Effects of Particle Size of Bulk Drug and food on the Bioavailability of U-78875 in Dogs

The effects of particle size and food on the absolute bioavailability of U-78875 in dogs after oral administration of either a suspension or tablet dosage form were investigated. A reduction of particle size caused a significant increase in bioavailability along with an increase in dissolution rate. Additionally, both suspension and tablet dosage forms administered after food caused an increase in bioavailability. Thus, to accelerate drug dissolution, a reduction of U-78875 particle size from the unmilled state is important for the optimization of formulation compositions. To increase the bioavailability of U-78875, postprandial dosing should be considered.     

State-of-the-Art on Wound Vitality Evaluation: A Systematic Review

The vitality demonstration refers to determining if an injury has been caused ante- or post-mortem, while wound age means to evaluate how long a subject has survived after the infliction of an injury. Histology alone is not enough to prove the vitality of a lesion. Recently, immunohistochemistry, biochemistry, and molecular biology have been introduced in the field of lesions vitality and age demonstration. The study was conducted according to the preferred reporting items for systematic review (PRISMA) protocol. The search terms were “wound”, “lesion”, “vitality”, “evaluation”, “immunohistochemistry”, “proteins”, “electrolytes”, “mRNAs”, and “miRNAs” in the title, abstract, and keywords. This evaluation left 137 scientific papers. This review aimed to collect all the knowledge on vital wound demonstration and provide a temporal distribution of the methods currently available, in order to determine the age of lesions, thus helping forensic pathologists in finding a way through the tangled jungle of wound vitality evaluation.     

CX3CL1 Action on Microglia Protects from Diet-Induced Obesity by Restoring POMC Neuronal Excitability and Melanocortin System Activity Impaired by High-Fat Diet Feeding

Both hypothalamic microglial inflammation and melanocortin pathway dysfunction contribute to diet-induced obesity (DIO) pathogenesis. Previous studies involving models of altered microglial signaling demonstrate altered DIO susceptibility with corresponding POMC neuron cytological changes, suggesting a link between microglia and the melanocortin system. We addressed this hypothesis using the specific microglial silencing molecule, CX3CL1 (fractalkine), to determine whether reducing hypothalamic microglial activation can restore POMC/melanocortin signaling to protect against DIO. We performed metabolic analyses in high fat diet (HFD)-fed mice with targeted viral overexpression of CX3CL1 in the hypothalamus. Electrophysiologic recording in hypothalamic slices from POMC-MAPT-GFP mice was used to determine the effects of HFD feeding and microglial silencing via minocycline or CX3CL1 on GFP-labeled POMC neurons. Finally, mice with hypothalamic overexpression of CX3CL1 received central treatment with the melanocortin receptor antagonist SHU9119 to determine whether melanocortin signaling is required for the metabolic benefits of CX3CL1. Hypothalamic overexpression of CX3CL1 increased leptin sensitivity and POMC gene expression, while reducing weight gain in animals fed an HFD. In electrophysiological recordings from hypothalamic slice preparations, HFD feeding was associated with reduced POMC neuron excitability and increased amplitude of inhibitory postsynaptic currents. Microglial silencing using minocycline or CX3CL1 treatment reversed these HFD-induced changes in POMC neuron electrophysiologic properties. Correspondingly, blockade of melanocortin receptor signaling in vivo prevented both the acute and chronic reduction in food intake and body weight mediated by CX3CL1. Our results show that suppressing microglial activation during HFD feeding reduces DIO susceptibility via a mechanism involving increased POMC neuron excitability and melanocortin signaling.     

Autotaxin Has a Negative Role in Systemic Inflammation

The pathogenesis of sepsis involves complex interactions and a systemic inflammatory response leading eventually to multiorgan failure. Autotaxin (ATX, ENPP2) is a secreted glycoprotein largely responsible for the extracellular production of lysophosphatidic acid (LPA), which exerts multiple effects in almost all cell types through its at least six G-protein-coupled LPA receptors (LPARs). Here, we investigated a possible role of the ATX/LPA axis in sepsis in an animal model of endotoxemia as well as in septic patients. Mice with 50% reduced serum ATX levels showed improved survival upon lipopolysaccharide (LPS) stimulation compared to their littermate controls. Similarly, mice bearing the inducible inactivation of ATX and presenting with >70% decreased ATX levels were even more protected against LPS-induced endotoxemia; however, no significant effects were observed upon the chronic and systemic transgenic overexpression of ATX. Moreover, the genetic deletion of LPA receptors 1 and 2 did not significantly affect the severity of the modelled disease, suggesting that alternative receptors may mediate LPA effects upon sepsis. In translation, ATX levels were found to be elevated in the sera of critically ill patients with sepsis in comparison with their baseline levels upon ICU admission. Therefore, the results indicate a role for ATX in LPS-induced sepsis and suggest possible therapeutic benefits of pharmacologically targeting ATX in severe, systemic inflammatory disorders.     

Modeling Lung Carcinoids with Zebrafish Tumor Xenograft

Lung carcinoids are neuroendocrine tumors that comprise well-differentiated typical (TCs) and atypical carcinoids (ACs). Preclinical models are indispensable for cancer drug screening since current therapies for advanced carcinoids are not curative. We aimed to develop a novel in vivo model of lung carcinoids based on the xenograft of lung TC (NCI-H835, UMC-11, and NCI-H727) and AC (NCI-H720) cell lines and patient-derived cell cultures in Tg(fli1a:EGFP)^y1 zebrafish embryos. We exploited this platform to test the anti-tumor activity of sulfatinib. The tumorigenic potential of TC and AC implanted cells was evaluated by the quantification of tumor-induced angiogenesis and tumor cell migration as early as 24 h post-injection (hpi). The characterization of tumor-induced angiogenesis was performed in vivo and in real time, coupling the tumor xenograft with selective plane illumination microscopy on implanted zebrafish embryos. TC-implanted cells displayed a higher pro-angiogenic potential compared to AC cells, which inversely showed a relevant migratory behavior within 48 hpi. Sulfatinib inhibited tumor-induced angiogenesis, without affecting tumor cell spread in both TC and AC implanted embryos. In conclusion, zebrafish embryos implanted with TC and AC cells faithfully recapitulate the tumor behavior of human lung carcinoids and appear to be a promising platform for drug screening.     

Electron Transfer in a Bio-Photoelectrode Based on Photosystem I Multilayer Immobilized on the Conducting Glass

A film of ~40 layers of partially oriented photosystem I (PSI) complexes isolated from the red alga Cyanidioschyzon merolae formed on the conducting glass through electrodeposition was investigated by time-resolved absorption spectroscopy and chronoamperometry. The experiments were performed at a range of electric potentials applied to the film and at different compositions of electrolyte solution being in contact with the film. The amount of immobilized proteins supporting light-induced charge separation (active PSI) ranged from ~10%, in the absence of any reducing agents (redox compounds or low potential), to ~20% when ascorbate and 2,6-dichlorophenolindophenol were added, and to ~35% when the high negative potential was additionally applied. The origin of the large fraction of permanently inactive PSI (65–90%) was unclear. Both reducing agents increased the subpopulation of active PSI complexes, with the neutral P700 primary electron donor, by reducing significant fractions of the photo-oxidized P700 species. The efficiencies of light-induced charge separation in the PSI film (10–35%) did not translate into an equally effective generation of photocurrent, whose internal quantum efficiency reached the maximal value of 0.47% at the lowest potentials. This mismatch indicates that the vast majority of the charge-separated states in multilayered PSI complexes underwent charge recombination.     

Harmonizing agriculture and health sector actions to improve household nutrition: policy experiences from Afghanistan (2002–2007)

Coordination across sectors to address undernutrition with its varied underlying causes remains a challenge in developing countries. In Afghanistan, harmonization of health and agriculture policies and actions to reduce endemic undernutrition occurred during 2002-2007. This qualitative case study explores the forms of harmonization, enabling features and constraints in the policy process. We interviewed 57 stakeholders (39 central level, 18 provincial) involved in public nutrition or food security issues. Forms of harmonization included written policies, reseach, training and advocacy. Important features of the policy process included: policy entrepreneurs with operational and strategic capacity, consensus-building using a shared causal framework, working groups and strategic alliances. This case presents an interesting alternative to a national nutrition coordinating body, an approach that has met with mixed results, often due to the lack of authority, budget, and operational capacity of such a body to oversee ministries and enforce national nutrition objectives. Mid-level professionals mobilized into task forces achieved much with the support of national and international partners. This study highlights the importance of building capacity for sustaining change through local institutions.     

Creep behavior of the ternary 95.5Sn-3.9Ag-0.6Cu solder—Part I: As-cast condition

The compression creep behavior was studied for the ternary solder alloy 95.5Sn-3.9Ag-0.6Cu in the as-cast condition. Samples were tested under stresses of 2–45 MPa and temperatures of −25–160°C. There was a significant variability in the creep curve shape, strain magnitude, and steady-state strain-rate properties. A multivariable linear-regression analysis of the steady-state strain-rate data, using the sinh-law stress representation, indicated two mechanisms distinguished by low- and high-temperature regimes of −25–75°C and 75–160°C, respectively. The sinh-law stress exponent (n) and apparent-activation energy (ΔH) in the −25–75°C regime were 4.4 ± 0.7 kJ/mol and 25 ± 7 kJ/mol (63% confidence intervals), respectively. Those same parameters in the 75–160°C regime were 5.2±0.8 kJ/mol and 95±14 kJ/mol, respectively, for the high-temperature regime. The values of ΔH suggested a short-circuit diffusion mechanism at low temperatures and a lattice or bulk-diffusion mechanism at high temperatures. The stress dependency of the steady-state strain rate did not indicate a strong power-law breakdown behavior or a threshold stress phenomenon. Cracks and grain-boundary sliding were not observed in any of the samples. As the creep temperature increased, a coarsened particle boundary and particle depletion zone formed in the region of fine Ag₃Sn particles that existed between the Sn-rich phase areas. The coarsened particle boundary, as well as accelerated coarsening of Ag₃Sn particles, were direct consequences of the creep deformation process.