A Vicious Cycle of Fear of Falling Avoidance Behavior in Parkinson’s Disease: A Path Analysis

Background: Postural instability (PI) in Parkinson\u27s disease (PD) is associated with several negative downstream consequences. Objective: The purpose was to explore the validity of a theoretical model of these downstream consequences arranged in a vicious cycle wherein PI leads to decreased balance confidence, which in turn leads to increased fear of falling (FOF) avoidance behavior, which in turn leads to decreased physical conditioning, which then feeds back and negatively affects PI. Methods: A path analysis of cross-sectional data from 55 participants with PD was conducted. The four constructs in the model connected in succession were: 1. PI (principal components analysis (PCA) composite of the Unified Parkinson\u27s Disease Rating Scale PI and Gait Difficulty score, Timed Up and Go test, and Berg Balance Scale); 2. balance confidence (Activities-Specific Balance Confidence Scale); 3. FOF avoidance behavior (PCA composite of the FOF Avoidance Behavior Questionnaire and average number of steps per day); and, 4. physical conditioning (2-Minute Step Test). Results: The path model was an excellent fit to the data, χ2 (7) = 7.910, p =.341, CFI = 0.985, TLI = 0.968, RMSEA = 0.049 (90% CI: 0.000 to 0.179). The moderate to strong and uniformly significant parameter estimates were −0.519, −0.651, −0.653, and −0.570, respectively (ps \u3c 0.01). Conclusions: PI directly and inversely predicted balance confidence, which in turn directly and inversely predicted FOF avoidance behavior. Furthermore, FOF avoidance behavior directly and inversely predicted physical conditioning, which directly and inversely predicted PI, thereby closing the cycle. These findings highlight the downstream consequences of PI in PD and support the notion of a vicious cycle of FOF avoidance behavior

Intravitreal Sirolimus for the Treatment of Noninfectious Uveitis: Evolution through Preclinical and Clinical Studies

In recent decades, the treatment paradigm for noninfectious intermediate uveitis, posterior uveitis, and panuveitis, a group of intraocular inflammatory diseases, has included systemic and local (periocular or intraocular) corticosteroids, biologics, and other steroid-sparing immunomodulatory therapy agents. Recently, an intravitreal formulation of sirolimus, an immunosuppressant that inhibits the mammalian target of rapamycin, a key regulator of cell growth in the immune system, was developed. On the basis of this mechanism and the local method of delivery, it was hypothesized that intravitreal sirolimus can improve ocular inflammation in patients with noninfectious intermediate uveitis, posterior uveitis, and panuveitis, with minimal systemic exposure and systemic adverse events (AEs). This review summarizes the pharmacokinetics, efficacy, and safety results of intravitreal sirolimus from 3 preclinical studies and 4 phase 1–3 clinical studies. Preclinical studies in rabbits showed that 22 to 220 μg intravitreal sirolimus results in sustained release of sirolimus in the vitreous for 2 months or more, with systemic concentrations below the threshold for systemic immunosuppression (approximately 8 ng/ml). Subsequently, 2 phase 1 studies (n = 50 and n = 30) established that intravitreal sirolimus improves ocular inflammation in humans. Further investigation in phase 2 and 3 studies (n = 24 and n = 347, respectively) suggested that 440 μg has the best benefit-to-risk profile. In the phase 3 study, the proportion of patients who showed complete resolution of ocular inflammation at month 5 was significantly higher in the 440-μg group than in the 44-μg group (22.8% vs. 10.3%; P = 0.025, Fisher exact test). In addition, 47 of 69 patients (68.1%) who were treated with systemic corticosteroids at baseline discontinued corticosteroid use at month 5. No sirolimus-related systemic AEs were reported in phase 1–3 studies. Collectively, these preclinical and clinical study data of intravitreal sirolimus support the therapeutic rationale of treating noninfectious uveitis with a local mammalian target of rapamycin inhibitor and suggest that 440 μg intravitreal sirolimus has the potential to be an effective and well-tolerated anti-inflammatory and corticosteroid-sparing treatment for noninfectious intermediate uveitis, posterior uveitis, and panuveitis

Evaluation of the Influence of Raw Almonds on Appetite Control: Satiation, Satiety, Hedonics and Consumer Perceptions.

Snack foods can be substantial contributors to daily energy intake, with different types of snacks exerting potentially different effects on satiety per calorie consumed. The present research compared the effect of consuming almonds as a mid-morning snack compared to an energy and weight-matched comparator snack (savoury crackers) or the equivalent weight of water (zero energy control). In a crossover design, 42 female participants (age: 26.0 ± 7.9, BMI: 22.0 ± 2.0) consumed a fixed breakfast then a mid-morning snack. Appetite, 24-h energy intake, food hedonics, and consumer perceptions of the snack foods were assessed under laboratory conditions. AUC analyses revealed a lower overall hunger drive after consuming almonds compared to crackers or water. There was no difference in 24-h energy intake in the almond compared to the cracker or the zero-energy control condition, however participants consumed more energy in the cracker condition compared to the zero-energy control condition. In addition, almonds suppressed hedonic preference (implicit wanting) for consuming high-fat foods and demonstrated a higher satiety quotient (SQ) than crackers. Almonds were perceived to have a more favourable consumer profile aligned with successful weight management. In conclusion, these findings demonstrate that in the context of a 24-h period of objectively measured energy intake, raw almonds are effective for controlling appetite compared to an energy matched alternative snack. This trial was registered at clinicaltrials.gov [NCT02480582]

The Moon as a Stepping Stone to Human Mars Missions

Human space mission designers stretching back to von Braun and beyond have envisioned the moon as a waypoint to the more challenging missions to Mars. The moon is seen as a potential proving ground for technologies, equipment and operations, and a venue upon which to learn the art of surface exploration. Mars missions are years in duration with very limited Earth return opportunities, but the moon provides the opportunity to perfect exploration concepts while being only a few days from Earth. Though the environment and gravity differ from Mars, and will thereby not provide a perfectly analogous environment, the remoteness, limited logistics, and harsh conditions on the Moon provide an environment that can be used to stress many systems that will be used or will be extensible to hardware and operations that will be used on Mars. This paper begins by describing the systems, or options for systems, that together comprise a human Mars architecture. With this human Mars operational concept as a basis of comparison, each of these systems is analyzed in the context of a range of potential exploration missions that first targets lunar exploration experience, examining how the lunar experience can be best used to prepare for the eventual human mission to Mars. The paper concludes with a concise summary of specific areas that have the strongest applicability between exploration experience on the lunar surface and extensibility to human Mars exploration

Platelet PECAM-1 Inhibits Thrombus Formation In Vivo

Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a cell surface glycoprotein receptor expressed on a range of blood cells including platelets, and is also on vascular endothelial cells. PECAM-1 possesses adhesive and signalling properties, the latter being mediated by an Immunoreceptor Tyrosine-based Inhibitory Motif present on the cytoplasmic tail of the protein. Recent studies in vitro have demonstrated that PECAM-1 signalling inhibits the aggregation of platelets. In the present study we have utilised PECAM-1 deficient mice and radiation chimeras to investigate the function of this receptor in the regulation of thrombus formation. Using intravital microscopy and laser induced injury to cremaster muscle arterioles, we show that thrombi formed in PECAM-1 deficient mice were larger, formed more rapidly than in control mice and were more stable. Larger thrombi were also formed in control mice transplanted with PECAM-1 deficient bone marrow, in comparison to control-transplanted mice. A ferric chloride model of thrombosis was used to investigate thrombus formation in carotid arteries. In PECAM-1 deficient mice the time to 75% vessel occlusion was significantly shorter than in control mice. These data provide evidence for the involvement of platelet PECAM-1 in the negative regulation of thrombus formation

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Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosis

Objective: To examine the impact on quality of life (QOL) of patients with hATTR amyloidosis with polyneuropathy treated with inotersen (Tegsedi™) versus placebo. Methods: Data were from the NEURO-TTR trial (ClinicalTrials.gov Identifier: NCT01737398), a phase 3, multinational, randomized, double-blind, placebo-controlled study of inotersen in patients with hATTR amyloidosis with polyneuropathy. At baseline and week 66, QOL measures-the Norfolk-QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2)-were assessed. Treatment differences in mean changes in QOL from baseline to week 66 were tested using mixed-effect models with repeated measures. Responder analyses compared the percentages of patients whose QOL meaningfully improved or worsened from baseline to week 66 in inotersen and placebo arms. Descriptive analysis of item responses examined treatment differences in specific activities and functions at week 66. Results: Statistically significant mean differences between treatment arms were observed for three of five Norfolk-QOL-DN domains and five of eight SF-36v2 domains, with better outcomes for inotersen than placebo in physical functioning, activities of daily living, neuropathic symptoms, pain, role limitations due to health problems, and social functioning. A larger percentage of patients in the inotersen arm than the placebo arm showed preservation or improvement in Norfolk-QOL-DN and SF-36v2 scores from baseline to week 66. Responses at week 66 showed more substantial problems with daily activities and functioning for patients in the placebo arm than in the inotersen arm. Conclusion: Patients with hATTR amyloidosis with polyneuropathy treated with inotersen showed preserved or improved QOL at 66 weeks compared to those who received placebo.This research was funded by Akcea Therapeutics and Ionis Pharmaceuticals, Incinfo:eu-repo/semantics/publishedVersio

The Moon as a Stepping Stone to Human Mars Missions

As we venture back to the Moon with a longer term goal of future Mars missions, lunar missions can provide an important testbed for technologies, systems and operations that directly feed forward to future Mars needs. Gateway missions can provide good in-space transportation feed forward to human Mars missions. Modest operations on the Moon such as the GER (Global Exploration Roadmap)-class missions, can provide key Mars human performance and surface mission capability development and risk reduction. A human return to the Moon can, if done correctly, serve as an excellent down payment to Mars