abstract</p> <p>Background</p> <p>Methicillin-resistant <it>Staphylococcus aureus </it>(MRSA) has emerged as a prevalent pathogen of necrotizing fasciitis (NF) in Taiwan. A four-year NF cases and clinical and genetic differences between hospital acquired (HA)- and community-acquired (CA)-MRSA infection and isolates were investigated.</p> <p>Methods</p> <p>A retrospective study of 247 NF cases in 2004-2008 and antimicrobial susceptibilities, staphylococcal chromosomal cassette <it>mec </it>(SCC<it>mec</it>) types, pulsed field gel electrophoresis (PFGE) patterns, virulence factors, and multilocus sequence typing (MLST) of 16 NF-associated MRSA in 2008 were also evaluated.</p> <p>Results</p> <p>In 247 cases, 42 microbial species were identified. <it>S. aureus </it>was the major prevalent pathogen and MRSA accounted for 19.8% of NF cases. Most patients had many coexisting medical conditions, including diabetes mellitus, followed by hypertension, chronic azotemia and chronic hepatic disease in order of decreasing prevalence. Patients with MRSA infection tended to have more severe clinical outcomes in terms of amputation rate (p < 0.05) and reconstruction rate (p = 0.001) than those with methicillin-sensitive <it>S. aureus </it>or non-<it>S. aureus </it>infection. NF patients infected by HA-MRSA had a significantly higher amputation rate, comorbidity, C-reactive protein level, and involvement of lower extremity than those infected by CA-MRSA. In addition to over 90% of MRSA resistant to erythromycin and clindamycin, HA-MRSA was more resistant than CA-MRSA to trimethoprim-sulfamethoxazole (45.8% <it>vs</it>. 4%). ST59/pulsotype C/SCC<it>mec </it>IV and ST239/pulsotype A/SCC<it>mec </it>III isolates were the most prevalent CA- and HA-MRSA, respectively in 16 isolates obtained in 2008. In contrast to the gene for γ-hemolysin found in all MRSA, the gene for Panton-Valentine leukocidin was only identified in ST59 MRSA isolates. Other three virulence factors TSST-1, ETA, and ETB were occasionally identified in MRSA isolates tested.</p> <p>Conclusion</p> <p>NF patients with MRSA infection, especially HA-MRSA infection, had more severe clinical outcomes than those infected by other microbial. The prevalent NF-associated MRSA clones in Taiwan differed distinctly from the most predominant NF-associated USA300 CA-MRSA clone in the USA. Initial empiric antimicrobials with a broad coverage for MRSA should be considered in the treatment of NF patients in an endemic area.</p

Perfused Gills Reveal Fundamental Principles of pH Regulation and Ammonia Homeostasis in the Cephalopod Octopus vulgaris

In contrast to terrestrial animals most aquatic species can be characterized by relatively higher blood [Formula: see text] concentrations despite its potential toxicity to the central nervous system. Although many aquatic species excrete [Formula: see text] via specialized epithelia little information is available regarding the mechanistic basis for NH3/[Formula: see text] homeostasis in molluscs. Using perfused gills of Octopus vulgaris we studied acid-base regulation and ammonia excretion pathways in this cephalopod species. The octopus gill is capable of regulating ammonia (NH3/[Formula: see text]) homeostasis by the accumulation of ammonia at low blood levels (<260 μM) and secretion at blood ammonia concentrations exceeding in vivo levels of 300 μM. [Formula: see text] transport is sensitive to the adenylyl cyclase inhibitor KH7 indicating that this process is mediated through cAMP-dependent pathways. The perfused octopus gill has substantial pH regulatory abilities during an acidosis, accompanied by an increased secretion of [Formula: see text]. Immunohistochemical and qPCR analyses revealed tissue specific expression and localization of Na+/K+-ATPase, V-type H+-ATPase, Na+/H+-exchanger 3, and Rhesus protein in the gill. Using the octopus gill as a molluscan model, our results highlight the coupling of acid-base regulation and nitrogen excretion, which may represent a conserved pH regulatory mechanism across many marine taxa

Enhanced light harvesting in bulk heterojunction photovoltaic devices with shape-controlled Ag nanomaterials: Ag nanoparticles versus Ag nanoplates

Enhanced power conversion efficiency (PCE(%)) with improved optical path length from two types of shape controlled silver (Ag) materials (Ag nanoplates versus Ag nanoparticles (NPs)) was studied in poly(3-hexylthiophene) (P3HT)/[6,6]-phenyl C 71 butyric acid methyl-ester (PC 71BM) or poly[N-9′′-hepta-decanyl-2,7-carbazole-alt-5,5-(4′, 7′-di-2-thienyl-2′,1′,3′-benzothiadiazole)] (PCDTBT)/[6,6]-phenyl C 71 butyric acid methyl-ester (PC 71BM) bulk heterojunction (BHJ) devices. The Ag nanoplates and Ag NPs can be synthesized by simple solution polyol chemistry with well defined size and shape. A BHJ with a 0.5 wt% optimized blend ratio of Ag nanoplates shows improved cell performance and photo-current density than a BHJ with Ag NPs owing to the enhanced light absorption with the results of an excitation of localized surface plasmon and efficient light scattering by the Ag nanoplates embedded BHJ film. When the BHJ is combined with the Ag nanoplates at an optimized ratio of 0.5 wt%, the PCE (%) increases from 3.2% to 4.4% in P3HT/PC 71BM, and from 5.9% to 6.6% in PCDTBT/PC 71BM BHJ devices. © 2012 The Royal Society of Chemistry.1

Extract From Plectranthus amboinicus Inhibit Maturation and Release of Interleukin 1β Through Inhibition of NF-κB Nuclear Translocation and NLRP3 Inflammasome Activation

Uncontrolled inflammation may produce massive inflammatory cytokines, in which interleukin 1β (IL-1β) plays a key role, resulting in tissue damage and serious disorders. The activation of NLRP3 inflammasome is one of the major mechanisms in maturation and release of IL-1β. Plectranthus amboinicus is a perennial herb. Several pharmacological activities of natural components and crude extracts from P. amboinicus have been reported including anti-inflammation; however, the underlying mechanism is not clear. Phorbol-12-myristate 13-acetate-differentiated THP-1 monocytic leukemia cells were used as a reliable model in this study to examine the effect on inflammasome signaling pathway by PA-F4, an extract from Plectranthus amboinicus. PA-F4 inhibited ATP-induced release of caspase-1, IL-1β, and IL-18 from lipopolysaccharides (LPS)-primed cells. PA-F4 induced a concentration-dependent inhibition of both ASC dimerization and oligomerization in cells under LPS priming plus ATP stimulation. Co-immunoprecipitation of NLRP3 and ASC demonstrated that PA-F4 significantly blunted the interaction between NLRP3 and ASC. Furthermore, PA-F4 completely abolished ATP-induced K+ efflux reaction in LPS-primed cells. Taken together, PA-F4 displayed an inhibitory activity on NLRP3 inflammasome activation. Moreover, PA-F4 also inhibited LPS-induced p65 NF-κB activation, suggesting an inhibitory activity on LPS priming step. Further identification showed that rosmarinic acid, cirsimaritin, salvigenin, and carvacrol, four constituents in PA-F4, inhibited LPS-induced IL-6 release. In contrast, rosmarinic acid, cirsimaritin and carvacrol but not salvigenin inhibited ATP-induced caspase-1 release from LPS-primed cells. In conclusion, PA-F4 displayed an inhibitory activity on activation of NLRP3 inflammasome. PA-F4 inhibited LPS priming step through block of p65 NF-κB activation. It also inhibited ATP-induced signaling pathways in LPS-primed cells including the inhibition of both ASC dimerization and oligomerization, K+ efflux reaction, and the release reaction of caspase-1, IL-1β, and IL-18. Rosmarinic acid, cirsimaritin, salvigenin, and carvacrol could partly explain PA-F4-mediated inhibitory activity on blocking the activation of NLRP3 inflammasome

Preventing type 2 diabetes mellitus in Qatar by reducing obesity, smoking, and physical inactivity: mathematical modeling analyses.

BACKGROUND: The aim of this study was to estimate the impact of reducing the prevalence of obesity, smoking, and physical inactivity, and introducing physical activity as an explicit intervention, on the burden of type 2 diabetes mellitus (T2DM), using Qatar as an example. METHODS: A population-level mathematical model was adapted and expanded. The model was stratified by sex, age group, risk factor status, T2DM status, and intervention status, and parameterized by nationally representative data. Modeled interventions were introduced in 2016, reached targeted level by 2031, and then maintained up to 2050. Diverse intervention scenarios were assessed and compared with a counter-factual no intervention baseline scenario. RESULTS: T2DM prevalence increased from 16.7% in 2016 to 24.0% in 2050 in the baseline scenario. By 2050, through halting the rise or reducing obesity prevalence by 10-50%, T2DM prevalence was reduced by 7.8-33.7%, incidence by 8.4-38.9%, and related deaths by 2.1-13.2%. For smoking, through halting the rise or reducing smoking prevalence by 10-50%, T2DM prevalence was reduced by 0.5-2.8%, incidence by 0.5-3.2%, and related deaths by 0.1-0.7%. For physical inactivity, through halting the rise or reducing physical inactivity prevalence by 10-50%, T2DM prevalence was reduced by 0.5-6.9%, incidence by 0.5-7.9%, and related deaths by 0.2-2.8%. Introduction of physical activity with varying intensity at 25% coverage reduced T2DM prevalence by 3.3-9.2%, incidence by 4.2-11.5%, and related deaths by 1.9-5.2%. CONCLUSIONS: Major reductions in T2DM incidence could be accomplished by reducing obesity, while modest reductions could be accomplished by reducing smoking and physical inactivity, or by introducing physical activity as an intervention

Evolution of extreme stomach pH in bilateria inferred from gastric alkalization mechanisms in basal deuterostomes

The stomachs of most vertebrates operate at an acidic pH of 2 generated by the gastric H+/K+-ATPase located in parietal cells. The acidic pH in stomachs of vertebrates is believed to aid digestion and to protect against environmental pathogens. Little attention has been placed on whether acidic gastric pH regulation is a vertebrate character or a deuterostome ancestral trait. Here, we report alkaline conditions up to pH 10.5 in the larval digestive systems of ambulacraria (echinoderm + hemichordate), the closest relative of the chordate. Microelectrode measurements in combination with specific inhibitors for acid-base transporters and ion pumps demonstrated that the gastric alkalization machinery in sea urchin larvae is mainly based on direct H+ secretion from the stomach lumen and involves a conserved set of ion pumps and transporters. Hemichordate larvae additionally utilized HCO 3- transport pathways to generate even more alkaline digestive conditions. Molecular analyses in combination with acidification experiments supported these findings and identified genes coding for ion pumps energizing gastric alkalization. Given that insect larval guts were also reported to be alkaline, our discovery raises the hypothesis that the bilaterian ancestor utilized alkaline digestive system while the vertebrate lineage has evolved a strategy to strongly acidify their stomachs