Long-Term Treatment with Extended-Release Carbidopa– Levodopa (IPX066) in Early and Advanced Parkinson’s Disease: A 9-Month Open-Label Extension Trial

Background and Objective IPX066 is a multiparticulate extended-release formulation of carbidopa–levodopa, designed to produce prolonged therapeutic levodopa plasma concentrations. This 9-month open-label extension study assessed its long-term safety and clinical utility in early and advanced Parkinson’s disease (PD). Methods Participants were enrolled from two phase III IPX066 studies and one open-label phase II study. Early PD patients were titrated to an appropriate dosing regimen while advanced patients started with regimens established in the antecedent studies. Adjustment was allowed throughout the extension. Clinical utility measures included the Unified Parkinson’s Disease Rating Scale (UPDRS) and Patient Global Impression (PGI) ratings. Results Among 268 early PD patients, 53.4 % reported adverse events (AEs) and 1.1 % (three patients) discontinued due to AEs; the most frequent AEs were nausea (5.6 %) and insomnia (5.6 %). Among 349 advanced patients, 60.2 % reported AEs and 3.7 % (13 patients) discontinued due to AEs; the most frequent AEs were dyskinesia (6.9 %) and fall (6.6 %). At month 9 (or early termination), 78.3 % of early patients were taking IPX066 three times daily (median: 720 mg/day) and 87.7 % of advanced patients were taking IPX066 three or four times daily (median: 1450 mg/day). Adjusting for 70 % bioavailability relative to immediate-release (IR) carbidopa–levodopa, the median dosages correspond to *500 and *1015 mg/day of IR levodopa in early and advanced PD, respectively. Based on the plasma profiles previously observed in PD patients, the IPX066 regimens in the extension can be estimated to provide a levodopa Cmax (maximum plasma drug concentration) similar to or lower than that provided by IR regimens during the antecedent trials. UPDRS and PGI findings showed sustained treatment effects throughout the extension. Conclusion During 9 months of extended use, IPX066 exhibited a safety/tolerability profile consistent with dopaminergic PD therapy

Long-term treatment with extended-release carbidopa-levodopa (IPX066) in early and advanced Parkinson's Disease : a 9-month open-label extension trial

Background and Objective IPX066 is a multiparticulate extended-release formulation of carbidopa–levodopa, designed to produce prolonged therapeutic levodopa plasma concentrations. This 9-month open-label extension study assessed its long-term safety and clinical utility in early and advanced Parkinson’s disease (PD). Methods Participants were enrolled from two phase III IPX066 studies and one open-label phase II study. Early PD patients were titrated to an appropriate dosing regimen while advanced patients started with regimens established in the antecedent studies. Adjustment was allowed throughout the extension. Clinical utility measures included the Unified Parkinson’s Disease Rating Scale (UPDRS) and Patient Global Impression (PGI) ratings. Results Among 268 early PD patients, 53.4 % reported adverse events (AEs) and 1.1 % (three patients) discontinued due to AEs; the most frequent AEs were nausea (5.6 %) and insomnia (5.6 %). Among 349 advanced patients, 60.2 % reported AEs and 3.7 % (13 patients) discontinued due to AEs; the most frequent AEs were dyskinesia (6.9 %) and fall (6.6 %). At month 9 (or early termination), 78.3 % of early patients were taking IPX066 three times daily (median: 720 mg/day) and 87.7 % of advanced patients were taking IPX066 three or four times daily (median: 1450 mg/day). Adjusting for 70 % bioavailability relative to immediate-release (IR) carbidopa–levodopa, the median dosages correspond to *500 and *1015 mg/day of IR levodopa in early and advanced PD, respectively. Based on the plasma profiles previously observed in PD patients, the IPX066 regimens in the extension can be estimated to provide a levodopa Cmax (maximum plasma drug concentration) similar to or lower than that provided by IR regimens during the antecedent trials. UPDRS and PGI findings showed sustained treatment effects throughout the extension. Conclusion During 9 months of extended use, IPX066 exhibited a safety/tolerability profile consistent with dopaminergic PD therapy

A comparison of taxon co-occurrence patterns for macro- and microorganisms

We examine co-occurrence patterns of microorganisms to evaluate community assembly “rules.” We use methods previously applied to macroorganisms, both to evaluate their applicability to microorganisms and to allow comparison of co-occurrence patterns observed in microorganisms to those found in macroorganisms. We use a null model analysis of 124 incidence matrices from microbial communities, including bacteria, archaea, fungi, and algae, and we compare these results to previously published findings from a meta-analysis of almost 100 macroorganism data sets. We show that assemblages of microorganisms demonstrate nonrandom patterns of co-occurrence that are broadly similar to those found in assemblages of macroorganisms. These results suggest that some taxon co-occurrence patterns may be general characteristics of communities of organisms from all domains of life. We also find that co-occurrence in microbial communities does not vary among taxonomic groups or habitat types. However, we find that the degree of co-occurrence does vary among studies that use different methods to survey microbial communities. Finally, we discuss the potential effects of the undersampling of microbial communities on our results, as well as processes that may contribute to nonrandom patterns of co-occurrence in both macrobial and microbial communities such as competition, habitat filtering, historical effects, and neutral processes

Isolation and characterization of resident endogenous c-Kit⁺ cardiac stem cells from the adult mouse and rat heart

This protocol describes the isolation of endogenous c-Kit (also known as CD117)-positive (c-Kit⁺), CD45-negative (CD45⁻) cardiac stem cells (eCSCs) from whole adult mouse and rat hearts. The heart is enzymatically digested via retrograde perfusion of the coronary circulation, resulting in rapid and extensive breakdown of the whole heart. Next, the tissue is mechanically dissociated further and cell fractions are separated by centrifugation. The c-Kit⁺ CD45⁻ eCSC population is isolated by magnetic-activated cell sorting technology and purity and cell numbers are assessed by flow cytometry. This process takes ∼4 h for mouse eCSCs or 4.5 h for rat eCSCs. We also describe how to characterize c-Kit⁺ CD45⁻ eCSCs. The c-Kit⁺ CD45⁻eCSCs exhibit the defining characteristics of stem cells: they are self-renewing, clonogenic and multipotent. This protocol also describes how to differentiate eCSCs into three main cardiac lineages: functional, beating cardiomyocytes, smooth muscle, and endothelial cells. These processes take 17-20 d

Neuropsychological Correlates of Cystic Fibrosis in Patients 5 to 8 Years Old

Intellectual, academic, and neuropsychological tests were administered to 20 children with cystic fibrosis (CF). Results were compared to test results from 20 controls matched for gender, age, and socioeconomic status. No differences between the groups were found. For children with CF, Verbal IQ, sensory-perceptual skills, and incidental learning correlated (rs = .39-.67) with Shwachman criteria of disease severity, with significant positive relations with the Growth and Nutrition measure, an index of the severity of the disease. Processing of tactile-perceptual information may be particularly vulnerable to disease severity. This study provides more information than previously available on the neuropsychological status of young children with CF, and it offers some hypotheses regarding the relation between disease severity and neuropsychological function.published_or_final_versio

Narcissistic Features in Young Adolescents: Relations to Aggression and Internalizing Symptoms

Recent research and theory suggest narcissistic features contribute to aggression in adults. The present study examined the association of narcissistic features with aggression and internalizing symptoms in 233 students of 5th–8th grade at three inner-city schools. A factor analysis of the Narcissistic Personality Inventory in this sample revealed three factors: Adaptive Narcissism, Exploitativeness, and Exhibitionism. Regression analyses were used to predict the association of these three narcissistic features with self-, teacher-, and peer-reported aggression and self-reported internalizing symptoms. Results indicate narcissistic exploitativeness positively predicted self-reported proactive aggression, and narcissistic exhibitionism positively predicted internalizing symptoms. Narcissism and self-esteem interacted to predict teacher-reported aggression and self-reported internalizing symptoms. Results are discussed in the context of existing theories of narcissism, threatened egotism, and self-perception bias.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45298/1/10964_2004_Article_485227.pd

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Stability of Arithmetic Disability Subtypes

Cross-sectional research has identified subtypes of children with learning disabilities who may have distinctive cognitive ability patterns. This study examined the stability over 19 months of academic subtyping classifications for 80 children ages 9 to 13 representing four subtypes of arithmetic disabilities (AD), using three criteria for learning disability identification. Approximately half of the sample retained AD regardless of identification method. Children with pervasive deficits in arithmetic, reading, and spelling displayed the greatest subtype stability. Only one third of the children with the other subtypes, including those with isolated arithmetic deficits, retained their original subtypes. Thus, drawing conclusions and making recommendations based on academic subtyping at a single point in time may be unwise