Administration of IL-18BP by gene therapy reduces inflammation and prevents joint destruction by downregulation of MMP-9 in rat AIA Role of MMP-9 in bone and joint destruction in arthritis

Background and objectives: Interleukin-18 (IL-18) is a pleiotropic cytokine involved in rheumatoid arthritis (RA) pathogenesis. This studywas carried out to evaluate the efficicacy of interleukin-18 binding protein (IL-18BP) gene therapy in the rat adjuvant-induced arthritis (AIA) model and to decipher the mechanisms by which IL-18BP delivery lessens bone destruction. Materials and methods: Arthritis was induced in female Lewis rat by Mycobacterium butyricum and the mRNA expression of IL-18 and IL-18BP was determined in the joints. In a preventative study, rats were divided into an adenovirus producing IL-18BP-Fc (AdmIL-18BP-Fc) group (n=8) and an adenovirus producing green fluorescent protein (AdGFP) group (n=7). On day 8 after AIA induction, adenoviruses were injected. Clinical parameters were assessed. At day 18, during maximal arthritis, the rats were euthanized, ankles were collected, and X-rays were performed. mRNA and protein were extracted from joints for analyses by qRT-PCR, multiplex, Western blot, and zymography. Results: We observed a decrease in the [IL-18BP/IL-18] ratio from day 7 to day 45. Administration of AdmIL-18BPd-Fc decreased clinical parameters and prevented bone and joint destruction compared to AdGFP administration. IL-18BP delivery reduced the metalloproteinase 9 (MMP-9) levels by 33% (at protein level (Fig. 1B) and functional level (Fig. 1C) and the tartrate-resistant acid phosphatase (TRAP) level by 44% (Fig. 1D) in the joint homogenates from AdmIL-18BPd-Fc compared to AdGFP treated rats.However, no variationwas observed forMMP-2 at the protein level (Fig.1A) and functional level (Fig. 1C). Conclusions: In rat AIA, a decrease in the [IL-18BP/ IL-18] ratio was observed. IL-18BP delivery prevented joint and bone destruction by downregulating MMP-9 and TRAP, suggesting a potential benefit of a similar therapy in RA.

Effects of paralysis with pancuronium bromide on joint mobility in premature infants.

To study the effects of muscle paralysis on joint mobility, we compared eight premature infants treated with pancuronium bromide with a control group. A significant reduction was observed in hip and knee flexion, and in ankle dorsal extension, which tended to resolve in time. We conclude that muscle paralysis reduces the mobility of selected joints; spontaneous activity appears to prevent long-term contractures.

Conditional predictive density evaluation in the presence of instabilities

We propose new methods for evaluating predictive densities. The methods includeKolmogorov-Smirnov and Cram?r-von Mises-type tests for the correct specification ofpredictive densities robust to dynamic mis-specification. The novelty is that the testscan detect mis-specification in the predictive densities even if it appears only overa fraction of the sample, due to the presence of instabilities. Our results indicatethat our tests are well sized and have good power in detecting mis-specification inpredictive densities, even when it is time-varying. An application to density forecastsof the Survey of Professional Forecasters demonstrates the usefulness of the proposedmethodologies.

Saving lives: Evidence from a conditional food supplementation program

Many governments in developing countries implement programs that aim to address nutrionalfailures in early childhood, yet evidence on the effectiveness of these interventions is scant. Thispaper evaluates the impact of a conditional food supplementation program on child mortality inEcuador. The Programa de Alimentaci?n y Nutrici?n Nacional (PANN) 2000 was implementedby regular staff at local public health posts and consisted of offering a free micronutrient-fortifiedfood, Mi Papilla, for children aged 6 to 24 months in exchange for routine health check-ups forthe children. Our regression discontinuity design exploits the fact that at its inception, the PANN2000 was running for about 8 months only in the poorest communities (parroquias) of certainprovinces. Our main result is that the presence of the program reduced child mortality in cohortswith 8 months of differential exposure from a level of about 2.5 percent by 1 to 1.5 percentagepoints.

Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis

Deficiency of carbohydrate sulfotransferase 3 (CHST3; also known as chondroitin-6-sulfotransferase) has been reported in a single kindred so far and in association with a phenotype of severe chondrodysplasia with progressive spinal involvement. We report eight CHST3 mutations in six unrelated individuals who presented at birth with congenital joint dislocations. These patients had been given a diagnosis of either Larsen syndrome (three individuals) or humero-spinal dysostosis (three individuals), and their clinical features included congenital dislocation of the knees, elbow joint dysplasia with subluxation and limited extension, hip dysplasia or dislocation, clubfoot, short stature, and kyphoscoliosis developing in late childhood. Analysis of chondroitin sulfate proteoglycans in dermal fibroblasts showed markedly decreased 6-O-sulfation but enhanced 4-O-sulfation, confirming functional impairment of CHST3 and distinguishing them from diastrophic dysplasia sulphate transporter (DTDST)-deficient cells. These observations provide a molecular basis for recessive Larsen syndrome and indicate that recessive Larsen syndrome, humero-spinal dysostosis, and spondyloepiphyseal dysplasia Omani type form a phenotypic spectrum.

Photoreceptor types and distributions in the retinae of insectivores.

The retinae of insectivores have been rarely studied, and their photoreceptor arrangements and expression patterns of visual pigments are largely unknown. We have determined the presence and distribution of cones in three species of shrews (common shrew Sorex araneus, greater white-toothed shrew Crocidura russula, dark forest shrew Crocidura poensis; Soricidae) and in the lesser hedgehog tenrec Echinops telfairi (Tenrecidae). Special cone types were identified and quantified in flattened whole retinae by antisera/antibodies recognizing the middle-to-long-wavelength-sensitive (M/L-)cone opsin and the short-wavelength-sensitive (S-)cone opsin, respectively. A combination of immunocytochemistry with conventional histology was used to assess rod densities and cone/rod ratios. In all four species the rods dominate at densities of about 230,000-260,000/mm2. M/L- and S-cones are present, comprising between 2% of the photoreceptors in the nocturnal Echinops telfairi and 13% in Sorex araneus that has equal diurnal and nocturnal activity phases. This suggests dichromatic color vision like in many other mammals. A striking feature in all four species are dramatically higher S-cone proportions in ventral than in dorsal retina (0.5% vs. 2.5-12% in Sorex, 5-15% vs. 30-45% in Crocidura poensis, 3-12% vs. 20-50% in Crocidura russula, 10-30% vs. 40-70% in Echinops). The functional and comparative aspects of these structural findings are discussed.

Essays in equilibrium asset pricing

Introduction This dissertation consists of three essays in equilibrium asset pricing. The first chapter studies the asset pricing implications of a general equilibrium model in which real investment is reversible at a cost. Firms face higher costs in contracting than in expanding their capital stock and decide to invest when their productive capital is scarce relative to the overall capital of the economy. Positive shocks to the capital of the firm increase the size of the firm and reduce the value of growth options. As a result, the firm is burdened with more unproductive capital and its value lowers with respect to the accumulated capital. The optimal consumption policy alters the optimal allocation of resources and affects firm's value, generating mean-reverting dynamics for the M/B ratios. The model (1) captures convergence of price-to-book ratios -negative for growth stocks and positive for value stocks - (firm migration), (2) generates deviations from the classic CAPM in line with the cross-sectional variation in expected stock returns and (3) generates a non-monotone relationship between Tobin's q and conditional volatility consistent with the empirical evidence. The second chapter proposes a standard portfolio-choice problem with transaction costs and mean reversion in expected returns. In the presence of transactions costs, no matter how small, arbitrage activity does not necessarily render equal all riskless rates of return. When two such rates follow stochastic processes, it is not optimal immediately to arbitrage out any discrepancy that arises between them. The reason is that immediate arbitrage would induce a definite expenditure of transactions costs whereas, without arbitrage intervention, there exists some, perhaps sufficient, probability that these two interest rates will come back together without any costs having been incurred. Hence, one can surmise that at equilibrium the financial market will permit the coexistence of two riskless rates that are not equal to each other. For analogous reasons, randomly fluctuating expected rates of return on risky assets will be allowed to differ even after correction for risk, leading to important violations of the Capital Asset Pricing Model. The combination of randomness in expected rates of return and proportional transactions costs is a serious blow to existing frictionless pricing models. Finally, in the last chapter I propose a two-countries two-goods general equilibrium economy with uncertainty about the fundamentals' growth rates to study the joint behavior of equity volatilities and correlation at the business cycle frequency. I assume that dividend growth rates jump from one state to other, while countries' switches are possibly correlated. The model is solved in closed-form and the analytical expressions for stock prices are reported. When calibrated to the empirical data of United States and United Kingdom, the results show that, given the existing degree of synchronization across these business cycles, the model captures quite well the historical patterns of stock return volatilities. Moreover, I can explain the time behavior of the correlation, but exclusively under the assumption of a global business cycle.

Official Positions for FRAX® clinical regarding biochemical markers from Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX®.

The best indirect evidence that increased bone turnover contributes to fracture risk is the fact that most of the proven therapies for osteoporosis are inhibitors of bone turnover. The evidence base that we can use biochemical markers of bone turnover in the assessment of fracture risk is somewhat less convincing. This relates to natural variability in the markers, problems with the assays, disparity in the statistical analyses of relevant studies and the independence of their contribution to fracture risk. More research is clearly required to address these deficiencies before biochemical markers might contribute a useful independent risk factor for inclusion in FRAX(®).

Audit report on the Iowa Water Pollution Control Works Financing Program and the Iowa Drinking Water Facilities Financing Program, joint programs of the Iowa Finance Authority and the Iowa Department of Natural Resources, for the year ended June 30, 2014

Audit report on the Iowa Water Pollution Control Works Financing Program and the Iowa Drinking Water Facilities Financing Program, joint programs of the Iowa Finance Authority and the Iowa Department of Natural Resources, for the year ended June 30, 2014

Prediction of Childhood Asthma Using Conditional Probability and Discrete Event Simulation

Abstract: Asthma prevalence in children and adolescents in Spain is 10-17%. It is the most common chronic illness during childhood. Prevalence has been increasing over the last 40 years and there is considerable evidence that, among other factors, continued exposure to cigarette smoke results in asthma in children. No statistical or simulation model exist to forecast the evolution of childhood asthma in Europe. Such a model needs to incorporate the main risk factors that can be managed by medical authorities, such as tobacco (OR = 1.44), to establish how they affect the present generation of children. A simulation model using conditional probability and discrete event simulation for childhood asthma was developed and validated by simulating realistic scenario. The parameters used for the model (input data) were those found in the bibliography, especially those related to the incidence of smoking in Spain. We also used data from a panel of experts from the Hospital del Mar (Barcelona) related to actual evolution and asthma phenotypes. The results obtained from the simulation established a threshold of a 15-20% smoking population for a reduction in the prevalence of asthma. This is still far from the current level in Spain, where 24% of people smoke. We conclude that more effort must be made to combat smoking and other childhood asthma risk factors, in order to significantly reduce the number of cases. Once completed, this simulation methodology can realistically be used to forecast the evolution of childhood asthma as a function of variation in different risk factors.

Official Positions for FRAX® clinical regarding falls and frailty: can falls and frailty be used in FRAX®? From Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX®.

Risk factors for fracture can be purely skeletal, e.g., bone mass, microarchitecture or geometry, or a combination of bone and falls risk related factors such as age and functional status. The remit of this Task Force was to review the evidence and consider if falls should be incorporated into the FRAX® model or, alternatively, to provide guidance to assist clinicians in clinical decision-making for patients with a falls history. It is clear that falls are a risk factor for fracture. Fracture probability may be underestimated by FRAX® in individuals with a history of frequent falls. The substantial evidence that various interventions are effective in reducing falls risk was reviewed. Targeting falls risk reduction strategies towards frail older people at high risk for indoor falls is appropriate. This Task Force believes that further fracture reduction requires measures to reduce falls risk in addition to bone directed therapy. Clinicians should recognize that patients with frequent falls are at higher fracture risk than currently estimated by FRAX® and include this in decision-making. However, quantitative adjustment of the FRAX® estimated risk based on falls history is not currently possible. In the long term, incorporation of falls as a risk factor in the FRAX® model would be ideal.

Transverse Joint Sealing with Various Sealants, HR-203, 1983

Iowa's first portland cement concrete pavement was constructed in 1904 in the City of LeMars. A portion of that pavement served traffic until 1974 at which time it was resurfaced. The first rural Iowa pee pavement (16' wide, 6" to 7" thick) was constructed under the direction of the Iowa State Highway Commission in 1913. Some of Iowa's early pavements had transverse joints at 25-foot spacings. At that time, joint spacings across the nation ranged from 24 to 100 ft. There have been many changes in joint design over the years with some pavements being constructed without transverse joints. Joint spacing on Iowa primary pavements has generally remained around 20 feet with this spacing having been adopted as an Iowa standard in 1954. Until 1978 it was common to specify a 40-foot joint spacing on secondary pavements. The performance of the pavements with joint spacings greater than 20 feet, and in some cases no contraction joints, generated a 1955 research project on joint spacing. This project was 16 miles long containing sections without contraction joints and sections with joints sawed at intervals of 20, 50 and 80 feet. Approximately half of the sawed joints were left unsealed. The results of this research supported the 20-foot spacing, but were inconclusive regarding the benefits of sealing. One of the desired characteristics of joint sealing material is that it should act as a moisture barrier and prevent the intrusion of surface water. It was generally accepted from past experience that the hot poured type joint seals did not provide this effective moisture barrier.