A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems

The link between off-target anticholinergic effects of medications and acute cognitive impairment in older adults requires urgent investigation. We aimed to determine whether a relevant in vitro model may aid the identification of anticholinergic responses to drugs and the prediction of anticholinergic risk during polypharmacy. In this preliminary study we employed a co-culture of human-derived neurons and astrocytes (NT2.N/A) derived from the NT2 cell line. NT2.N/A cells possess much of the functionality of mature neurons and astrocytes, key cholinergic phenotypic markers and muscarinic acetylcholine receptors (mAChRs). The cholinergic response of NT2 astrocytes to the mAChR agonist oxotremorine was examined using the fluorescent dye fluo-4 to quantitate increases in intracellular calcium [Ca2+]i. Inhibition of this response by drugs classified as severe (dicycloverine, amitriptyline), moderate (cyclobenzaprine) and possible (cimetidine) on the Anticholinergic Cognitive Burden (ACB) scale, was examined after exposure to individual and pairs of compounds. Individually, dicycloverine had the most significant effect regarding inhibition of the astrocytic cholinergic response to oxotremorine, followed by amitriptyline then cyclobenzaprine and cimetidine, in agreement with the ACB scale. In combination, dicycloverine with cyclobenzaprine had the most significant effect, followed by dicycloverine with amitriptyline. The order of potency of the drugs in combination frequently disagreed with predicted ACB scores derived from summation of the individual drug scores, suggesting current scales may underestimate the effect of polypharmacy. Overall, this NT2.N/A model may be appropriate for further investigation of adverse anticholinergic effects of multiple medications, in order to inform clinical choices of suitable drug use in the elderly.

Identification of Mechanical Parameters in Mathematical Model of Human Abdominal Fascia

Миглена Г. Кирилова-Донева - Едномерен експеримент на релаксация беше извършен с 14 образци от човешка пъпна фасция. Механичното поведение на фасцията по време на релаксация беше моделирано прилагайки нелинейната теория на Максвел-Гуревич-Рабинович. Параметрите на модела за изследваните образци бяха определени и стойностите им бяха сравнени в зависимост от посоката на натоварване на образците по време на експеримента. Установено бе, че стойностите на началния вискозитет ∗η0 и на параметъра ∗m, който се влияе от скоростта на деформация на материала се изменят в много широки граници не само за образци от различни донори, но и за образци от един донор. В резултат от прилагането на модела бе изчислено изменението на вискозитета и вискозната деформация на материала по време на релаксацията. Бе показано, че изменението на вискозитета и вискозната деформация зависи от посоката на натоварване на образците.

Intellectual disability and being human:a care ethics model

This pioneering book, in considering intellectually disabled people's lives, sets out a care ethics model of disability that outlines the emotional caring sphere, where love and care are psycho-socially questioned, the practical caring sphere, where day-to-day care is carried out, and the socio-political caring sphere, where social intolerance and aversion to difficult differences are addressed. This book draws from an understanding of how intellectual disability is represented in all forms of media, a feminist ethics of care, and capabilities, as well as other theories, to provide a critique and alternative to the social model of disability.

Using an in vitro human airway model to study the toxic effects of components of e-cigarettes

Cigarette smoke is a complex mixture of more than 4000 hazardous chemicals including the carcinogenic benzopyrenes. Nicotine, the most potent component of tobacco, is responsible for the addictive nature of cigarettes and is a major component of e-cigarette cartridges. Our study aims to investigate the toxicity of nicotine with special emphasis on the replacement of animals. Furthermore, we intend to study the effect of nicotine, cigarette smoke and e-cigarette vapours on human airways. In our current work, the BEAS 2B human bronchial epithelial cell line was used to analyse the effect of nicotine in isolation, on cell viability. Concentrations of nicotine from 1.1µM to 75µM were added to 5x105 cells per well in a 96 well plate and incubated for 24 hours. Cell titre blue results showed that all the nicotine treated cells were more metabolically active than the control wells (cells alone). These data indicate that, under these conditions, nicotine does not affect cell viability and in fact, suggests that there is a stimulatory effect of nicotine on metabolism. We are now furthering this finding by investigating the pro-inflammatory response of these cells to nicotine by measuring cytokine secretion via ELISA. Further work includes analysing nicotine exposure at different time points and on other epithelial cells lines like Calu-3.

A Human Resource Development Performance Improvement Model for Workers with Mental Retardation in Supported Employment

This literature review discusses the factors for successful job retention of adult workers with mental retardation, including external factors related to work environments and internal issues of the individual worker. Through the synthesis of the literature, a performance improvement model for supported employment is discussed based on Holton’s (1999) human resource development/performance improvement model.

Food Safety in Restaurants: A Human Relations Model

Barry Reece and Rhonda Brandt use a human relations perspective to explain behavior at work. Following a review of the six components of their model, the author presents research to illustrate how it can be used by managers to help them understand why food safety violations occur in restaurants. An additional variable not included in the model is discusses and recommendations for managers are made.

Robotic Outcome Assessment in a Non-Human Primate Model of Middle Cerebral Artery Stroke

Stroke is a prevalent disorder with immense socioeconomic impact. A variety of chronic neurological deficits result from stroke. In particular, sensorimotor deficits are a significant barrier to achieving post-stroke independence. Unfortunately, the majority of pre-clinical studies that show improved outcomes in animal stroke models have failed in clinical trials. Pre-clinical studies using non-human primate (NHP) stroke models prior to initiating human trials are a potential step to improving translation from animal studies to clinical trials. Robotic assessment tools represent a quantitative, reliable, and reproducible means to assess reaching behaviour following stroke in both humans and NHPs. We investigated the use of robotic technology to assess sensorimotor impairments in NHPs following middle cerebral artery occlusion (MCAO). Two cynomolgus macaques underwent transient MCAO for 90 minutes. Approximately 1.5 years following the procedure these NHPs and two non-stroke control monkeys were trained in a reaching task with both arms in the KINARM exoskeleton. This robot permits elbow and shoulder movements in the horizontal plane. The task required NHPs to make reaching movements from a centrally positioned start target to 1 of 8 peripheral targets uniformly distributed around the first target. We analyzed four movement parameters: reaction time, movement time (MT), initial direction error (IDE), and number of speed maxima to characterize sensorimotor deficiencies. We hypothesized reduced performance in these attributes during a neurobehavioural task with the paretic limb of NHPs following MCAO compared to controls. Reaching movements in the non-affected limbs of control and experimental NHPs showed bell-shaped velocity profiles. In contrast, the reaching movements with the affected limbs were highly variable. We found distinctive patterns in MT, IDE, and number of speed peaks between control and experimental monkeys and between limbs of NHPs with MCAO. NHPs with MCAO demonstrated more speed peaks, longer MTs, and greater IDE in their paretic limb compared to controls. These initial results qualitatively match human stroke subjects’ performance, suggesting that robotic neurobehavioural assessment in NHPs with stroke is feasible and could have translational relevance in subsequent human studies. Further studies will be necessary to replicate and expand on these preliminary findings.

Survival, differentiation, and neuroprotective mechanisms of human stem cells complexed with neurotrophin-3-releasing pharmacologically active microcarriers in an ex vivo model of Parkinson's disease

International audience

MRI indices of functional recovery following intracerebral implantation of a human neural stem cell line in a pre-clinical model of ischaemic stroke

Stem cell therapy for ischaemic stroke is an emerging field in light of an increasing number of patients surviving with permanent disability. Several allogenic and autologous cells types are now in clinical trials with preliminary evidence of safety. Some clinical studies have reported functional improvements in some patients. After initial safety evaluation in a Phase 1 study, the conditionally immortalised human neural stem cell line CTX0E03 is currently in a Phase 2 clinical trial (PISCES-II). Previous pre-clinical studies conducted by ReNeuron Ltd, showed evidence of functional recovery in the Bilateral Asymmetry test up to 6 weeks following transplantation into rodent brain, 4 weeks after middle cerebral artery occlusion. Resting-state fMRI is increasingly used to investigate brain function in health and disease, and may also act as a predictor of recovery due to known network changes in the post-stroke recovery period. Resting-state methods have also been applied to non-human primates and rodents which have been found to have analogous resting-state networks to humans. The sensorimotor resting-state network of rodents is impaired following experimental focal ischaemia of the middle cerebral artery territory. However, the effects of stem cell implantation on brain functional networks has not previously been investigated. Prior studies assessed sensorimotor function following sub-cortical implantation of CTX0E03 cells in the rodent post-stroke brain but with no MRI assessments of functional improvements. This thesis presents research on the effect of sub-cortical implantation of CTX0E03 cells on the resting- state sensorimotor network and sensorimotor deficits in the rat following experimental stroke, using protocols based on previous work with this cell line. The work in this thesis identified functional tests of appropriate sensitivity for long-term dysfunction suitable for this laboratory, and investigated non-invasive monitoring of physiological variables required to optimize BOLD signal stability within a high-field MRI scanner. Following experimental stroke, rats demonstrated expected sensorimotor dysfunction and changes in the resting-state sensorimotor network. CTX0E03 cells did not improve post-stroke functional outcome (compared to previous studies) and with no changes in resting-state sensorimotor network activity. However, in control animals, we observed changes in functional networks due to the stereotaxic procedure. This illustrates the sensitivity of resting-state fMRI to stereotaxic procedures. We hypothesise that the damage caused by cell or vehicle implantation may have prevented functional and network recovery which has not been previously identified due to the application of different functional tests. The findings in this thesis represent one of few pre-clinical studies in resting-state fMRI network changes post-stroke and the only to date applying this technique to evaluate functional outcomes following a clinically applicable human neural stem cell treatment for ischaemic stroke. It was found that injury caused by stereotaxic injection should be taken into account when assessing the effectiveness of treatment.

Recombinant human endostatin reduces hypertrophic scar formation in rabbit ear model through down- regulation of VEGF and TIMP-1.

Background: Recombinant human endostatin (Endostar) has been widely used to suppress angiogenesis in carcinoma patients. Hypertrophic scar (HS) tissue, much like a carcinoma, is often associated with angiogenesis. However, there have been few studies conducted on the effects of Endostar on HS or its mechanism. Objective: This paper investigated the effects Endostar on the HS of rabbit ears and studied the effects of Endostar on VEGF and TIMP-1 expression. Methods: Sixteen New Zealand white rabbits were used to establish HS models. Then, rabbit ears containing HS were randomly assigned to either the Endostar group or the control group. The changes of appearance and histology were evaluated using the naked eye, hematoxylin eosin staining, and a scar elevation index. The VEGF and TIMP-1 expressions were detected by immunohistochemical staining, RT-PCR, and western blot. Results: The thickness of the connective tissue in the Endostar group were thinner, the numbers of micro vessels and fibroblasts were fewer, and the collagen fibers were smoother. Moreover, the mRNA and protein expressions of VEGF and TIMP-1 in the Endostar group were significantly lower than those in the control group. Conclusion: The results suggested that Endostar reduced the formation of HS by down-regulation of VEGF and TIMP-1 expressions.

Volcanic processes and human exposure as elements to build a risk model for Volcan de Fuego, Guatemala

The activity of Fuego volcano during the 1999 - 2013 eruptive episode is studied through field, remote sensing and observatory records. Mapping of the deposits allows quantifying the erupted volumes and areas affected by the largest eruptions during this period. A wide range of volcanic processes results in a diversity of products and associated deposits, including minor airfall tephra, rockfall avalanches, lava flows, and pyroclastic flows. The activity can be characterized by long term, low level background activity, and sporadic larger explosive eruptions. Although the background activity erupts lava and ash at a low rate (~ 0.1 m3/s), the persistence of such activity over time results in a significant contribution (~ 30%) to the eruption budget during the studied period. Larger eruptions produced the majority of the volume of products during the studied period, mainly during three large events (May 21, 1999, June 29, 2003, and September 13, 2012), mostly in the form of pyroclastic flows. A total volume of ~ 1.4 x 108 m3 was estimated from the mapped deposits and the estimated background eruption rate. Posterior remobilization of pyroclastic flow material by stream erosion in the highly confined Barranca channels leads to lahar generation, either by normal rainfall, or by extreme rainfall events. A reassessment of the types of products and volumes erupted during the decade of 1970's allows comparing the activity happening since 1999 with the older activity, and suggests that many of the eruptive phenomena at Fuego may have similar mechanisms, despite the differences in scale between. The deposits of large pyroclastic flows erupted during the 1970's are remarkably similar in appearance to the deposit of pyroclastic flows from the 1999 - 2013 period, despite their much larger volume; this is also the case for prehistoric eruptions. Radiocarbon dating of pyroclastic flow deposits suggests that Fuego has produced large eruptions many times during the last ~ 2 ka, including larger eruptions during the last 500 years, which has important hazard implications. A survey was conducted among the local residents living near to the volcano, about their expectations of possible future crises. The results show that people are aware of the risk they could face in case of a large eruption, and therefore they are willing to evacuate in such case. However, their decision to evacuate may also be influenced by the conditions in which the evacuation could take place. If the evacuation represents a potential loss of their livelihood or property they will be more hesitant to leave their villages during a large eruption. The prospect of facing hardship conditions during the evacuation and in the shelters may further cause reluctance to evacuate. A short discussion on some of the issues regarding risk assessment and management through an early warning system is presented in the last chapter.

A NATURALISTIC COMPUTATIONAL MODEL OF HUMAN BEHAVIOR IN NAVIGATION AND SEARCH TASKS

Planning, navigation, and search are fundamental human cognitive abilities central to spatial problem solving in search and rescue, law enforcement, and military operations. Despite a wealth of literature concerning naturalistic spatial problem solving in animals, literature on naturalistic spatial problem solving in humans is comparatively lacking and generally conducted by separate camps among which there is little crosstalk. Addressing this deficiency will allow us to predict spatial decision making in operational environments, and understand the factors leading to those decisions. The present dissertation is comprised of two related efforts, (1) a set of empirical research studies intended to identify characteristics of planning, execution, and memory in naturalistic spatial problem solving tasks, and (2) a computational modeling effort to develop a model of naturalistic spatial problem solving. The results of the behavioral studies indicate that problem space hierarchical representations are linear in shape, and that human solutions are produced according to multiple optimization criteria. The Mixed Criteria Model presented in this dissertation accounts for global and local human performance in a traditional and naturalistic Traveling Salesman Problem. The results of the empirical and modeling efforts hold implications for basic and applied science in domains such as problem solving, operations research, human-computer interaction, and artificial intelligence.

Adaptation of the ABCDE model from human medicine to communicate bad news to the owner of the oncologic patient in veterinary medicine

Similar to what occurs in Human Medicine, also in Veterinary Medicine, the prevalence of oncological diseases has significantly increased. The evolution of Veterinary Medicine, in last decades has brought changes in clinical paradigms, particularly concerning the relationship with the animal and also with the owner. More than any other specialty, members of the Veterinary Medical Team that work in the oncology field, are unavoidably forced to break bad news. This paper proposes the adaptation of the ABCDE model from Human Medicine to Veterinary Medicine. The adaptation of the ABCDE model for Veterinary Medicine improves communication with the owner and offers all the members of the Veterinary Medical Team better communication skills.