A comparative pharmacokinetic study of conventional propranolol and long acting preparation of propranolol in patients with cirrhosis and normal controls

1 Six male patients with alcoholic cirrhosis and seven normal control subjects were each given 80 mg twice daily of conventional propranolol for 1 week and 160 mg once daily of a long acting preparation (LA) of propranolol for 1 week. 2 Plasma propranolol levels were measured at regular intervals on the first and seventh days of both weeks and also following an acute intravenous infusion of 10 mg propranolol on a separate occasion. 3 After the single intravenous dose the elimination half-life tended to be prolonged in the cirrhotic group (median 7.15 h) compared with controls (median 2.92 h) (P = 0.055). 4 After multiple oral dosing with 80 mg twice daily of conventional propranolol the steady-state plasma concentration (Css), area under the curve (AUC tau), peak concentration (Cmax) and trough concentration (Cmin) were significantly higher in cirrhotic patients and the peak: trough ratio (Cmax/Cmin) was significantly lower than controls. 5 After multiple oral dosing with 160 mg LA once daily Cmin was significantly higher than Cmax/min significantly lower in cirrhotic patients; Css, AUC and Cmax were higher than controls but not statistically different. 6 Within both subject groups the bioavailability of 80 mg twice daily of conventional propranolol tended to be greater than 160 mg LA once daily. Cmax was significantly higher in both groups and Css higher in the cirrhotic group with conventional propranolol. 7 In the cirrhotic group the mean reduction in supine heart rate in the steady state was 31.8% with conventional 80 mg twice daily propranolol and 23.75% with 160 mg LA once daily.(ABSTRACT TRUNCATED AT 250 WORDS)

The development of effective biomarkers for Alzheimer's disease:a review

OBJECTIVE: There is a widely recognised need to develop effective Alzheimer's disease (AD) biomarkers to aid the development of disease-modifying treatments, to facilitate early diagnosis and to improve clinical care. This overview aims to summarise the utility of key neuroimaging and cerebrospinal fluid (CSF) biomarkers for AD, before focusing on the latest efforts to identify informative blood biomarkers. DESIGN: A literature search was performed using PubMed up to September 2011 for reviews and primary research studies of neuroimaging (magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography and amyloid imaging), CSF and blood-based (plasma, serum and platelet) biomarkers in AD and mild cognitive impairment. Citations within individual articles were examined to identify additional studies relevant to this review. RESULTS: Evidence of AD biomarker potential was available for imaging techniques reflecting amyloid burden and neurodegeneration. Several CSF measures are promising, including 42 amino acid ß-amyloid peptide (Aß(42) ); total tau (T-tau) protein, reflecting axonal damage; and phosphorylated tau (P-tau), reflecting neurofibrillary tangle pathology. Studies of plasma Aß have produced inferior diagnostic discrimination. Alternative plasma and platelet measures are described, which represent potential avenues for future research. CONCLUSIONS: Several imaging and CSF markers demonstrate utility in predicting AD progression and determining aetiology. These require standardisation before forming core elements of diagnostic criteria. The enormous potential available for identifying a minimally-invasive, easily-accessible blood measure as an effective AD biomarker currently remains unfulfilled. Copyright © 2012 John Wiley & Sons, Ltd.

The renin-angiotensin system and antihypertensive drugs in Alzheimer's disease:current standing of the angiotensin hypothesis?

There is an urgent need to improve upon Alzheimer's disease (AD) treatments. Limitations of existing drugs are that they target specific downstream neurochemical abnormalities while the upstream underlying pathology continues unchecked. Preferable treatments would be those that can target a number of the broad range of molecular and cellular abnormalities that occur in AD such as amyloid-ß (Aß) and hyperphosphorylated tau-mediated damage, inflammation, and mitochondrial dysfunction, as well more systemic abnormalities such as brain atrophy, impaired cerebral blood flow (CBF), and cerebrovascular disease. Recent pre-clinical, epidemiological, and a limited number of clinical investigations have shown that prevention of the signaling of the multifunctional and potent vasoconstrictor angiotensin II (Ang II) may offer broad benefits in AD. In addition to helping to ameliorate co-morbid hypertension, these drugs also likely improve diminished CBF which is common in AD and can contribute to focal Aß pathology. These drugs, angiotensin converting enzyme (ACE) inhibitors, or angiotensin receptor antagonists (ARAs) may also help deteriorating cognitive function by preventing Ang II-mediated inhibition of acetylcholine release as well as interrupt the upregulation of deleterious inflammatory pathways that are widely recognized in AD. Given the current urgency to find better treatments for AD and the relatively immediate availability of drugs that are already widely prescribed for the treatment of hypertension, one of the largest modifiable risk factors for AD, this article reviews current knowledge as to the eligibility of ACE-inhibitors and ARAs for consideration in future clinical trials in AD.

Clinical practice with anti-dementia drugs:a revised (second) consensus statement from the British Association for Psychopharmacology

The British Association for Psychopharmacology (BAP) coordinated a meeting of experts to review and revise its first (2006) Guidelines for clinical practice with anti-dementia drugs. As before, levels of evidence were rated using accepted standards which were then translated into grades of recommendation A to D, with A having the strongest evidence base (from randomized controlled trials) and D the weakest (case studies or expert opinion). Current clinical diagnostic criteria for dementia have sufficient accuracy to be applied in clinical practice (B) and brain imaging can improve diagnostic accuracy (B). Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) are effective for mild to moderate Alzheimer's disease (A) and memantine for moderate to severe Alzheimer's disease (A). Until further evidence is available other drugs, including statins, anti-inflammatory drugs, vitamin E and Ginkgo biloba, cannot be recommended either for the treatment or prevention of Alzheimer's disease (A). Neither cholinesterase inhibitors nor memantine are effective in those with mild cognitive impairment (A). Cholinesterase inhibitors are not effective in frontotemporal dementia and may cause agitation (A), though selective serotonin reuptake inhibitors may help behavioural (but not cognitive) features (B). Cholinesterase inhibitors should be used for the treatment of people with Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)), especially for neuropsychiatric symptoms (A). Cholinesterase inhibitors and memantine can produce cognitive improvements in DLB (A). There is no clear evidence that any intervention can prevent or delay the onset of dementia. Although the consensus statement focuses on medication, psychological interventions can be effective in addition to pharmacotherapy, both for cognitive and non-cognitive symptoms. Many novel pharmacological approaches involving strategies to reduce amyloid and/or tau deposition are in progress. Although results of pivotal studies are awaited, results to date have been equivocal and no disease-modifying agents are either licensed or can be currently recommended for clinical use.

Temporal guidance of musicians’ performance movement is an acquired skill

The ancillary (non-sounding) body movements made by expert musicians during performance have been shown to indicate expressive, emotional, and structural features of the music to observers, even if the sound of the performance is absent. If such ancillary body movements are a component of skilled musical performance, then it should follow that acquiring the temporal control of such movements is a feature of musical skill acquisition. This proposition is tested using measures derived from a theory of temporal guidance of movement, “General Tau Theory” (Lee in Ecol Psychol 10:221–250, 1998; Lee et al. in Exp Brain Res 139:151–159, 2001), to compare movements made during performances of intermediate-level clarinetists before and after learning a new piece of music. Results indicate that the temporal control of ancillary body movements made by participants was stronger in performances after the music had been learned and was closer to the measures of temporal control found for an expert musician’s movements. These findings provide evidence that the temporal control of musicians’ ancillary body movements develops with musical learning. These results have implications for other skillful behaviors and nonverbal communication.

Modelling the H Lyman lines in evolved late-type stars

The importance of partial redistribution (PRD) in the modelling of the Lyman a and Lyman ß emission lines of hydrogen in stellar atmospheres is examined using simple atmospheric models of a range of late-type stars. These models represent the subgiant Procyon (F5 IV-V), and the two giants ß Gem (K0 III) and a Tau (K5 III). These stars are selected to span a wide range of surface gravities: 1.25 <log g <4.00. The calculations are performed using the computer code MULTI with the modifications made by Hubeny & Lites. It is found that PRD effects are highly significant, both in the direct prediction of the Lyman line profiles and in the application of hydrostatic equilibrium to calculate the atmospheric electron density in static atmospheric models.

The Postmodernist Critique of Evidence-Based Practice

In this paper, we examine the postmodernist argument that evidence-based practice (EBP) should be rejected by nurses because it restricts the sources of knowledge used by practitioners. Three main postmodernist criticisms are identified and discussed. First, that the notion of ‘best evidence’ implies a hierarchical and exclusivist approach to knowledge. We accept this argument, noting that such a hierarchy is accepted and justified by many of its proponents. Second, that the hierarchy embraced by the evidence-based practice movement damages health care because it excludes other forms of evidence that are needed to understand the complexity of care. We accept that some manifestations of EBP, notably the Cochrane Collaboration, have devalued qualitative evidence. Using our previous experience of conducting Cochrane reviews (McGaughey et al. 2007), we argue that this limits explanatory scope. Third, that it fails to take account of individuals or their experience. Here, we use evidence of the use by midwives of EBP policies and protocols to the detriment of including women in decision-making processes (Porter et al. 2007) to accept that there is also some merit to this critique. We conclude that, while it is not necessary to concur with the total rejection of EBP that postmodernists advocate, it is necessary to address the issues they raise in order to ensure that EBP better fits the requirements of nursing.
McGaughey, J., Alderdice, F., Fowler, R., Kapila, A., Mayhew, A., Moutray, M., 2007. Outreach and Early Warning Systems (EWS) for the prevention of Intensive Care admission and death of critically ill adult patients on general hospital wards. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD005529. DOI: 10.1002/14651858.CD005529.pub2.
Porter, S., Crozier, K., Sinclair, M., Kernohan, W., 2007. New midwifery? A qualitative analysis of midwives’ decision-making strategies. Journal of Advanced Nursing 60 (6), 525-534.

Complex organic molecules in protoplanetary disks

Context. Protoplanetary disks are vital objects in star and planet formation, possessing all the material, gas and dust, which may form a planetary system orbiting the new star. Small, simple molecules have traditionally been detected in protoplanetary disks; however, in the ALMA era, we expect the molecular inventory of protoplanetary disks to significantly increase.

Aims. We investigate the synthesis of complex organic molecules (COMs) in protoplanetary disks to put constraints on the achievable chemical complexity and to predict species and transitions which may be observable with ALMA.

Methods. We have coupled a 2D steady-state physical model of a protoplanetary disk around a typical T Tauri star with a large gas-grain chemical network including COMs. We compare the resulting column densities with those derived from observations and perform ray-tracing calculations to predict line spectra. We compare the synthesised line intensities with current observations and determine those COMs which may be observable in nearby objects. We also compare the predicted grain-surface abundances with those derived from cometary comae observations.

Results. We find COMs are efficiently formed in the disk midplane via grain-surface chemical reactions, reaching peak grain-surface fractional abundances similar to 10(-6)-10(-4) that of the H nuclei number density. COMs formed on grain surfaces are returned to the gas phase via non-thermal desorption; however, gas-phase species reach lower fractional abundances than their grain-surface equivalents, similar to 10(-12)-10(-7). Including the irradiation of grain mantle material helps build further complexity in the ice through the replenishment of grain-surface radicals which take part in further grain-surface reactions. There is reasonable agreement with several line transitions of H2CO observed towards T Tauri star-disk systems. There is poor agreement with HC3(N) lines observed towards LkCa 15 and GO Tau and we discuss possible explanations for these discrepancies. The synthesised line intensities for CH3OH are consistent with upper limits determined towards all sources. Our models suggest CH3OH should be readily observable in nearby protoplanetary disks with ALMA; however, detection of more complex species may prove challenging, even with ALMA "Full Science" capabilities. Our grain-surface abundances are consistent with those derived from cometary comae observations providing additional evidence for the hypothesis that comets (and other planetesimals) formed via the coagulation of icy grains in the Sun's natal disk.

Quantitative Measurement of [Na+] and [K+] in Postmortem Human Brain Tissue Indicates Disturbances in Subjects with Alzheimer's Disease and Dementia with Lewy Bodies

Alzheimer’s disease (AD) is associated with significant disturbances in the homeostasis of Na+ and K+ ions as well as reduced levels of Na+/K+ ATPase in the brain. This study used ICP-MS to accurately quantify Na+ and K+ concentrations in human postmortem brain tissue. We analyzed parietal cortex (Brodmann area 7) from 28 cognitively normal age-matched controls, 15 cases of moderate AD, 30 severe AD, and 15 dementia with Lewy bodies (DLB). Associations were investigated between [Na+] and [K+] and a number of variables including diagnosis, age, gender, Braak tangle stage, amyloid-β (Aβ) plaque load, tau load, frontal tissue pH, and APOE genotype. Brains from patients with severe AD had significantly higher (26%; p<0.001) [Na+] (mean 65.43 ± standard error 2.91 mmol/kg) than controls, but the concentration was not significantly altered in moderate AD or DLB. [Na+] correlated positively with Braak stage (r=0.45; p<0.0001), indicating association with disease severity. [K+] in tissue was 10% lower (p<0.05) in moderate AD than controls. However, [K+] in severe AD and DLB (40.97±1.31 mmol/kg) was not significantly different from controls. There was a significant positive correlation between [K+] and Aβ plaque load (r=0.46; p=0.035), and frontal tissue pH (r=0.35; p=0.008). [Na+] was not associated with [K+] across the groups, and neither ion was associated with tau load or APOE genotype. We have demonstrated disturbances of both [Na+] and [K+] in relation to the severity of AD and markers of AD pathology, although it is possible that these relate to late-stage secondary manifestations of the disease pathology.

Temperature dependence of the mid-infrared dielectric function of YBCO in the ab plane

We have excited mid-infrared surface plasmons in two YBCO thin films of contrasting properties using attenuated total reflection of light and found that the imaginary part of the dielectric function decreases linearly with reduction in temperature. This result is in contrast with the commonly reported conclusion of infrared normal reflectance studies. If sustained it may clarify the problem of understanding the normal state properties of YBCO and the other cuprates. The dielectric function of the films, epsilon = epsilon(1) + i epsilon(2), was determined between room temperature and 80K: epsilon(1) was found to be only slightly temperature dependent but somewhat sample dependent, probably as a result of surface and grain boundary contamination. The imaginary part, epsilon(2), (and the real part of the conductivity, sigma(1),) decreased linearly with reduction in temperature in both films. Results obtained were: for film 1: epsilon(1) = - 14.05 - 0.0024T and epsilon(2) - 4.11 + 0.086T and for film 2: epsilon(1) = - 24.09 + 0.0013T and epsilon(2) = 7.66 + 0.067T where T is the temperature in Kelvin. An understanding of the results is offered in terms of temperature-dependent intrinsic intragrain inelastic scattering and temperature-independent contributions: elastic and inelastic grain boundary scattering and optical interband (or localised charge) absorption. The relative contribution of each is estimated. A key conclusion is that the interband (or localised charge) absorption is only similar to 10%. Most importantly, the intrinsic scattering rate, 1/tau, decreases linearly with fall in temperature, T, in a regime where current theory predicts dependence on frequency, omega, to dominate. The coupling constant, lambda, between the charge carriers and the thermal excitations has a value of 1.7, some fivefold greater than the far infrared value. These results imply a need to restate the phenomenology of the normal state of high temperature superconductors and seek a corresponding theoretical understanding.

גבול (Border)

This paper is a reexamination of the concept of the geopolitical border through a critical analysis of prevalent conceptualizations of borders, as they are articulated in the fields of geopolitics, political theory and international relations. Suggesting that thinking of borders as the derivative of territorial definitions disregards the dependency of territoriality and sovereign space on the praxes of border making, this paper offers an analytic distinction between normative articulations of borders and the border as a political practice. This distinction enables the identification of partial and incoherent border making processes. Consequently, the creation of borders can be analyzed as an effect of a multiplicity of performative praxes, material, juridical and otherwise discursive, that operate in relation to the management of space and attribute it with geopolitical distinctions. Furthermore, the paper suggests that these praxes, which appear in dispersed sites and in a wide variety of loci, are intrinsically linked to different spatial practices of population management, of governmentality. Thus, I offer a reading of borders as a praxis which manages binary differentiations of matrixes of governmentality, which create schisms in the population as a totality, through the deployment of the evocation of sovereignty as the legitimizing source of this differentiation or for the means necessary for its sustainment.

(Dis‑)Harmony in movement: effects of musical dissonance on movement timing and form

While the origins of consonance and dissonance in terms of acoustics, psychoacoustics and physiology have been debated for centuries, their plausible effects on movement synchronization have largely been ignored. The present study aims to address this by investigating whether, and if so how, consonant/dissonant pitch intervals affect the spatiotemporal properties of regular reciprocal aiming movements. We compared movements synchronized either to consonant or to dissonant sounds, and showed that they were differently influenced by the degree of consonance of the sound presented. Interestingly, the difference was present after the sound stimulus was removed. In this case, the performance measured after consonant sound exposure was found to be more stable and accurate, with a higher percentage of information/movement coupling (tau-coupling) and a higher degree of movement circularity when compared to performance measured after the exposure to dissonant sounds. We infer that the neural resonance representing consonant tones leads to finer perception/action coupling which in turn may help explain the prevailing preference for these types of tones.