Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

Background: The development of effective therapies for acute liver failure (ALF) is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method: 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results: Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n=4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8+/-5.9 vs 59+/-2.0 mmHg), increased cardiac output (7.26+/-1.86 vs 3.30+/-0.40 l/min) and decreased systemic vascular resistance (8.48+/-2.75 vs 16.2+/-1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636+/-95 vs 301+/-26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23+/-0.05 vs 7.45+/-0.02) and prothrombin time (36+/-2 vs 8.9+/-0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5+/-210 vs 42+/-8.14) coincided with a marked reduction in serum albumin (11.5+/-1.71 vs 25+/-1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2+/-36.5 vs 131.6+/-9.33 mumol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06. Conclusion: We have developed a reproducible large animal model of acetaminophen-induced liver failure, which allows in-depth investigation of the pathophysiological basis of this condition. Furthermore, this represents an important large animal model for testing artificial liver support systems

Effect of Dietary Components on Larval Life History Characteristics in the Medfly (Ceratitis capitata: Diptera, Tephritidae)

Background: The ability to respond to heterogenous nutritional resources is an important factor in the adaptive radiation of insects such as the highly polyphagous Medfly. Here we examined the breadth of the Medfly’s capacity to respond to different developmental conditions, by experimentally altering diet components as a proxy for host quality and novelty. Methodology/Principal Findings: We tested responses of larval life history to diets containing protein and carbohydrate components found in and outside the natural host range of this species. A 40% reduction in the quantity of protein caused a significant increase in egg to adult mortality by 26.5%±6% in comparison to the standard baseline diet. Proteins and carbohydrates had differential effects on larval versus pupal development and survival. Addition of a novel protein source, casein (i.e. milk protein), to the diet increased larval mortality by 19.4%±3% and also lengthened the duration of larval development by 1.93±0.5 days in comparison to the standard diet. Alteration of dietary carbohydrate, by replacing the baseline starch with simple sugars, increased mortality specifically within the pupal stage (by 28.2%±8% and 26.2%±9% for glucose and maltose diets, respectively). Development in the presence of the novel carbohydrate lactose (milk sugar) was successful, though on this diet there was a decrease of 29.8±1.6 µg in mean pupal weight in comparison to pupae reared on the baseline diet. Conclusions: The results confirm that laboratory reared Medfly retain the ability to survive development through a wide range of fluctuations in the nutritional environment. We highlight new facets of the responses of different stages of holometabolous life histories to key dietary components. The results are relevant to colonisation scenarios and key to the biology of this highly invasive species

Paecilomyces lilacinus causing debilitating sinusitis in an immunocompetent patient: a case report

<p>Abstract</p> <p>Introduction</p> <p>Since the discovery of the first documented case of <it>Paecilomyces </it>in 1963, only five cases of <it>Paecilomyces </it>sinusitis have been described to date and all of them have predisposing factors such as immunocompromised status or prior nasal surgery. We present the first case of <it>Paecilomyces lilacinus </it>sinusitis in a fit young woman with no identified predisposing factors. To the best of our knowledge, this is the first known case in the UK and in Europe.</p> <p>Case presentation</p> <p>A 20-year-old Iraqi woman who has lived in the UK for the past five years presented with rhinorrhea, hyposmia, and nasal obstruction. She was previously fit and well and had no significant medical history. Imaging revealed a fungal infection that was eventually revealed on cytological examination to be <it>P. lilacinus</it>.</p> <p>Conclusions</p> <p><it>P. lilacinus </it>is both a difficult and important organism to identify because it has intrinsic anti-fungal resistance. In our case, the infection was severe and recurrent, and the organism demonstrated resistance to common oral anti-fungal agents. There was a delay in its diagnosis, owing to its similarity in appearance to <it>Penicillium </it>and a difficulty in distinguishing between the two without specialized knowledge of fungal taxonomy. In the field of otolaryngology, <it>Paecilomyces </it>is relatively unknown. Our intention is to raise awareness of this organism as well as to describe the challenges in its management.</p

A new family of giardial cysteine-rich non-VSP protein genes and a novel cyst protein

© 2006 Davids et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The definitive version was published in PLoS ONE 1 (2006): e44, doi:10.1371/journal.pone.0000044.Since the Giardia lamblia cyst wall is necessary for survival in the environment and host infection, we tested the hypothesis that it contains proteins other than the three known cyst wall proteins. Serial analysis of gene expression during growth and encystation revealed a gene, “HCNCp” (High Cysteine Non-variant Cyst protein), that was upregulated late in encystation, and that resembled the classic Giardia variable surface proteins (VSPs) that cover the trophozoite plasmalemma. HCNCp is 13.9% cysteine, with many “CxxC” tetrapeptide motifs and a transmembrane sequence near the C-terminus. However, HCNCp has multiple “CxC” motifs rarely found in VSPs, and does not localize to the trophozoite plasmalemma. Moreover, the HCNCp C-terminus differed from the canonical VSP signature. Full-length epitope-tagged HCNCp expressed under its own promoter was upregulated during encystation with highest expression in cysts, including 42 and 21 kDa C-terminal fragments. Tagged HCNCp targeted to the nuclear envelope in trophozoites, and co-localized with cyst proteins to encystation-specific secretory vesicles during encystation. HCNCp defined a novel trafficking pathway as it localized to the wall and body of cysts, while the cyst proteins were exclusively in the wall. Unlike VSPs, HCNCp is expressed in at least five giardial strains and four WB subclones expressing different VSPs. Bioinformatics identified 60 additional large high cysteine membrane proteins (HCMp) containing ≥20 CxxC/CxC's lacking the VSP-specific C-terminal CRGKA. HCMp were absent or rare in other model or parasite genomes, except for Tetrahymena thermophila with 30. MEME analysis classified the 61 gHCMp genes into nine groups with similar internal motifs. Our data suggest that HCNCp is a novel invariant cyst protein belonging to a new HCMp family that is abundant in the Giardia genome. HCNCp and the other HCMp provide a rich source for developing parasite-specific diagnostic reagents, vaccine candidates, and subjects for further research into Giardia biology

Percutaneous Exposure Incidents of the Health Care Personnel in a Newly Founded Tertiary Hospital: A Prospective Study

BACKGROUND: Percutaneous exposure incidents (PEIs) and blood splashes on the skin of health care workers are a major concern, since they expose susceptible employees to the risk of infectious diseases. We undertook this study in order to estimate the overall incidence of such injuries in a newly founded tertiary hospital, and to evaluate possible changes in their incidence over time. METHODOLOGY/PRINCIPAL FINDINGS: We prospectively studied the PEIs and blood splashes on the skin of employees in a newly founded (October 2000) tertiary hospital in Athens, Greece, while a vaccination program against hepatitis B virus, as well as educational activities for avoidance of injuries, were taking place. The study period ranged from October 1, 2002 to February 28, 2005. Serologic studies for hepatitis B (HBV) and C virus (HCV) as well as human immunodeficiency virus (HIV) were performed in all injured employees and the source patients, when known. High-titer immunoglobulin (250 IU anti-HBs intramuscularly) and HBV vaccination were given to non-vaccinated or previously vaccinated but serologically non-responders after exposure. Statistical analysis of the data was performed using Mc Nemar's and Fisher's tests. 60 needlestick, 11 sharp injuries, and two splashes leading to exposure of the skin or mucosa to blood were reported during the study period in 71 nurses and two members of the cleaning staff. The overall incidence (percutaneous injuries and splashes) per 100 full-time employment-years (100 FTEYs) for high-risk personnel (nursing, medical, and cleaning staff) was 3.48, whereas the incidence of percutaneous injuries (needlestick and sharp injuries) alone per 100 FTEYs was 3.38. A higher incidence of injuries was noted during the first than in the second half of the study period (4.67 versus 2.29 per 100 FTEYs, p = 0.005). No source patient was found positive for HCV or HIV. The use of high-titer immunoglobulin after adjustment for the incidence of injuries was higher in the first than in the second half of the study period, although the difference was not statistically significant [9/49 (18.37%) vs 1/24 (4.17%), p = 0.15]. CONCLUSIONS/SIGNIFICANCE: Our data show that nurses are the healthcare worker group that reports most of PEIs. Doctors did not report such injuries during the study period in our setting. However, the possibility of even relatively frequent PEIs in doctors cannot be excluded. This is due to underreporting of such events that has been previously described for physicians and surgeons. A decrease of the incidence of PEIs occurred during the operation of this newly founded hospital

Sales promotions and channel coordination

Consumer sales promotions are usually the result of the decisions of two marketing channel parties, the manufacturer and the retailer. In making these decisions, each party normally follows its own interest: i.e. maximizes its own profit. Unfortunately, this results in a suboptimal outcome for the channel as a whole. Independent profit maximization by channel parties leads to a lack of channel coordination with the implication of leaving money on the table. This may well contribute to the notoriously low profitability of sales promotions. This paper first shows analytically why the suboptimality occurs, and then presents an empirical demonstration, using a unique dataset from an Efficient Consumer Response (ECR) project; ECR is a movement in which parties work together to optimize the distribution channel). In this dataset, actual profit is only a small fraction of potential profit, implying that there is a large degree of suboptimality. It is important that (1) channel parties are aware of this suboptimality; and (2) that they have tools to deal with it. Solutions to the channel coordination problem should ensure that the goals of the individual channel parties are aligned with the goals of the channel as a whole. The paper proposes one particular agreement for this purpose, called proportional discount sharing. Application to the ECR data shows a win-win result for both the manufacturer and the retailer. Recognition of the channel coordination problem by the manufacturer and the retailer is the necessary starting point for agreeing on a way of solving it in a win-win fashion

Statins in Candidemia: clinical outcomes from a matched cohort study

<p>Abstract</p> <p>Background</p> <p>HMG CoA reductase inhibitors (statins) in patients with bacteremic sepsis have shown significant survival benefits in several studies. There is no data on the effect of statins in candidemic patients, however in-vitro models suggest that statins interfere with ergesterol formation in the wall of yeasts.</p> <p>Methods</p> <p>This retrospective matched- cohort study from 1/2003 to 12/2006 evaluated the effects of statins on patients with candidemia within intensive care units. Statin-users had candidemia as a cause of their systemic inflammatory response and were on statins throughout their antifungal therapy, while non-statin users were matched based on age +/- 5 years and co-morbid factors. Primary analysis was 30-day survival or discharge using bivariable comparisons. Multivariable comparisons were completed using conditional logistic regression. All variables with a p-value less than 0.10 in the bivariable comparisons were considered for inclusion in the conditional logistic model.</p> <p>Results</p> <p>There were 15 statin-users and 30 non-statin users that met inclusion criteria, all with similar demographics and co-morbid conditions except the statin group had more coronary artery disease (P < 0.01) and peripheral vascular disease (P = 0.03) and lower median APCAHE II scores (14.6 vs 17, p = 0.03). There were no differences in duration of candidemia, antifungal therapy or <it>Candida </it>species between the groups. Statins were associated with lower mortality on bivariable (OR 0.09, 95% CI 0.11-0.75, p = 0.03) and multivariable (OR 0.22, 95% CI 0.02-2.4, p = 0.21) analyses compared to controls; although, in the latter the protective effect lacked statistical signficance.</p> <p>Conclusion</p> <p>In our small, single-center matched-cohort study, statins may provide a survival benefit in candidemia, however further studies are warranted to validate and further explore this association.</p

Segmental correction of adolescent idiopathic scoliosis by all-screw fixation method in adolescents and young adults. minimum 5 years follow-up with SF-36 questionnaire

<p>Abstract</p> <p>Background</p> <p>In our institution, the fixation technique in treating idiopathic scoliosis was shifted from hybrid fixation to the all-screw method beginning in 2000. We conducted this study to assess the intermediate -term outcome of all-screw method in treating adolescent idiopathic scoliosis (AIS).</p> <p>Methods</p> <p>Forty-nine consecutive patients were retrospectively included with minimum of 5-year follow-up (mean, 6.1; range, 5.1-7.3 years). The average age of surgery was 18.5 ± 5.0 years. We assessed radiographic measurements at preoperative (Preop), postoperative (PO) and final follow-up (FFU) period. Curve correction rate, correction loss rate, complications, accuracy of pedicle screws and SF-36 scores were analyzed.</p> <p>Results</p> <p>The average major curve was corrected from 58.0 ± 13.0° Preop to 16.0 ± 9.0° PO(<it>p </it>< 0.0001), and increased to 18.4 ± 8.6°(<it>p </it>= 0.12) FFU. This revealed a 72.7% correction rate and a correction loss of 2.4° (3.92%). The thoracic kyphosis decreased little at FFU (22 ± 12° to 20 ± 6°, (<it>p </it>= 0.25)). Apical vertebral rotation decreased from 2.1 ± 0.8 PreOP to 0.8 ± 0.8 at FFU (Nash-Moe grading, <it>p </it>< 0.01). Among total 831 pedicle screws, 56 (6.7%) were found to be malpositioned. Compared with 2069 age-matched Taiwanese, SF-36 scores showed inferior result in 2 variables: physical function and role physical.</p> <p>Conclusion</p> <p>Follow-up more than 5 years, the authors suggest that all-screw method is an efficient and safe method.</p

Measurement of the branching fraction and CP content for the decay B(0) -> D(*+)D(*-)

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APS.We report a measurement of the branching fraction of the decay B0→D*+D*- and of the CP-odd component of its final state using the BABAR detector. With data corresponding to an integrated luminosity of 20.4  fb-1 collected at the Υ(4S) resonance during 1999–2000, we have reconstructed 38 candidate signal events in the mode B0→D*+D*- with an estimated background of 6.2±0.5 events. From these events, we determine the branching fraction to be B(B0→D*+D*-)=[8.3±1.6(stat)±1.2(syst)]×10-4. The measured CP-odd fraction of the final state is 0.22±0.18(stat)±0.03(syst).This work is supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the A.P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation