Pharmacometabonomics in humans: a new tool for personalized medicine

Pharmacogenomics is now over 50 years old and has had some impact in clinical practice, through its use to select patient subgroups who will enjoy efficacy without side effects when treated with certain drugs. However, pharmacogenomics, has had less impact than initially predicted. One reason for this is that many diseases, and the way in which the patients respond to drug treatments, have both genetic and environmental elements. Pure genomics is almost blind to the environmental elements. A new methodology has emerged, termed pharmacometabonomics that is concerned with the prediction of drug effects through the analysis of predose, biofluid metabolite profiles, which reflect both genetic and environmental influences on human physiology. In this review we will cover what pharmacometabonomics is, how it works, what applications exist and what the future might hold in this exciting new area

Coherent imager module with a large field of view for synthetic aperture interferometry applications

Optical areal profilometry of large precision-engineered surfaces require high-resolution measurements over large fields of view. Synthetic Aperture Interferometry (SAI) offers an alternative to the conventional approach of stitching small fields of view (FOV) obtained with Coherent Scanning Interferometry (CSI) using high-NA objectives. In SAI, lowresolution digital holograms are recorded for different illumination and observation directions and they are added coherently to produce a high-resolution reconstruction over a large FOV. This paper describes the design, fabrication and characterization of a large FOV, compact and low-cost coherent imager (CI) as a building block of a coherent sensor array for a SAI system. The CI consists of a CMOS photodetector array with 1.12 µm pixel pitch, a square entrance pupil and a highly divergent reference beam that emerges from a pinhole milled with a focused ion beam on the cylindrical cladding at the tip of an optical fibre. In order to accurately reconstruct the digital holograms, the wavefront of the reference beam is estimated by localizing the reference source relative to the photodetector array. This is done using an optimization approach that simultaneously reconstructs plane waves that reach the aperture from 121 different illumination directions and guarantees a phase root-mean-squared (RMS) error of less than a fifth of the wavelength across the CI entrance pupil at a boundary of the FOV. The CI performance is demonstrated with a holographic reconstruction of a 0.110 m wide object placed at a distance of 0.085 m, i.e. a FOV = ±0.57 rad, the highest reported to date with a holographic camera.</div

Hydrostatic pressure does not cause detectable changes to survival of human retinal ganglion

Purpose: Elevated intraocular pressure (IOP) is a major risk factor for glaucoma. One consequence of raised IOP is that ocular tissues are subjected to increased hydrostatic pressure (HP). The effect of raised HP on stress pathway signaling and retinal ganglion cell (RGC) survival in the human retina was investigated. Methods: A chamber was designed to expose cells to increased HP (constant and fluctuating). Accurate pressure control (10-100mmHg) was achieved using mass flow controllers. Human organotypic retinal cultures (HORCs) from donor eyes (<24h post mortem) were cultured in serum-free DMEM/HamF12. Increased HP was compared to simulated ischemia (oxygen glucose deprivation, OGD). Cell death and apoptosis were measured by LDH and TUNEL assays, RGC marker expression by qRT-PCR (THY-1) and RGC number by immunohistochemistry (NeuN). Activated p38 and JNK were detected by Western blot. Results: Exposure of HORCs to constant (60mmHg) or fluctuating (10-100mmHg; 1 cycle/min) pressure for 24 or 48h caused no loss of structural integrity, LDH release, decrease in RGC marker expression (THY-1) or loss of RGCs compared with controls. In addition, there was no increase in TUNEL-positive NeuN-labelled cells at either time-point indicating no increase in apoptosis of RGCs. OGD increased apoptosis, reduced RGC marker expression and RGC number and caused elevated LDH release at 24h. p38 and JNK phosphorylation remained unchanged in HORCs exposed to fluctuating pressure (10-100mmHg; 1 cycle/min) for 15, 30, 60 and 90min durations, whereas OGD (3h) increased activation of p38 and JNK, remaining elevated for 90min post-OGD. Conclusions: Directly applied HP had no detectable impact on RGC survival and stress-signalling in HORCs. Simulated ischemia, however, activated stress pathways and caused RGC death. These results show that direct HP does not cause degeneration of RGCs in the ex vivo human retina

Myeloid sarcoma with ulnar nerve entrapment: A case report

BACKGROUND: Myeloid sarcoma (MS) is relatively rare, occurring mainly in the skin and lymph nodes, and MS invasion of the ulnar nerve is particularly unusual. The main aim of this article is to present a case of MS invading the brachial plexus, causing ulnar nerve entrapment syndrome, and to further clinical understanding of the possibility of MS invasion of peripheral nerves. CASE SUMMARY: We present the case of a 46-year-old man with a 13-year history of well-treated acute nonlymphocytic leukaemia who was admitted to the hospital after presenting with numbness and pain in his left little finger. The initial diagnosis was considered a simple case of nerve entrapment disease, with magnetic resonance imaging showing slightly abnormal left brachial plexus nerve alignment with local thickening, entrapment, and high signal on compression lipid images. Due to the severity of the ulnar nerve compression, we surgically investigated and cleared the entrapment and nerve tissue hyperplasia; however, subsequent pathological biopsy results revealed evidence of MS. The patient had significant relief from his neurological symptoms, with no postoperative complications, and was referred to the haemato-oncology department for further consultation about the primary disease. This is the first report of safe treatment of ulnar nerve entrapment from MS. It is intended to inform hand surgeons that nerve entrapment may be associated with extramedullary MS, as a rare presenting feature of the disease. CONCLUSION: MS invasion of the brachial plexus and surrounding tissues of the upper arm, resulting in ulnar nerve entrapment and degeneration with significant neurological pain and numbness in the little finger, is uncommon. Surgical treatment significantly relieved the patient’s nerve entrapment symptoms and prevented further neurological impairment. This case is reported to highlight the rare presenting features of MS

Validation of the Kidney Disease Quality of Life-Short Form: a cross-sectional study of a dialysis-targeted health measure in Singapore

<p>Abstract</p> <p>Background</p> <p>In Singapore, the prevalence of end-stage renal disease (ESRD) and the number of people on dialysis is increasing. The impact of ESRD on patient quality of life has been recognized as an important outcome measure. The Kidney Disease Quality Of Life-Short Form (KDQOL-SF™) has been validated and is widely used as a measure of quality of life in dialysis patients in many countries, but not in Singapore. We aimed to determine the reliability and validity of the KDQOL-SF™ for haemodialysis patients in Singapore.</p> <p>Methods</p> <p>From December 2006 through January 2007, this cross-sectional study gathered data on patients ≥21 years old, who were undergoing haemodialysis at National Kidney Foundation in Singapore. We used exploratory factor analysis to determine construct validity of the eight KDQOL-SF™ sub-scales, Cronbach's alpha coefficient to determine internal consistency reliability, correlation of the overall health rating with kidney disease-targeted scales to confirm validity, and correlation of the eight sub-scales with age, income and education to determine convergent and divergent validity.</p> <p>Results</p> <p>Of 1980 haemodialysis patients, 1180 (59%) completed the KDQOL-SF™. Full information was available for 980 participants, with a mean age of 56 years. The sample was representative of the total dialysis population in Singapore, except Indian ethnicity that was over-represented. The instrument designers' proposed eight sub-scales were confirmed, which together accounted for 68.4% of the variance. All sub-scales had a Cronbach's α above the recommended minimum value of 0.7 to indicate good reliability (range: 0.72 to 0.95), except for Social function (0.66). Correlation of items within subscales was higher than correlation of items outside subscales in 90% of the cases. The overall health rating positively correlated with kidney disease-targeted scales, confirming validity. General health subscales were found to have significant associations with age, income and education, confirming convergent and divergent validity.</p> <p>Conclusions</p> <p>The psychometric properties of the KDQOL-SF™ resulting from this first-time administration of the instrument support the validity and reliability of the KDQOL-SF™ as a measure of quality of life of haemodialysis patients in Singapore. It is, however, necessary to determine the test-retest reliability of the KDQOL-SF™ among the haemodialysis population of Singapore.</p

One-step fabrication of hollow-channel gold nanoflowers with excellent catalytic performance and large single-particle SERS activity.

Hollow metallic nanostructures have shown potential in various applications including catalysis, drug delivery and phototherapy, owing to their large surface areas, reduced net density, and unique optical properties. In this study, novel hollow gold nanoflowers (HAuNFs) consisting of an open hollow channel in the center and multiple branches/tips on the outer surface are fabricated for the first time, via a facile one-step synthesis using an auto-degradable nanofiber as a bifunctional template. The one-dimensional (1D) nanofiber acts as both a threading template as well as a promoter of the anisotropic growth of the gold crystal, the combination of which leads to the formation of HAuNFs with a hollow channel and nanospikes. The synergy of favorable structural/surface features, including sharp edges, open cavity and high-index facets, provides our HAuNFs with excellent catalytic performance (activity and cycling stability) coupled with large single-particle SERS activity (including ∼30 times of activity in ethanol electro-oxidation and ∼40 times of single-particle SERS intensity, benchmarked against similar-sized solid gold nanospheres with smooth surfaces, as well as retaining 86.7% of the initial catalytic activity after 500 cycles in ethanol electro-oxidation). This innovative synthesis gives a nanostructure of the geometry distinct from the template and is extendable to fabricating other systems for example, hollow-channel silver nanoflowers (HAgNFs). It thus provides an insight into the design of hollow nanostructures via template methods, and offers a versatile synthetic strategy for diverse metal nanomaterials suited for a broad range of applications

Host Plant Adaptation in Drosophila mettleri Populations

The process of local adaptation creates diversity among allopatric populations, and may eventually lead to speciation. Plant-feeding insect populations that specialize on different host species provide an excellent opportunity to evaluate the causes of ecological specialization and the subsequent consequences for diversity. In this study, we used geographically separated Drosophila mettleri populations that specialize on different host cacti to examine oviposition preference for and larval performance on an array of natural and non-natural hosts (eight total). We found evidence of local adaptation in performance on saguaro cactus (Carnegiea gigantea) for populations that are typically associated with this host, and to chemically divergent prickly pear species (Opuntia spp.) in a genetically isolated population on Santa Catalina Island. Moreover, each population exhibited reduced performance on the alternative host. This finding is consistent with trade-offs associated with adaptation to these chemically divergent hosts, although we also discuss alternative explanations for this pattern. For oviposition preference, Santa Catalina Island flies were more likely to oviposit on some prickly pear species, but all populations readily laid eggs on saguaro. Experiments with non-natural hosts suggest that factors such as ecological opportunity may play a more important role than host plant chemistry in explaining the lack of natural associations with some hosts

Decision tools in health care: focus on the problem, not the solution

BACKGROUND: Systematic reviews or randomised-controlled trials usually help to establish the effectiveness of drugs and other health technologies, but are rarely sufficient by themselves to ensure actual clinical use of the technology. The process from innovation to routine clinical use is complex. Numerous computerised decision support systems (DSS) have been developed, but many fail to be taken up into actual use. Some developers construct technologically advanced systems with little relevance to the real world. Others did not determine whether a clinical need exists. With NHS investing £5 billion in computer systems, also occurring in other countries, there is an urgent need to shift from a technology-driven approach to one that identifies and employs the most cost-effective method to manage knowledge, regardless of the technology. The generic term, 'decision tool' (DT), is therefore suggested to demonstrate that these aids, which seem different technically, are conceptually the same from a clinical viewpoint. DISCUSSION: Many computerised DSSs failed for various reasons, for example, they were not based on best available knowledge; there was insufficient emphasis on their need for high quality clinical data; their development was technology-led; or evaluation methods were misapplied. We argue that DSSs and other computer-based, paper-based and even mechanical decision aids are members of a wider family of decision tools. A DT is an active knowledge resource that uses patient data to generate case specific advice, which supports decision making about individual patients by health professionals, the patients themselves or others concerned about them. The identification of DTs as a consistent and important category of health technology should encourage the sharing of lessons between DT developers and users and reduce the frequency of decision tool projects focusing only on technology. The focus of evaluation should become more clinical, with the impact of computer-based DTs being evaluated against other computer, paper- or mechanical tools, to identify the most cost effective tool for each clinical problem. SUMMARY: We suggested the generic term 'decision tool' to demonstrate that decision-making aids, such as computerised DSSs, paper algorithms, and reminders are conceptually the same, so the methods to evaluate them should be the same

Consequences of converting graded to action potentials upon neural information coding and energy efficiency

Information is encoded in neural circuits using both graded and action potentials, converting between them within single neurons and successive processing layers. This conversion is accompanied by information loss and a drop in energy efficiency. We investigate the biophysical causes of this loss of information and efficiency by comparing spiking neuron models, containing stochastic voltage-gated Na+ and K+ channels, with generator potential and graded potential models lacking voltage-gated Na+ channels. We identify three causes of information loss in the generator potential that are the by-product of action potential generation: (1) the voltage-gated Na+ channels necessary for action potential generation increase intrinsic noise and (2) introduce non-linearities, and (3) the finite duration of the action potential creates a ‘footprint’ in the generator potential that obscures incoming signals. These three processes reduce information rates by ~50% in generator potentials, to ~3 times that of spike trains. Both generator potentials and graded potentials consume almost an order of magnitude less energy per second than spike trains. Because of the lower information rates of generator potentials they are substantially less energy efficient than graded potentials. However, both are an order of magnitude more efficient than spike trains due to the higher energy costs and low information content of spikes, emphasizing that there is a two-fold cost of converting analogue to digital; information loss and cost inflation