Cosmological Hydrodynamics with Multi-Species Chemistry and Nonequilibrium Ionization and Cooling

We have developed a method of solving for multi-species chemical reaction flows in non--equilibrium and self--consistently with the hydrodynamic equations in an expanding FLRW universe. The method is based on a backward differencing scheme for the required stability when solving stiff sets of equations and is designed to be efficient for three-dimensional calculations without sacrificing accuracy. In all, 28 kinetic reactions are solved including both collisional and radiative processes for the following nine separate species: H, H+, He, He+, He++, H-, H2+, H2, and e-. The method identifies those reactions (involving H- and H2+) ocurring on the shortest time scales, decoupling them from the rest of the network and imposing equilibrium concentrations to good accuracy over typical cosmological dynamical times. Several tests of our code are presented, including radiative shock waves, cosmological sheets, conservation constraints, and fully three-dimensional simulations of CDM cosmological evolutions in which we compare our method to results obtained when the packaged routine LSODAR is substituted for our algorithms.Comment: Latex and postscript, 24 pages, with 6 figures. The paper is also available at http://zeus.ncsa.uiuc.edu:8080/~abel/PGas/bib.html Submitted to New Astronom

Optical Imaging with a Cathepsin B Activated Probe for the Enhanced Detection of Esophageal Adenocarcinoma by Dual Channel Fluorescent Upper GI Endoscopy

Despite significant advances in diagnosis and treatment, the prognosis of esophageal adenocarcinoma remains poor highlighting the importance of early detection. Although white light (WL) upper endoscopy can be used for screening of the esophagus, it has limited sensitivity for early stage disease. Thus, development of new imaging technology to improve the diagnostic capabilities of upper GI endoscopy for early detection of esophageal adenocarcinoma is an important unmet need. The goal of this study was to develop a method for the detection of malignant lesions in the esophagus using WL upper endoscopy combined with near infrared (NIR) imaging with a protease activatable probe (Prosense750) selective for cathepsin B (CTSB). An orthotopic murine model for distal esophageal adenocarcinoma was generated through the implantation of OE-33 and OE-19 human esophageal adenocarcinoma lines in immunocompromised mice. The mice were imaged simultaneously for WL and NIR signal using a custom-built dual channel upper GI endoscope. The presence of tumor was confirmed by histology and target to background ratios (TBR) were compared for both WL and NIR imaging. NIR imaging with ProSense750 significantly improved upon the TBRs of esophageal tumor foci, with a TBR of 3.64$\pm$0.14 and 4.50$\pm$0.11 for the OE-33 and OE-19 tumors respectively, compared to 0.88$\pm$0.04 and 0.81$\pm$0.02 TBR for WL imaging. The combination of protease probes with novel imaging devices has the potential to improve esophageal tumor detection by fluorescently highlighting neoplastic regions

The Structure of Radiative Shock Waves. IV. Effects of Electron Thermal Conduction

We considered the structure of steady-state radiative shock waves propagating in the partially ionized hydrogen gas with density rho1 = 1e-10 gm/cm^3 and temperature 3000K <= T1 <= 8000K. The radiative shock wave models with electron thermal conduction in the vicinity of the viscous jump are compared with pure radiative models. The threshold shock wave velocity above of which effects of electron thermal conduction become perceptible is of U1=70 km/s and corresponds to the upstream Mach numbers from M1= 6 at T1=8000K to M1=11 at T1=3000K. In shocks with efficient electron heat conduction more than a half of hydrogen atoms are ionized in the radiative precursor, whereas behind the viscous jump the hydrogen gas undergoes the full ionization. The existence of the electron conductive precursor leads to the enhancement of the Lyman continuum flux trapped in the surroundings of the discontinuous jump. For upstream velocities ranged within 70 km/s <= U1 <= 85 km/s the partially ionized hydrogen gas of the radiative precursor undergoes the additional ionization (<= 5%), whereas the total radiave flux emerging from the shock wave increases by 10% <= delta(FRad) <= 25% .Comment: 6 pages, 5 figures, LaTeX, accepted for publication in A

Benefício da terapia de ondas de choque no tratamento de úlceras cutâneas: uma revisão da literatura

Extracorporeal shockwave therapy (ESWT) has analgesic and anti-inflammatory effects. With the evolution and comprehension of its biological and physical mechanisms, the application of ESWT on other pathologies has also been studied, especially in musculoskeletal diseases. Recently, studies on animal models have shown its angiogenic capacity and a higher rate of local re-epithelization. These small studies led to few trials using low-energy, radial ESWT to treat problematic chronic skin ulcers. Skin ulcers have diverse etiologies, ranging from pressure ulcers, burns, venous or arterial ulcers, and even diabetic ulcers. Their treatment is usually a challenge, due to the long-term treatment and high costs. Objective: To review the literature and evaluate the efficacy of ESWT in caring for skin ulcers of various etiologies: diabetic ulcers, pressure ulcers, burns, post-traumatic ulcers, venous and arterial ulcers. Method: A literature review was made, with only human trials included. Results: 9 articles were selected that fulfilled the eligibility criteria. The studies included evaluations of 788 patients. The manuscripts demonstrated a large variability regarding the interventions made. There was heterogeneity regarding intervention time, number of pulses, frequency of sessions, and also the number of sessions, energy density used, and the type of shock wave used in therapies. Some of the included trials found a higher rate of complete wound healing and faster epithelization in patients with chronic lesions, unresponsive to the traditional measures. However, there were few studies in the literature with proper methodological quality. Conclusion: ESWT is a promising alternative for the treatment of patients unresponsive to conventional measures. The results are promising, although the evidence regarding wound healing and acceleration of wound healing is still limited. The studies selected did not report any significant side effectsA terapia de ondas de choque (TOC) extracorpórea possui ação analgésica e anti-inflamatória. Com a evolução e compreensão de seus mecanismos físicos e biológicos, foi se estudando a sua aplicação em outras patologias, principalmente em afecções ósseas e musculo-tendíneas. Recentemente, estudos em modelos animais demonstraram a sua capacidade angiogênica e maior taxa de re-epitelização local. Estas pesquisas levaram ao início do uso de TOC radial de baixa energia no tratamento e manejo de diversas lesões de pele de difícil tratamento. As úlceras cutâneas possuem diversas etiologias, variando desde úlceras de pressão, queimaduras, úlceras venosas ou arteriais e também úlceras diabéticas. Seu tratamento é um desafio, devido ao seu tempo prolongado de tratamento (resultando em dificuldades quanto ao seguimento clínico) e também elevados custos. Objetivo: Avaliar a eficácia da TOC na cicatrização de úlceras de diversas etiologias: diabéticas, por pressão, queimaduras, pós-traumáticas, vasculares venosas e arteriais, por meio de uma revisão da literatura. Métodos: Foi realizada uma revisão da literatura, sendo incluídos estudos clínicos em humanos Resultados: 9 artigos preencheram os critérios de inclusão. Os estudos inclusos compreenderam 788 pacientes. Os manuscritos trouxeram uma variedade de padrão de intervenções diferentes. Houve heterogeneidade no tempo de intervenção, número de pulsos e na frequência de sessões, bem como na quantidade de sessões, densidade de energia aplicada, e também no tipo de ondas de choque utilizados nas terapias. Alguns dos trabalhos descritos encontraram uma maior taxa na cicatrização e fechamento completo de lesões em pacientes com lesões crônicas, que não responderam ao tratamento conservador. Porém, há poucos estudos na literatura com qualidade metodológica adequada. Conclusão: A TOC surge como uma alternativa promissora para pacientes que não respondem bem à terapia conservadora. Os resultados são promissores porém com evidências limitadas quanto a diminuição do tempo de cicatrização e na aceleração do fechamento de lesões. Os estudos selecionados não relataram efeitos colaterais significativos, sendo uma terapia segur

Shot noise in ferromagnet--normal metal systems

A semiclassical theory of the low frequency shot noise in ferromagnet - normal metal systems is formulated. Non-collinear magnetization directions of the ferromagnetic leads, arbitrary junctions and the elastic and inelastic scattering regimes are considered. The shot noise is governed by a set of mesoscopic parameters that are expressed in terms of the microscopic details of the junctions in the circuit. Explicit results in the case of ballistic, tunnel, and diffusive junctions are evaluated. The shot noise, the current and the Fano factor are calculated for a double barrier ferromagnet - normal metal - ferromagnet system. It is demonstrated that the shot noise can have a non-monotonic behavior as a function of the relative angle between the magnetizations of the ferromagnetic reservoirs.Comment: 17 pages, 7 figure

Subset- and tissue-defined STAT5 thresholds control homeostasis and function of innate lymphoid cells

Innate lymphoid cells (ILCs) patrol environmental interfaces to defend against infection and protect barrier integrity. Using a genetic tuning model, we demonstrate that the signal-dependent transcription factor (TF) STAT5 is critical for accumulation of all known ILC subsets in mice and reveal a hierarchy of STAT5 dependency for populating lymphoid and nonlymphoid tissues. We apply transcriptome and genomic distribution analyses to define a STAT5 gene signature in natural killer (NK) cells, the prototypical ILC subset, and provide a systems-based molecular rationale for its key functions downstream of IL-15. We also uncover surprising features of STAT5 behavior, most notably the wholesale redistribution that occurs when NK cells shift from tonic signaling to acute cytokine-driven signaling, and genome-wide coordination with T-bet, another key TF in ILC biology. Collectively, our data position STAT5 as a central node in the TF network that instructs ILC development, homeostasis, and function and provide mechanistic insights on how it works at cellular and molecular levels

Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration

Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies

Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review

Background: KRAS mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that KRAS codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with KRAS codon 61 or 146 mutation remain unclear. Methods: We utilized a molecular pathological epidemiology database of 1267 colon and rectal cancers in the Nurse’s Health Study and the Health Professionals Follow-up Study. We examined KRAS mutations in codons 12, 13, 61 and 146 (assessed by pyrosequencing), in relation to clinicopathological features, and tumor molecular markers, including BRAF and PIK3CA mutations, CpG island methylator phenotype (CIMP), LINE-1 methylation, and microsatellite instability (MSI). Survival analyses were performed in 1067 BRAF-wild-type cancers to avoid confounding by BRAF mutation. Cox proportional hazards models were used to compute mortality hazard ratio, adjusting for potential confounders, including disease stage, PIK3CA mutation, CIMP, LINE-1 hypomethylation, and MSI. Results: KRAS codon 61 mutations were detected in 19 cases (1.5%), and codon 146 mutations in 40 cases (3.2%). Overall KRAS mutation prevalence in colorectal cancers was 40% (=505/1267). Of interest, compared to KRAS-wild-type, overall, KRAS-mutated cancers more frequently exhibited cecal location (24% vs. 12% in KRAS-wild-type; P < 0.0001), CIMP-low (49% vs. 32% in KRAS-wild-type; P < 0.0001), and PIK3CA mutations (24% vs. 11% in KRAS-wild-type; P < 0.0001). These trends were evident irrespective of mutated codon, though statistical power was limited for codon 61 mutants. Neither KRAS codon 61 nor codon 146 mutation was significantly associated with clinical outcome or prognosis in univariate or multivariate analysis [colorectal cancer-specific mortality hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.29-2.26 for codon 61 mutation; colorectal cancer-specific mortality HR = 0.86, 95% CI = 0.42-1.78 for codon 146 mutation]. Conclusions: Tumors with KRAS mutations in codons 61 and 146 account for an appreciable proportion (approximately 5%) of colorectal cancers, and their clinicopathological and molecular features appear generally similar to KRAS codon 12 or 13 mutated cancers. To further assess clinical utility of KRAS codon 61 and 146 testing, large-scale trials are warranted