A transgenic model for conditional induction and rescue of portal hypertension reveals a role of VEGF-mediated regulation of sinusoidal fenestrations

Portal hypertension (PH) is a common complication and a leading cause of death in patients with chronic liver diseases. PH is underlined by structural and functional derangement of liver sinusoid vessels and its fenestrated endothelium. Because in most clinical settings PH is accompanied by parenchymal injury, it has been difficult to determine the precise role of microvascular perturbations in causing PH. Reasoning that Vascular Endothelial Growth Factor (VEGF) is required to maintain functional integrity of the hepatic microcirculation, we developed a transgenic mouse system for a liver-specific-, reversible VEGF inhibition. The system is based on conditional induction and de-induction of a VEGF decoy receptor that sequesters VEGF and preclude signaling. VEGF blockade results in sinusoidal endothelial cells (SECs) fenestrations closure and in accumulation and transformation of the normally quiescent hepatic stellate cells, i.e. provoking the two processes underlying sinusoidal capillarization. Importantly, sinusoidal capillarization was sufficient to cause PH and its typical sequela, ascites, splenomegaly and venous collateralization without inflicting parenchymal damage or fibrosis. Remarkably, these dramatic phenotypes were fully reversed within few days from lifting-off VEGF blockade and resultant re-opening of SECs' fenestrations. This study not only uncovered an indispensible role for VEGF in maintaining structure and function of mature SECs, but also highlights the vasculo-centric nature of PH pathogenesis. Unprecedented ability to rescue PH and its secondary manifestations via manipulating a single vascular factor may also be harnessed for examining the potential utility of de-capillarization treatment modalities.

Factor Structure of the Neck Disability Index

BACKGROUND CONTEXT: The Neck Disability Index frequently is used to measure outcomes of the neck. The statistical rigor of the Neck Disability Index has been assessed with conflicting outcomes. To date, Confirmatory Factor Analysis of the Neck Disability Index has not been reported for a suitably large population study. Because the Neck Disability Index is not a condition-specific measure of neck function, initial Confirmatory Factor Analysis should consider problematic neck patients as a homogenous group. PURPOSE: We sought to analyze the factor structure of the Neck Disability Index through Confirmatory Factor Analysis in a symptomatic, homogeneous, neck population, with respect to pooled populations and gender subgroups. STUDY DESIGN: This was a secondary analysis of pooled data. PATIENT SAMPLE: A total of 1,278 symptomatic neck patients (67.5% female, median age 41 years), 803 nonspecific and 475 with whiplash-associated disorder. OUTCOME MEASURES: The Neck Disability Index was used to measure outcomes. METHODS: We analyzed pooled baseline data from six independent studies of patients with neck problems who completed Neck Disability Index questionnaires at baseline. The Confirmatory Factor Analysis was considered in three scenarios: the full sample and separate sexes. Models were compared empirically for best fit. RESULTS: Two-factor models have good psychometric properties across both the pooled and sex subgroups. However, according to these analyses, the one-factor solution is preferable from both a statistical perspective and parsimony. The two-factor model was close to significant for the male subgroup (p<.07) where questions separated into constructs of mental function (pain, reading headaches and concentration) and physical function (personal care, lifting, work, driving, sleep, and recreation). CONCLUSIONS: The Neck Disability Index demonstrated a one-factor structure when analyzed by Confirmatory Factor Analysis in a pooled, homogenous sample of neck problem patients. However, a two-factor model did approach significance for male subjects where questions separated into constructs of mental and physical function. Further investigations in different conditions, subgroup and sex-specific populations are warranted.

Analgesic activity of a non-peptide imidazolidinedione somatostatin agonist: in vitro and in vivo studies in rat

Several lines of evidence support an important role for somatostatin receptors (SSTRs) in pain modulation. The therapeutic use of established SSTR peptide agonists for this indication is limited by their broad range of effects, need for intrathecal delivery, and short half-life. Therefore, the goal of the present study was to investigate the analgesic effect of SCR007, a new, highly selective SSTR2 non-peptide agonist. Behavioral studies demonstrated that paw withdrawal latencies to heat were significantly increased following intraplantar SCR007. Furthermore, both intraperitoneal and intraplantar injection of SCR007 significantly reduced formalin- and capsaicin-induced flinching and lifting/licking nociceptive behaviors. Recordings from nociceptors using an in vitro glabrous skin-nerve preparation showed that SCR007 reduced heat responses in a dose-dependent fashion, bradykinin-induced excitation, heat sensitization and capsaicin-induced excitation. In both the behavioral and single fiber studies, the SCR007 effects were reversed by the SSTR antagonist cyclo-somatostatin, demonstrating receptor specificity. In the single fiber studies, the opioid antagonist naloxone did not reverse SCR007-induced anti-nociception suggesting that SCR007 did not exert its effects through activation of opioid receptors. Analysis of cAMP/protein kinase A (PKA) involvement demonstrated that SCR007 prevented forskolin- and Sp-8-Br-cAMPS (a PKA activator)-induced heat sensitization, supporting the hypothesis that SCR007-induced inhibition could involve a down-regulation of the cAMP/PKA pathway. These data provide several lines of evidence that the non-peptide imidazolidinedione SSTR2 agonist SCR007 is a promising anti-nociceptive and analgesic agent for the treatment of pain of peripheral and/or central origin.

Evidence and structural mechanism for late lung alveolarization

According to the current view, the formation of new alveolar septa from preexisting ones ceases due to the reduction of a double- to a single-layered capillaries network inside the alveolar septa (microvasculature maturation postnatal days 14-21 in rats). We challenged this view by measuring stereologically the appearance of new alveolar septa and by studying the alveolar capillary network in three-dimensional (3-D) visualizations obtained by high-resolution synchrotron radiation X-ray tomographic microscopy. We observed that new septa are formed at least until young adulthood (rats, days 4-60) and that roughly half of the new septa are lifted off of mature septa containing single-layered capillary networks. At the basis of newly forming septa, we detected a local duplication of the capillary network. We conclude that new alveoli may be formed in principle at any time and at any location inside the lung parenchyma and that lung development continues into young adulthood. We define two phases during developmental alveolarization. Phase one (days 4-21), lifting off of new septa from immature preexisting septa, and phase two (day 14 through young adulthood), formation of septa from mature preexisting septa. Clinically, our results ask for precautions using drugs influencing structural lung development during both phases of alveolarization.

Water harvesting: guidelines to good practice

These guidelines provide an overview of proven good practice in water harvesting from all over the world. They form a practical reference guide while providing support and specific technical expertise for the integration of water harvesting technologies into the planning and design of projects. Thus existing information and experience is strengthened. On a broader scale, the guidelines’ objective is to facilitate, share and upscale good practice in water harvesting given the state of current knowledge. Targeted end users include local and regional planners / advisors, rural development consultants, rainwater harvesting networks and communitiesof- practice, project managers, extension agents and other implementing staff. Through informing these professionals, the aim is to stimulate discussion and new thinking about improved water management in general, and water harvesting in particular, within rainfed agriculture, particularly in the drylands. The ultimate goal is to contribute to lifting 80 million rural people out of poverty by 2015: water security is a prerequisite to achieve food security for these people.

Compressive strength of elderly vertebrae is reduced by disc degeneration and additional flexion

Computer tomography (CT)-based finite element (FE) models assess vertebral strength better than dual energy X-ray absorptiometry. Osteoporotic vertebrae are usually loaded via degenerated intervertebral discs (IVD) and potentially at higher risk under forward bending, but the influences of the IVD and loading conditions are generally overlooked. Accordingly, magnetic resonance imaging was performed on 14 lumbar discs to generate FE models for the healthiest and most degenerated specimens. Compression, torsion, bending, flexion and extension conducted experimentally were used to calibrate both models. They were combined with CT-based FE models of 12 lumbar vertebral bodies to evaluate the effect of disc degeneration compared to a loading via endplates embedded in a stiff resin, the usual experimental paradigm. Compression and lifting were simulated, load and damage pattern were evaluated at failure. Adding flexion to the compression (lifting) and higher disc degeneration reduces the failure load (8–14%, 5–7%) and increases damage in the vertebrae. Under both loading scenarios, decreasing the disc height slightly increases the failure load; embedding and degenerated IVD provides respectively the highest and lowest failure load. Embedded vertebrae are more brittle, but failure loads induced via IVDs correlate highly with vertebral strength. In conclusion, osteoporotic vertebrae with degenerated IVDs are consistently weaker—especially under lifting, but clinical assessment of their strength is possible via FE analysis without extensive disc modelling, by extrapolating measures from the embedded situation.

The impact of pelvic venous pressure on blood loss during open radical cystectomy and urinary diversion: Results from a secondary analysis of a randomized clinical trial

PURPOSE Blood loss and blood substitution are associated with higher morbidity after major abdominal surgery. During major liver resection, low local venous pressure, has been shown to reduce blood loss. Ambiguity persists concerning the impact of local venous pressure on blood loss during open radical cystectomy. We aimed to determine the association between intraoperative blood loss and pelvic venous pressure (PVP) and determine factors affecting PVP. MATERIAL AND METHODS In the frame of a single-center, double-blind, randomized trial, PVP was measured in 82 patients from a norepinephrine/low-volume group and in 81 from a control group with liberal hydration. For this secondary analysis, patients from each arm were stratified into subgroups with PVP <5 mmHg or ≥5 mmHg measured after cystectomy (optimal cut-off value for discrimination of patients with relevant blood loss according to the Youden's index). RESULTS Median blood loss was 800 ml [range: 300-1600] in 55/163 patients (34%) with PVP <5 mmHg and 1200 ml [400-3000] in 108/163 patients (66%) with PVP ≥5 mmHg; (P<0.0001). A PVP <5 mmHg was measured in 42/82 patients (51%) in the norepinephrine/low-volume group and 13/81 (16%) in the control group (P<0.0001). PVP dropped significantly after removal of abdominal packing and abdominal lifting in both groups at all time points (at begin and end of pelvic lymph node dissection, end of cystectomy) (P<0.0001). No correlation between PVP and central venous pressure could be detected. CONCLUSIONS Blood loss was significantly reduced in patients with low PVP. Factors affecting PVP were fluid management and abdominal packing.

Reconstruction and electrochemical oxidation of Au(110) surface in 0.1 M H2SO4

Variations of the surface structure and composition of the Au(110) electrode during the formation/lifting of the surface reconstruction and during the surface oxidation/reduction in 0.1 M aqueous sulfuric acid were studied by cyclic voltammetry, scanning tunneling microscopy and shell-isolated nanoparticle enhanced Raman spectroscopy. Annealing of the Au(110) electrode leads to a thermally-induced reconstruction formed by intermixed (1×3) and (1×2) phases. In a 0.1 M H2SO4 solution, the decrease of the potential of the atomically smooth Au(110)-(1×1) surface leads to the formation of a range of structures with increasing surface corrugation. The electrochemical oxidation of the Au(110) surface starts by the formation of anisotropic atomic rows of gold oxide. At higher potentials we observed a disordered structure of the surface gold oxide, similar to the one found for the Au(111) surface.

Climatology of Vb cyclones, physical mechanisms and their impact on extreme precipitation over Central Europe

Cyclones, which develop over the western Mediterranean and move northeastward are a major source of extreme weather and known to be responsible for heavy precipitation over the northern side of the Alpine range and Central Europe. As the relevant processes triggering these so-called Vb events and their impact on extreme precipitation are not yet fully understood, this study focuses on gaining insight into the dynamics of past events. For this, a cyclone detection and tracking tool is applied to the ERA-Interim reanalysis (1979–2013) to identify prominent Vb situations. Precipitation in the ERA-Interim and the E-OBS data sets is used to evaluate case-to-case precipitation amounts and to assess consistency between the two data sets. Both data sets exhibit high variability in precipitation amounts among different Vb events. While only 23 % of all Vb events are associated with extreme precipitation, around 15 % of all extreme precipitation days (99 percentile) over the northern Alpine region and Central Europe are induced by Vb events, although Vb cyclones are rare events (2.3 per year). To obtain a better understanding of the variability within Vb events, the analysis of the 10 heaviest and lowest precipitation Vb events reveals noticeable differences in the state of the atmosphere. These differences are most pronounced in the geopotential height and potential vorticity field, indicating a much stronger cyclone for heavy precipitation events. The related differences in wind direction are responsible for the moisture transport around the Alps and the orographical lifting along the northern slopes of the Alps. These effects are the main reasons for a disastrous outcome of Vb events, and consequently are absent in the Vb events associated with low precipitation. Hence, our results point out that heavy precipitation related to Vb events is mainly related to large-scale dynamics rather than to thermodynamic processes.

Probing the moduli dependence of refined topological amplitudes

With the aim of providing a worldsheet description of the refined topological string, we continue the study of a particular class of higher derivative couplings Fg,n in the type II string effective action compactified on a Calabi–Yau threefold. We analyse first order differential equations in the anti-holomorphic moduli of the theory, which relate the Fg,n to other component couplings. From the point of view of the topological theory, these equations describe the contribution of non-physical states to twisted correlation functions and encode an obstruction for interpreting the Fg,n as the free energy of the refined topological string theory. We investigate possibilities of lifting this obstruction by formulating conditions on the moduli dependence under which the differential equations simplify and take the form of generalised holomorphic anomaly equations. We further test this approach against explicit calculations in the dual heterotic theory.

Electrostatic sampling of trace DNA from clothing.

During acts of physical aggression, offenders frequently come into contact with clothes of the victim, thereby leaving traces of DNA-bearing biological material on the garments. Since tape-lifting and swabbing, the currently established methods for non-destructive trace DNA sampling from clothing, both have their shortcomings in collection efficiency and handling, we thought about a new collection method for these challenging samples. Testing two readily available electrostatic devices for their potential to sample biological material from garments made of different fabrics, we found one of them, the electrostatic dust print lifter (DPL), to perform comparable to well-established sampling with wet cotton swabs. In simulated aggression scenarios, we had the same success rate for the establishment of single aggressor profiles, suitable for database submission, with both the DPL and wet swabbing. However, we lost a substantial amount of information with electrostatic sampling, since almost no mixed aggressor-victim profiles suitable for database entry could be established, compared to conventional swabbing. This study serves as a proof of principle for electrostatic DNA sampling from items of clothing. The technique still requires optimization before it might be used in real casework. But we are confident that in the future it could be an efficient and convenient contribution to the toolbox of forensic practitioners.