The relative roles of portal hypertension and of cirrhosis in the pathogenesis of pulmonary lesions associated with chronic liver disease

There have been numerous reports of cardiovascular and pulmonary abnormalities in patients with cirrhosis and portal hypertension. The role of portal hypertension in the pathogenesis of pulmonary abnormalities in patients with liver disease has not been defined. The present study was therefore undertaken to clarify this. Pulmonary function, including exercise testing, was evaluated in two groups of patients, 11 with portal hypertension due to cirrhosis and 10 with extrahepatic portal vein thrombosis and normal liver histology. Carbon monoxide gas transfer (TLCOsb) was less than 75% of predicted values in four patients from each group. One patient from each group had clinical and catheter confirmed evidence of pulmonary hypertension. Abnormal cardiorespiratory responses to exercise occurred in three patients in the extrahepatic group. Two had associated low TLCOsb and one developed arterial desaturation on exercise. A similar pattern was seen in three patients with cirrhosis. All had low TLCOsb and one developed arterial desaturation during exercise. In the cirrhotic group however three additional patients showed reduction in Pa02 unassociated with elevated heart rate response on exercise. There was no significant correlation with the presence of autoimmune antibodies which appear to be a secondary phenomenon. Our results suggest that pulmonary hypertension is linked to the presence of portal hypertension. Reduction in arterial P02, appears to occur only in patients with liver disease, presumably on the basis of intrapulmonary shunting

Cleaved intracellular SNARE peptides are implicated in a novel cytotoxicity mechanism of botulinum serotype C

Recent advances in intracellular protein delivery have enabled more in-depth analyses of cellular functions. A specialized family of SNARE proteases, known as Botulinum Neurotoxins, blocks neurotransmitter exocytosis, which leads to systemic toxicity caused by flaccid paralysis. These pharmaceutically valuable enzymes have also been helpful in the study of SNARE functions. As can be seen in Figure 1A, SNARE bundle formation causes vesicle docking at the presynapse. Although these toxins are systemically toxic, no known cytotoxic effects have been reported with the curious exception of the Botulinum serotype C [1]. This enzyme cleaves intracellular SNAP25, as does serotype A and E, but also, exceptionally, cleaves Syntaxin 1. Using an array of lipid and polymer transfection reagents we were able to deliver different combinations of Botulinum holoenzymes into the normally unaffected, Neuro2A, SH-SY5Y, PC12, and Min6 cells to analyze the individual contribution of each SNARE protein and their cleaved peptide products

Nano-biolistics: a method of biolistic transfection of cells and tissues using a gene gun with novel nanometer-sized projectiles.

BACKGROUND: Biolistic transfection is proving an increasingly popular method of incorporating DNA or RNA into cells that are difficult to transfect using traditional methods. The technique routinely uses 'microparticles', which are ~1 μm diameter projectiles, fired into tissues using pressurised gas. These microparticles are efficient at delivering DNA into cells, but cannot efficiently transfect small cells and may cause significant tissue damage, thus limiting their potential usefulness. Here we describe the use of 40 nm diameter projectiles--nanoparticles--in biolistic transfections to determine if they are a suitable alternative to microparticles. RESULTS: Examination of transfection efficiencies in HEK293 cells, using a range of conditions including different DNA concentrations and different preparation procedures, reveals similar behaviour of microparticles and nanoparticles. The use of nanoparticles, however, resulted in ~30% fewer damaged HEK293 cells following transfection. Biolistic transfection of mouse ear tissue revealed similar depth penetration for the two types of particles, and also showed that 20% in microparticle-transfected samples. Visualising details of small cellular structures was also considerably enhanced when using nanoparticles. CONCLUSIONS: We conclude that nanoparticles are as efficient for biolistic transfection as microparticles, and are more appropriate for use in small cells, when examining cellular structures and/or where tissue damage is a problem.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

The Market for Teacher Quality

Much of education policy focuses on improving teacher quality, but most policies lack strong research support. We use student achievement gains to estimate teacher value-added, our measure of teacher quality. The analysis reveals substantial variation in the quality of instruction, most of which occurs within rather than between schools. Although teacher quality appears to be unrelated to advanced degrees or certification, experience does matter -- but only in the first year of teaching. We also find that good teachers tend to be effective with all student ability levels but that there is a positive value of matching students and teachers by race. In the second part of the analysis, we show that teachers staying in our sample of urban schools tend to be as good as or better than those who exit. Thus, the main cost of large turnover is the introduction of more first year teachers. Finally, there is little or no evidence that districts that offer higher salaries and have better working conditions attract the higher quality teachers among those who depart the central city district. The overall results have a variety of direct policy implications for the design of school accountability and the compensation of teachers.

Hydrodynamic mean field solutions of 1D exclusion processes with spatially varying hopping rates

We analyze the open boundary partially asymmetric exclusion process with smoothly varying internal hopping rates in the infinite-size, mean field limit. The mean field equations for particle densities are written in terms of Ricatti equations with the steady-state current $J$ as a parameter. These equations are solved both analytically and numerically. Upon imposing the boundary conditions set by the injection and extraction rates, the currents $J$ are found self-consistently. We find a number of cases where analytic solutions can be found exactly or approximated. Results for $J$ from asymptotic analyses for slowly varying hopping rates agree extremely well with those from extensive Monte Carlo simulations, suggesting that mean field currents asymptotically approach the exact currents in the hydrodynamic limit, as the hopping rates vary slowly over the lattice. If the forward hopping rate is greater than or less than the backward hopping rate throughout the entire chain, the three standard steady-state phases are preserved. Our analysis reveals the sensitivity of the current to the relative phase between the forward and backward hopping rate functions.Comment: 12 pages, 4 figure

The application of chiroptical spectroscopy (circular dichroism) in quantifying binding events in lanthanide directed synthesis of chiral luminescent self-assembly structures

The binding of asymmetrical and optically pure tridentate ligands (L = 1(S) and 1(R)) containing one carboxylic group and 2-naphthyl as an antenna to lanthanide ions (M = La(III) and Eu(III)) was studied in CH3CN, showing the successive formation of M:L, M:L2 and M:L3 stoichiometric species in solution. The europium complexes EuL3 were also synthesised, structurally characterised and their photophysical properties probed in CH3OH and CH3CN. The changes in the chiroptical properties of both 1(S) and 1(R) were used (by circular dichroism (CD) spectroscopy) to monitor the formation of these chiral selfassemblies in solution. While circularly polarised luminescence (CPL) showed the formation of Eu(1(S))3 and Eu(1(R))3 as enantiomers, with high luminescence dissymmetry factors (glum), fitting the CD changes allowed for binding constants to be determined that were comparable to those seen in the analyses of absorbance and luminescence changes

Dating the time of viral subtype divergence

Precise dating of viral subtype divergence enables researchers to correlate divergence with geographic and demographic occurrences. When historical data are absent (that is, the overwhelming majority), viral sequence sampling on a time scale commensurate with the rate of substitution permits the inference of the times of subtype divergence. Currently, researchers use two strategies to approach this task, both requiring strong conditions on the molecular clock assumption of substitution rate. As the underlying structure of the substitution rate process at the time of subtype divergence is not understood and likely highly variable, we present a simple method that estimates rates of substitution, and from there, times of divergence, without use of an assumed molecular clock. We accomplish this by blending estimates of the substitution rate for triplets of dated sequences where each sequence draws from a distinct viral subtype, providing a zeroth-order approximation for the rate between subtypes. As an example, we calculate the time of divergence for three genes among influenza subtypes A-H3N2 and B using subtype C as an outgroup. We show a time of divergence approximately 100 years ago, substantially more recent than previous estimates which range from 250 to 3800 years ago

Apparent Size as the Determinant of Prey Selection by Bluegill Sunfish (Lepomis Macrochirus)

Copyright by the Ecological Society of America. This is the publisher's version, also available electronically from http://www.jstor.org/stable/1935055.Although it is known that visual predation by planktivorous fish tends to be size selective, the mechanism by which fish select their prey has not previously been described. Experiments in which bluegill sunfish (Lepomis macrochirus) were given a binary choice between prey of different sizes presented at different distances showed the fish selected the prey that appeared largest, either because of its actual size or its proximity to the fish. This paper incorporates this mechanism of prey selection by apparent size into a model of bluegill predation. According to the model, bluegill, in choosing the apparently largest prey under all conditions, alter their diet composition depending upon the abundance of prey. When prey are abundant, bluegill predominantly select prey of the largest size class available because these have the greatest probability of appearing largest; as large prey become scarce and smaller prey have a greater chance of appearing large, the fish tend to eat more prey from smaller size classes. When the model is tested against data from published fish-feeding experiments, the predicted size ratios of prey eaten correlate accurately with the observed ratios and numbers of prey eaten

Construction and Preliminary Characterization of a Series of Mouse and Rat Testis cDNA Libraries

We have constructed a series of 23 cDNA libraries from mouse and rat testicular cells. These include libraries made from whole, intact adult testes; seminiferous tubule cells from adult testes; combined populations of primary spermatocytes from 18‐day‐old mouse testes; and isolated populations of primitive type A spermatogonia, type A spermatogonia, type B spermatogonia, preleptotene spermatocytes, leptotene plus zygotene spermatocytes, juvenile pachytene spermatocytes, adult pachytene spermatocytes, round spermatids, Sertoli cells from 6‐, 8‐, 17‐, and 18–20‐day‐old mice, and peritubular cells from 18–20 day old mice, all recovered from outbred white Swiss (CD‐1) mice. We also constructed libraries from whole adult testes from five other lines of mice: C57 BI6/J, C3 HEB, BDF‐1, Balb/c, and 129 Sv. Finally, there are two libraries made from populations of Sertoli cells and peritubular cells isolated from testes of 20‐day‐old Sprague‐Dawley rats. Enzymatic dissociation, followed by gradient separation or plating/lysing techniques, was used to prepare populations of specific cell types in purities of 85–98%. cDNAs were synthesized from poly A+ mRNA primed with oligo dT and unidirectionally cloned into the lambda Uni‐Zap XR expression vector from Stratagene. Primary titers ranged from 2.1 ± 105 to 2.9 × 108 plaque‐forming units, and insert sizes averaged 1.0–1.2 kb. These libraries have been amplified once and submitted to the American Type Culture Collection (ATCC) for distribution to interested investigators. ATCC accession numbers are provided

Village-Integrated Eye Worker trial (VIEW): rationale and design of a cluster-randomised trial to prevent corneal ulcers in resource-limited settings.

IntroductionCorneal opacity is a leading cause of blindness worldwide. In resource-limited settings, untreated traumatic corneal abrasions may result in infection and ultimately, opacity. Although antimicrobial treatment of corneal ulcers may successfully cure infections, the scarring that accompanies the resolution of infection can still result in visual impairment. Prevention may be the optimal approach for reducing corneal blindness. Studies have employed community health workers to provide prompt administration of antimicrobials after corneal abrasions to prevent infections, but these studies were not designed to determine the effectiveness of such a programme.Methods and analysisThe Village-Integrated Eye Worker trial (VIEW) is a cluster-randomised trial designed to assess the effectiveness of a community health worker intervention to prevent corneal ulcers. Twenty-four Village Development Committees (VDCs) in Nepal were randomised to receive a corneal ulcer prevention programme or to no intervention. Female Community Health Volunteers (FCHVs) in intervention VDCs are trained to diagnose corneal abrasions, provide antimicrobials and to refer participants when needed. An annual census is conducted over 3 years in all study VDCs to assess the incidence of corneal ulceration via corneal photography (primary outcome). Masked outcome assessors grade corneal photographs to determine the presence or absence of incident corneal opacities. The primary analysis is negative binomial regression to compare the incidence of corneal ulceration by study arm.Ethics and disseminationThe University of California San Francisco Committee on Human Research, Nepal Netra Jyoti Sangh and the Nepal Health Research Council have given ethical approval for the trial. The results of this trial will be presented at local and international meetings and submitted to peer-reviewed journals for publication.Trial registration numberNCT01969786; Pre-results