Successful use of axonal transport for drug delivery by synthetic molecular vehicles

We report the use of axonal transport to achieve intraneural drug delivery. We constructed a novel tripartite complex of an axonal transport facilitator conjugated to a linker molecule bearing up to a hundred reversibly attached drug molecules. The complex efficiently enters nerve terminals after intramuscular or intradermal administration and travels within axonal processes to neuron cell bodies. The tripartite agent provided 100-fold amplification of saturable neural uptake events, delivering multiple drug molecules per complex. _In vivo_, analgesic drug delivery to systemic and to non-targeted neural tissues was greatly reduced compared to existing routes of administration, thus exemplifying the possibility of specific nerve root targeting and effectively increasing the potency of the candidate drug gabapentin 300-fold relative to oral administration

Tri-partite complex for axonal transport drug delivery achieves pharmacological effect.

BACKGROUND: Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. RESULTS: We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. CONCLUSION: Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [11 C]UCB-J Positron Emission Tomography Study

BACKGROUND: Synaptic loss is characteristic of many neurodegenerative diseases; it occurs early and is strongly related to functional deficits. OBJECTIVE: In this longitudinal observational study, we determine the rate at which synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and we test the relationship with disease progression. METHODS: Our cross-sectional cohort included 32 participants with probable PSP and 16 with probable CBD (all amyloid-negative corticobasal syndrome), recruited from tertiary care centers in the United Kingdom, and 33 sex- and age-matched healthy control subjects. Synaptic density was estimated by positron emission tomography imaging with the radioligand [11 C]UCB-J that binds synaptic vesicle 2A. Clinical severity and cognition were assessed by the PSP Rating Scale and the Addenbrooke's cognitive examination. Regional [11 C]UCB-J nondisplaceable binding potential was estimated in Hammersmith Atlas regions of interest. Twenty-two participants with PSP/CBD had a follow-up [11 C]UCB-J positron emission tomography scan after 1 year. We calculated the annualized change in [11 C]UCB-J nondisplaceable binding potential and correlated this with the change in clinical severity. RESULTS: We found significant annual synaptic loss within the frontal lobe (-3.5%, P = 0.03) and the right caudate (-3.9%, P = 0.046). The degree of longitudinal synaptic loss within the frontal lobe correlated with the rate of change in the PSP Rating Scale (R = 0.47, P = 0.03) and cognition (Addenbrooke's Cognitive Examination-Revised, R = -0.62, P = 0.003). CONCLUSIONS: We provide in vivo evidence for rapid progressive synaptic loss, correlating with clinical progression in primary tauopathies. Synaptic loss may be an important therapeutic target and outcome variable for early-phase clinical trials of disease-modifying treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

How to Adapt to Changing Markets: Experience and Personality in a Repeated Investment Game

Investment behavior is traditionally investigated with the assumption that it is on average advantageous to invest. However, this may not always be the case. In this paper, we experimentally studied investment choices made by students and financial professionals facing alternately an advantageous and disadvantageous environment in a multi-round investment game. Expected returns from investment in the advantageous environment were higher than a safe alternative, while expected returns were lower in the disadvantageous environment. We investigate how experience and personality are related to choices. Investment behavior does not differ dependent on expected returns and professionals do not significantly differ from students. Personality predicts behavior and in particular we observe that openness to experience was an asset in unfavorable markets, leading to reduced risk taking

Stimulated monocyte IL-6 secretion predicts survival of patients with head and neck squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>This study was performed in order to determine whether monocyte <it>in vitro </it>function is associated with presence, stage and prognosis of head and neck squamous cell carcinoma (HNSCC) disease.</p> <p>Methods</p> <p>Prospective study describing outcome, after at least five years observation, of patients treated for HNSCC disease in relation to their monocyte function. Sixty-five patients with newly diagnosed HNSCC and eighteen control patients were studied. Monocyte responsiveness was assessed by measuring levels of monocyte <it>in vitro </it>interleukin (IL)-6 and monocyte chemotactic peptide (MCP)-1 secretion after 24 hours of endotoxin stimulation in cultures supplied either with 20% autologous serum (AS) or serum free medium (SFM). Survival, and if relevant, cause of death, was determined at least 5 years following primary diagnosis.</p> <p>Results</p> <p>All patients, as a group, had higher <it>in vitro </it>monocyte responsiveness in terms of IL-6 (AS) (<it>t </it>= 2.03; <it>p </it>< 0.05) and MCP-1 (SFM) (<it>t </it>= 2.49; <it>p </it>< 0.05) compared to controls. Increased <it>in vitro </it>monocyte IL-6 endotoxin responsiveness under the SFM condition was associated with decreased survival rate (Hazard ratio (HR) = 2.27; Confidence interval (CI) = 1.05–4.88; <it>p </it>< 0.05). The predictive value of monocyte responsiveness, as measured by IL-6, was also retained when adjusted for age, gender and disease stage of patients (HR = 2.67; CI = 1.03–6.92; <it>p </it>< 0.05). With respect to MCP-1, low endotoxin-stimulated responsiveness (AS), analysed by Kaplan-Meier method, predicted decreased survival (χ = 4.0; <it>p </it>< 0.05).</p> <p>Conclusion</p> <p>In HNSCC patients, changed monocyte <it>in vitro </it>response to endotoxin, as measured by increased IL-6 (SFM) and decreased MCP-1 (AS) responsiveness, are negative prognostic factors.</p

The Vehicle, Fall 1982

Vol. 24, No. 1 Table of Contents Winter SurveillanceB.L. Davidsonpage 3 The InvitationBecky Lawsonpage 4 Check In, Check OutSteve Sandstrompage 4 On The Front Porch StepKeila Tooleypage 5 Old Greek ManDevon Flesorpage 5 Exotic PassionsBecky Lawsonpage 6 PhotographLisa Owenspage 7 Beyond The ThornsBrook Wilsonpage 8 Ritual Of HeatB.L. Davidsonpage 11 The GamerBecky Lawsonpage 12 It\u27s OverKeila Tooleypage 13 DreamJohn Stockmanpage 14 Silver DollarGina J. Grillopage 15 The DancerJessica Lewispage 16 Snapshots Of Rural IllinoisIsabel M. Parrottpage 16 The Last SeasonTheresa Whitesidepage 17 DrawingKaren Haneypage 17 Rotary LuncheonJessica Lewispage 18 Factory TourLinda Fraembspage 18 The ImmigrantsD.L. Lewispage 19 At Shedd AquariumLinda Fraembspage 20 The GuardianBecky Lewispage 20 Digital LifeEverett Tackettpage 21 Full ServiceScott Graypage 22 Dust ShowLinda A. Brownpage 23 At SixMaureen Foertschpage 24 DrawingJean Imherrpage 24 ReflectionMaggie Kennedypage 25 Cat DefiningBecky Lawsonpage 26 Ode To An Unread NewspaperLinda Fraembspage 26 GumSteve Sandstrompage 27 The DancerChrystal Clarkpage 27 PoemD.L. Lewispage 28 For LucyStacey Flanniganpage 29 An AbortionDevon Flesorpage 29 ReveriesKeila Tooleypage 30 Sunday Morning After Tequila With LemonScott Graypage 33 Staging A Living Jewel BoxMichelle Mitchellpage 34 The Other WomanStacey Flanniganpage 35 The Natural LookMichelle Mitchellpage 35 Poem To A Girl Named SandalsJohn Stockmanpage 36 PhotographLisa Owenspage 37 In The Balcony Of The Bijou On A Saturday NightScott Graypage 38 The Canadian Soccer PlayerBecky Lawsonpage 39 The HealingJohn Stockmanpage 39 AppeasedDevon Flesorpage 40 CodaJohn Stockmanpage 40https://thekeep.eiu.edu/vehicle/1040/thumbnail.jp

Impulsivity-related cognition in alcohol dependence: is it moderated by DRD2/ANKK1 gene status and executive dysfunction?

Perceived impaired control over alcohol use is a key cognitive construct in alcohol dependence that has been related prospectively to treatment outcome and may mediate the risk for problem drinking conveyed by impulsivity in non-dependent drinkers. The aim of the current study was to investigate whether perceived impaired control may mediate the association between impulsivity-related measures (derived from the Short-form Eysenck Personality Questionnaire Revised) and alcohol-dependence severity in alcohol-dependent drinkers. Furthermore, the extent to which this hypothesized relationship was moderated by genetic risk (Taq1A polymorphism in the DRD2/ANKK1 gene cluster) and verbal fluency as an indicator of executive cognitive ability (Controlled Oral Word Association Test) was also examined. A sample of 143 alcohol-dependent inpatients provided an extensive clinical history of their alcohol use, gave 10 ml of blood for DNA analysis, and completed self-report measures relating to impulsivity, impaired control and severity of dependence. As hypothesized, perceived impaired control (partially) mediated the association between impulsivity-related measures and alcohol-dependence severity. This relationship was not moderated by the DRD2/ANICK1 polymorphism or verbal fluency. These results suggest that, in alcohol dependence, perceived impaired control is a cognitive mediator of impulsivity-related constructs that may be unaffected by DRD2/ANKK1 and neurocognitive processes underlying the retrieval of verbal information. (C) 2014 Elsevier Ltd. All rights reserved

Contextualising the pervasive impact of macroeconomic austerity on prison health in England: A qualitative study among international policymakers

Background: Prisons offer the state the opportunity to gain access to a population that is at particularly high risk of ill-health. Despite the supportive legal and policy structures surrounding prison rehabilitation, the oppressive nature of the austerity policy in England threatens its advanced improvement.Methods: Using grounded theory methodology, this is the first interdisciplinary qualitative study to explore the impact of macroeconomic austerity on prison health in England from the perspective of 29 international prison policymakers.Results: The far-reaching impact of austerity in England has established a regressive political system that shapes the societal attitude towards social issues, which has exacerbated the existing poor health of the prisoners. Austerity has undermined the notion of social collectivism, imposed a culture of acceptance among prison bureaucrats and the wider community, and normalised the devastating impacts of prison instability. These developments are evidenced by the increasing levels of suicide, violence, radicalisation and prison gangs among prisoners, as well as the imposition of long working hours and the high levels of absenteeism among prison staff.Conclusions: This study underscores an important and yet unarticulated phenomenon that despite being the fifth largest economy in the world, England’s poorest, marginalised and excluded population continues to bear the brunt of austerity. Reducing the prison population, using international obligations as minimum standards to protect prisoners’ right to health and providing greater resources would create a more positive and inclusive system, in line with England’s international and domestic commitments to the humane treatment of all people