Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer

Pre-clinical and retrospective studies of patients using statins to reduce plasma cholesterol have suggested that statins may be useful to treat cancer. However, prospective clinical trials have yet to demonstrate significant efficacy. We have previously shown that this is in part because a hydrophobic statin with a long half-life is necessary. Pitavastatin, the only statin with this profile, has not undergone clinical evaluation in oncology. The target of pitavastatin, hydroxymethylglutarate coenzyme-A reductase (HMGCR), was found to be over-expressed in all ovarian cancer cell lines examined and upregulated by mutated TP53, a gene commonly altered in ovarian cancer. Pitavastatin-induced apoptosis was blocked by geranylgeraniol and mevalonate, products of the HMGCR pathway, confirming that pitavastatin causes cell death through inhibition of HMGCR. Solvent extracts of human and mouse food were also able to block pitavastatin-induced apoptosis, suggesting diet might influence the outcome of clinical trials. When nude mice were maintained on a diet lacking geranylgeraniol, oral pitavastatin caused regression of Ovcar-4 tumour xenografts. However, when the animal diet was supplemented with geranylgeraniol, pitavastatin failed to prevent tumour growth. This suggests that a diet containing geranylgeraniol can limit the anti-tumour activity of pitavastatin and diet should be controlled in clinical trials of statins

Cost-effectiveness of high dose versus adjuvanted trivalent influenza vaccines in England and Wales

Aims: High dose trivalent influenza vaccine (HD TIV) and adjuvant TIV (aTIV) have been developed specifically for adults aged 65 and older (65+) who are at high risk of life-threatening complications. However, there is a scarcity of evidence comparing the clinical and cost-effectiveness of HD TIV and aTIV. The aim of this study was to determine the cost-effectiveness of HD TIV versus aTIV in the England and Wales 65+ population. Methods: A cost-utility analysis was conducted using a decision tree with two influenza related outcomes: Laboratory confirmed cases that could result in GP consultation, and hospitalizations that may result in premature mortality. Due to a lack of comparative evidence, the effectiveness of HD TIV versus aTIV was calculated indirectly, based on relative effectiveness estimates for each vaccine versus a common comparator, standard dose (SD) TIV. The primary analysis included hospitalizations explicitly due to influenza/pneumonia. Cost-effectiveness was established for three scenarios applying differing relative effectiveness estimates for aTIV versus SD TIV. Uncertainty was analysed in one-way deterministic sensitivity analyses. A secondary analysis included hospitalizations due to any respiratory illness. Results: The minimum population impact of vaccination with HD TIV rather than aTIV was 13,092 fewer influenza cases, 1,109 fewer influenza related deaths, 4,673 fewer hospitalizations, and 3,245 fewer GP appointments. HD TIV was cost-effective versus aTIV for all three effectiveness scenarios, with incremental cost-effectiveness ratios (ICER) equal to £1,932, £4,181, and £8,767 per quality adjusted life year. Results were consistent across the secondary analysis and deterministic sensitivity analyses. Limitations: The analysis was limited by a lack of robust and consistent effectiveness data for aTIV. Conclusion: HD TIV is cost-effective versus aTIV in people aged 65+ in England and Wales. Use of HD TIV over aTIV could increase clinical benefits and reduce the public health and economic burden of influenza

Idiopathic adult intussusception

Intussusception is an uncommon cause of abdominal pain in adults and poses diagnostic challenges for emergency physicians, due to its varied presenting symptoms and time course. Diagnosis is thus often delayed and results in surgical intervention due to the development of bowel ischaemia. We report on a young patient who presented with an ileo-ileal intussusception in whom there were no underlying lesions identified as a causal factor

OPV strains circulation in HIV infected infants after National Immunisation Days in Bangui, Central African Republic

<p>Abstract</p> <p>Background</p> <p>Humans are the only host of polioviruses, thus the prospects of global polio eradication look reasonable. However, individuals with immunodeficiencies were shown to excrete vaccine derived poliovirus for long periods of time which led to reluctance to prolong the vaccination campaign for fear of this end result. Therefore, we aimed to assess the duration of excretion of poliovirus after the 2001 National Immunization Days according to Human immunodeficiency virus status.</p> <p>Findings</p> <p>Fifty three children were enrolled. Sequential stool samples were collected in between National Immunisation Days rounds and then every month during one year. Children were classified into 2 groups: no immunodepression (n = 38), immunodepression (n = 15) according to CD4+ lymphocytes cells count. Thirteen poliovirus strains were isolated from 11 children: 5 Human immunodeficiency virus positive and 6 Human immunodeficiency virus negative. None of the children excreted poliovirus for more than 4 weeks. The restriction fragment length polymorphism analysis showed that all strains were of Sabin origin including a unique Polio Sabine Vaccine types 2 and 3 (S2/S3) recombinant.</p> <p>Conclusions</p> <p>From these findings we assume that Human immunodeficiency virus positive children are not a high risk population for long term poliovirus excretion. More powerful studies are needed to confirm our findings.</p

The Satellite Cell in Male and Female, Developing and Adult Mouse Muscle: Distinct Stem Cells for Growth and Regeneration

Satellite cells are myogenic cells found between the basal lamina and the sarcolemma of the muscle fibre. Satellite cells are the source of new myofibres; as such, satellite cell transplantation holds promise as a treatment for muscular dystrophies. We have investigated age and sex differences between mouse satellite cells in vitro and assessed the importance of these factors as mediators of donor cell engraftment in an in vivo model of satellite cell transplantation. We found that satellite cell numbers are increased in growing compared to adult and in male compared to female adult mice. We saw no difference in the expression of the myogenic regulatory factors between male and female mice, but distinct profiles were observed according to developmental stage. We show that, in contrast to adult mice, the majority of satellite cells from two week old mice are proliferating to facilitate myofibre growth; however a small proportion of these cells are quiescent and not contributing to this growth programme. Despite observed changes in satellite cell populations, there is no difference in engraftment efficiency either between satellite cells derived from adult or pre-weaned donor mice, male or female donor cells, or between male and female host muscle environments. We suggest there exist two distinct satellite cell populations: one for muscle growth and maintenance and one for muscle regeneration

Genes left behind: Climate change threatens cryptic genetic diversity in the canopy-forming seaweed bifurcaria bifurcata

The global redistribution of biodiversity will intensify in the coming decades of climate change, making projections of species range shifts and of associated genetic losses important components of conservation planning. Highly-structured marine species, notably brown seaweeds, often harbor unique genetic variation at warmer low-latitude rear edges and thus are of particular concern. Here, a combination of Ecological Niche Models (ENMs) and molecular data is used to forecast the potential near-future impacts of climate change for a warm-temperate, canopy forming seaweed, Bifurcaria bifurcata. ENMs for B. bifurcata were developed using marine and terrestrial climatic variables, and its range projected for 2040-50 and 2090-2100 under two greenhouse emission scenarios. Geographical patterns of genetic diversity were assessed by screening 18 populations spawning the entire distribution for two organelle genes and 6 microsatellite markers. The southern limit of B. bifurcata was predicted to shift northwards to central Morocco by the mid-century. By 2090-2100, depending on the emission scenario, it could either retreat further north to western Iberia or be relocated back to Western Sahara. At the opposing margin, B. bifurcata was predicted to expand its range to Scotland or even Norway. Microsatellite diversity and endemism were highest in Morocco, where a unique and very restricted lineage was also identified. Our results imply that B. bifurcata will maintain a relatively broad latitudinal distribution. Although its persistence is not threatened, the predicted extirpation of a unique southern lineage or even the entire Moroccan diversity hotspot will erase a rich evolutionary legacy and shrink global diversity to current (low) European levels. NW Africa and similarly understudied southern regions should receive added attention if expected range changes and diversity loss of warm-temperate species is not to occur unnoticed.Portuguese FCT (Fundacao para a Ciencia e a Tecnologia) [PTDC/AAC-CLI/109108/2008, EXPL/BIA-BIC/1471/2012, EXCL/AAG-GLO/0661/2012]; [SFRH/BPD/88935/2012]info:eu-repo/semantics/publishedVersio

Serum biomarkers in Acute Respiratory Distress Syndrome an ailing prognosticator

The use of biomarkers in medicine lies in their ability to detect disease and support diagnostic and therapeutic decisions. New research and novel understanding of the molecular basis of the disease reveals an abundance of exciting new biomarkers who present a promise for use in the everyday clinical practice. The past fifteen years have seen the emergence of numerous clinical applications of several new molecules as biologic markers in the research field relevant to acute respiratory distress syndrome (translational research). The scope of this review is to summarize the current state of knowledge about serum biomarkers in acute lung injury and acute respiratory distress syndrome and their potential value as prognostic tools and present some of the future perspectives and challenges