Medication prescribing in frail older people HUBBARD, Ruth E; SINEAD O'MAHONY, M; WOODHOUSE, Kenneth W
European journal of clinical pharmacology,
03/2013, Letnik:
69, Številka:
3
Journal Article
Stem cell systems regulate tissue development and maintenance. The germline stem cell system is essential for animal reproduction, controlling both the timing and number of progeny through its ...influence on gamete production. In this review, we first draw general comparisons to stem cell systems in other organisms, and then present our current understanding of the germline stem cell system in
In contrast to stereotypic somatic development and cell number stasis of adult somatic cells in
, the germline stem cell system has a variable division pattern, and the system differs between larval development, early adult peak reproduction and age-related decline. We discuss the cell and developmental biology of the stem cell system and the Notch regulated genetic network that controls the key decision between the stem cell fate and meiotic development, as it occurs under optimal laboratory conditions in adult and larval stages. We then discuss alterations of the stem cell system in response to environmental perturbations and aging. A recurring distinction is between processes that control stem cell fate and those that control cell cycle regulation.
is a powerful model for understanding germline stem cells and stem cell biology.
After 20 years of sometimes quiet growth, fragment-based drug discovery (FBDD) has become mainstream. More than 30 drug candidates derived from fragments have entered the clinic, with two approved ...and several more in advanced trials. FBDD has been widely applied in both academia and industry, as evidenced by the large number of papers from universities, non-profit research institutions, biotechnology companies and pharmaceutical companies. Moreover, FBDD draws on a diverse range of disciplines, from biochemistry and biophysics to computational and medicinal chemistry. As the promise of FBDD strategies becomes increasingly realized, now is an opportune time to draw lessons and point the way to the future. This Review briefly discusses how to design fragment libraries, how to select screening techniques and how to make the most of information gleaned from them. It also shows how concepts from FBDD have permeated and enhanced drug discovery efforts.
As the population ages, increasing numbers of older adults are undergoing surgery. Frailty is prevalent in older adults and may be a better predictor of post-operative morbidity and mortality than ...chronological age. The aim of this review was to examine the impact of frailty on adverse outcomes in the 'older old' and 'oldest old' surgical patients.
A systematic review was undertaken. Electronic databases from 2010 to 2015 were searched to identify articles which evaluated the relationship between frailty and post-operative outcomes in surgical populations with a mean age of 75 and older. Articles were excluded if they were in non-English languages or if frailty was measured using a single marker only. Demographic data, type of surgery performed, frailty measure and impact of frailty on adverse outcomes were extracted from the selected studies. Quality of the studies and risk of bias was assessed by the Epidemiological Appraisal Instrument.
Twenty-three studies were selected for the review and they were assessed as medium to high quality. The mean age ranged from 75 to 87 years, and included patients undergoing cardiac, oncological, general, vascular and hip fracture surgeries. There were 21 different instruments used to measure frailty. Regardless of how frailty was measured, the strongest evidence in terms of numbers of studies, consistency of results and study quality was for associations between frailty and increased mortality at 30 days, 90 days and one year follow-up, post-operative complications and length of stay. A small number of studies reported on discharge to institutional care, functional decline and lower quality of life after surgery, and also found a significant association with frailty.
There was strong evidence that frailty in older-old and oldest-old surgical patients predicts post-operative mortality, complications, and prolonged length of stay. Frailty assessment may be a valuable tool in peri-operative assessment. It is possible that different frailty tools are best suited for different acuity and type of surgical patients. The association between frailty and return to pre-morbid function, discharge destination, and quality of life after surgery warrants further research.
Identification of chemical compounds with specific biological activities is an important step in both chemical biology and drug discovery. When the structure of the intended target is available, one ...approach is to use molecular docking programs to assess the chemical complementarity of small molecules with the target; such calculations provide a qualitative measure of affinity that can be used in virtual screening (VS) to rank order a list of compounds according to their potential to be active. rDock is a molecular docking program developed at Vernalis for high-throughput VS (HTVS) applications. Evolved from RiboDock, the program can be used against proteins and nucleic acids, is designed to be computationally very efficient and allows the user to incorporate additional constraints and information as a bias to guide docking. This article provides an overview of the program structure and features and compares rDock to two reference programs, AutoDock Vina (open source) and Schrödinger's Glide (commercial). In terms of computational speed for VS, rDock is faster than Vina and comparable to Glide. For binding mode prediction, rDock and Vina are superior to Glide. The VS performance of rDock is significantly better than Vina, but inferior to Glide for most systems unless pharmacophore constraints are used; in that case rDock and Glide are of equal performance. The program is released under the Lesser General Public License and is freely available for download, together with the manuals, example files and the complete test sets, at http://rdock.sourceforge.net/
It is over 20 years since the first fragment-based discovery projects were disclosed. The methods are now mature for most 'conventional' targets in drug discovery such as enzymes (kinases and ...proteases) but there has also been growing success on more challenging targets, such as disruption of protein-protein interactions. The main application is to identify tractable chemical startpoints that non-covalently modulate the activity of a biological molecule. In this essay, we overview current practice in the methods and discuss how they have had an impact in lead discovery - generating a large number of fragment-derived compounds that are in clinical trials and two medicines treating patients. In addition, we discuss some of the more recent applications of the methods in chemical biology - providing chemical tools to investigate biological molecules, mechanisms and systems.
Highlights • Frailty is prevalent in CKD patients with those on dialysis being the most frail. • Frailty is associated with an increased risk of mortality and hospitalization. • Most common method of ...frailty assessment in the CKD cohort is the Fried phenotype. • Reported frailty prevalence changes depending on the method of frailty assessment.
Reading primary research literature is an essential skill for all scientists and students on science degree programmes, however little is known about how researchers at different career stages ...interact with and interpret scientific papers. To explore this, we conducted a survey of 260 undergraduate students and researchers in Biological Sciences at a research intensive UK university. Responses to Likert scale questions demonstrated increases in confidence and skill with reading the literature between individuals at each career stage, including between postdoctoral researchers and faculty academics. The survey indicated that individuals at different career stages valued different sections of scientific papers, and skill in reading the results section develops slowly over the course of an academic career. Inexperienced readers found the methods and results sections of research papers the most difficult to read, and undervalued the importance of the results section and critical interpretation of data. These data highlight a need for structured support with reading scientific literature at multiple career stages, and for senior academics to be aware that junior colleagues may prioritise their reading differently. We propose a model for the development of literature processing skills, and consider the need for training strategies to help inexperienced readers engage with primary literature, and therefore develop important skills that underpin scientific careers. We also encourage researchers to be mindful of language used when writing papers, and to be more inclusive of diverse audiences when disseminating their work.
frailty is proposed as a summative measure of health status and marker of individual vulnerability. We aimed to investigate the discriminative capacity of a frailty index (FI) derived from interRAI ...Comprehensive Geriatric Assessment for Acute Care (AC) in relation to multiple adverse inpatient outcomes.
in this prospective cohort study, an FI was derived for 1,418 patients ≥70 years across 11 hospitals in Australia. The interRAI-AC was administered at admission and discharge by trained nurses, who also screened patients daily for geriatric syndromes.
in adjusted logistic regression models an increase of 0.1 in FI was significantly associated with increased likelihood of length of stay >28 days (odds ratio OR: 1.29 1.10-1.52), new discharge to residential aged care (OR: 1.31 1.10-1.57), in-hospital falls (OR: 1.29 1.10-1.50), delirium (OR: 2.34 2.08-2.63), pressure ulcer incidence (OR: 1.51 1.23-1.87) and inpatient mortality (OR: 2.01 1.66-2.42). For each of these adverse outcomes, the cut-point at which optimal sensitivity and specificity occurred was for an FI > 0.40. Specificity was higher than sensitivity with positive predictive values of 7-52% and negative predictive values of 88-98%. FI-AC was not significantly associated with readmissions to hospital.
the interRAI-AC can be used to derive a single score that predicts multiple adverse outcomes in older inpatients. A score of ≤0.40 can well discriminate patients who are unlikely to die or experience a geriatric syndrome. Whether the FI-AC can result in management decisions that improve outcomes requires further study.
The plant hormone abscisic acid (ABA) regulates many key processes in plants, including seed germination and development and abiotic stress tolerance, particularly drought resistance. Understanding ...early events in ABA signal transduction has been a major goal of plant research. The recent identification of the PYRABACTIN (4-bromo-N-pyridin-2-yl methylnaphthalene-1-sulfonamide) RESISTANCE (PYR)/REGULATORY COMPONENT OF ABA RECEPTOR (RCAR) family of ABA receptors and their biochemical mode of action represents a major breakthrough in the field. The solving of PYR/RCAR structures provides a context for resolving mechanisms mediating ABA control of protein-protein interactions for downstream signaling. Recent studies show that a pathway based on PYR/RCAR ABA receptors, PROTEIN PHOSPHATASE 2Cs (PP2Cs), and SNF1-RELATED PROTEIN KINASE 2s (SnRK2s) forms the primary basis of an early ABA signaling module. This pathway interfaces with ion channels, transcription factors, and other targets, thus providing a mechanistic connection between the phytohormone and ABA-induced responses. This emerging PYR/RCAR-PP2C-SnRK2 model of ABA signal transduction is reviewed here, and provides an opportunity for testing novel hypotheses concerning ABA signaling. We address newly emerging questions, including the potential roles of different PYR/RCAR isoforms, and the significance of ABA-induced versus constitutive PYR/RCAR-PP2C interactions. We also consider how the PYR/RCAR-PP2C-SnRK2 pathway interfaces with ABA-dependent gene expression, ion channel regulation, and control of small molecule signaling. These exciting developments provide researchers with a framework through which early ABA signaling can be understood, and allow novel questions about the hormone response pathway and possible applications in stress resistance engineering of plants to be addressed.
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