A Fluorescent Kinase Inhibitor that Exhibits Diagnostic Changes in Emission upon Binding

The development of a fluorescent LCK inhibitor that exhibits favourable solvatochromic properties upon binding the kinase is described. Fluorescent properties were realised through the inclusion of a prodan-derived fluorophore into the pharmacophore of an ATP-competitive kinase inhibitor. Fluorescence titration experiments demonstrate the solvatochromic properties of the inhibitor, in which dramatic increase in emission intensity and hypsochromic shift in emission maxima are clearly observed upon binding LCK. Microscopy experiments in cellular contexts together with flow cytometry show that the fluorescence intensity of the inhibitor correlates with the LCK concentration. Furthermore, multiphoton microscopy experiments demonstrate both the rapid cellular uptake of the inhibitor and that the two-photon cross section of the inhibitor is amenable for excitation at 700 nm

Vision and Foraging in Cormorants: More like Herons than Hawks?

Background Great cormorants (Phalacrocorax carbo L.) show the highest known foraging yield for a marine predator and they are often perceived to be in conflict with human economic interests. They are generally regarded as visually-guided, pursuit-dive foragers, so it would be expected that cormorants have excellent vision much like aerial predators, such as hawks which detect and pursue prey from a distance. Indeed cormorant eyes appear to show some specific adaptations to the amphibious life style. They are reported to have a highly pliable lens and powerful intraocular muscles which are thought to accommodate for the loss of corneal refractive power that accompanies immersion and ensures a well focussed image on the retina. However, nothing is known of the visual performance of these birds and how this might influence their prey capture technique. Methodology/Principal Findings We measured the aquatic visual acuity of great cormorants under a range of viewing conditions (illuminance, target contrast, viewing distance) and found it to be unexpectedly poor. Cormorant visual acuity under a range of viewing conditions is in fact comparable to unaided humans under water, and very inferior to that of aerial predators. We present a prey detectability model based upon the known acuity of cormorants at different illuminances, target contrasts and viewing distances. This shows that cormorants are able to detect individual prey only at close range (less than 1 m). Conclusions/Significance We conclude that cormorants are not the aquatic equivalent of hawks. Their efficient hunting involves the use of specialised foraging techniques which employ brief short-distance pursuit and/or rapid neck extension to capture prey that is visually detected or flushed only at short range. This technique appears to be driven proximately by the cormorant's limited visual capacities, and is analogous to the foraging techniques employed by herons

Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases

PURPOSE: Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients' pain, analgesic use, and pain interference with daily functioning. METHODS: Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials (N = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm. RESULTS: The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function. CONCLUSIONS: SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning

Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases

PURPOSE: Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients' pain, analgesic use, and pain interference with daily functioning. METHODS: Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials (N = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm. RESULTS: The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function. CONCLUSIONS: SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning

The role of the right temporoparietal junction in perceptual conflict: detection or resolution?

The right temporoparietal junction (rTPJ) is a polysensory cortical area that plays a key role in perception and awareness. Neuroimaging evidence shows activation of rTPJ in intersensory and sensorimotor conflict situations, but it remains unclear whether this activity reflects detection or resolution of such conflicts. To address this question, we manipulated the relationship between touch and vision using the so-called mirror-box illusion. Participants' hands lay on either side of a mirror, which occluded their left hand and reflected their right hand, but created the illusion that they were looking directly at their left hand. The experimenter simultaneously touched either the middle (D3) or the ring finger (D4) of each hand. Participants judged, which finger was touched on their occluded left hand. The visual stimulus corresponding to the touch on the right hand was therefore either congruent (same finger as touch) or incongruent (different finger from touch) with the task-relevant touch on the left hand. Single-pulse transcranial magnetic stimulation (TMS) was delivered to the rTPJ immediately after touch. Accuracy in localizing the left touch was worse for D4 than for D3, particularly when visual stimulation was incongruent. However, following TMS, accuracy improved selectively for D4 in incongruent trials, suggesting that the effects of the conflicting visual information were reduced. These findings suggest a role of rTPJ in detecting, rather than resolving, intersensory conflict

Cell Growth & Differentiation Structure and DNA-binding Properties of Pax-QNR, a Paired Box-and Homeobox-containing Gene1

Abstrac

Climate and species affect fine root production with long-term fertilization in acidic tussock tundra near Toolik Lake, Alaska

Author Posting. © The Author(s), 2007. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Oecologia 153 (2007): 643-652, doi:10.1007/s00442-007-0753-8.Long-term fertilization of acidic tussock tundra has led to changes in plant species composition, increases in aboveground production and biomass and substantial losses of soil organic carbon (SOC). Root litter is an important input to SOC pools, though little is known about fine root demography in tussock tundra. In this study, we examined the response of fine root production and live standing fine root biomass to short- and long-term fertilization, as changes in fine root demography may contribute to observed declines in SOC. Live standing fine root biomass increased with long-term fertilization, while fine root production declined, reflecting replacement of the annual fine root system of Eriophorum vaginatum, with the long-lived fine roots of Betula nana. Fine root production increased in fertilized plots during an unusually warm growing season, but remained unchanged in control plots, consistent with observations that B. nana shows a positive response to climate warming. Calculations based on a few simple assumptions suggest changes in fine root demography with long-term fertilization and species replacement could account for between 20 and 39% of observed declines in SOC stocks.This project was supported by National Science Foundation research grants 9810222, 9911681, 0221606 and 0528748

Development and Validation of a Bedside Score to Predict Early Death in Cancer of Unknown Primary Patients

BACKGROUND: We have investigated predictors of 90-day-mortality in a large cohort of non-specific cancer of unknown primary patients. METHODS: Predictors have been identified by univariate and then logistic regression analysis in a single-center cohort comprising 429 patients (development cohort). We identified four predictors that produced a predictive score that has been applied to an independent multi-institutional cohort of 409 patients (validation cohort). The score was the sum of predictors for each patient (0 to 4). RESULTS: The 90-day-mortality-rate was 33 and 26% in both cohorts. Multivariate analysis has identified 4 predictors for 90-day-mortality: performance status>1 (OR = 3.03, p = 0.001), at least one co-morbidity requiring treatment (OR = 2.68, p = 0.004), LDH>1.5 x the upper limit of normal (OR = 2.88, p = 0.007) and low albumin or protein levels (OR = 3.05, p = 0.007). In the development cohort, 90-day-mortality-rates were 12.5%, 32% and 64% when the score was [0-1], 2 and [3]-[4], respectively. In the validation cohort, risks were 13%, 25% and 62% according to the same score values. CONCLUSIONS: We have validated a score that is easily calculated at the beside that estimates the 90-days mortality rate in non-specific CUP patients. This could be helpful to identify patients who would be better served with palliative care rather than aggressive chemotherapy

Potential and Actual Terrestrial Rabies Exposures in People and Domestic Animals, Upstate South Carolina, 1994–2004: A Surveillance Study

<p>Abstract</p> <p>Background</p> <p>Although there has been a reduction of rabies in pets and domestic animals during recent decades in the United States, rabies remains enzootic among bats and several species of terrestrial wildlife. Spillover transmission of wildlife rabies to domestic animals therefore remains a public health threat</p> <p>Methods</p> <p>Retrospective analysis of surveillance data of reported animal incidents (bites, scratches, mucous membrane contacts) from South Carolina, 1995 to 2003, was performed to assess risk factors of potential rabies exposures among human and animal victims.</p> <p>Results</p> <p>Dogs and cats contributed the majority (66.7% and 26.4%, respectively) of all reported incidents, with stray dogs and cats contributing 9.0% and 15.1 respectively. Current rabies vaccination status of dogs and cats (40.2% and 13.8%, respectively) were below World Health Organization recommended levels. Owned cats were half as likely to be vaccinated for rabies as dogs (OR 0.53, 95% CI 0.48, 0.58). Animal victims were primarily exposed to wildlife (83.0%), of which 27.5% were rabid. Almost 90% of confirmed rabies exposures were due to wildlife. Skunks had the highest prevalence of rabies among species of exposure animals (63.2%). Among rabid domestic animals, stray cats were the most commonly reported (47.4%).</p> <p>Conclusion</p> <p>While the majority of reported potential rabies exposures are associated with dog and cat incidents, most rabies exposures derive from rabid wildlife. Stray cats were most frequently rabid among domestic animals. Our results underscore the need for improvement of wildlife rabies control and the reduction of interactions of domestic animals, including cats, with wildlife.</p

Artifactual measurement of low serum HDL-cholesterol due to paraproteinemia

High levels of serum low density lipoprotein cholesterol (LDL-C) and low levels of high density lipoprotein cholesterol (HDL-C) are well-known risk factors for premature atherosclerotic vascular disease [1, 2]. They are targets for primary and secondary prevention. Interpreting lipid profiles is part of the daily routine for a cardiologist. The most common cause of low HDL-C in western society is metabolic syndrome. More rare are primary lipid disorders (e.g., Tangier syndrome due to an ABCA transporter deficiency or deficiency of apolipoprotein A1) and secondary causes like (ab)use of androgens (Table 1). Extremely low serum HDL levels are associated with an increased risk of death, sepsis and malignancy [3]. A rare but important cause is interference in the biochemical assay by paraproteins, yielding an artifactually low HDL-C measurement result. We present the case of a patient who had his lipid profile repeatedly tested over the course of 4 years and had progressive decline in HDL-C measurements