Kinase inhibitors in the treatment of immune-mediated disease

Protein kinases are fundamental components of diverse signaling pathways, including immune cells. Their essential functions have made them effective therapeutic targets. Initially, the expectation was that a high degree of selectivity would be critical; however, with time, the use of “multikinase” inhibitors has expanded. Moreover, the spectrum of diseases in which kinase inhibitors are used has also expanded to include not only malignancies but also immune-mediated diseases. At present, thirteen kinase inhibitors have been approved in the United States, all for oncologic indications. However, there are a growing number of molecules, including several Janus kinase inhibitors, that are being tested in clinical trials for autoimmune diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel diseases. It appears likely that this new class of immunomodulatory drugs will have a major impact on the treatment of immune-mediated diseases in the near future

Direct measurement of molecular stiffness and damping in confined water layers

We present {\em direct} and {\em linear} measurements of the normal stiffness and damping of a confined, few molecule thick water layer. The measurements were obtained by use of a small amplitude (0.36 $\textrm{\AA}$), off-resonance Atomic Force Microscopy (AFM) technique. We measured stiffness and damping oscillations revealing up to 7 layers separated by 2.56 $\pm$ 0.20 $\textrm{\AA}$. Relaxation times could also be calculated and were found to indicate a significant slow-down of the dynamics of the system as the confining separation was reduced. We found that the dynamics of the system is determined not only by the interfacial pressure, but more significantly by solvation effects which depend on the exact separation of tip and surface. Thus ` solidification\rq seems to not be merely a result of pressure and confinement, but depends strongly on how commensurate the confining cavity is with the molecule size. We were able to model the results by starting from the simple assumption that the relaxation time depends linearly on the film stiffness.Comment: 7 pages, 6 figures, will be submitted to PR

Educational Attainment Moderates the Association Between Hippocampal Volumes and Memory Performances in Healthy Older Adults

Objective: To examine whether educational attainment, as a proxy of cognitive reserve, moderated the association between hippocampal volumes and episodic verbal memory performances in healthy older adults.Methods: Data from 76 community dwelling older adults were included in the present study. Measures of hippocampal volumes (total, left, and right) were obtained using FreeSurfer software. Immediate and delayed verbal recall scores were derived from performances on the California Verbal Learning Test-Second Edition and the Wechsler Memory Scale- Third Edition. Educational attainment was defined by years of education. Linear regression analyses were performed using immediate and delayed recall as dependent variables and hippocampal volumes, years of education, and their interaction terms as independent variables. All analyses were controlled for age, sex, depression, and health status.Results: Total and left Hippocampal volumes had a positive main effect on delayed recall only. Additionally, the interaction between total, left, and right hippocampal volumes and education was a significant predictor for delayed recall performance but not for immediate recall performance. The positive association between hippocampal volumes and delayed recall was greatest in those with more years of education.Conclusion: Larger hippocampal volumes were associated with better delayed verbal recall and the effect on delayed recall was greatest in those with more years of education. Having higher levels of education, or cognitive reserve, may enable individuals to capitalize on greater structural integrity in the hippocampus to support delayed recall in old age. However, longitudinal research is needed to investigate the directionality of these associations

Effects of ecstasy/polydrug use on memory for associative information

Rationale Associative learning underpins behaviours that are fundamental to the everyday functioning of the individual. Evidence pointing to learning deficits in recreational drug users merits further examination. Objectives A word pair learning task was administered to examine associative learning processes in ecstasy/polydrug users. Methods After assignment to either single or divided attention conditions, 44 ecstasy/polydrug users and 48 non-users were presented with 80 word pairs at encoding. Following this, four types of stimuli were presented at the recognition phase: the words as originally paired (old pairs), previously presented words in different pairings (conjunction pairs), old words paired with new words, and pairs of new words (not presented previously). The task was to identify which of the stimuli were intact old pairs. Results Ecstasy/ploydrug users produced significantly more false-positive responses overall compared to non-users. Increased long-term frequency of ecstasy use was positively associated with the propensity to produce false-positive responses. It was also associated with a more liberal signal detection theory decision criterion value. Measures of long term and recent cannabis use were also associated with these same word pair learning outcome measures. Conjunction word pairs, irrespective of drug use, generated the highest level of false-positive responses and significantly more false-positive responses were made in the divided attention condition compared to the single attention condition. Conclusions Overall, the results suggest that long-term ecstasy exposure may induce a deficit in associative learning and this may be in part a consequence of users adopting a more liberal decision criterion value

The Underestimation Of Egocentric Distance: Evidence From Frontal Matching Tasks

There is controversy over the existence, nature, and cause of error in egocentric distance judgments. One proposal is that the systematic biases often found in explicit judgments of egocentric distance along the ground may be related to recently observed biases in the perceived declination of gaze (Durgin & Li, Attention, Perception, & Psychophysics, in press), To measure perceived egocentric distance nonverbally, observers in a field were asked to position themselves so that their distance from one of two experimenters was equal to the frontal distance between the experimenters. Observers placed themselves too far away, consistent with egocentric distance underestimation. A similar experiment was conducted with vertical frontal extents. Both experiments were replicated in panoramic virtual reality. Perceived egocentric distance was quantitatively consistent with angular bias in perceived gaze declination (1.5 gain). Finally, an exocentric distance-matching task was contrasted with a variant of the egocentric matching task. The egocentric matching data approximate a constant compression of perceived egocentric distance with a power function exponent of nearly 1; exocentric matches had an exponent of about 0.67. The divergent pattern between egocentric and exocentric matches suggests that they depend on different visual cues

Manfaat Retribusi TPI Terhadap Pendapatan Nelayan Di PPN Pekalongan : Sebuah Tinjauan Kebijakan

Pekalongan Archipelagic Fishing Port is one of many ports which it has not executed appeal wipping out of fisheries retribution include fish auction fee. Objectives of this research are analysis implementation of auction fee policy and its benefit for fishermen income on Pekalongan Archipelagic Fishing Port. Methods that it used on this research were study case. This research used analysis of both qualitative and quantitative approach. Results of this research explained that fish auction fee referred to Perda No 12 in 2009. Fish auction fee is allocated both routine and incidental every year. Each fishermen who landed fish felt receiving benefit, but it were not equal which they were pay. If fish auction fee is stopped, operation of fish auction will be depend on both local government budget and particular alocation fund from center government.Key word : benefit, income, fish auction fe

A randomized trial of epinephrine in out-of-hospital cardiac arrest

Background Concern about the use of epinephrine as a treatment for out-of-hospital cardiac arrest led the International Liaison Committee on Resuscitation to call for a placebo-controlled trial to determine whether the use of epinephrine is safe and effective in such patients. Methods In a randomized, double-blind trial involving 8014 patients with out-of-hospital cardiac arrest in the United Kingdom, paramedics at five National Health Service ambulance services administered either parenteral epinephrine (4015 patients) or saline placebo (3999 patients), along with standard care. The primary outcome was the rate of survival at 30 days. Secondary outcomes included the rate of survival until hospital discharge with a favorable neurologic outcome, as indicated by a score of 3 or less on the modified Rankin scale (which ranges from 0 [no symptoms] to 6 [death]). Results At 30 days, 130 patients (3.2%) in the epinephrine group and 94 (2.4%) in the placebo group were alive (unadjusted odds ratio for survival, 1.39; 95% confidence interval [CI], 1.06 to 1.82; P=0.02). There was no evidence of a significant difference in the proportion of patients who survived until hospital discharge with a favorable neurologic outcome (87 of 4007 patients [2.2%] vs. 74 of 3994 patients [1.9%]; unadjusted odds ratio, 1.18; 95% CI, 0.86 to 1.61). At the time of hospital discharge, severe neurologic impairment (a score of 4 or 5 on the modified Rankin scale) had occurred in more of the survivors in the epinephrine group than in the placebo group (39 of 126 patients [31.0%] vs. 16 of 90 patients [17.8%]). Conclusions In adults with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group. (Funded by the U.K. National Institute for Health Research and others; Current Controlled Trials number, ISRCTN73485024.