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RATIONALE: Cannabidiol (CBD) is increasingly used as a sleep aid for insomnia; yet neurocognitive and subjective state effects following daily therapeutic use are unclear. OBJECTIVES: To measure the effect of daily CBD use on neurocognitive performance and daily subjective mood in a population with primary insomnia. METHODS: This study used a randomized, placebo-controlled, parallel design incorporating a single-blind placebo run-in week followed by a two-week double-blind dosing period, during which participants consumed 150 mg CBD (N = 15) or placebo (N = 15) sublingually 60-minutes daily before bed. Attention, executive function, reasoning, information processing, working and episodic memory were assessed using the CogPro system at the beginning of the placebo run-in, after 1-week and 2-weeks of dosing. Subjective states using visual analogue scales and side effects were recorded daily. RESULTS: Cognitive performance was unaffected by nightly CBD supplementation (all p > 0.05). From baseline to trial conclusion, those receiving CBD reported greater experience of calmness, clear-headedness, coordination and were more likely to report side-effects of dry mouth relative to placebo (all p < 0.05). CONCLUSIONS: Relative to placebo, daytime cognitive functioning following nightly supplementation as a therapeutic aid for primary insomnia was preserved under trial conditions. Results suggested an overall favourable safety profile, with larger controlled trials and thorough analyses of varying insomnia phenotypes necessary to corroborate these findings.
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BACKGROUND: Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism that, if untreated, causes Phe accumulation in the brain leading to neurophysiologic alterations and poor outcomes. Lifelong management centers on dietary Phe restriction, yet long-term complete metabolic control is unachievable for many adults. High blood Phe levels or chronic Phe and intact protein restriction in the diet may lead to somatic comorbidities. A systematic literature review was conducted to evaluate somatic comorbidities experienced by adults with PKU. METHODS: Clinical and observational studies reporting somatic comorbidities experienced by individuals with PKU aged ≥ 16 years (or classified as adults) evaluating a Phe-restricted diet with or without pharmacologic therapy versus no therapeutic intervention (including healthy controls), or pharmacologic therapy versus a Phe-restricted diet alone, were identified. PubMed® was searched (February 1, 2022 and updated November 1, 2023), using a pre-defined search strategy, followed by two-stage screening and data extraction. Included studies were grouped by PKU population comparison. RESULTS: 1185 records were screened; 51 studies across 12,602 individuals were extracted. Bone-related abnormalities were the most reported outcome (n = 21); several outcome measures were used. Original study groupings included: Phe-restricted diet versus healthy controls or reference values (n = 40); treatment-adherent versus those non-adherent (n = 12). Additional groups added as part of a protocol amendment included: different Phe-restricted diets (n = 4); severe versus less severe disease (n = 5). Vote counting indicated a higher burden of ≥ 1 comorbidity (or outcome measure) for the Phe-restricted diet group by 37 of 38 studies included in the analysis of Phe-restricted diet versus healthy controls; higher burden in healthy controls was reported in 12 studies. Vote counting was similar between those treatment adherent (n = 7) versus non-adherent (n = 10). CONCLUSIONS: Adults with PKU have a higher comorbidity burden than a non-PKU population. More robust studies are needed to better understand the relationship between effective metabolic control and comorbidity burden, using consistent outcome measures. This SLR was supported by BioMarin Pharmaceutical Inc., Novato, CA, and is registered with the Research Registry (reviewregistry1476).
Subject(s)
Comorbidity , Phenylketonurias , Humans , Phenylketonurias/diet therapy , Phenylketonurias/epidemiology , Adult , Phenylalanine/bloodABSTRACT
Occupational gender stereotypes develop from early age and contribute to occupational gender imbalance. Previous research used questionnaires or interviews to investigate children's explicit stereotypes and where drawings have been used, mostly men-dominated occupations have been considered. This study used drawings and interviews to assess implicit stereotypes of both men and women-dominated occupations and whether children's sex, age and cultural background predicted these stereotypes. Two hundred and forty-three 6-to-7-year-olds and 10-to-11-year-olds in Britain and Argentina-encompassing both Global South and Global North perspectives- drew five human figures: (i) person of their choice, (ii) dancer, (iii) nanny (iv) firefighter and (v) pilot. In interviews, children confirmed and justified their gender choices for each drawing. Results indicate gender stereotypes in children from both countries, especially towards women-dominated occupations. Girls exhibited more rigid gender views than boys. These findings suggest widespread and culturally consistent occupational gender stereotypes, potentially limiting children's future job choices.
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Contrary to Pemetrexed-containing chemo-immunotherapy studies, Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel (ABCP) treatment has consistently shown clinical benefit in prospective studies in patients with lung cancer and actionable mutations, where intracranial metastases are common. Here, we aimed to describe the real-life population of patients fit to receive ABCP after targeted therapy and quantify its clinical effect in patients with brain metastases. Patients treated in Cheshire and Merseyside between 2019 and 2022 were identified. Data were collected retrospectively. A total of 34 patients with actionable EGFR or ALK alterations had treatment with a median age of 59 years (range 32-77). The disease control rate was 100% in patients with PDL1 ≥ 1% (n = 10). In total, 19 patients (56%) had brain metastases before starting ABCP, 17 (50%) had untreated CNS disease, and 4 (22%) had PDL1 ≥ 1%. The median time to symptom improvement was 12.5 days (range 4-21 days), with 74% intracranial disease control rates and 89.5% synchronous intracranial (IC) and extracranial (EC) responses. IC median Progression Free Survival (mPFS) was 6.48 months, EC mPFS was 10.75 months, and median Overall Survival 11.47 months. ABCP in real-life patients with brain metastases (treated or untreated) was feasible and showed similar efficacy to that described in patients without actionable mutations treated with upfront chemo-immunotherapy.
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Background: Increased activity across corticostriatal glutamatergic synapses may contribute to L-DOPA-induced dyskinesia in Parkinson's disease. Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated. Metabotropic glutamate receptor 4 (mGlu4) is a promising target since its activation would reduce glutamate release. Objective: We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1âS,2âR)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia. Methods: The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats. Results: Neither Lu AF21934 (10 or 30âmg/kg p.o.) nor ADX88178 (10 or 30âmg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10âmg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats. Conclusions: This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.
Subject(s)
Anilides , Cyclohexanecarboxylic Acids , Dyskinesia, Drug-Induced , Parkinson Disease , Pyrimidines , Receptors, Metabotropic Glutamate , Thiazoles , Rats , Animals , Levodopa/therapeutic use , Callithrix , Parkinson Disease/drug therapy , Oxidopamine , Dyskinesia, Drug-Induced/drug therapy , Dyskinesia, Drug-Induced/etiology , Dyskinesia, Drug-Induced/metabolism , Antiparkinson Agents/therapeutic use , Amantadine/pharmacology , Amantadine/therapeutic use , Glutamates/therapeutic use , Disease Models, AnimalABSTRACT
Phenylketonuria (PKU), a genetic disorder characterized by phenylalanine hydroxylase (PAH) deficiency and phenylalanine (Phe) accumulation, is primarily managed with a protein-restricted diet and PKU-specific medical foods. Pegvaliase is an enzyme substitution therapy approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 µmol/L) despite prior management. This analysis assessed the effect of pegvaliase on dietary intake using data from the Phase 3 PRISM-1 (NCT01819727), PRISM-2 (NCT01889862), and 165-304 (NCT03694353) clinical trials. Participants (N = 250) had a baseline diet assessment, blood Phe ≥600 µmol/L, and had discontinued sapropterin; they were not required to follow a Phe-restricted diet. Outcomes were analyzed by baseline dietary group, categorized as >75%, some (>0% but ≤75%), or no protein intake from medical food. At baseline, mean age was 29.1 years, 49.2% were female, mean body mass index was 28.4 kg/m2, and mean blood Phe was 1237.0 µmol/L. Total protein intake was stable up to 48 months for all 3 baseline dietary groups. Over this time, intact protein intake increased in all groups, and medical protein intake decreased in those who consumed any medical protein at baseline. Of participants consuming some or >75% medical protein at baseline, 49.1% and 34.1% were consuming no medical protein at last assessment, respectively. Following a first hypophenylalaninemia (HypoPhe; 2 consecutive blood Phe measurements <30 µmol/L) event, consumption of medical protein decreased and consumption of intact protein increased. Substantial and sustained Phe reductions were achieved in all 3 baseline dietary groups. The probability of achieving sustained Phe response (SPR) at ≤600 µmol/L was significantly greater for participants consuming medical protein versus no medical protein in an unadjusted analysis, but no statistically significant difference between groups was observed for probability of achieving SPR ≤360 or SPR ≤120 µmol/L. Participants with alopecia (n = 49) had longer pegvaliase treatment durations, reached HypoPhe sooner, and spent longer in HypoPhe than those who did not have alopecia. Most (87.8%) had an identifiable blood Phe drop before their first alopecia episode, and 51.0% (n = 21/41) of first alopecia episodes with known duration resolved before the end of the HypoPhe episode. In conclusion, pegvaliase treatment allowed adults with PKU to lower their blood Phe, reduce their reliance on medical protein, and increase their intact and total protein intake. Results also suggest that HypoPhe does not increase the risk of protein malnutrition in adults with PKU receiving pegvaliase.
Subject(s)
Phenylketonurias , Adult , Humans , Female , Male , Phenylalanine Ammonia-Lyase/therapeutic use , Phenylalanine , Diet, Protein-Restricted/adverse effects , Alopecia/drug therapy , Recombinant ProteinsABSTRACT
STUDY OBJECTIVES: Low-dose cannabidiol (CBD) has become readily available in numerous countries; however, little consensus exists on its efficacy as a sleep aid. This trial explored the efficacy of 150 mg of CBD (n = 15) compared with placebo (n = 15) as a sleep aid in primary insomnia. CBD supplementation was hypothesized to decrease insomnia symptoms and improve aspects of psychological health, relative to placebo. METHODS: Using a randomized, placebo-controlled, parallel design featuring a single-blind placebo run-in week followed by a 2-week double-blind randomized dosing phase, participants consumed the assigned treatment sublingually 60 minutes before bed nightly. Wrist-actigraphy and sleep diaries measured daily sleep. Sleep quality, sleep effort, and well-being were measured weekly over 4 in-laboratory visits. Insomnia severity and trait anxiety were measured at screening and study conclusion. RESULTS: Insomnia severity, self-reported sleep-onset latency, sleep efficiency, and wake after sleep onset did not differ between treatments throughout the trial (all P > .05). Compared with placebo, the CBD group reported greater well-being scores throughout the trial (trial end mean difference = 2.60; standard error: 1.20), transient elevated behavior following wakefulness scores after 1 week of treatment (mean difference = 3.93; standard error: 1.53), and had superior objective sleep efficiency after 2 weeks of treatment (mean difference = 6.85; standard error: 2.95) (all P < .05). No other significant treatment effects were observed. CONCLUSIONS: Nightly supplementation of 150 mg CBD was similar to placebo regarding most sleep outcomes while sustaining greater well-being, suggesting more prominent psychological effects. Additional controlled trials examining varying treatment periods and doses are crucial. CLINICAL TRIAL REGISTRATION: Registry: Australian New Zealand Clinical Trials Registry; Name: Cannabidiol (CBD) treatment for insomnia; URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12620000070932; Identifier: ACTRN12620000070932. CITATION: Narayan AJ, Downey LA, Rose S, Di Natale L, Hayley AC. Cannabidiol for moderate-severe insomnia: a randomized controlled pilot trial of 150 mg of nightly dosing. J Clin Sleep Med. 2024;20(5):753-763.
Subject(s)
Cannabidiol , Sleep Initiation and Maintenance Disorders , Humans , Sleep Initiation and Maintenance Disorders/drug therapy , Cannabidiol/administration & dosage , Cannabidiol/therapeutic use , Male , Female , Pilot Projects , Double-Blind Method , Adult , Middle Aged , Single-Blind Method , Treatment Outcome , Actigraphy , Severity of Illness IndexABSTRACT
BACKGROUND: Pegvaliase, an enzyme substitution therapy, is a treatment option for phenylketonuria (PKU). Due to the neuropathophysiology and disease burden of PKU, individuals can experience baseline anxiety unrelated to pegvaliase therapy. In addition, there are aspects of pegvaliase therapy that may be anxiety-inducing for those considering or receiving treatment. The aim of this manuscript is to present best practice recommendations for the identification and management of anxiety symptoms that can occur along the pegvaliase journey. METHODS: A modified Delphi approach was used to seek consensus among a multidisciplinary panel of experts. To this end, an in-person meeting was held that was preceded by a medical specialist- and patient-specific survey to develop preliminary recommendations on ways to address anxiety along the pegvaliase journey. After the meeting, an additional survey was conducted to rank the proposed solutions and mitigation strategies from which a set of recommendations was developed. All recommendations were voted on with the aim of consensus generation, defined as achieving ≥75% agreement among experts. RESULTS: The panel reached consensus on a total of 28 best practice recommendations for the management of anxiety during the pre-treatment, induction and titration, early maintenance (pre-efficacy), and late maintenance (post-efficacy) stages. The recommendations offer strategies to identify and address the most common causes of pegvaliase-related anxiety, including self-injection, side effects, the titration schedule, prescribed dietary changes, and variable time to efficacy. Overall, managing anxiety in those considering or receiving pegvaliase involves patient-centered communication, shared decision-making, and personalized treatment plans. CONCLUSIONS: The best practice recommendations described herein can guide healthcare providers in proactively addressing anxiety during the different stages of pegvaliase treatment, and support providers with initiating and managing pegvaliase in individuals who may experience baseline and treatment-related anxiety.
Subject(s)
Phenylalanine , Phenylketonurias , Humans , Phenylalanine Ammonia-Lyase/therapeutic use , Phenylketonurias/drug therapy , Anxiety/therapy , Recombinant ProteinsABSTRACT
BACKGROUND: Within the same school class, it is usual to find children who differ in age by almost a full calendar year. Although associations between being relatively young and poor academic outcomes are well documented, and relatively consistent, the associations between being relatively young and psychosocial outcomes are less clearly documented. AIMS: To review research which presents data relating to associations between a child's relative age and their psychosocial development. METHODS: A systematic review was conducted and reported in accordance with PRISMA guidelines. RESULTS: Fifty-nine papers met the inclusion criteria. The outcomes of the narrative synthesis and three meta-analyses found consistent, but very small, associations with relative age indicating that those who are relatively young are more likely to have more negative behaviour, mental well-being, and social experiences. CONCLUSIONS: Although being relatively young is associated with more negative psychosocial outcomes, the magnitude of these associations is consistently small. Furthermore, many of the outcome measures used are likely to be the result of multiple influences, not limited to the effects of relative age. Therefore, the findings are reassuring as they suggest that relative age itself is unlikely to substantially increase an individual's risk of poor psychosocial development.
Subject(s)
Mental Health , Schools , Child , Humans , PersonalityABSTRACT
There has been substantial concern about the mental health effects of the COVID-19 pandemic, particularly for those with obsessive-compulsive disorder (OCD) given the overlap between OCD symptoms (e.g., excessive handwashing) and appropriate disease prevention measures. However, the pandemic has demonstrated heterogeneous mental health effects, suggesting that individual-level factors could play a role in buffering or exacerbating its deleterious impact. This study aimed to understand how individual differences in resilience were associated with trajectories of obsessive-compulsive, depression, and anxiety symptoms among healthy adults and those with OCD residing in New York City, considered the epicenter of the pandemic in the United States at its onset. The sample consisted of healthy individuals (n = 30) and people with OCD (n = 33) who completed clinical interviews and self-report questionnaires that assessed baseline resilience, OCD symptoms, depression, anxiety, and perceived positive effects of the pandemic at four assessment timepoints: baseline (April 2020) and one, two, and six months later. Linear mixed-effects growth models revealed that greater resilience was associated with stable trajectories of symptoms over time. Conversely, less resilience was associated with worsening obsessive-compulsive symptoms from the two-month to six-month assessment timepoints and worsening depressive symptoms at six months across both groups, and with worsening anxiety symptoms in individuals with OCD at six months. Resilience was correlated with the ability to appreciate "silver linings" of the pandemic. These findings highlight resilience as a potential treatment target for bolstering mental health outcomes among individuals with and without psychopathology during sustained and unprecedented periods of stress.
Subject(s)
COVID-19 , Obsessive-Compulsive Disorder , Adult , Anxiety Disorders/epidemiology , Humans , Obsessive-Compulsive Disorder/psychology , Outcome Assessment, Health Care , PandemicsABSTRACT
Multiple myeloma, a malignant neoplasm of plasma cells that accumulate in bone marrow, accounts for approximately 18% of hematologic malignancies in the United States. Patients are often treated with triplet therapy and may undergo stem cell transplantation. Despite effective therapies, multiple myeloma remains incurable. Patients often require maintenance therapy, and many will progress or relapsed following upfront treatment. Selection of treatment in the relapse/refractory setting is complex due numerous active therapeutic agents and combinations. Treatment is often tailored to prior exposure and duration. In 2020, three novel pharmacological agents were approved in the relapsed setting. We highlight the clinical safety and efficacy of selinexor, isatuximab-irfc, and belantamab mafodotin for patients with multiple myeloma.
Subject(s)
Antineoplastic Agents , Multiple Myeloma , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Humans , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local/drug therapyABSTRACT
Screen time has been linked to obesity in young children. Therefore, this systematic review aims to investigate which Behavior Change Techniques (BCTs) are associated with the effectiveness of interventions to reduce screen time in 0-5 year olds. Seven databases were searched, including PsycInfo, PubMed, and Medline. Grey literature searches were conducted. Inclusion criteria were interventions reporting pre- and post- outcomes with the primary objective of reducing screen time in 0-5 year olds. Studies were quality assessed using the Effective Public Health Practice Project criteria. Data extracted included participant characteristics, intervention characteristics and screen time outcomes. The BCT Taxonomy was used to extract BCTs. Interventions were categorised as "very", "quite" or "non" promising based on effect sizes. BCTs were deemed promising if they were in twice as many very/quite promising interventions as non-promising interventions. Seven randomised controlled trials were included, involving 642 participants between 2.5 and 5.0 years old. One very promising, four quite promising, and two non-promising interventions were identified. Screen time decreased by 25-39 min per day in very/quite promising interventions. Eleven BCTs were deemed promising, including "behavior substitution" and "information about social and environmental consequences". This review identified eleven promising BCTs, which should be incorporated into future screen time interventions with young children. However, most included studies were of weak quality and limited by the populations targeted. Therefore, future methodologically rigorous interventions targeting at-risk populations with higher screen time, such as those of a low socioeconomic status and children with a high BMI, should be prioritized.
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The pathological changes underlying gastrointestinal (GI) dysfunction in Parkinson's disease (PD) are poorly understood and the symptoms remain inadequately treated. In this study we compared the functional and neurochemical changes in the enteric nervous system in the colon of adult, L-DOPA-responsive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset, with naïve controls. Measurement of mucosal vectorial ion transport, spontaneous longitudinal smooth muscle activity and immunohistochemical assessment of intrinsic innervation were each performed in discrete colonic regions of naïve and MPTP-treated marmosets. The basal short circuit current (Isc) was lower in MPTP-treated colonic mucosa while mucosal resistance was unchanged. There was no difference in basal cholinergic tone, however, there was an increased excitatory cholinergic response in MPTP-treated tissues when NOS was blocked with L-Nω-nitroarginine. The amplitude and frequency of spontaneous contractions in longitudinal smooth muscle as well as carbachol-evoked post-junctional contractile responses were unaltered, despite a decrease in choline acetyltransferase and an increase in the vasoactive intestinal polypeptide neuron numbers per ganglion in the proximal colon. There was a low-level inflammation in the proximal but not the distal colon accompanied by a change in α-synuclein immunoreactivity. This study suggests that MPTP treatment produces long-term alterations in colonic mucosal function associated with amplified muscarinic mucosal activity but decreased cholinergic innervation in myenteric plexi and increased nitrergic enteric neurotransmission. This suggests that long-term changes in either central or peripheral dopaminergic neurotransmission may lead to adaptive changes in colonic function resulting in alterations in ion transport across mucosal epithelia that may result in GI dysfunction in PD.
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BACKGROUND: Increased firing across glutamatergic synapses may contribute to both the motor dysfunction and L-DOPA-induced dyskinesia seen in Parkinson's disease. Given their ability to reduce glutamate release, activation of group III metabotropic glutamate receptors such as metabotropic glutamate receptor 4 may prove effective against both motor dysfunction and dyskinesia in Parkinson's disease. OBJECTIVE: We hypothesised that activation of metabotropic glutamate receptor 4 by an orthosteric agonist ((2S)-2-amino-4-(hydroxy(hydroxy(4-hydroxy-3-methoxy-5-nitrophenyl)methyl)phosphoryl)butanoic acid, LSP1-2111) would produce antiparkinsonian activity and reduce expression of dyskinesia in a 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated marmoset model of Parkinson's disease. METHODS: Common marmosets were previously treated with MPTP and pre-primed with L-DOPA for up to 28 days to express dyskinesia. LSP1-2111 (1, 3, or 6âmg/kg s.c.) or vehicle (0.9% saline s.c.) were administered immediately prior to L-DOPA (8âmg/kgâ+âbenserazide (10âmg/kg) p.o.) or vehicle (10% sucrose p.o.). Locomotor activity was measured in automated test cages and animals were scored for dyskinesia and disability. RESULTS: As expected, L-DOPA reversed motor disability and induced moderate dyskinesia. By contrast, LSP1-2111 alone significantly reduced the motor disability without any accompanying expression of dyskinesia. When administered in combination with L-DOPA, LSP1-2111 did not significantly reduce the severity of L-DOPA-induced dyskinesia. CONCLUSION: Systemic administration of LSP1-2111 reduces motor disability without causing dyskinesia in MPTP-treated marmosets, supporting a role for metabotropic glutamate receptor 4 orthosteric agonists as promising monotherapy for PD. Conversely, this study found no evidence to support their use as antidyskinetic agents within the dose range tested.
Subject(s)
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology , Motor Disorders/drug therapy , Parkinson Disease/drug therapy , Receptors, Metabotropic Glutamate/agonists , Animals , Callithrix , Disabled Persons/rehabilitation , Disease Models, Animal , Dyskinesia, Drug-Induced/drug therapy , Female , Levodopa/therapeutic use , Male , Motor Activity/drug effects , Motor Activity/physiology , Parkinson Disease/metabolism , Receptors, Metabotropic Glutamate/metabolismABSTRACT
l-DOPA is the gold-standard pharmacotherapy for treatment of Parkinson's disease (PD) but can lead to the appearance of troubling dyskinesia which are attributable to 'false neurotransmitter' release of dopamine by serotonergic neurons. Reducing the activity of these neurons diminishes l-DOPA-induced dyskinesia (LID), but there are currently no clinically approved selective, high efficacy 5-HT1A receptor agonists. Here we describe the effects of NLX-112, a highly selective and efficacious 5-HT1A receptor agonist, on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets, a non-human primate model of PD. NLX-112 exhibited modest plasma half-life (~2h) and marked plasma protein binding (96%). When administered to parkinsonian marmosets with l-DOPA (7 mg/kg p.o.), NLX-112 (0.025, 0.1 and 0.4 mg/kg p.o.) reduced LID scores at early time-points after administration, whilst only minimally interfering with the l-DOPA-induced reversal of motor disability. In contrast, the prototypical 5-HT1A receptor agonist, (+)8-OH-DPAT (0.6 and 2 mg/kg p. o.), reduced LID but also abolished l-DOPA's anti-disability activity. Administered by itself, NLX-112 (0.1, 0.2 mg/kg p.o.) produced very little dyskinesia or locomotor activity, but reduced motor disability scores by about half the extent elicited by l-DOPA, suggesting that it may have motor facilitation effects of its own. Both NLX-112 and (+)8-OH-DPAT induced unusual and dose-limiting behaviors in marmoset that resembled 'serotonin behavioral syndrome' observed previously in rat. Overall, the present study showed that NLX-112 has anti-LID activity at the doses tested as well as reducing motor disability. The data suggest that additional investigation of NLX-112 is desirable to explore its potential as a treatment for PD and PD-LID.
Subject(s)
Anti-Dyskinesia Agents/therapeutic use , Antiparkinson Agents/therapeutic use , Dyskinesia, Drug-Induced/drug therapy , MPTP Poisoning/drug therapy , Piperidines/therapeutic use , Pyridines/therapeutic use , Serotonin 5-HT1 Receptor Agonists/therapeutic use , Animals , Anti-Dyskinesia Agents/pharmacology , Antiparkinson Agents/pharmacology , Callithrix , Dyskinesia, Drug-Induced/metabolism , Dyskinesia, Drug-Induced/physiopathology , Female , Levodopa/toxicity , Locomotion/drug effects , Locomotion/physiology , MPTP Poisoning/metabolism , MPTP Poisoning/physiopathology , Male , Piperidines/pharmacology , Pyridines/pharmacology , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Agonists/pharmacology , Treatment OutcomeABSTRACT
An irreversible extrapyramidal syndrome occurs in man after intravenous abuse of "homemade" methcathinone (ephedrone, Mcat) that is contaminated with manganese (Mn) and is accompanied by altered basal ganglia function. Both Mcat and Mn can cause alterations in nigrostriatal function but it remains unknown whether the effects of the 'homemade' drug seen in man are due to Mcat or to Mn or to a combination of both. To determine how toxicity occurs, we have investigated the effects of 4-week intraperitoneal administration of Mn (30 mg/kg t.i.d) and Mcat (100 mg/kg t.i.d.) given alone, on the nigrostriatal function in male C57BL6 mice. The effects were compared to those of the 'homemade' mixture which contained about 7 mg/kg of Mn and 100 mg/kg of Mcat. Motor function, nigral dopaminergic cell number and markers of pre- and postsynaptic dopaminergic neuronal integrity including SPECT analysis were assessed. All three treatments had similar effects on motor behavior and neuronal markers. All decreased motor activity and induced tyrosine hydroxylase positive cell loss in the substantia nigra. All reduced 123I-epidepride binding to D2 receptors in the striatum. Vesicular monoamine transporter 2 (VMAT2) binding was not altered by any drug treatment. However, Mcat treatment alone decreased levels of the dopamine transporter (DAT) and Mn alone reduced GAD immunoreactivity in the striatum. These data suggest that both Mcat and Mn alone could contribute to the neuronal damage caused by the 'homemade' mixture but that both produce additional changes that contribute to the extrapyramidal syndrome seen in man.
Subject(s)
Basal Ganglia Diseases/chemically induced , Corpus Striatum/drug effects , Manganese/toxicity , Propiophenones/toxicity , Substantia Nigra/drug effects , Animals , Basal Ganglia Diseases/diagnostic imaging , Basal Ganglia Diseases/metabolism , Basal Ganglia Diseases/pathology , Behavior, Animal , Corpus Striatum/diagnostic imaging , Corpus Striatum/metabolism , Corpus Striatum/pathology , Disease Models, Animal , Male , Manganese/administration & dosage , Mice , Mice, Inbred C57BL , Motor Activity , Propiophenones/administration & dosage , Substantia Nigra/diagnostic imaging , Substantia Nigra/metabolism , Substantia Nigra/pathology , Tomography, Emission-Computed, Single-PhotonABSTRACT
Bowel dysfunction is a common non-motor symptom in Parkinson's disease (PD). The main contractile neurotransmitter in the GI tract is acetylcholine (ACh), while nitric oxide (NO) causes the relaxation of smooth muscle in addition to modulating ACh release. The aim of this study was to characterise functional and neurochemical changes in the isolated ileum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmoset, an established model of PD motor dysfunction. While NO-synthase inhibitor L-NAME concentration dependently augmented the neurogenically-evoked contractions and inhibited the relaxations in normal tissues, it had no effects on the MPTP ileum. Immunohistochemical analyses of the myenteric plexus showed that ChAT-immunoreactivity (-ir) was significantly reduced and the density of the enteric glial cells as shown by SOX-10-ir was increased. However, no change in TH-, 5-HT-, VIP- or nNOS-ir was observed in the MPTP tissues. The enhancement of the neurogenically-evoked contractions and the inhibition of the relaxation phase by L-NAME in the control tissues is in line with NO's direct relaxing effect on smooth muscle and its indirect inhibitory effect on ACh release. The absence of the relaxation and the inefficacy of L-NAME in the MPTP tissues suggests that central dopaminergic loss dopamine may eventually lead to the impairment of NO signal coupling that affects bowel function, and this may be the result of a complex dysregulation at the level of the neuroeffector junction.
ABSTRACT
INTRODUCTION: The adenoma detection rate (ADR) is the best validated colonoscopy performance quality indicator. The ASGE/ACG Task Force on Colonoscopy Quality set an ADR benchmark of ≥25% in a mixed male/female population. We propose a novel means for defining locally relevant ADR benchmarks using data from the population of interest and for applying ADR benchmarks using 95% confidence intervals (CIs) of an endoscopist's ADR. We further propose that ADR benchmarks should be raised to reflect what can be achieved by high-performing endoscopists. METHODS: We used endoscopists' performance in a baseline year to develop and apply benchmarks in an assessment year. We defined assessment year benchmarks (Minimally Acceptable, Standard of Care, and Aspirational) based on the average ADR of performance groups defined by baseline year ADR quartiles. We demonstrated the use of these benchmarks in endoscopists performing screening colonoscopies by determining if the upper bound of the 95% CI of the endoscopist's ADR included the ADR benchmark. RESULTS: The study included 8,492 colonoscopies (mean ADR 29%) in 2014 and 5,193 colonoscopies (mean ADR 32%) in 2015, completed at a regional screening center in Calgary, Canada. The Minimally Acceptable, Standard of Care, and Aspirational benchmarks for 2015 were 25%, 30%, and 39%, respectively. The 95% CI of the ADR of 1 (3%), 3 (10%), and 12 (39%) endoscopists did not include the benchmark. DISCUSSION: We have proposed methods for defining and applying benchmarks for ADR in average-risk patients that go beyond the "minimally acceptable" threshold currently recommended.
Subject(s)
Adenoma/diagnosis , Benchmarking/methods , Colonoscopy/standards , Colorectal Neoplasms/diagnosis , Quality Indicators, Health Care , Aged , Cohort Studies , Colonic Polyps/diagnosis , Colorectal Surgery , Early Detection of Cancer , Female , Gastroenterology , Humans , Male , Middle AgedABSTRACT
OBJECTIVE: This article identifies the prevalence and associated factors of hypophosphatemia (HP) in very low birth weight (VLBW) infants in the first week of life. STUDY DESIGN: Prospective exploratory cohort study of 106 consecutive VLBW infants admitted to neonatal intensive care at Foothills Hospital, Calgary, Canada. HP was defined as at least one measurement of serum phosphate < 1.5 mmol/L (4.5 mg/dL). RESULTS: Seventy-seven percent (82/106) of the VLBW infants had HP, with significantly higher prevalence in infants < 1,000 g (94%) compared to infants ≥ 1,000 g (61%) (p < 0.001). Hypophosphatemic infants had lower birth weight (p < 0.001), gestational age (p < 0.001), and their increase in phosphate intake was slower (p = 0.003). Respiratory distress syndrome (RDS) (p = 0.002), intraventricular hemorrhage (IVH) ≥ grade III (p = 0.020), and hyperglycemia (p = 0.013) were more frequent among hypophosphatemic infants, especially among those < 1,000 g. Mortality, seizures, arrhythmias, and need for transfusion were not different between groups. Birth weight modified the association between RDS, IVH, hyperglycemia, and HP. CONCLUSION: HP was ubiquitous among infants < 1,000 g and highly prevalent among those weighing 1,000 to 1,500 g. While the direction of effect was not clear, RDS, IVH, and hyperglycemia were associated with HP. Prevention of HP in these physiologically immature neonates might improve neonatal outcomes.
Subject(s)
Hypophosphatemia/epidemiology , Infant, Premature, Diseases/epidemiology , Infant, Premature/blood , Infant, Very Low Birth Weight/blood , Phosphates/blood , Female , Gestational Age , Humans , Hypophosphatemia/complications , Infant, Extremely Low Birth Weight/blood , Infant, Newborn/blood , Infant, Premature, Diseases/blood , Male , Oxygen/blood , Prevalence , Prospective StudiesABSTRACT
BACKGROUND: Creutzfeldt-Jakob disease is a rare and rapidly fatal neurodegenerative disease. Since clinicians may see only very few cases during their professional career, it is important to be familiar with the clinical presentation and progression, to perform appropriate investigations, and allow for quick diagnosis. CASE PRESENTATION: A 73-year-old British Caucasian woman presented with acute confusion of 2 weeks' duration on a background of low mood following a recent bereavement. Her symptoms included behavioral change, visual hallucinations, vertigo, and recent falls. She was mildly confused, with left-sided hyperreflexia, a wide-based gait, and intention tremor in her left upper limb. Initial blood tests, computed tomography, and magnetic resonance imaging of her brain showed no significant abnormality. Following admission, she had rapid cognitive decline and developed florid and progressive neurological signs; a diagnosis of prion disease was suspected. A lumbar puncture was performed; cerebrospinal fluid was positive for 14-3-3 protein, real-time quaking-induced conversion, and raised levels of s-100b proteins were detected. An electroencephalogram showed bilateral periodic triphasic waves on a slow background. The diagnosis of probable Creutzfeldt-Jakob disease was made. CONCLUSIONS: This case report highlights key features in the initial presentation and clinical development of a rare but invariably rapidly progressive and fatal disease. It emphasizes the importance of considering a unifying diagnosis for multifaceted clinical presentations. Although it is very rare, Creutzfeldt-Jakob disease should be considered a diagnosis for a mixed neuropsychiatric presentation, particularly with rapid progressive cognitive decline and development of neurological signs. However, to avoid overlooking early signal change on magnetic resonance imaging, it is important to take diffusion-weighted magnetic resonance imaging for all patients with neuropsychological symptoms. Importantly, early diagnosis also ensures the arrangement of suitable contamination control measures to minimize the risk of infection to health care professionals and other patients.