Some of the early events underlying Th2 cell maturation and susceptibility to Leishmania major infection in BALB/c mice.

The first experimental evidence for the development of polarized CD4+ Th1 and Th2 responses in vivo has been obtained using the murine model of infection with Leishmania major, an intracellular parasite of macrophages in their vertebrate host. Genetically determined resistance and susceptibility to infection with this parasite have been clearly demonstrated to result from the development of polarized Th1 and Th2 responses, respectively. Using this model system, the dominant role of cytokines in the induction of polarized CD4+ responses has been validated in vivo. The requisite role of IL-4 in mediating both Th2 differentiation and susceptibility to infection in BALB/c mice has directed interest towards the search for evidence of IL-4 production early after infection and identification of its cellular source. We have been able to demonstrate a burst of IL-4 production in susceptible BALB/c mice within the first day of infection with L. major and could establish that this rapidly produced IL-4 instructed Th2 lineage commitment of subsequently activated CD4+ T cells and stabilized this commitment by downregulating IL-12 Rbeta2 chain expression, resulting in susceptibility to infection. Strikingly, this early IL-4 response to infection resulted from the cognate recognition of a single epitope in a distinctive antigen, LACK, from this complex microorganism by a restricted population of CD4+ T cells that express Vbeta4-Valpha8 T cell receptors.

Estimating Design-Flood Discharges for Streams in Iowa Using Drainage-Basin and Channel-Geometry Characteristics, HR-322, 1993

Drainage-basin and channel-geometry multiple-regression equations are presented for estimating design-flood discharges having recurrence intervals of 2, 5, 10, 25, 50, and 100 years at stream sites on rural, unregulated streams in Iowa. Design-flood discharge estimates determined by Pearson Type-III analyses using data collected through the 1990 water year are reported for the 188 streamflow-gaging stations used in either the drainage-basin or channel-geometry regression analyses. Ordinary least-squares multiple-regression techniques were used to identify selected drainage-basin and channel-geometry regions. Weighted least-squares multiple-regression techniques, which account for differences in the variance of flows at different gaging stations and for variable lengths in station records, were used to estimate the regression parameters. Statewide drainage-basin equations were developed from analyses of 164 streamflow-gaging stations. Drainage-basin characteristics were quantified using a geographic-information-system (GIS) procedure to process topographic maps and digital cartographic data. The significant characteristics identified for the drainage-basin equations included contributing drainage area, relative relief, drainage frequency, and 2-year, 24-hour precipitation intensity. The average standard errors of prediction for the drainage-basin equations ranged from 38.6% to 50.2%. The GIS procedure expanded the capability to quantitatively relate drainage-basin characteristics to the magnitude and frequency of floods for stream sites in Iowa and provides a flood-estimation method that is independent of hydrologic regionalization. Statewide and regional channel-geometry regression equations were developed from analyses of 157 streamflow-gaging stations. Channel-geometry characteristics were measured on site and on topographic maps. Statewide and regional channel-geometry regression equations that are dependent on whether a stream has been channelized were developed on the basis of bankfull and active-channel characteristics. The significant channel-geometry characteristics identified for the statewide and regional regression equations included bankfull width and bankfull depth for natural channels unaffected by channelization, and active-channel width for stabilized channels affected by channelization. The average standard errors of prediction ranged from 41.0% to 68.4% for the statewide channel-geometry equations and from 30.3% to 70.0% for the regional channel-geometry equations. Procedures provided for applying the drainage-basin and channel-geometry regression equations depend on whether the design-flood discharge estimate is for a site on an ungaged stream, an ungaged site on a gaged stream, or a gaged site. When both a drainage-basin and a channel-geometry regression-equation estimate are available for a stream site, a procedure is presented for determining a weighted average of the two flood estimates.

Iowa Workforce Development Annual Report Fiscal Year 2013

The past fiscal year brought some improvements in the Iowa economy that should position the state for stronger hiring in the year ahead. The housing market is on solid footing, and hiring is broader in scope, including a number of the service-providing industries that had been on hold for some time. State and local government fiscal conditions have also stabilized due to a rise in tax revenues. This means that government cutbacks will be less of a drag on overall job growth. During FY 2013, Iowa’s non-farm jobs advanced by 19,200 (+1.3 percent) compared to 23,000 (+1.6 percent) for the prior fiscal year. Although manufacturing continued to post the largest over the year job gain at close to 5,600, job growth shifted away from manufacturing to the service providing industries by mid-year. Annual job gains of 2,000 or more were reflected in professional and business services, education and health, leisure and hospitality, retail trade and financial activities. Statewide non-farm employment averaged 1,517,700 in FY 2013, the highest level achieved since the record of 1,524,800 in FY 2008.

The inhibition of fat cell proliferation by n-3 fatty acids in dietary obese mice.

ABSTRACT: BACKGROUND: Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) of marine origin exert multiple beneficial effects on health. Our previous study in mice showed that reduction of adiposity by LC n-3 PUFA was associated with both, a shift in adipose tissue metabolism and a decrease in tissue cellularity. The aim of this study was to further characterize the effects of LC n-3 PUFA on fat cell proliferation and differentiation in obese mice. METHODS: A model of inducible and reversible lipoatrophy (aP2-Cre-ERT2 PPARgammaL2/L2 mice) was used, in which the death of mature adipocytes could be achieved by a selective ablation of peroxisome proliferator-activated receptor gamma in response to i.p. injection of tamoxifen. Before the injection, obesity was induced in male mice by 8-week-feeding a corn oil-based high-fat diet (cHF) and, subsequently, mice were randomly assigned (day 0) to one of the following groups: (i) mice injected by corn-oil-vehicle only, i.e."control" mice, and fed cHF; (ii) mice injected by tamoxifen in corn oil, i.e. "mutant" mice, fed cHF; (iii) control mice fed cHF diet with 15% of dietary lipids replaced by LC n-3 PUFA concentrate (cHF+F); and (iv) mutant mice fed cHF+F. Blood and tissue samples were collected at days 14 and 42. RESULTS: Mutant mice achieved a maximum weight loss within 10 days post-injection, followed by a compensatory body weight gain, which was significantly faster in the cHF as compared with the cHF+F mutant mice. Also in control mice, body weight gain was depressed in response to dietary LC n-3 PUFA. At day 42, body weights in all groups stabilized, with no significant differences in adipocyte size between the groups, although body weight and adiposity was lower in the cHF+F as compared with the cHF mice, with a stronger effect in the mutant than in control mice. Gene expression analysis documented depression of adipocyte maturation during the reconstitution of adipose tissue in the cHF+F mutant mice. CONCLUSION: Dietary LC n-3 PUFA could reduce both hypertrophy and hyperplasia of fat cells in vivo. Results are in agreement with the involvement of fat cell turnover in control of adiposity.

Differentiated chemical reactivity of nanoparticles toward DTT

RATIONALE: Induction of oxidative stress and impairment of the antioxidant defense are considered important biological responses following nanoparticle (NP) exposure. The acellular in vitro dithiothreitol (DTT) assay is proposed to measure the oxidative potential of NP. In addition, DTT can be considered as a model compound of sulfur containing antioxidants. The objective of this work is to evaluate the surface reactivity in solution of a NP panel toward DTT. METHOD: The NP panel was composed of four carbonaceous particles, six types of metal oxides and silver with primary size ranged from 7 to 300 nm. Suspensions were prepared in surfactant solution with 30 min sonication. DTT was used as reductant to evaluate the oxidative properties of the different NP. The determination of the NP ability to catalyze electron transfer from DTT to oxygen was carried out as described in Sauvain et al., Nanotoxicology, 2008, 2:3, 121−129. RESULTS: All the carbonaceous NP catalyzed the oxidation of DTT by oxygen following the mass based order: carbon black > diesel exhaust particle > nanotubes > fullerene. A contrasting reactivity was observed for the metallic NP. Except for nickel oxide and metallic silver, which reacted similarly to the carbonaceous NP, all other metal oxides hindered the oxidation of DTT by oxygen, with ZnO being the most effective one. CONCLUSIONS : DTT was stabilized against oxidation in the presence of metal oxide NP in the solution. This suggests that different chemical interactions take place compared with carbonaceous NP. To explain these differences, we hypothesize that DTT could form complexes with the metal oxide surface (or dissolved metal ions), rendering it less susceptible to oxidation. By analogy, such a process could be thought to apply in biological systems with sulfur−containing antioxidants, reducing their buffer capacity. Such NP could thus contribute to oxidative stress by an alternative mechanism.

Macadam Base Shoulders, HR-181, 1977

Highway safety and pavement performance can be directly influenced by the type of shoulders that are constructed. Shoulder design alternatives have always been rather limited. Moreover, the use of some of the alternatives has always been restricted by funding limitations. This research project seeks to explore the use of modified macadam base construction for shoulders. This type of shoulder design could offer the designer another option when paved or stabilized shoulders are being considered. Macadam base construction has in the past been shown to be quite strong and freedraining. Two macadam base shoulder designs were developed and constructed for this research project. A new roadway embankment and P.C.C. pavement were constructed on a section of US 6 east of Adel in Dallas County. The macadam base shoulders were constructed adjacent to the pavement as part of the project. The north shoulder was finished with a choke stone course and bituminous surface treatment and the south shoulder was finished with a two (2) inch layer of Type B Class II asphalt concrete. The initial results are considered satisfactory. Follow-up performance evaluation and load bearing tests are planned.

Performance of Randomly Oriented, Fiber-Reinforced Roadway Soils, HR-211, 1982

Several primary techniques have been developed through which soil aggregate road material properties may be improved. Such techniques basically involve a mechanism of creating a continuous matrix system of soil and/or aggregate particles, interlocked through the use of some additive such as portland cement, lime, or bituminous products. Details by which soils are stabilized vary greatly, but they are dependent on the type of stabilizing agent and nature of the soil, though the overall approach to stabilization has the common feature that improvement is achieved by some mechanism(s) forcing individual particles to adhere to one another. This process creates a more rigid material, most often capable of resisting the influx of water during freezing, loss of strength due to high moisture content and particle dispersion during thawing, and loss of strength due to migration of fines and/or water by capillarity and pumping. The study reported herein, took a new and relatively different approach to strengthening of soils, i.e., improvement of roadway soils and/or soil-aggregate materials by structural reinforcement with randomly oriented fibers. The purpose of the study was to conduct a laboratory and field investigation into the potential of improving (a) soil-aggregate surfaced and subgrade materials, including those that are frost-prone and/or highly moisture susceptible, and (b) localized base course materials, by uniting such materials through fibrous reinforcement. The envisioned objective of the project was the development of a simple construction technique(s) that could be (a) applied on a selective basis to specific areas having a history of poor performance, or (b) used for improvement of potential base materials prior to surfacing. Little background information on such purpose and objective was available. Though the envisioned process had similarities to fibrous reinforced concrete, and to fibrous reinforced resin composites, the process was devoid of a cementitious binder matrix and thus highly dependent on the cohesive and frictional interlocking processes of a soil and/or aggregate with the fibrous reinforcement; a condition not unlike the introduction of reinforcing bars into a concrete sand/aggregate mixture without benefit of portland cement. Thus the study was also directed to answering some fundamental questions: (1) would the technique work; (2) what type or types of fibers are effective; (3) are workable fibers commercially available; and (4) can such fibers be effectively incorporated with conventional construction equipment, and employed in practical field applications? The approach to obtaining answers to these questions, was guided by the philosophy that an understanding of basic fundamentals was essential to developing a body of engineering knowledge, that would serve as the basis for eventual development of design procedures with fibrous products for the applications previously noted.

Characteristics of Chemical Treated Roadway Surfaces, HR-33, 1963

Iowa Highway Commission Project HR-33, "Characteristics of Chemically Treated Roadway Surfaces", was investigated at the Iowa Engineering Experiment Station under Project 375-S. The purpose of the project as originally proposed was to study the physical and chemical characteristics of chemically treated roadway surfaces. All chemical treatments were to be included, but only sodium chloride and calcium chloride treated roadways were investigated. The uses of other types of chemical treatment were not discovered until recently, notably spent sulfite liquor and a commercial additive. Costs of stabilized secondary roads in Hamilton County averaged $4300.00 per mile even though remanent soil-aggregate material was used. The cost of similar roads in Franklin County was $4400.00 per mile. The Franklin County road surfaces were constructed entirely from materials that were hauled to the road site. Costs in Butler County were a little over $3000.00 per mile some eight years ago. Chemical investigations indicate that calcium chloride and sodium chloride are lost through leaching. Approximately 95 percent of the sodium chloride appears to have been lost, and nearly 65 percent of the calcium chloride has disappeared. The latter value may be much in error since surface dressings of calcium chloride are commonly used and have not been taken into account. Clay contents of the soil-aggregate-chemical stabilized roads range from about 6 to ll percent, averaging 8 or 9 percent. The thicknesses of stabilized mats are usually 2 to 4 inches, with in-place densities ranging from 130 to 145 pcf. Generally the densities found in sodium chloride stabilized roads were slightly higher than those found in the calcium chloride stabilized roads.

Treating Iowa's Marginal Aggregates and Soils by Foamix Process, HR-212, 1980

Quality granular materials suitable for building all-weather roads are not uniformly distributed throughout the state of Iowa. For this reason the Iowa Highway Research Board has sponsored a number of research programs for the purpose of developing new and effective methods for making use of whatever materials are locally available. This need is ever more pressing today due to the decreasing availability of road funds and quality materials, and the increasing costs of energy and all types of binder materials. In the 1950s, Professor L. H. Csanyi of Iowa State University had demonstrated both in the laboratory and in the field, in Iowa and in a number of foreign countries, the effectiveness of preparing low cost mixes by stabilizing ungraded local aggregates such as gravel, sand and loess with asphalt cements using the foamed asphalt process. In this process controlled foam was produced by introducing saturated steam at about 40 psi into heated asphalt cement at about 25 psi through a specially designed and properly adjusted nozzle. The reduced viscosity and the increased volume and surface energy in the foamed asphalt allowed intimate coating and mixing of cold, wet aggregates or soils. Through the use of asphalt cements in a foamed state, materials normally considered unsuitable could be used in the preparation of mixes for stabilized bases and surfaces for low traffic road construction. By attaching the desired number of foam nozzles, the foamed asphalt can be used in conjunction with any type of mixing plant, either stationary or mobile, batch or continuous, central plant or in-place soil stabilization.

Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells.

Deregulation of the ubiquitin/proteasome system has been implicated in the pathogenesis of many human diseases, including cancer. Ubiquitin-specific proteases (USP) are cysteine proteases involved in the deubiquitination of protein substrates. Functional connections between USP7 and essential viral proteins and oncogenic pathways, such as the p53/Mdm2 and phosphatidylinositol 3-kinase/protein kinase B networks, strongly suggest that the targeting of USP7 with small-molecule inhibitors may be useful for the treatment of cancers and viral diseases. Using high-throughput screening, we have discovered HBX 41,108, a small-molecule compound that inhibits USP7 deubiquitinating activity with an IC(50) in the submicromolar range. Kinetics data indicate an uncompetitive reversible inhibition mechanism. HBX 41,108 was shown to affect USP7-mediated p53 deubiquitination in vitro and in cells. As RNA interference-mediated USP7 silencing in cancer cells, HBX 41,108 treatment stabilized p53, activated the transcription of a p53 target gene without inducing genotoxic stress, and inhibited cancer cell growth. Finally, HBX 41,108 induced p53-dependent apoptosis as shown in p53 wild-type and null isogenic cancer cell lines. We thus report the identification of the first lead-like inhibitor against USP7, providing a structural basis for the development of new anticancer drugs.

Endovascular treatment of active splenic bleeding after colonoscopy: a systematic review of the literature.

PURPOSE: Colonoscopy is reported to be a safe procedure that is routinely performed for the diagnosis and treatment of colorectal diseases. Splenic rupture is considered to be a rare complication with high mortality and morbidity that requires immediate diagnosis and management. Nonoperative management (NOM), surgical treatment (ST), and, more recently, proximal splenic artery embolization (PSAE) have been proposed as treatment options. The goal of this study was to assess whether PSAE is safe even in high-grade ruptures. METHODS: We report two rare cases of post colonoscopy splenic rupture. A systematic review of the literature from 2002 to 2010 (first reported case of PSAE) was performed and the three types of treatment compared. RESULTS: All patients reviewed (77 of 77) presented with intraperitoneal hemorrhage due to isolated splenic trauma. Splenic rupture was high-grade in most patients when grading was possible. Six of 77 patients (7.8 %) were treated with PSAE, including the 2 cases reported herein. Fifty-seven patients (74 %) underwent ST. NOM was attempted first in 25 patients with a high failure rate (11 of 25 [44 %]) and requiring a salvage procedure, such as PSAE or ST. Previous surgery (31 of 59 patients), adhesions (10 of 13), diagnostic colonoscopies (49 of 71), previous biopsies or polypectomies (31 of 57) and female sex (56 of 77) were identified as risk factors. In contrast, splenomegaly (0 of 77 patients), medications that increase the risk of bleeding (13 of 30) and difficult colonoscopies (16 of 51) were not identified as risk factors. PSAE was safe and effective even in elderly patients with comorbidities and those taking medications that increase the risk of bleeding, and the length of the hospital stay was similar to that after ST. CONCLUSION: We propose a treatment algorithm based on clinical and radiological criteria. Because of the high failure rate after NOM, PSAE should be the treatment of choice to manage grade I through IV splenic ruptures after colonoscopy in hemodynamically stabilized patients.

Avaluació de l'aptitud de bioestabilitzats com a esmena orgànica per a la rehabilitació de sòls

L’objectiu d’aquest estudi ha estat avaluar l’efecte que té sobre algunes propietats fisicoquímiques del sòl i el creixement de plantes, l’adició del producte compostat obtingut a partir de la fracció orgànica dels residus sòlids urbans de recollida no selectiva, material anomenat bioestabilitzat. S’ha dut a terme un bioassaig amb blat (Triticum aestivum), utilitzant bioestabilitzat procedent de dues plantes de tractament mecànic i biològic, Vacarisses i Mataró, que s’ha aplicat a diferents dosis en un sòl de baixa qualitat. S’ha observat una relació positiva entre el creixement del blat i la dosis de bioestabilitzat aplicada. Pel que fa a la germinació, ha estat lleugerament estimulada per les dosis intermèdies de bioestabilitzat assajades. En quant a les propietats fisicoquímiques del sòl, s’ha observat un increment de la salinitat en funció de la dosis de bioestabilitzat aplicada, que en les més elevades podria ser problemàtica. També, el contingut de matèria orgànica ha augmentat de manera proporcional a la dosis, cosa que ha millorat les propietats físiques del sòl. Per altra banda, s’han trobat continguts d’impropis (vidre, plàstic ...) i concentracions d’alguns metalls pesants bastant elevades, així com una considerable variabilitat entre les partides de bioestabilitzat. Finalment, es conclou que abans de permetre l’aplicació de bioestabilitzat per a la rehabilitació de sòls degradats, cal aprofundir més en l’estudi d’aquest material.

Airflow decline after myeloablative allogeneic hematopoietic cell transplantation: the role of community respiratory viruses.

We conducted a 12-year retrospective study to determine the effects that the community respiratory-virus species and the localization of respiratory-tract virus infection have on severe airflow decline, a serious and fatal complication occurring after hematopoietic cell transplantation (HCT). Of 132 HCT recipients with respiratory-tract virus infection during the initial 100 days after HCT, 50 (38%) developed airflow decline < or =1 year after HCT. Lower-respiratory-tract infection with parainfluenza (odds ratio [OR], 17.9 [95% confidence interval {CI}, 2.0-160]; P=.01) and respiratory syncytial virus (OR, 3.6 [95% CI, 1.0-13]; P=.05) independently increased the risk of development of airflow decline < or =1 year after HCT. The airflow decline was immediately detectable after infection and was strongest for lower-respiratory-tract infection with parainfluenza virus; it stabilized during the months after the respiratory-tract virus infection, but, at < or =1 year after HCT, the initial lung function was not restored. Thus, community respiratory virus-associated airflow decline seems to be specific to viral species and infection localization.

Rufinamide Attenuates Mechanical Allodynia in a Model of Neuropathic Pain in the Mouse and Stabilizes Voltage-gated Sodium Channel Inactivated State.

BACKGROUND:: Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide. METHODS:: We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine. RESULTS:: In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6-1.9) (median [95% CI]) to 2.3 g (2.2-2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4-15.5) to 30.0 s (21.8-31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons. CONCLUSIONS:: At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain.

A novel approach to characterize clonality and differentiation of human melanoma-specific T cell responses: spontaneous priming and efficient boosting by vaccination.

Despite major progress in T lymphocyte analysis in melanoma patients, TCR repertoire selection and kinetics in response to tumor Ags remain largely unexplored. In this study, using a novel ex vivo molecular-based approach at the single-cell level, we identified a single, naturally primed T cell clone that dominated the human CD8(+) T cell response to the Melan-A/MART-1 Ag. The dominant clone expressed a high-avidity TCR to cognate tumor Ag, efficiently killed tumor cells, and prevailed in the differentiated effector-memory T lymphocyte compartment. TCR sequencing also revealed that this particular clone arose at least 1 year before vaccination, displayed long-term persistence, and efficient homing to metastases. Remarkably, during concomitant vaccination over 3.5 years, the frequency of the pre-existing clone progressively increased, reaching up to 2.5% of the circulating CD8 pool while its effector functions were enhanced. In parallel, the disease stabilized, but subsequently progressed with loss of Melan-A expression by melanoma cells. Collectively, combined ex vivo analysis of T cell differentiation and clonality revealed for the first time a strong expansion of a tumor Ag-specific human T cell clone, comparable to protective virus-specific T cells. The observed successful boosting by peptide vaccination support further development of immunotherapy by including strategies to overcome immune escape.