Carcinogenic Effects in a Phenylketonuria Mouse Model

Phenylketonuria (PKU) is a metabolic disorder caused by impaired phenylalanine hydroxylase (PAH). This condition results in hyperphenylalaninemia and elevated levels of abnormal phenylalanine metabolites, among which is phenylacetic acid/phenylacetate (PA). In recent years, PA and its analogs were found to have anticancer activity against a variety of malignancies suggesting the possibility that PKU may offer protection against cancer through chronically elevated levels of PA. We tested this hypothesis in a genetic mouse model of PKU (PAHenu2) which has a biochemical profile that closely resembles that of human PKU. Plasma levels of phenylalanine in homozygous (HMZ) PAHenu2 mice were >12-fold those of heterozygous (HTZ) littermates while tyrosine levels were reduced. Phenylketones, including PA, were also markedly elevated to the range seen in the human disease. Mice were subjected to 7,12 dimethylbenz[a]anthracene (DMBA) carcinogenesis, a model which is sensitive to the anticancer effects of the PA derivative 4-chlorophenylacetate (4-CPA). Tumor induction by DMBA was not significantly different between the HTZ and HMZ mice, either in total tumor development or in the type of cancers that arose. HMZ mice were then treated with 4-CPA as positive controls for the anticancer effects of PA and to evaluate its possible effects on phenylalanine metabolism in PKU mice. 4-CPA had no effect on the plasma concentrations of phenylalanine, phenylketones, or tyrosine. Surprisingly, the HMZ mice treated with 4-CPA developed an unexplained neuromuscular syndrome which precluded its use in these animals as an anticancer agent. Together, these studies support the use of PAHenu2 mice as a model for studying human PKU. Chronically elevated levels of PA in the PAHenu2 mice were not protective against cancer

Turkdean Roman Villa, Gloucestershire: archaeological investigations 1997-1998

Before the transmission of the first ‘live’ Time Team television programme on 23 August 1997, the existence of a Roman villa near Chalkhill Barn in the parish of Turkdean, 12 miles north-east of Cirencester and 2 miles from the Fosse Way, was hardly known to the archaeological community (FIG. 1). That a Roman building did exist in this location had, however, been suspected for a number of years by the landowner, the late Mr Wilf Mustoe. Distinctive linear parchmarks suggestive of buildings had been clearly visible at ground level in the grass pasture each dry summer, and in 1976 Mr Mustoe made a measured sketch plan of them on the back of an envelope. Subsequently the sketch was drawn up into a scale plan entitled ‘Roman villa’ by Simon Goddard, a relation. There was little knowledge of the site outside of Mr Mustoe's family until it was independently ‘discovered’ by local archaeologist Roger Box in August 1996 whilst fortuitously flying over the site in a helicopter. In the evening light Mr Box instantly recognised the parchmarks of an unmistakable Roman villa and took a series of photographs (FIG. 2). Mr Box showed his photographs to Mr Mustoe, and with his agreement wrote to Time Team suggesting that this would be an excellent site for a television programme. Arrangements were duly set in place and the evidence of the cropmarks was confirmed by a trial geophysical survey in March 199

Kožna dekontaminacija živčanoga bojnog otrova sarina s apsorpcijskim pripravkom u uvjetima in vivo

Our Institute’s nuclear, biological, and chemical defense research team continuously investigates and develops preparations for skin decontamination against nerve agents. In this in vivo study, we evaluated skin decontamination efficacy against sarin by a synthetic preparation called Mineral Cationic Carrier (MCC®) with known ion exchange, absorption efficacy and bioactive potential. Mice were treated with increasing doses of sarin applied on their skin, and MCC® was administered immediately after contamination. The results showed that decontamination with MCC® could achieve therapeutic efficacy corresponding to 3 x LD50 of percutaneous sarin and call for further research.Istraživački tim NBKO (nuklearno-biološko-kemijske obrane) radi na pronalasku i razvoju pripravka za dekontaminaciju kože od živčanih bojnih otrova. Cilj ovog istraživanja bio je ispitati dekontaminacijska svojstva (adsorpcijska i/ili kemisorpcijska) pripravka MCC® rabeći živčani bojni otrov sarin kao kožni kontaminant u uvjetima in vivo. MCC® je sintetski pripravak koji je biokemijski aktivan i ima ionskoizmjenjivačka i adsorpcijska svojstva. Istraživanje u uvjetima in vivo napravljeno je na miševima aplikacijom rastućih doza sarina na kožu životinje. Pripravak MCC® uporabljen je kao kožni dekontaminant neposredno nakon kožne kontaminacije sarinom. Istraživanja su pokazala da pripravak MCC® posjeduje adsorpcijska svojstva, ujedno važna za dekontaminaciju živčanih bojnih otrova. Eksperimenti u uvjetima in vivo na miševima (NOD-soj) pokazali su da se dekontaminacijom pripravkom MCC® može postići terapijski učinak od 3 LD50 (perkutano, sarin)

Pralidoxime in Acute Organophosphorus Insecticide Poisoning-A Randomised Controlled Trial

Background: Poisoning with organophosphorus (OP) insecticides is a major global public health problem, causing an estimated 200,000 deaths each year. Although the World Health Organization recommends use of pralidoxime, this antidote's effectiveness remains unclear. We aimed to determine whether the addition of pralidoxime chloride to atropine and supportive care offers benefit. Methods and Findings: We performed a double-blind randomised placebo-controlled trial of pralidoxime chloride (2 g loading dose over 20 min, followed by a constant infusion of 0.5 g/h for up to 7 d) versus saline in patients with organophosphorus insecticide self-poisoning. Mortality was the primary outcome; secondary outcomes included intubation, duration of intubation, and time to death. We measured baseline markers of exposure and pharmacodynamic markers of response to aid interpretation of clinical outcomes. Two hundred thirty-five patients were randomised to receive pralidoxime (121) or saline placebo (114). Pralidoxime produced substantial and moderate red cell acetylcholinesterase reactivation in patients poisoned by diethyl and dimethyl compounds, respectively. Mortality was nonsignificantly higher in patients receiving pralidoxime: 30/121 (24.8%) receiving pralidoxime died, compared with 18/114 (15.8%) receiving placebo (adjusted hazard ratio HR] 1.69, 95% confidence interval CI] 0.88-3.26, p = 0.12). Incorporating the baseline amount of acetylcholinesterase already aged and plasma OP concentration into the analysis increased the HR for patients receiving pralidoxime compared to placebo, further decreasing the likelihood that pralidoxime is beneficial. The need for intubation was similar in both groups (pralidoxime 26/121 21.5%], placebo 24/114 21.1%], adjusted HR 1.27 95% CI 0.71-2.29]). To reduce confounding due to ingestion of different insecticides, we further analysed patients with confirmed chlorpyrifos or dimethoate poisoning alone, finding no evidence of benefit. Conclusions: Despite clear reactivation of red cell acetylcholinesterase in diethyl organophosphorus pesticide poisoned patients, we found no evidence that this regimen improves survival or reduces need for intubation in patients with organophosphorus insecticide poisoning. The reason for this failure to benefit patients was not apparent. Further studies of different dose regimens or different oximes are required

Implementing a quality improvement programme in palliative care in care homes: a qualitative study

<p>Abstract</p> <p>Background</p> <p>An increasing number of older people reach the end of life in care homes. The aim of this study is to explore the perceived benefits of, and barriers to, implementation of the Gold Standards Framework for Care Homes (GSFCH), a quality improvement programme in palliative care.</p> <p>Methods</p> <p>Nine care homes involved in the GSFCH took part. We conducted semi-structured interviews with nine care home managers, eight nurses, nine care assistants, eleven residents and seven of their family members. We used the Framework approach to qualitative analysis. The analysis was deductive based on the key tasks of the GSFCH, the 7Cs: communication, coordination, control of symptoms, continuity, continued learning, carer support, and care of the dying. This enabled us to consider benefits of, and barriers to, individual components of the programme, as well as of the programme as a whole.</p> <p>Results</p> <p>Perceived benefits of the GSFCH included: improved symptom control and team communication; finding helpful external support and expertise; increasing staff confidence; fostering residents' choice; and boosting the reputation of the home. Perceived barriers included: increased paperwork; lack of knowledge and understanding of end of life care; costs; and gaining the cooperation of GPs. Many of the tools and tasks in the GSFCH focus on improving communication. Participants described effective communication within the homes, and with external providers such as general practitioners and specialists in palliative care. However, many had experienced problems with general practitioners. Although staff described the benefits of supportive care registers, coding predicted stage of illness and advance care planning, which included improved communication, some felt the need for more experience of using these, and there were concerns about discussing death.</p> <p>Conclusions</p> <p>Most of the barriers described by participants are relevant to other interventions to improve end of life care in care homes. There is a need to investigate the impact of quality improvement programmes in care homes, such as the GSFCH, on a wider range of outcomes for residents and their families, and to monitor the sustainability of any resulting improvements. It is also important to explore the impact of the different components of these complex interventions.</p

Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors

The differentiation stage of tumors is a central aspect in the histopathological classification of solid malignancies. The differentiation stage is strongly associated with tumor behavior, and generally an immature tumor is more aggressive than the more differentiated counterpart. While this is common knowledge in surgical pathology, the contribution of differentiation-related gene expression and functions to tumor behavior is often overlooked in the experimental, tumor biological setting. The mechanisms by which tumor cell differentiation stages are perturbed or affected are poorly explored but have recently come into focus with the introduction.of the tumor stem cell concept. While developmental biologists view the differentiation as a unidirectional event, pathologists and tumor biologists have introduced the concept of dedifferentiation to explain phenotypic changes occurring in solid tumors. In this review we discuss the impact of the tumor cell differentiation stage as used in surgical pathology. We further discuss knowledge gained from exploring the molecular basis of the differentiation and dedifferentiation processes in neuroblastoma and breast cancer, two tumor forms where the tumor cell differentiation concept is used in the clinical diagnostic work and where the tumor stem cell theory has been applied

Differential Loss and Retention of Cytoglobin, Myoglobin, and Globin-E during the Radiation of Vertebrates

If rates of postduplication gene retention are positively correlated with levels of functional constraint, then gene duplicates that have been retained in a restricted number of taxonomic lineages would be expected to exhibit relatively low levels of sequence conservation. Paradoxical patterns are presented by gene duplicates that have been retained in a small number of taxa but which are nonetheless subject to strong purifying selection relative to paralogous members of the same multigene family. This pattern suggests that such genes may have been co-opted for novel, lineage-specific functions. One possible example involves the enigmatic globin-E gene (GbE), which appears to be exclusively restricted to birds. Available data indicate that this gene is expressed exclusively in the avian eye, but its physiological function remains a mystery. In contrast to the highly restricted phyletic distribution of GbE, the overwhelming majority of jawed vertebrates (gnathostomes) possess copies of the related cytoglobin (Cygb) and myoglobin (Mb) genes. The purpose of the present study was 1) to assess the phyletic distribution of the Cygb, Mb, and GbE genes among vertebrates, 2) to elucidate the duplicative origins and evolutionary histories of these three genes, and 3) to evaluate the relative levels of functional constraint of these genes based on comparative sequence analysis. To accomplish these objectives, we conducted a combined phylogenetic and comparative genomic analysis involving taxa that represent each of the major lineages of gnathostome vertebrates. Results of synteny comparisons and phylogenetic topology tests revealed that GbE is clearly not the product of a recent, bird-specific duplication event. Instead, GbE originated via duplication of a proto-Mb gene in the stem lineage of gnathostomes. Unlike the Mb gene, which has been retained in all major gnathostome lineages other than amphibians, the GbE gene has been retained only in the lineage leading to modern birds and has been independently lost in at least four major lineages: teleost fish, amphibians, mammals, and nonavian reptiles. Despite the restricted phyletic distribution of this gene, our results indicate that GbE is one of the most highly conserved globins in the avian genome

Reverse logistics, stakeholders' influence, organizational slack, and managers' posture

Reverse logistics (RL) has strategic importance. However, little is known concerning what motivates firms to adopt RL systems. Drawing on stakeholder theory formulations, organizational slack, and the manager's strategic stance concept, this article develops a model that proposes external, internal, and individual factors that affect the implementation of RL programs. Our framework considers three major explicative variables: the attributes of the stakeholder (power, legitimacy and urgency), organizational slack for RL programs, and the manager's strategic posture. The study draws on a sample of 118 Spanish companies and uses a probit model to determine the influence of these factors on the probability of firms to implement RL systems. The study finds that customers, employees, and the government salience in terms of RL activities and manager's progressive posture have a significant influence on the final decision of implanting RL programs. Conversely, the study finds that shareholder salience negatively impacts the decision.Fundación BBVA and the project “Estrategias en las empresas europeas internacionales y medioambiente: análisis de recursos humanos, producción y negocio” for supporting this research. They also acknowledge the help of Prof. Dr. Carlos Larrinaga in providing access to financial statements. They are indebted as well to the Spanish Minister of Education and Science and the Comunidad Autónoma de Madrid which have provided financial support under the research projects entitled “Diseño e implantación de las estrategias medioambientales de aprovisionamiento, fabricación y comercialización: relación con el rendimiento organizativo” (sec2001-1578-c02- 01), “La dirección de operaciones y las teorías de stakeholders y de recursos y capacidades. Implicaciones estratégicas en la gestión del ciclo de vida de los equipos informáticos” (SEJ04- 07877-C02-02),. “Efectos de los distintos tipos de relaciones entre las empresas y sus mercados: prácticas de marketing, orientación al mercado y resultados económicos”, and “ Innovación versus imitacón: un test de la capacidad innovadora de las empresas de la Comunidad de Madrid “.Publicad