Using artificial intelligence to identify drugs for repurposing to treat l-DOPA-induced dyskinesia.

Repurposing regulatory agency-approved molecules, with proven safety in humans, is an attractive option for developing new treatments for disease. We identified and assessed the efficacy of 3 drugs predicted by an in silico screen as having the potential to treat l-DOPA-induced dyskinesia (LID) in Parkinson's disease. We analysed ∼1.

Beneficial Effects of Trehalose on Striatal Dopaminergic Deficits in Rodent and Primate Models of Synucleinopathy in Parkinson's Disease.

Disease modification in Parkinson's disease (PD) is an unmet medical need. In the current study, we evaluated trehalose, a safe and well-tolerated disaccharide that has previously demonstrated efficacy in rodent models of neurodegenerative diseases, including PD. In a rat model of PD, based on delivery of adeno-associated virus serotype 1/2 containing the mutated human A53T -synuclein gene (AAV1/2-hourA53T-aSyn) to the substantia nigra (SN), we showed that rats administered trehalose (2.

Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques.

Background: Pridopidine, in development for Huntington's disease, may modulate aberrant l-dopa-induced effects including l-dopa-induced dyskinesia (LID).

Objective: This study investigated whether pridopidine could reduce LID in the MPTP macaque model of Parkinson's disease and characterized the observed behavioral effects in terms of receptor occupancy.

Methods: The pharmacokinetic profile and effects of pridopidine (15-30 mg/kg) on parkinsonism, dyskinesia, and quality of on-time, in combination with l-dopa, were assessed in MPTP macaques with LID.

DPI-289, a novel mixed delta opioid agonist / mu opioid antagonist (DAMA), has L-DOPA-sparing potential in Parkinson's disease.

L-DOPA-induced dyskinesia (LID) remains a significant problem in the management of Parkinson's disease (PD). In rodent and macaque models of PD, delta opioid receptor agonists have anti-parkinsonian actions while mu opioid antagonists can reduce the expression of LID. DPI-289 is a novel molecule with a unique combination of opioid receptor DAMA actions: delta agonist (K: 0.

The public health significance of latrines discharging to groundwater used for drinking.

Faecal contamination of groundwater from pit latrines is widely perceived as a major threat to the safety of drinking water for several billion people in rural and peri-urban areas worldwide. On the floodplains of the Ganges-Brahmaputra-Meghna delta in Bangladesh, we constructed latrines and monitored piezometer nests monthly for two years. We detected faecal coliforms (FC) in 3.

RGS4 is involved in the generation of abnormal involuntary movements in the unilateral 6-OHDA-lesioned rat model of Parkinson's disease.

Regulators of G-protein signalling (RGS) proteins are implicated in striatal G-protein coupled receptor (GPCR) sensitisation in the pathophysiology of l-DOPA-induced abnormal involuntary movements (AIMs), also known as dyskinesia (LID), in Parkinson's disease (PD). In this study, we investigated RGS protein subtype 4 in the expression of AIMs in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of LID. The effects of RGS4 antisense brain infusion on the behavioural and molecular correlates of l-DOPA priming in 6-OHDA-lesioned rats were assessed.

Rotigotine polyoxazoline conjugate SER-214 provides robust and sustained antiparkinsonian benefit.

Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to significant motor complications including "wearing-off" and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects.

Stable groundwater quality in deep aquifers of Southern Bangladesh: the case against sustainable abstraction.

In forty six wells >150 m deep, from across the arsenic-polluted area of south-central Bangladesh, groundwater composition remained unchanged between 1998 and 2011. No evidence of deteriorating water quality was found in terms of arsenic, iron, manganese, boron, barium or salinity over this period of 13 years. These deep tubewells have achieved operating lives of more than 20 years with minimal institutional support.

Alternative splicing of AMPA receptor subunits in the 6-OHDA-lesioned rat model of Parkinson's disease and L-DOPA-induced dyskinesia.

Abnormal corticostriatal plasticity is a key mechanism of L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). Antagonists at glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, such as IEM 1460, reduce induction and expression of dyskinesia in rat and non-human primate models of PD. AMPA receptor function is regulated by post-transcriptional splicing of subunit mRNA to produce flip and flop isoforms, which may therefore influence corticostriatal plasticity.

Synergistic antidyskinetic effects of topiramate and amantadine in animal models of Parkinson's disease.

L-Dopa-induced dyskinesia in patients with Parkinson's disease can be alleviated by amantadine, an antagonist at N-methyl-D-aspartate glutamate receptors. The antiepileptic drug topiramate, which blocks α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, has also been shown to reduce dyskinesia. The purpose of this study was to examine the behavioral pharmacology of topiramate alone and in combination with amantadine in animal models of PD and L-dopa-induced dyskinesia.

Dopamine transporter binding is unaffected by L-DOPA administration in normal and MPTP-treated monkeys.

Background: Radiotracer imaging of the presynaptic nigrostriatal dopaminergic system is used to assess disease progression in Parkinson's disease (PD) and may provide a useful adjunct to clinical assessment during therapeutic trials of potential neuroprotective agents. Several clinical trials comparing dopamine agonists to L-DOPA or early vs. late L-DOPA have revealed differences between clinical assessment and imaging of the presynaptic dopaminergic system, hence questioning the comparability of these measures as neuroprotection outcome variables.

Neuroanatomical study of the A11 diencephalospinal pathway in the non-human primate.

Background: The A11 diencephalospinal pathway is crucial for sensorimotor integration and pain control at the spinal cord level. When disrupted, it is thought to be involved in numerous painful conditions such as restless legs syndrome and migraine. Its anatomical organization, however, remains largely unknown in the non-human primate (NHP).

Migration of As, and (3)H/(3)He ages, in groundwater from West Bengal: Implications for monitoring.

From 2002 to 2010 inclusive we monitored concentrations of arsenic (As) and major ions (Ca, Mg, Sr, Na, K, Fe, Mn, Cl, and SO(4)) in groundwater from 14 domestic wells and three piezometer nests in a shallow aquifer (<60 m depth), and 3 wells in a deep aquifer (>70 m depth), in southern West Bengal, India. In the deep aquifer, concentrations of As did not change over time despite increases in the concentration of Fe in two wells. The shallow aquifer occurs in two sedimentological settings: palaeo-channel and palaeo-interfluve.

Migration and differentiation of human mesenchymal stem cells in the normal rat brain.

Objectives: Transplanted mesenchymal stem cells migrate toward brain lesions and differentiate into neurons, glial cells, and neural stem cells in diseased or injured animal models. The migratory routes and differentiation patterns of mesenchymal stem cells in normal rats are, however, unknown. Here, labelled human mesenchymal stem cells (or saline) were transplanted into the striatum of adult rats to observe their migration and differentiation.

Calcium-permeable AMPA receptors are involved in the induction and expression of l-DOPA-induced dyskinesia in Parkinson's disease.

Overactivity of striatal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors is implicated in the pathophysiology of L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). In this study, we evaluated the behavioural and molecular effects of acute and chronic blockade of Ca(2+)-permeable AMPA receptors in animal models of PD and LID. The acute effects of the Ca(2+)-permeable AMPA receptor antagonist 1-trimethylammonio-5-(1-adamantane-methylammoniopentane) dibromide hydrobromide (IEM 1460) on abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat and LID in the MPTP-lesioned non-human primate were assessed.

Arsenic in groundwater: a threat to sustainable agriculture in South and South-east Asia.

The problem of arsenic pollution of groundwater used for domestic water supplies is now well recognised in Bangladesh, India and some other countries of South and South-east Asia. However, it has recently become apparent that arsenic-polluted water used for irrigation is adding sufficient arsenic to soils and rice to pose serious threats to sustainable agricultural production in those countries and to the health and livelihoods of affected people. This paper reviews the nature of those threats, taking into account the natural sources of arsenic pollution, areas affected, factors influencing arsenic uptake by soils and plants, toxicity levels and the dietary risk to people consuming arsenic-contaminated rice.

Medically assisted nutrition for palliative care in adult patients.

Background: Many palliative care patients have a reduced oral intake during their illness. The management of this can include the provision of medically assisted nutrition with the aim of prolonging the length of life of a patient, improving their quality of life, or both.

Objectives: To determine the effect of medically assisted nutrition on the quality and length of life of palliative care patients.

Do ponds cause arsenic-pollution of groundwater in the Bengal basin? An answer from West Bengal.

We report time-series data collected over two years for delta18O, delta2H, and Ca, Mg, K, and Cl, concentrations for 10 ponds in, and upflow of, an As-polluted region of southern West Bengal. We compare the compositions of As-polluted groundwaters from wells with the compositions of waters in ponds upflow, and within the range of influence, of the wells. Conservative tracers (delta18O, delta2H, K), and other tracers (Ca, Mg) that are likely conservative in the waters, showthat pondwater and groundwater are distinct and do not overlap in composition.

Using national health policies to improve access to palliative care medications in the community.

Access to affordable priority palliative care medicines needs to be informed by good clinical data from well-conducted clinical trials designed to address efficacy, cost-effectiveness, and safety. Availability of priority palliative care symptom control medicines improves the provision of palliation in the place of patient's choice including the community. Within Australia, a National Medicines Policy and a Palliative Care Strategy endorsed by Federal and State and Territory health ministers have facilitated a process to improve the evidence for palliative clinical practice and, through this, improve community availability of key medications for people at the end of life.

Medically assisted hydration for palliative care patients.

Background: Many palliative care patients have reduced oral intake during their illness. The management of this can include the provision of medically assisted hydration with the aim of prolonging the length of life of a patient, improving their quality of life, or both.

Objectives: To determine the effect of medically assisted hydration in palliative care patients on their quality and length of life.

Striatal histone modifications in models of levodopa-induced dyskinesia.

Despite recent advances in the treatment of Parkinson disease (PD), levodopa remains the most effective and widely used therapy. A major limitation to the use of levodopa is the development of abnormal involuntary movements, termed levodopa-induced dyskinesia (LDID), following chronic levodopa treatment. Since recent studies have suggested that modifications of chromatin structure may be responsible for many long-lasting changes in brain function, we have examined post-translational modifications of striatal histones in two models of LDID: an acute murine model and a chronic macaque monkey model, both exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Survey of bereavement support provided by Australian palliative care services.

Objective: To determine the prevalence, staffing, methods, timing and allocation of bereavement programs in Australian palliative care services.

Design: Questionnaire-based postal survey.

Setting And Participants: The questionnaire was mailed in January 2007 to all 324 palliative care centres identified from the Australian Palliative care national directory 2004.

Neuroprotective effects of rotigotine in the acute MPTP-lesioned mouse model of Parkinson's disease.

Dopamine agonists used to manage Parkinsonian motor symptoms have been suggested to be neuroprotective. The study was designed to assess the neuroprotective potential of the D(3)/D(2)/D(1) dopamine receptor agonist rotigotine in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned (MPTP) mouse model of Parkinson's disease by measuring mesencephalic degenerating neurons using FluoroJade staining and the remaining dopaminergic nerve endings in the striatum using dopamine transporter binding. Continuous administration of rotigotine at a dose of 3mg/kg significantly attenuated MPTP-induced acute cell degeneration in the FluoroJade-staining paradigm.