Access routes, devices and guidance methods for intrapericardial delivery in cardiac conditions

Drug deposition into the intrapericardial space is favourable for achieving localised effects and targeted cardiac delivery owing to its proximity to the myocardium as well as facilitating optimised pharmacokinetic profiles and a reduction in systemic side effects. Access to the pericardium requires invasive procedures but the risks associated with this have been reduced with technological advances, such as combining transatrial and subxiphoid access with different guidance methods. A variety of introducer devices, ranging from needles to loop-catheters, have also been developed and validated in pre-clinical studies investigating intrapericardial delivery of therapeutic agents. Access techniques are generally well-tolerated, self-limiting and safe, although some rare complications associated with certain approaches have been reported. This review covers these access techniques and how they have been applied to the delivery of drugs, cells, and biologicals, demonstrating the potential of intrapericardial delivery for treatments in cardiac arrhythmia, vascular damage, and myocardial infarction

Elevated Liver Enzymes and Mortality in Older Individuals: A Prospective Cohort Study

Aim of the study: The aim of the study was to determine the excess risk of all-cause and cardiovascular mortality in older people with elevated liver enzymes [alanine transaminase (ALT) and gamma glutamyltransferase (GGT)]. Methods: We utilized data from a large, prospective, population based study of 2061 people aged 50 to 99 years with linkage to a National Death Registry. Participants were categorized as having elevated liver enzymes using standard thresholds (for males, GGT>51 and ALT>40 IU/L, and GGT>33 and ALT>31 IU/L for females). Adjusted Cox proportional hazards models assessed the association of elevated liver enzymes and mortality with long duration follow-up. Results: Over a median follow-up of 10 years (20,145 person years), 701 people died, including 203 (34%) from cardiovascular disease. Cox regression models adjusted for sex, age, smoking, and alcohol intake indicated that people with elevated liver enzymes had an increased risk of all-cause mortality that was modified by age (test for interaction P=0.01). Age-stratified analyses demonstrated no increased risk at younger ages [age 59 y and below; hazard ratio (HR): 0.46; 95% confidence interval, 0.06-3.49], but increased risk with age; age 60 to 69, HR: 1.05 (0.53-2.07), age 70 to 79 years, HR: 1.54 (0.81 to 2.93), and age 80 years and above, HR: 3.53 (1.55 to 8.04). Similarly, the risk of cardiovascular mortality with elevated liver enzymes was also modified by, and increased with age (test for interaction P=0.02); age 70 to 79, HR: 3.15 (1.37 to 7.23), age 80 years and above, HR: 6.86 (2.44 to 19.30). Conclusions: In community-dwelling elderly persons, an elevation in both ALT and GGT are associated with an excess risk of all-cause and cardiovascular mortality which increases with age

Directional emission of light from a nano-optical Yagi-Uda antenna

The plasmon resonance of metal nanoparticles can enhance and direct light from optical emitters in much the same way that radio frequency (RF) antennas enhance and direct the emission from electrical circuits. In the RF regime, a typical antenna design for high directivity is the Yagi-Uda antenna, which basically consists of a one-dimensional array of antenna elements driven by a single feed element. Here, we present the experimental demonstration of directional light emission from a nano-optical Yagi-Uda antenna composed of an array of appropriately tuned gold nanorods. Our results indicate that nano-optical antenna arrays are a simple but efficient tool for the spatial control of light emission.Comment: 4 pages, including 4 figure

Role of oxidative stress in oxaliplatin-induced enteric neuropathy and colonic dysmotility in mice

BACKGROUND AND PURPOSE: Oxaliplatin is a platinum‐based chemotherapeutic drug used as a first‐line therapy for colorectal cancer. However, its use is associated with severe gastrointestinal side‐effects resulting in dose limitations and/or cessation of treatment. In this study, we tested whether oxidative stress, caused by chronic oxaliplatin treatment, induces enteric neuronal damage and colonic dysmotility. EXPERIMENTAL APPROACH: Oxaliplatin (3 mg·kg(−1) per day) was administered in vivo to Balb/c mice intraperitoneally three times a week. The distal colon was collected at day 14 of treatment. Immunohistochemistry was performed in wholemount preparations of submucosal and myenteric ganglia. Neuromuscular transmission was studied by intracellular electrophysiology. Circular muscle tone was studied by force transducers. Colon propulsive activity studied in organ bath experiments and faeces were collected to measure water content. KEY RESULTS: Chronic in vivo oxaliplatin treatment resulted in increased formation of reactive oxygen species (O(2)ˉ), nitration of proteins, mitochondrial membrane depolarisation resulting in the release of cytochrome c, loss of neurons, increased inducible NOS expression and apoptosis in both the submucosal and myenteric plexuses of the colon. Oxaliplatin treatment enhanced NO‐mediated inhibitory junction potentials and altered the response of circular muscles to the NO donor, sodium nitroprusside. It also reduced the frequency of colonic migrating motor complexes and decreased circular muscle tone, effects reversed by the NO synthase inhibitor, Nω‐Nitro‐L‐arginine. CONCLUSION AND IMPLICATIONS: Our study is the first to provide evidence that oxidative stress is a key player in enteric neuropathy and colonic dysmotility leading to symptoms of chronic constipation observed in oxaliplatin‐treated mice

The psychological-type profile of lay church leaders in Australia

A sample of 845 lay church leaders (444 women and 401 men) from a range of 24 different denominations and movements (including house churches and independent churches) completed the Francis Psychological-Type Scales within the context of the 2006 Australian National Church Life Survey. The psychological-type profiles of these lay church leaders were almost identical to the type profiles of 1527 Australian churchgoers (936 women and 591 men) published in an earlier study by Robbins and Francis. The predominant types among female lay church leaders were ISFJ (21%), ESFJ (21%), and ISTJ (18%). The predominant types among male lay church leaders were ISTJ (28%), ISFJ (17%), ESTJ (13%), and ESFJ (12%). The SJ temperament accounted for 67% of the female lay church leaders and for 70% of the male lay church leaders. The strengths and weaknesses of the SJ leadership style are discussed

Phase Mixing of Alfvén Waves Near a 2D Magnetic Null Point

The propagation of linear Alfvén wave pulses in an inhomogeneous plasma near a 2D coronal null point is investigated. When a uniform plasma density is considered, it is seen that an initially planar Alfvén wavefront remains planar, despite the varying equilibrium Alfvén speed, and that all the wave collects at the separatrices. Thus, in the non-ideal case, these Alfvénic disturbances preferentially dissipate their energy at these locations. For a non-uniform equilibrium density, it is found that the Alfvén wavefront is significantly distorted away from the initially planar geometry, inviting the possibility of dissipation due to phase mixing. Despite this however, we conclude that for the Alfvén wave, current density accumulation and preferential heating still primarily occur at the separatrices, even when an extremely non-uniform density profile is considered

The Effects of Serotonin Receptor Antagonists on Contraction and Relaxation Responses Induced by Electrical Stimulation in the Rat Small Intestine

Background: The main source of 5-HT in body is in enterchromafin cells of intestine, different studies mentioned different roles for endogenous 5-HT and receptors involved and it is not clearified the mechanism of action of endogenous 5-HT. Objectives: To study the role of endogenous 5-HT on modulation of contraction and relaxation responses induced by electrical field stimulation (EFS) in different regions of the rat intestine. Materials and Methods: Segments taken from the rat duodenum, jejunum, mid and terminal ileum were vertically mounted, connected to a transducer and exposed to EFS with different frequencies in the absence and presence of various inhibitors of enteric mediators i. e. specific 5-HT receptor antagonists. Results: EFS-induced responses were sensitive to TTX and partly to atropine, indicating a major neuronal involvement and a cholinergic system. Pre-treatment with WAY100635 (a 5-HT1A receptor antagonist) and granisetron up to 10.0 µM, GR113808 (a 5-HT4 receptor antagonist), methysergide and ritanserin up to 1.0 µM, failed to modify responses to EFS inall examined tissues. In the presence of SB258585 1.0 µM (a 5-HT6 receptor antagonist) there was a trend to enhance contraction in the proximal part of the intestine and reduce contraction in the distal part. Pre-treatment with SB269970A 1.0 µM (5-HT7 receptor antagonist) induced a greater contractile response to EFS at 0.4 Hz only in the duodenum. Conclusions: The application of 5-HT1A, 5-HT2, 5-HT3, 5-HT4, 5-HT6 and 5-HT7 receptor antagonists, applied at concentrations lower than 1.0 µM did not modify the EFS-induced contraction and relaxation responses, whichsuggests the unlikely involvement of endogenous 5-HT in mediating responses to EFS in the described test conditions. Keywords: Electric Stimulation Therapy; Serotonin 5-HT1 Receptor Antagonists; Intestine, Smal

Finding a way: long-term care homes to support dementia

An ageing demographic has increased the number of people with dementia. Although dementia is commonly associated with memory loss, other early symptoms include difficulty with wayfinding. Dementia alters visuo-spatial perception and the processes used to interpret the physical environment. The role of the design of the physical environment for people with dementia has gained increased recognition. Despite this, design for dementia is often overlooked, focusing on issues relating to physical impairment. This paper presents the results of a PhD study and aims to examine the role of the design of the physical environment in supporting wayfinding for people with dementia living in long-term care settings in Northern Ireland. Mixed methods combined the observation of wayfinding walks and conversational style interviews to elicit perspectives and experiences of residents with dementia. The findings aim to promote well-being for those with dementia living in long-term care settings

Effect of dietary nitrate supplementation on conduit artery blood flow, muscle oxygenation, and metabolic rate during handgrip exercise

Dietary nitrate supplementation has positive effects on mitochondrial and muscle contractile efficiency during large muscle mass exercise in humans and on skeletal muscle blood flow (Q̇) in rats. However, concurrent measurement of these effects has not been performed in humans. Therefore, we assessed the influence of nitrate supplementation on Q̇ and muscle oxygenation characteristics during moderate- (40 %peak) and severe-intensity(85% peak) handgrip exercise in a randomized, double-blind, crossover design. Nine healthy men (age: 25 ± 2 yr) completed four constant-power exercise tests (2/intensity) randomly assigned to condition [nitrate-rich (nitrate) or nitrate-poor (placebo) beetroot supplementation] and intensity (40 or 85% peak). Resting mean arterial pressure was lower after nitrate compared with placebo (84 ± 4 vs. 89 ± 4 mmHg, P &lt; 0.01). All subjects were able to sustain 10 min of exercise at 40% peak in both conditions. Nitrate had no effect on exercise tolerance during 85% peak (nitrate: 358 ± 29; placebo: 341 ± 34 s; P = 0.3). Brachial artery Q̇ was not different after nitrate at rest or any time during exercise. Deoxygenated [hemoglobin + myoglobin] was not different for 40% peak ( P &gt; 0.05) but was elevated throughout 85% peak ( P &lt; 0.05) after nitrate. The metabolic cost (V̇o2) was not different at the end of exercise; however, the V̇o2 primary amplitude at the onset of exercise was elevated after nitrate for the 85% peak work rate (96 ± 20 vs. 72 ± 12 ml/min, P &lt; 0.05) and had a faster response. These findings suggest that an acute dose of nitrate reduces resting blood pressure and speeds V̇o2 kinetics in young adults but does not augment Q̇ or reduce steady-state V̇o2 during small muscle mass handgrip exercise. NEW &amp; NOTEWORTHY We show that acute dietary nitrate supplementation via beetroot juice increases the amplitude and speed of local muscle V̇o2 on kinetics parameters during severe- but not moderate-intensity handgrip exercise. These changes were found in the absence of an increased blood flow response, suggesting that the increased V̇o2 was attained via improvements in fractional O2 extraction and/or spatial distribution of blood flow within the exercising muscle. </jats:p

MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments

Background: Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development. Objective: MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design. Methods and Findings: We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03). Conclusions: Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy. Trial Registration: ClinicalTrials.gov NCT00592124