5,293 research outputs found
Ī±<sub>1L</sub>-adrenoceptors mediate contraction of human erectile tissue
Ī±1-adrenoceptor antagonists can impact upon sexual function and have potential in the treatment of erectile dysfunction. Human erectile tissue contains predominantly Ī±1A-adrenoceptors, and here we examined whether contractions of this tissue are mediated by the functional phenotype, the Ī±1L-adrenoceptor. Functional experiments using subtype selective agonists and antagonists, along with radioligand ([3H]tamsulosin) binding assays, were used to determine the Ī±1-adrenoceptor population. A61603, a Ī±1A-adrenoceptor agonist, was a full agonist with a potency 21-fold greater than that of noradrenaline. The Ī±1A- and Ī±1D-adrenoceptor antagonist tamsulosin antagonized noradrenaline responses with high affinity (pKDĀ =Ā 9.7Ā Ā±Ā 0.3), whilst BMY7378 (100Ā nM) (Ī±1D-adrenoceptor antagonist) failed to antagonize responses. In contrast, relatively low affinity estimates were obtained for both prazosin (pKDĀ =Ā 8.2Ā Ā±Ā 0.1) and RS17053 (pKDĀ =Ā 6.9Ā Ā±Ā 0.2), antagonists which discriminate between the Ī±1A- and Ī±1L-adrenoceptors. [3H]Tamsulosin bound with high affinity to the receptors of human erectile tissue (pKDĀ =Ā 10.3Ā Ā±Ā 0.1) with a receptor density of 28.1Ā Ā±Ā 1.4Ā fmolĀ mgā1 protein. Prazosin displacement of [3H]tamsulosin binding revealed a single homogenous population of binding sites with a relatively low affinity for prazosin (pKiĀ =Ā 8.9). Taken together these data confirm that the receptor mediating contraction in human erectile tissue has the pharmacological properties of the Ī±1L-adrenoceptor. Keywords: Erectile tissue, Ī±1-adrenoceptor subtypes, Ī±1L-adrenoceptor, Tamsulosin, Prazosi
North African Jewish and non-Jewish populations form distinctive, orthogonal clusters
Campbell, Christopher L. et al.North African Jews constitute the second largest Jewish Diaspora group. However, their relatedness to each other; to European, Middle Eastern, and other Jewish Diaspora groups; and to their former North African non-Jewish neighbors has not been well defined. Here, genome-wide analysis of five North African Jewish groups (Moroccan, Algerian, Tunisian, Djerban, and Libyan) and comparison with other Jewish and non-Jewish groups demonstrated distinctive North African Jewish population clusters with proximity to other Jewish populations and variable degrees of Middle Eastern, European, and North African admixture. Two major subgroups were identified by principal component, neighbor joining tree, and identity-by-descent analysis - Moroccan/ Algerian and Djerban/Libyan - that varied in their degree of European admixture. These populations showed a high degree of endogamy and were part of a larger Ashkenazi and Sephardic Jewish group. By principal component analysis, these North African groups were orthogonal to contemporary populations from North and South Morocco, Western Sahara, Tunisia, Libya, and Egypt. Thus, this study is compatible with the history of North African Jews - founding during Classical Antiquity with proselytism of local populations, followed by genetic isolation with the rise of Christianity and then Islam, and admixture following the emigration of Sephardic Jews during the Inquisition.This work was supported in part by the Lewis and Rachel Rudin Foundation, the Iranian-American Jewish Federation of New York, the USāIsrael Binational Science Foundation, National Institutes of Health Grant 5 U54 CA121852, and Ruth and Sidney Lapidus. L.R.B. and D.C. were supported by Ministerio de Ciencia e InnovaciĆ³n Grant CGL2010-14944/BOS.Peer Reviewe
Novel dimeric Ī²-helical model of an ice nucleation protein with bridged active sites
<p>Abstract</p> <p>Background</p> <p>Ice nucleation proteins (INPs) allow water to freeze at high subzero temperatures. Due to their large size (>120 kDa), membrane association, and tendency to aggregate, an experimentally-determined tertiary structure of an INP has yet to be reported. How they function at the molecular level therefore remains unknown.</p> <p>Results</p> <p>Here we have predicted a novel Ī²-helical fold for the INP produced by the bacterium <it>Pseudomonas borealis</it>. The protein uses internal serine and glutamine ladders for stabilization and is predicted to dimerize via the burying of a solvent-exposed tyrosine ladder to make an intimate hydrophobic contact along the dimerization interface. The manner in which <it>Pb</it>INP dimerizes also allows for its multimerization, which could explain the aggregation-dependence of INP activity. Both sides of the <it>Pb</it>INP structure have tandem arrays of amino acids that can organize waters into the ice-like clathrate structures seen on antifreeze proteins.</p> <p>Conclusions</p> <p>Dimerization dramatically increases the 'ice-active' surface area of the protein by doubling its width, increasing its length, and presenting identical ice-forming surfaces on both sides of the protein. We suggest that this allows sufficient anchored clathrate waters to align on the INP surface to nucleate freezing. As <it>Pb</it>INP is highly similar to all known bacterial INPs, we predict its fold and mechanism of action will apply to these other INPs.</p
Usability and feasibility of consumer-facing technology to reduce unsafe medication use by older adults
Background
Mobile health technology can improve medication safety for older adults, for instance, by educating patients about the risks associated with anticholinergic medication use.
Objective
This study's objective was to test the usability and feasibility of Brain Buddy, a consumer-facing mobile health technology designed to inform and empower older adults to consider the risks and benefits of anticholinergics.
Methods
Twenty-three primary care patients aged ā„60 years and using anticholinergic medications participated in summative, task-based usability testing of Brain Buddy. Self-report usability was assessed by the System Usability Scale and performance-based usability data were collected for each task through observation. A subset of 17 participants contributed data on feasibility, assessed by self-reported attitudes (feeling informed) and behaviors (speaking to a physician), with confirmation following a physician visit.
Results
Overall usability was acceptable or better, with 100% of participants completing each Brain Buddy task and a mean System Usability Scale score of 78.8, corresponding to āGoodā to āExcellentā usability. Observed usability issues included higher rates of errors, hesitations, and need for assistance on three tasks, particularly those requiring data entry. Among participants contributing to feasibility data, 100% felt better informed after using Brain Buddy and 94% planned to speak to their physician about their anticholinergic related risk. On follow-up, 82% reported having spoken to their physician, a rate independently confirmed by physicians.
Conclusion
Consumer-facing technology can be a low-cost, scalable intervention to improve older adultsā medication safety, by informing and empowering patients. User-centered design and evaluation with demographically heterogeneous clinical samples uncovers correctable usability issues and confirms the value of interventions targeting consumers as agents in shared decision making and behavior change
Adherence and Tolerability of Alzheimer's Disease Medications: A Pragmatic Randomized Trial
BACKGROUND/OBJECTIVES:
Post-marketing comparative trials describe medication use patterns in diverse, real-world populations. Our objective was to determine if differences in rates of adherence and tolerability exist among new users to acetylcholinesterase inhibitors (AChEI's).
DESIGN:
Pragmatic randomized, open label comparative trial of AChEI's currently available in the United States.
SETTING:
Four memory care practices within four healthcare systems in the greater Indianapolis area.
PARTICIPANTS:
Eligibility criteria included older adults with a diagnosis of possible or probable Alzheimer's disease (AD) who were initiating treatment with an AChEI. Participants were required to have a caregiver to complete assessments, access to a telephone, and be able to understand English. Exclusion criteria consisted of a prior severe adverse event from AChEIs.
INTERVENTION:
Participants were randomized to one of three AChEIs in a 1:1:1 ratio and followed for 18 weeks.
MEASUREMENTS:
Caregiver-reported adherence, defined as taking or not taking study medication, and caregiver-reported adverse events, defined as the presence of an adverse event.
RESULTS:
196 participants were included with 74.0% female, 30.6% African Americans, and 72.9% who completed at least twelfth grade. Discontinuation rates after 18 weeks were 38.8% for donepezil, 53.0% for galantamine, and 58.7% for rivastigmine (P = .063) in the intent to treat analysis. Adverse events and cost explained 73.1% and 25.4% of discontinuation. No participants discontinued donepezil due to cost. Adverse events were reported by 81.2% of all participants; no between-group differences in total adverse events were statistically significant.
CONCLUSIONS:
This pragmatic comparative trial showed high rates of adverse events and cost-related non-adherence with AChEIs. Interventions improving adherence and persistence to AChEIs may improve AD management.
TRIAL REGISTRATION:
Clinicaltrials.gov: NCT01362686 (https://clinicaltrials.gov/ct2/show/NCT01362686)
The difference in blood pressure readings between arms and survival: primary care cohort study
Objective To determine whether a difference in systolic blood pressure readings between arms can predict a reduced event free survival after 10 years
Effect of abdominal binding on respiratory mechanics during exercise in athletes with cervical spinal cord injury
West CR, Goosey-Tolfrey VL, Campbell IG, Romer LM. Effect of
abdominal binding on respiratory mechanics during exercise in athletes
with cervical spinal cord injury. J Appl Physiol 117: 36ā45, 2014. First
published May 22, 2014; doi:10.1152/japplphysiol.00218.2014.āWe
asked whether elastic binding of the abdomen influences respiratory
mechanics during wheelchair propulsion in athletes with cervical
spinal cord injury (SCI). Eight Paralympic wheelchair rugby players
with motor-complete SCI (C5-C7) performed submaximal and maximal
incremental exercise tests on a treadmill, both with and without
abdominal binding. Measurements included pulmonary function,
pressure-derived indices of respiratory mechanics, operating lung
volumes, tidal flow-volume data, gas exchange, blood lactate, and
symptoms. Residual volume and functional residual capacity were
reduced with binding (77 18 and 81 11% of unbound, P 0.05),
vital capacity was increased (114 9%, P 0.05), whereas total lung
capacity was relatively well preserved (99 5%). During exercise,
binding introduced a passive increase in transdiaphragmatic pressure,
due primarily to an increase in gastric pressure. Active pressures
during inspiration were similar across conditions. A sudden, sustained
rise in operating lung volumes was evident in the unbound condition,
and these volumes were shifted downward with binding.
Expiratory flow limitation did not occur in any subject and there
was substantial reserve to increase flow and volume in both
conditions. V Ė O2 was elevated with binding during the final stages
of exercise (8 ā12%, P 0.05), whereas blood lactate concentration
was reduced (16 ā19%, P 0.05). V Ė O2/heart rate slopes were
less steep with binding (62 35 vs. 47 24 ml/beat, P 0.05).
Ventilation, symptoms, and work rates were similar across conditions.
The results suggest that abdominal binding shifts tidal
breathing to lower lung volumes without influencing flow limitation,
symptoms, or exercise tolerance. Changes in respiratory
mechanics with binding may benefit O2 transport capacity by an
improvement in central circulatory function.This article has been made available through the Brunel Open Access Publishing Fund
Nurse led interventions to improve control of blood pressure in people with hypertension: systematic review and meta-analysis
Objective To review trials of nurse led interventions for hypertension in primary care to clarify the evidence base, establish whether nurse prescribing is an important intervention, and identify areas requiring further study
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