Striatal plasticity in L-DOPA- and graft-induced dyskinesia:the common link?

One of the major symptoms of the neurodegenerative condition Parkinson’s disease (PD) is a slowness or loss of voluntary movement, yet frustratingly therapeutic strategies designed to restore movement can result in the development of excessive abnormal movements known as dyskinesia. These dyskinesias commonly develop as a result of pharmacotherapy in the form of L-DOPA administration, but have also been identified following deep brain stimulation (DBS) and intrastriatal cell transplantation. In the case of L-DOPA these movements can be treatment limiting, and whilst they are not long lasting or troubling following DBS, recognition of their development had a near devastating effect on the field of cell transplantation for PD.Understanding the relationship between these therapeutic approaches and the development of dyskinesia may improve our ability to restore function without disabling side effects. Interestingly, despite the fact that dopaminergic cell transplantation repairs many of the changes induced by the disease process and through L-DOPA treatment, there appears to be a relationship between the two. In rodent models of the disease, the severity of dyskinesia induced by L-DOPA prior to the transplantation procedure correlated with post-transplantation, graft-induced dyskinesia. A review of clinical data also suggested that the worse preoperational dyskinesia causes worsened graft-induced dyskinesia (GID). Understanding how these aberrant behaviors come about has been of keen interest to open up these therapeutic options more widely and one major underlying theory is the effects of these approaches on the plasticity of synapses within the basal ganglia. This review uniquely brings together developments in understanding the role of striatal synaptic plasticity in both L-DOPA and GID to guide and stimulate further investigations on the important striatal plasticity

A systematic review of omega-3 enriched foods and health

Purpose – To review evidence from high quality randomised controlled trials reporting links between omega-3 enriched functional foods and health. Design/methodology/approach – Using Medline, a search was made for all randomised controlled trials published between 2002 and 2012 that met defined inclusion criteria. Studies had minimum durations of 28-days, clearly stated the food vehicle, dose and type of long chain omega-3 polyunsaturated fatty acids (LC3PUFA) used and did not include studies where participants only took LC3PUFA supplements. Findings - A total of eleven studies were located, ten of which reported potential health benefits linked to omega-3 functional food consumption. Five studies reported significant improvements in markers of cardiovascular (CV) health while ten bioavailability studies reported increases in omega-3 blood levels when doses of 460mg or more were integrated into food vehicles. Research limitations/implication – In the future a meta-analysis would be useful in terms of determining the dose of LC3PUFA associated with overall health benefits. Practical implications - The present review concludes that omega-3 enriched functional foods are a useful way to improve LC3PUFA status and have been linked to improved health outcomes, namely markers of CV health. More work is now needed to determine whether particular population groups could benefit from consumption of these foods e.g. vegetarians and children in relation to a range of health outcomes, such as cognitive function. Originality/value – This review provides evidence that integrating omega-3 enriched functional foods within the daily diet could be an effective strategy for helping to improve LC3PUFA status and attenuating CV disease risk

Carbon-13 in groundwater from English and Norwegian crystalline rock aquifers: a tool for deducing the origin of alkalinity?

The 13C signature is evaluated for various environmental compartments (vegetation, soils, soil gas, rock and groundwater) for three crystalline rock terrains in England and Norway. The data are used to evaluate the extent to which stable carbon isotopic data can be applied to deduce whether the alkalinity in crystalline bedrock groundwaters has its origin in hydrolysis of carbonate or silicate minerals by CO2. The resolution of this issue has profound implications for the role of weathering of crystalline rocks as a global sink for CO2. In the investigated English terrain (Isles of Scilly), groundwaters are hydrochemically immature and DIC is predominantly in the form of carbonic acid with a soil gas signature. In the Norwegian terrains, the evidence is not conclusive but is consistent with a significant fraction of the groundwater DIC being derived from silicate hydrolysis by CO2. A combined consideration of pH, alkalinity and carbon isotope data, plotted alongside theoretical evolutionary pathways on bivariate diagrams, strongly suggests real evolutionary pathways are likely to be hybrid, potentially involving both open and closed CO2 conditions

A preliminary investigation of adult defence style and physiological reactivity to infant distress signals

Species whose offspring require extended care-giving ought to be predisposed to being biologically responsive to their infant\u27s signalling. This paper examined the interplay between biological and psychological aspects of adult response to an infant\u27s distress. HR (heart rate) and GSR (galvanic skin response) were recorded continuously, while 50 adults listened to white noise and an infant cry audio recording. Participants completed the defence style questionnaire and the state trait anxiety inventory. HR acceleration occurred in response to the control sound, while HR decelerated in response to the infant cry. GSR responsiveness was positively correlated with immature and neurotic defence styles. When controlling for other variables, immature defence was a unique and independent predictor of GSR change in response to infant distress. Defence demonstrated a stronger relationship than self-reported anxiety, than that with physiological responsiveness. Employing defence mechanisms appears to reduce an individual\u27s perceived anxiety, though it has little effect on physiological arousal levels

L-DOPA for Parkinson's disease-a bittersweet pill

3,4‐dihydroxy‐L‐phenylalanine (L‐DOPA) is the gold standard treatment for Parkinson's disease. It has earned that title through its highly effective treatment of some of the motor symptoms in the early stages of the disease but it is a far from perfect drug. The inevitable long‐term treatment that comes with this chronic neurodegenerative condition raises the risk significantly of the development of motor fluctuations including disabling L‐DOPA‐induced dyskinesia. Being unsurpassed as a therapy means that understanding the mechanisms of dyskinesia priming and induction is vital to the search for therapies to treat these side effects and allow optimal use of L‐DOPA. However, L‐DOPA use may also have consequences (positive or negative) for the development of other interventions, such as cell transplantation, which are designed to treat or repair the ailing brain. This review looks at the issues around the use of L‐DOPA with a focus on its potential impact on advanced reparative interventions

L-dopa-Dependent Effects of GLP-1R Agonists on the Survival of Dopaminergic Cells Transplanted into a Rat Model of Parkinson Disease

Cell therapy is a promising treatment for Parkinson’s disease (PD), however clinical trials to date have shown relatively low survival and significant patient-to-patient variability. Glucagon Like Peptide-1 receptor (GLP-1R) agonists have potential neuroprotective effects on endogenous dopaminergic neurons. This study explores whether these agents could similarly support the growth and survival of newly transplanted neurons. 6-OHDA lesioned Sprague Dawley rats received intra-striatal grafts of dopaminergic ventral mesencephalic cells from embryonic day 14 Wistar rat embryos. Transplanted rats then received either saline or L-dopa (12 mg/kg) administered every 48 h prior to, and following cell transplantation. Peripheral GLP-1R agonist administration (exendin-4, 0.5 μg/kg twice daily or liraglutide, 100 μg/kg once daily) commenced immediately after cell transplantation and was maintained throughout the study. Graft survival increased under administration of exendin-4, with motor function improving significantly following treatment with both exendin-4 and liraglutide. However, this effect was not observed in rats administered with L-dopa. In contrast, L-dopa treatment with liraglutide increased graft volume, with parallel increases in motor function. However, this improvement was accompanied by an increase in leukocyte infiltration around the graft. The co-administration of L-dopa and exendin-4 also led to indicators of insulin resistance not seen with liraglutide, which may underpin the differential effects observed between the two GLP1-R agonists. Overall, there may be some benefit to the supplementation of grafted patients with GLP-1R agonists but the potential interaction with other pharmacological treatments needs to be considered in more depth

Over Rock and Under Stone: Carved Rocks and Subterranean Burials at Kipia, Ancash, AD 1000-1532

Research in the Andes has yielded evidence for a complex association between settlement sites and mortuary monuments, tied to concepts of death, ancestor veneration and water. The Huaylas-Inca and later Spanish colonial site of Kipia in the Cordillera Negra of the Ancash Highlands, North-Central Andes is a multi-faceted site, that contains a small settlement core, and a cosmological centre which includes carved rocks (huancas), niches and offerings. This, in turn backs onto a necropolis composed of a series of subterranean tombs (pukullo). In association, these features directly reference the surrounding agro-pastoralist landscape. In particular they evoke neighbouring lakes as possible foci of ethnogenesis or pacarinas. The relation between ceremonial sites and cemeteries is crucial to understanding Andean concepts of death and renewal. In this article, alongside a detailed description of the site, we provide a preliminary analysis of the contents of one of the pukullo. In turn, these results are placed within their landscape context to discuss issues related to sacrality, water and death.Fil: Lane, Kevin John. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Arqueología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pomeroy, Emma. No especifíca;Fil: Lújan Davila, Milton Reynaldo. No especifíca

PCNA binding proteins in Drosophila melanogaster : the analysis of a conserved PCNA binding domain

The eukaryotic polymerase processivity factor, PCNA, interacts with cell cycle regulatory proteins such as p21^(WAF1/Cip1) and Gadd45, as well as with proteins involved in the mechanics of DNA repair and replication. A conserved PCNA-binding motif is found in a subset of PCNA-interacting proteins, including p21, suggesting that the regulation of these interactions is important for the co-ordination of DNA replication and repair. We have identified several classes of protein which bind to Drosophila PCNA. Two of these proteins contain the consensus PCNA-binding domain: one is the Dacapo protein, a Drosophila homologue of p21^(WAF1/Cip1), and the second is the transposase encoded by the Pogo DNA transposon. A conserved PCNA-binding domain is also present in a human relative of Pogo, named Tigger, suggesting that this domain has a functional role in this class of transposable element. This raises interesting possibilities for a novel method of transposition in which the transposase might be targeted to replicating DNA. Finally, we have investigated the use of this conserved PCNAbinding domain as a predictor of PCNA-binding capacity

PCNA binding proteins in Drosophila melanogaster : the analysis of a conserved PCNA binding domain

The eukaryotic polymerase processivity factor, PCNA, interacts with cell cycle regulatory proteins such as p21^(WAF1/Cip1) and Gadd45, as well as with proteins involved in the mechanics of DNA repair and replication. A conserved PCNA-binding motif is found in a subset of PCNA-interacting proteins, including p21, suggesting that the regulation of these interactions is important for the co-ordination of DNA replication and repair. We have identified several classes of protein which bind to Drosophila PCNA. Two of these proteins contain the consensus PCNA-binding domain: one is the Dacapo protein, a Drosophila homologue of p21^(WAF1/Cip1), and the second is the transposase encoded by the Pogo DNA transposon. A conserved PCNA-binding domain is also present in a human relative of Pogo, named Tigger, suggesting that this domain has a functional role in this class of transposable element. This raises interesting possibilities for a novel method of transposition in which the transposase might be targeted to replicating DNA. Finally, we have investigated the use of this conserved PCNAbinding domain as a predictor of PCNA-binding capacity

Patterns and determinants of prescribing for Parkinson's Disease: A systematic literature review

Since the discovery of levodopa (L-dopa) in 1967, the range of medications available to treat Parkinson’s disease has increased significantly and guidance on the use, efficacy, and safety of these medications has evolved. To assess levels of adherence to national prescribing guidelines and awareness of changes in the efficacy and safety data published in the profiles of medications for the treatment of PD, we have reviewed studies on patterns and determinants of prescribing PD medications conducted in the last 50 years (since the discovery of L-dopa). A systematic literature review was conducted using EMBASE (1967 to March, 2018), Ovid MEDLINE(R) ALL (1967 to March 16, 2018), PsycINFO (1967 to the 2nd week of March, 2018), and PubMed to identify all studies measuring prescribing patterns of PD medication between 1967 and 2017. Study design, source of data, country, year of study, number of patients and/or prescriptions, unit of analysis, prescribing determinants, and percentage utilisation of PD medications were extracted where possible. 44 studies examining prescribing patterns and/or prescribing determinants across 17 countries were identified. Unsurprisingly, L-dopa was the most commonly prescribed medication in all studies, accounting for 46.50% to 100% of all prescriptions for PD. In several studies, the prescribing rate of ergot-derived dopamine agonists (DAs) decreased over time in concordance with guidance. In contrast, the prescribing rates of non-ergot DAs increased over the last ten years in most of the included studies. In examining prescribing factors, two major categories were exemplified, patients’ factors and prescribers’ factors, with patients’ age being the most common factor that affected the prescription in most studies. In conclusion, L-dopa is now the most commonly prescribed medication for cases of PD but there is large variation in the prescribing rates of catechol-O-methyltransferase (COMT) inhibitors, monoamine oxidase B (MAO-B) inhibitors, amantadine, and anticholinergics between countries. New studies examining the effects of recent clinical trials and measuring the prescribing rates of newly approved medications are warranted