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If Parkinson's disease patients only present motorically when 50% of their dopamine cells are lost, then the condition must have been slowly evolving over 25 to 50 years. Thereafter, the pathology progresses at the rate of 1% to 2% of dopamine cells per year even though the pathological species was there from day zero- given the cells were placed into the brains of patients with moderately advanced PD. I would say this paper has fundamentally challenged the long-held view that the pathogenesis of PD is primarily a cell-autonomous process - although even at the time it was published this was being challenged both for PD and other proteinopathies of the brain. [Extracted from the article]

Chronic graft-versus-host disease (cGVHD) represents a serious complication of allogeneic haematopoietic stem cell transplant that occurs in 20%-80% of patients. A leading hypothesis posits that chronic CNS-GHVD onset stems from sequential CNS infiltration of donor CD8 SP + sp T cells, donor CD4 SP + sp T cells and donor bone marrow-derived macrophages (BMDMs). 4 Polchlopek Blasiak K, Simonetta F, Vargas MI, Chalandon Y. Central nervous system graft-versus-host disease (CNS-GvHD) after allogeneic haematopoietic stem cell transplantation. [Extracted from the article]

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Pain is a hallmark of almost all bodily ailments and can be modulated by agents, including analgesics and anesthetics that suppress pain signals in the central nervous system. Defects in the modulatory systems, including the endogenous pain-inhibitory pathways, are a major factor in the initiation and chronicity of pain. Thus, pain modulation is particularly applicable to the practice of medicine. This review summarizes the existing literature on pain modulation. Here, we critically reviewed the literature from PubMed on pain modulation published primarily within the past 5 years in high impact journals. Specifically, we have discussed important anatomical landmarks of pain modulation and outlined the endogenous networks and underlying mechanisms of clinically relevant pain modulatory methods. The Gate Control Theory is briefly presented with discussion on the capacity of pain modulation to cause both hyper- and hypoalgesia. An emphasis has been given to highlight key areas in pain research that, because of unanswered questions or therapeutic potential, merit additional scientific scrutiny. The information presented in this paper would be helpful in developing novel therapies, metrics, and interventions for improved patient management. [ABSTRACT FROM AUTHOR]

Click here to view the accompanying paper in this issue. [ABSTRACT FROM AUTHOR]

The complex molecular pathways that mediate the effects of vitamin A and its derivatives, are increasingly recognized as a component of the repair capacity that could be activated to induce protection and regeneration in the mature nervous tissue. Retinoid and retinoid-associated signaling plays an essential role in normal neurodevelopment and appears to remain active in the adult CNS. In this paper, we review evidence which supports the hypothesis of an activation of retinoid-associated signaling molecular pathways in the mature nervous tissue and its significance in the context of neurodegenerative, trauma-induced and psychiatric disorders, at spinal and supra-spinal levels. Finally, we summarize the potential therapeutic avenues based on the modulation of retinoid targets undergoing reactivation under conditions of acute injury and chronic degeneration in the central nervous system, and discuss some of the unresolved issues linked to this treatment strategy. [ABSTRACT FROM AUTHOR]

This paper explores the oral narratives of five South Fore men who assisted with the scientific investigation of kuru. Drawing on the framework of the dramaturgic form of epidemics, the narratives start with childhood memories of the social crisis at the height of the kuru epidemic. With the arrival of the European scientists they build to a climax of optimism over the prospect of a cure for kuru and enhanced personal futures before descending into disillusionment over the scientists' departure and a return to traditional village life. [ABSTRACT FROM AUTHOR]

The nervous system is one of the most complex physiological systems, and central nervous system diseases (CNSDs) are serious diseases that affect human health. Ginseng (Panax L.), the root of Panax species, are famous Chinese herbs that have been used for various diseases in China, Japan, and Korea since ancient times, and remain a popular natural medicine used worldwide in modern times. Ginsenosides are the main active components of ginseng, and increasing evidence has demonstrated that ginsenosides can prevent CNSDs, including neurodegenerative diseases, memory and cognitive impairment, cerebral ischemia injury, depression, brain glioma, multiple sclerosis, which has been confirmed in numerous studies. Therefore, this review summarizes the potential pathways by which ginsenosides affect the pathogenesis of CNSDs mainly including antioxidant effects, anti‐inflammatory effects, anti‐apoptotic effects, and nerve protection, which provides novel ideas for the treatment of CNSDs. [ABSTRACT FROM AUTHOR]

Meningoencephalitis of unknown origin (MUO) is a common inflammatory CNS disease in dogs, with a variable and unpredictable outcome. MRI and cerebrospinal fluid (CSF) features were prospectively evaluated to establish their utility as prognostic markers for predicting mortality, relapse and long-term outcome in 39 dogs with MUO. MRI and CSF analysis were performed at initial diagnosis and three months into treatment with prednisolone and cytosine arabinoside. When possible, MRI was repeated every 12 months thereafter. Median survival time was 26 days. All deaths occurred within 52 days of diagnosis (22/39; 56 per cent). One-third (13/39) died within 72 hours of diagnosis. Outcome was good or excellent in 12/17 surviving dogs. Loss of the cerebral sulci and foramen magnum herniation on MRI were associated with increased risk of mortality. An abnormal CSF analysis at the three-month re-examination was associated with increased risk of relapse (P=0.04). The combination of MRI and CSF analysis provided a greater sensitivity for predicting relapse than one modality alone. Discontinuing treatment before MRI lesions resolved always resulted in relapse. The presence of certain MRI characteristics may indicate an increased risk of mortality. Dogs alive three months following diagnosis have a very low risk of death due to MUO. [ABSTRACT FROM AUTHOR]

Summary: Cryptococcal meningitis (CM) is one of the most common opportunistic infections of acquired immunodeficiency syndrome (AIDS), as well as an important cause of hospitalisation and death. In recent years, the mortality of CM has remained high in HIV/AIDS population, with up to 30%, including within developed countries. The treatment usually encompasses controls of Cryptococcus, HIV, and increased intracranial pressure. Recent progress on the management of HIV‐associated CM mainly centres in optimising induction regimens, looking for appropriate timing of initiating antiretroviral therapy and prevention of symptomatic onset and adverse consequences. This review compared several international guidelines combined with the results from some clinical researches to illustrate the similarities, differences and potential in CM treatment. The present practice is still far from satisfactory, and there remains much to explore due to our limited understanding of the pathogenesis of HIV‐associated CM. Thus, screening and monitoring should be strengthened, and better therapies in line with the actual situation of each country should be discovered. [ABSTRACT FROM AUTHOR]

Beta (β)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect. This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords "beta (β)-caryophyllene" and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action. A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer's disease. Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To examine how pharmaceutical products that were first marketed between 1950 and 1980 were promoted to physicians through advertisements and briefly review advertising regulations and accuracy of the advertisements in the light of modern knowledge. Methods: We systematically reviewed advertisements promoting drugs for specific therapeutic areas, namely central nervous system disorders (anxiety and sleep disorders, depression, psychoses, and Parkinson's disease), respiratory disorders, cardiovascular disorders, and gastrointestinal disorders. We examined about 800 issues of the British Medical Journal (1950–1980) and about 150 issues of World Medicine (1965–1984). Results: Advertising material was minimally regulated until the mid‐1970s. Many drugs were marketed with little preclinical or clinical knowledge and some with the expectation that prescribers would obtain further data. The peak of advertising occurred in parallel with the surge in the release of novel drugs during the 1960s, but declined markedly after the mid‐1970s. Advertisements generally contained little useful prescribing information. The period we investigated saw the release of many novel pharmaceuticals in the therapeutic areas we examined, and many (or their class successors) still play important therapeutic roles, including benzodiazepines, tricyclic antidepressants, phenothiazines, levodopa, selective and non‐selective β‐adrenoceptor antagonists, thiazide diuretics, β‐adrenoceptor agonists, and histamine H2 receptor antagonists. Conclusions: Advertising pharmaceuticals in the BMJ and World Medicine in 1950–1980 was poorly regulated and often lacked rigour. However, advertisements were gradually modified in the light of increasing clinical pharmacological knowledge, and they reflect an exciting period for the introduction of many drugs that continue to be of benefit today. [ABSTRACT FROM AUTHOR]

Aim: The aims of this study were: (1) to determine the incidence and nature of adverse effects on oral motor function after first injections of botulinum neurotoxin A (BoNT-A) in submandibular glands for excessive drooling in children with central nervous system disorders; and (2) to identify independent predictors of these adverse effects.Method: A cohort study involved 209 children (123 males, 86 females, aged 4-27y, median 8y 4mo), who received submandibular BoNT-A injections for drooling. Adverse effects were categorized into swallowing, eating, drinking, articulation, and other problems. Univariable logistic regression was used to study differences in patients with and without adverse effects. Possible predictors were identified using multivariable logistic regression.Results: Transient adverse effects occurred in 33% of the 209 BoNT-A treatments. Almost 80% of these were mild, versus 8.7% severe. Approximately 54% of the adverse effects spontaneously resolved within 4 weeks; 3% still existed after 32 weeks. A diagnosis of cerebral palsy, higher range of BoNT-A dosage, and a pre-treatment drooling quotient <18% were found to be independent predictors of adverse effects.Interpretation: Before using submandibular BoNT-A injections for drooling, potential adverse effects should be discussed. Oral motor function needs to be monitored, because existing dysphagia may be worsened. The identified clinical predictors could be helpful to optimize patient selection. [ABSTRACT FROM AUTHOR]

Key Clinical Message An acute ileus and/or urinary retention are recognized as emergent complications requiring appropriate depressurizing treatments. Meningitis should be suspected as a cause of these autonomic disturbances. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system, and monocytes contribute to MS-associated neuroinflammation. While classically activated monocytes promote inflammation, type II-activated monocytes improve the course of MS. This study investigated type II activation of monocytes and their two main subsets, namely CD14+ (CD14++CD16− subset) and CD16+ monocytes (CD14+CD16+ subset), by glatiramer acetate (GA) or intravenous immunoglobulin-associated immune complexes (IC), both of which are known MS treatments. Total monocytes and subsets were isolated from peripheral blood mononuclear cells (PBMC) of healthy controls, untreated MS patients (MS) and GA-treated MS patients (GA-MS). In contrast to the more activated ex vivo profile of monocytes from the MS group, monocytes from the GA-MS group resembled those from healthy controls. In vitro type II activation with GA primarily reduced CD40, CD86 and IL-12p40 whereas type II activation with IC consistently reduced CD40 but increased interleukin-10 (IL-10), suggesting that the GA and IC activation pathways are distinct. Moreover, while GA treatment reduced IL-12p40 by both CD14+ and CD16+ subsets, IC treatment only enhanced IL-10 by the CD16+ subset. Further analysis of the CD16+ subset revealed that MS patients had a greatly expanded CD14+CD16int population while both CD14+CD16int and CD14lowCD16high monocyte populations were expanded in GA-MS patients. Finally, a global analysis of the ex vivo monocyte data indicated that GA treatment distinctly altered the monocyte profile of MS patients, further supporting the idea that GA directly targets monocytes. [ABSTRACT FROM AUTHOR]

Background and purpose Clinically isolated syndrome ( CIS) is a first demyelinating event of the central nervous system and can be a single event. After CIS, a chronic disease course with ongoing inflammation and relapses might occur, resulting in a diagnosis of multiple sclerosis ( MS). As yet, there has been no prospective exploration of whether children and adults with CIS have the same disease course. Methods Patients with CIS, whose age ranged from 1 to 50 years, were prospectively followed. We divided the patients into three different age groups, i.e. 1-10, 11-17 and 18-50 years old. Demographic data, disease course, time to MS diagnosis and annualized relapse rates ( ARRs) were compared among these groups. Results We included 383 patients with CIS, of whom 218 (56.9%) were diagnosed with MS. Children of between 11 and 17 years old had the highest rate of MS conversion (83.5% vs. 50.0% in the other age groups together, P < 0.01) and the shortest time to MS diagnosis [median time 2.6 months (interquartile range, 0.6-6.0) vs. 8.2 months (interquartile range, 1.9-28.2) in the other age groups together, P < 0.01). ARRs corrected for follow-up were higher in children of <18 years old than in adults of ≥18 years old with MS (mean ARR, 0.65 vs. 0.43, P < 0.01). Conclusion Children with CIS tend to have a more inflammatory disease course appearing from higher ARRs in all children and the highest rate of MS conversion in 11-17-year-old children. This supports early initiation of disease-modifying therapy in children, perhaps even at the first event in children at high risk for MS in line with clinical practice in adults. [ABSTRACT FROM AUTHOR]

ABSTRACT Ephedrone encephalopathy is referred to as a group of symptoms of manganese deposition within the central nervous system (CNS), resulting from the abuse of ephedrone (methcathinone), obtained in reaction using the excess amount of manganese-containing oxidants. The diagnosis is based on the contrast-enhanced head MRI findings characteristic for this syndrome, clinical manifestation and history of ephedrone use. The syndrome has been reported in recent years in young people from Eastern Europe and Russia with a history of ephedrone overuse. However, no report has ever been published on ephedrone encephalopathy in Polish patients. [ABSTRACT FROM AUTHOR]

ABSTRACT Kyung-ok-ko (KOK) has been used for the treatment of central nervous system disorders such as amnesia, dementia, and cerebral ischemia. However, the effects of KOK on transient ischemic-induced neuronal damage are still unclear. We examined whether KOK improves functional recovery and has a neuroprotective effect on infarction volume after transient middle cerebral artery occlusion (MCAO). KOK (50, 100, and 200 mg/kg) was administered orally following reperfusion and twice per day for 14 days post-MCAO. Infarction volume was measured using 2% 2-3-5 triphenylterazolium (TTC) staining at 14 days post-MCAO and alteration in regional cerebral blood flow (rCBF) after KOK treatment was monitored. Functional improvement was evaluated using adhesive removal and treadmill tests at 1, 7, and 14 days post-MCAO. Also, apoptotic cell death was assessed by terminal deoxynucleotidyl-transferase mediated d-UTP-biotin nick end (TUNEL) in the peri-infarction region. The protein level of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), and interleukin-1β (IL-1β) was measured in the ischemic core, ischemic border zone, and contralateral hemisphere regions. The KOK-treated group showed both reduced infarction volume and behavior tests demonstrated a significant improvement as compared to the control. Also, in the KOK-treated group, rCBF was recovered to near normal levels. The apoptotic cells were significantly decreased as compared with the control group in the ischemic peri-infarction area. Furthermore, the level of TNF-α, IL-1β, and IL-1α was decreased. These results suggest that KOK may improve functional outcome by inhibiting inflammatory cytokines (TNF-α, IL-1β, and IL-1α) in neuronal injury such as ischemic stroke. [ABSTRACT FROM AUTHOR]

Aims To report the first three studies with SCH 900435, a selective glycine-1 re-uptake inhibitor in development for treating schizophrenia, using systematic evaluations of pharmacodynamics to understand the observed effects. Methods Three double-blind, placebo-controlled studies (single, visual effect and multiple dose) were performed. In the single and multiple dose study SCH 900435 (0.5-30 mg) was given to healthy males and frequent pharmacokinetic and pharmacodynamic measurements were performed. The visual effects study incorporated visual electrophysiological measures of macular, retinal and intracranial visual pathway function. Results In the single dose study (highest difference, 95% CI, P) increases in smooth pursuit eye movements (8, 12 mg (−6.09, 10.14, −2.04, 0.013), 30 mg), pupil : iris ratio (20 and 30 mg (−0.065, 0.09, −0.04, <0.0001)), VAS colour perception (30 mg (−9.48, 13.05, −5.91, <0.0001)) and changes in spontaneous reports of visual disturbance were found, while FSH (8 mg (0.42, 0.18, 0.66, 0.0015), 12, 20 mg), LH (8-30 mg (1.35, 0.65, 2.05, 0.0003)) and EEG alpha2 activity decreased (12, 20, 30 mg (0.27, 0.14, 0.41, 0.0002)). A subsequent dedicated visual effects study demonstrated that visual effects were transient without underlying electrophysiological changes. This provided enough safety information for starting a multiple ascending dose study, showing less visual symptoms after twice daily dosing and titration, possibly due to tolerance. Conclusions Several central nervous system ( CNS) effects and gonadotropic changes resulted from administration of 8 mg and higher, providing evidence for CNS penetration and pharmacological activity of SCH 900435. Antipsychotic activity in patients, specificity of the reported effects for this drug class and possible tolerance to visual symptoms remain to be established. [ABSTRACT FROM AUTHOR]

Many psychotropic substances used either for medications or illicit recreational purposes are able to produce an increase in extracellular serotonin (5 HT) in the CNS. 5 HT is well known to improve mood; however, only when the levels of its release are in an appropriate range. Excessive 5 HT is harmful, and will generally result in serotonin syndrome. To date, clinical diagnosis of serotonin syndrome relies exclusively on observation of symptoms because of a lack of available laboratory tests. The goal of this study was to characterize the onset of the syndrome using laboratory settings to determine excessive 5 HT-evoked neurological abnormalities. Experiments were carried out in rats with the syndrome being elicited by three groups of 5 HT-promoting drugs: (i) (±)-3,4-methylenedioxymethamphetamine ( MDMA); (ii) a combination of the monoamine oxidase inhibitor clorgyline with the 5 HT precursor 5-hydroxytryptophan; (iii) clorgyline combined with the serotonin-selective reuptake inhibitor paroxetine. The onset of the syndrome was characterized by electroencephalography ( EEG), tremor, and brain/plasma 5 HT tests. We found that a mild syndrome was associated with reduced EEG amplitudes while a severe syndrome strongly with seizure-like EEG activity and increased tremor activity. The occurrence of the syndrome was confirmed with microdialysis, showing excessive 5 HT efflux in brain dialysate and the increased concentration of unbound 5 HT in the plasma. Our findings suggest that the syndrome onset can be revealed with EEG recording, measurements of tremor activity and changes of unbound 5 HT concentration in the plasma. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2012) 122, 24-37. Abstract The metabotropic glutamate receptors (mGluRs) fine-tune the efficacy of synaptic transmission. This unique feature makes mGluRs potential targets for the treatment of various CNS disorders. There is ample evidence to show that the ubiquitin proteasome system mediates changes in synaptic strength leading to multiple forms of synaptic plasticity. The present study describes a novel interaction between post-synaptic adaptors, long Homer-3 proteins, and one of the 26S proteasome regulatory subunits, the S8 ATPase, that influences the degradation of the metabotropic glutamate receptor 1α (mGluR1α). We have shown that the two human long Homer-3 proteins specifically interact with human proteasomal S8 ATPase. We identified that mGluR1α and long Homer-3s immunoprecipitate with the 26S proteasome both in vitro and in vivo. We further found that the mGluR1α receptor can be ubiquitinated and degraded by the 26S proteasome and that Homer-3A facilitates this process. Furthermore, the siRNA mediated silencing of Homer-3 led to increased levels of total and plasma membrane-associated mGluR1α receptors. These results suggest that long Homer-3 proteins control the degradation of mGluR1α receptors by shuttling ubiquitinated mGluR-1α receptors to the 26S proteasome via the S8 ATPase which may modulate synaptic transmission. [ABSTRACT FROM AUTHOR]

AIMS To assess and compare the mechanisms of central nervous system (CNS) penetration of antimuscarinic overactive bladder (OAB) agents. METHODS Physical properties were computed or compiled from the literature. Rats were administered 5-hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin, tolterodine or trospium subcutaneously. At 1 h postdose, plasma, brain and cerebrospinal fluid (CSF) concentrations were determined using LC-MS/MS assays. Brain and plasma protein binding were determined in vitro. Permeability in the presence and absence of the efflux transporter P-glycoprotein (P-gp) was assessed in RRCK and MDCK-MDR1 transwell assays. RESULTS Oxybutynin displayed extensive CNS penetration, with brain : plasma ratios (B : P), unbound brain : unbound plasma ratios (Kp,free) and CSF : free plasma ratios each >1. Tolterodine (B : P = 2.95, Kp,free = 0.23 and CSF : free plasma = 0.16) and solifenacin (B : P = 3.04, Kp,free = 0.28 and CSF : free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly <1. 5-HMT, darifenacin and trospium displayed much lower B : P (0.03-0.16), Kp,free (0.01-0.04) and CSF : free plasma (0.004-0.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 × 10-6 cm s-1), moderate for 5-HMT (11.7 × 10-6 cm s-1) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5-38.2 × 10-6 cm s-1). In MDCK-MDR1 cells 5-HMT, darifenacin and trospium, were P-gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P-gp substrates. CONCLUSIONS Brain penetration was low for antimuscarinics that are P-gp substrates (5-HMT, darifenacin and trospium), and significant for those that are not P-gp substrates (oxybutynin, solifenacin and tolterodine).CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in this study. [ABSTRACT FROM AUTHOR]

The Pediatric Brain Tumor Consortium (PBTC) is a multidisciplinary cooperative research organization devoted to the study of correlative tumor biology and new therapies for primary central nervous system (CNS) tumors of childhood. The PBTC was created in 1999 to conduct early-phase studies in a rapid fashion in order to provide sound scientific foundation for the Children's Oncology Group to conduct definitive trials. The Operations and Biostatistics Center (OBC) of the PBTC is responsible for centrally administering study design and trial development, study conduct and monitoring, data collection and management as well as various regulatory and compliance processes. The phase I designs utilized for the consortium trials have accommodated challenges unique to pediatric trials such as body surface area (BSA)-based dosing in the absence of pediatric formulations of oral agents. Further during the past decade, the OBC has developed and implemented a state-of-the-art secure and efficient internet-based paperless distributed data management system. Additional web-based systems are also in place for tracking and distributing correlative study data as well as neuroimaging files. These systems enable effective communications among the members of the consortium and facilitate the conduct and timely reporting of multi-institutional early-phase clinical trials. [ABSTRACT FROM AUTHOR]

Examines the role of plasmapheresis in the treatment of severe central nervous system neuropsychiatric systemic lupus erythematosus (CNS-NPSLE). Need for an aggressive treatment option for young patients; Occurrence of side effects from central line placement; Benefits and cost profiles in considering the treatment of severe CNS-NPSLE.

The article presents information on a study related to the treatment of complex regional pain syndrome (CPRS) which can develop after fractures, or lesions in the peripheral or central nervous system (CNS). As stated, changes in the CNS can lead to motor and sensory impairments in CPRS patients. According to the article, mirror therapy can be beneficially used for acute stages of CRPS type I but not in chronic CRPS. The effectiveness of graded motor imagery for CPRS treatment is also discussed.

The author reflects on the clinical trials that evaluate symptomatic therapy in multiple sclerosis (MS), which is a chronic autoimmune disease presented with diffuse damage of central nervous system. He discusses the study by Novotna and colleagues which demonstrates the use of Nabixomols with oromucosal spray for management of refractory spasticity in patients with MS. He states that the study highlights the need for new trial designs to detect desirable efficacy in a subgroup.