Project description:The Cognitive Estimation Test (CET) is widely used by clinicians and researchers to assess the ability to produce reasonable cognitive estimates. Although several studies have published normative data for versions of the CET, many of the items are now outdated and parallel forms of the test do not exist to allow cognitive estimation abilities to be assessed on more than one occasion. In the present study, we devised two new 9-item parallel forms of the CET. These versions were administered to 184 healthy male and female participants aged 18-79 years with 9-22 years of education. Increasing age and years of education were found to be associated with successful CET performance as well as gender, intellect, naming, arithmetic and semantic memory abilities. To validate that the parallel forms of the CET were sensitive to frontal lobe damage, both versions were administered to 24 patients with frontal lobe lesions and 48 age-, gender- and education-matched controls. The frontal patients' error scores were significantly higher than the healthy controls on both versions of the task. This study provides normative data for parallel forms of the CET for adults which are also suitable for assessing frontal lobe dysfunction on more than one occasion without practice effects.
Project description:There is no good science in bad models. Cell culture is especially prone to artifacts. A number of novel cell culture technologies have become more broadly available in the 21st century, which allow overcoming limitations of traditional culture and are more physiologically relevant. These include the use of stem-cell derived human cells, cocultures of different cell types, scaffolds and extracellular matrices, perfusion platforms (such as microfluidics), 3D culture, organ-on-chip technologies, tissue architecture, and organ functionality. The physiological relevance of such models is further enhanced by the measurement of biomarkers (e.g., key events of pathways), organ specific functionality, and more comprehensive assessment cell responses by high-content methods. These approaches are still rarely combined to create microphysiological systems. The complexity of the combination of these technologies can generate results closer to the in vivo situation but increases the number of parameters to control, bringing some new challenges. In fact, we do not argue that all cell culture needs to be that sophisticated. The efforts taken are determined by the purpose of our experiments and tests. If only a very specific molecular target to cell response is of interest, a very simple model, which reflects this, might be much more suited to allow standardization and high-throughput. However, the less defined the end point of interest and cellular response are, the better we should approximate organ- or tissue-like culture conditions to make physiological responses more probable. Besides these technologic advances, important progress in the quality assurance and reporting on cell cultures as well as the validation of cellular test systems brings the utility of cell cultures to a new level. The advancement and broader implementation of Good Cell Culture Practice (GCCP) is key here. In toxicology, this is a major prerequisite for meaningful and reliable results, ultimately supporting risk assessment and product development decisions.
Project description:It has been nearly 50 years since the golden age of antibiotic discovery (1945-1975) ended; yet, we still struggle to identify novel drug targets and to deliver new chemical classes of antibiotics to replace those rendered obsolete by drug resistance. Despite herculean efforts utilizing a wide range of antibiotic discovery platform strategies, including genomics, bioinformatics, systems biology and postgenomic approaches, success has been at best incremental. Obviously, finding new classes of antibiotics is really hard, so repeating the old strategies, while expecting different outcomes, seems to boarder on insanity. The key questions dealt with in this review include: (1) If mutation based drug resistance is the major challenge to any new antibiotic, is it possible to find drug targets and new chemical entities that can escape this outcome; (2) Is the number of novel chemical classes of antibacterials limited by the number of broad spectrum drug targets; and (3) If true, then should we focus efforts on subgroups of pathogens like Gram negative or positive bacteria only, anaerobic bacteria or other group where the range of common essential genes is likely greater?. This review also provides some examples of existing drug targets that appear to escape the specter of mutation based drug resistance, and provides examples of some intermediate spectrum strategies as well as modern molecular and genomic approaches likely to improve the odds of delivering 21st century medicines to combat multidrug resistant pathogens.
Project description:BackgroundLong-increasing dementia incidence and prevalence trends may be shifting. Whether such shifts have reached the very old is unknown.ObjectiveTo investigate temporal trends in the incidence of dementia and cognitive impairment and prevalence of dementia, cognitive impairment, Alzheimer's disease, vascular dementia, and unclassified dementia among 85-, 90-, and ≥ 95-year-olds in Sweden during 2000-2017.MethodsThis study was conducted with Umeå 85 + /Gerontological Regional Database data from 2182 85-, 90-, and ≥ 95-year-olds in Sweden collected in 2000-2017. Using logistic regression, trends in the cumulative 5-year incidences of dementia and cognitive impairment; prevalences of dementia, cognitive impairment, Alzheimer's disease, and vascular dementia; and Mini-Mental State Examination thresholds for dementia diagnosis were estimated.ResultsDementia and cognitive impairment incidences decreased in younger groups, which generally showed more-positive temporal trends. The prevalences of overall dementia, cognitive impairment, and Alzheimer's disease were stable or increasing; longer disease durations and increasing dementia subtype classification success may mask positive changes in incidences. Vascular dementia increased while unclassified dementia generally decreased.ConclusionThe cognitive health of the very old may be changing in the 21st century, possibly indicating a trend break.
Project description:BackgroundPancreatic ductal adenocarcinoma is the deadliest cancer worldwide with a 98% loss-of-life expectancy and a 30% increase in the disability-adjusted life years during the last decade in Europe. The disease cannot be effectively prevented nor being early detected. When diagnosed, 80% of patients have tumors that are in incurable stages, while for those who undergo surgery, 80% of patients will present with local or distant metastasis. Importantly, chemotherapies are far from being effective.ObjectivePancreatic cancer represents a great challenge and, at the same time, a huge opportunity for advancing our understanding on the basis of the disease, the molecular profiles, that would lead to develop tools for early detection and effective treatments, thus, boosting patient survival.ResultsResearch on pancreatic cancer has being receiving little or minimal funds from European funding bodies. UEG is calling for public-private partnerships that would effectively fund research on pancreatic cancer.ConclusionThis would increase our understanding of this disease and better treatment, through pan-European efforts that take advantage of the strong academic European research landscape on pancreatic cancer, and the contribution by the industry of all sizes.
Project description:Haldane's Rule (HR), which states that 'when in the offspring of two different animal races one sex is absent, rare, or sterile, that sex is the heterozygous (heterogametic) sex', is one of the most general patterns in speciation biology. We review the literature of the past 15 years and find that among the ?85 new studies, many consider taxa that traditionally have not been the focus for HR investigations. The new studies increased to nine, the number of 'phylogenetically independent' groups that comply with HR. They continue to support the dominance and faster-male theories as explanations for HR, although due to increased reliance on indirect data (from, for example, differential introgression of cytoplasmic versus chromosomal loci in natural hybrid zones) unambiguous novel results are rare. We further highlight how research on organisms with sex determination systems different from those traditionally considered may lead to more insight in the underlying causes of HR. In particular, haplodiploid organisms provide opportunities for testing specific predictions of the dominance and faster X chromosome theory, and we present new data that show that the faster-male component of HR is supported in hermaphrodites, suggesting that genes involved in male function may evolve faster than those expressed in the female function.
Project description:We propose an integrated model of aqueous outflow control that employs a pump-conduit system in this article. Our model exploits accepted physiologic regulatory mechanisms such as those of the arterial, venous, and lymphatic systems. Here, we also provide a framework for developing novel diagnostic and therapeutic strategies to improve glaucoma patient care. In the model, the trabecular meshwork distends and recoils in response to continuous physiologic IOP transients like the ocular pulse, blinking, and eye movement. The elasticity of the trabecular meshwork determines cyclic volume changes in Schlemm's canal (SC). Tube-like SC inlet valves provide aqueous entry into the canal, and outlet valve leaflets at collector channels control aqueous exit from SC. Connections between the pressure-sensing trabecular meshwork and the outlet valve leaflets dynamically control flow from SC. Normal function requires regulation of the trabecular meshwork properties that determine distention and recoil. The aqueous pump-conduit provides short-term pressure control by varying stroke volume in response to pressure changes. Modulating TM constituents that regulate stroke volume provides long-term control. The aqueous outflow pump fails in glaucoma due to the loss of trabecular tissue elastance, as well as alterations in ciliary body tension. These processes lead to SC wall apposition and loss of motion. Visible evidence of pump failure includes a lack of pulsatile aqueous discharge into aqueous veins and reduced ability to reflux blood into SC. These alterations in the functional properties are challenging to monitor clinically. Phase-sensitive OCT now permits noninvasive, quantitative measurement of pulse-dependent TM motion in humans. This proposed conceptual model and related techniques offer a novel framework for understanding mechanisms, improving management, and development of therapeutic options for glaucoma.