In this trial involving patients with relapsing–remitting multiple sclerosis, BG-12 (dimethyl fumarate) reduced the annualized relapse rate and number of MRI lesions but not disability progression. ...BG-12 was associated with flushing, diarrhea, and decreased lymphocyte counts.
Multiple sclerosis is a chronic demyelinating and neurodegenerative disease of the central nervous system, which is commonly treated with parenteral agents (interferon beta and glatiramer acetate). Oxidative stress and proinflammatory stimuli are important pathologic factors in multiple sclerosis.
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Experimental data suggest that BG-12, an oral formulation of dimethyl fumarate, has antiinflammatory and cytoprotective properties that are mediated through activation of the nuclear factor (erythroid-derived 2)–like 2 transcriptional pathway, among others.
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Here, we report the results of the Comparator and an Oral Fumarate in Relapsing–Remitting Multiple Sclerosis (CONFIRM) trial, a randomized, multicenter, double-blind, 2-year study evaluating the efficacy and . . .
The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific ...prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Whether initial treatment for Parkinson's disease should consist of levodopa, dopamine agonists, or monoamine oxidase type B inhibitors (MAOBI) is uncertain. We aimed to establish ...which of these three classes of drug, as initial treatment, provides the most effective long-term control of symptoms and best quality of life for people with early Parkinson's disease. Methods In this pragmatic, open-label randomised trial, patients newly diagnosed with Parkinson's disease were randomly assigned (by telephone call to a central office; 1:1:1) between levodopa-sparing therapy (dopamine agonists or MAOBI) and levodopa alone. Patients and investigators were not masked to group assignment. Primary outcomes were the mobility dimension on the 39-item patient-rated Parkinson's disease questionnaire (PDQ-39) quality-of-life scale (range 0–100 with six points defined as the minimally important difference) and cost-effectiveness. Analysis was intention to treat. This trial is registered, number ISRCTN69812316. Findings Between Nov 9, 2000, and Dec 22, 2009, 1620 patients were assigned to study groups (528 to levodopa, 632 to dopamine agonist, 460 to MAOBI). With 3-year median follow-up, PDQ-39 mobility scores averaged 1·8 points (95% CI 0·5–3·0, p=0·005) better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy, with no increase or attrition of benefit during 7 years' observation. PDQ-39 mobility scores were 1·4 points (95% CI 0·0–2·9, p=0·05) better in patients allocated MAOBI than in those allocated dopamine agonists. EQ-5D utility scores averaged 0·03 (95% CI 0·01–0·05; p=0·0002) better with levodopa than with levodopa-sparing therapy; rates of dementia (hazard ratio HR 0·81, 95% CI 0·61–1·08, p=0·14), admissions to institutions (0·86, 0·63–1·18; p=0·4), and death (0·85, 0·69–1·06, p=0·17) were not significantly different, but the upper CIs precluded any substantial increase with levodopa compared with levodopa-sparing therapy. 179 (28%) of 632 patients allocated dopamine agonists and 104 (23%) of 460 patients allocated MAOBI discontinued allocated treatment because of side-effects compared with 11 (2%) of 528 patients allocated levodopa (p<0·0001). Interpretation Very small but persistent benefits are shown for patient-rated mobility scores when treatment is initiated with levodopa compared with levodopa-sparing therapy. MAOBI as initial levodopa-sparing therapy was at least as effective as dopamine agonists. Funding UK National Institute for Health Research Health Technology Assessment Programme and UK Department of Health.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The concept of reserve has been proposed to account for the disjunction between the degree of brain damage and its clinical outcome. This paper attempts to produce a coherent theoretical account the ...reserve in general and of cognitive reserve in particular. It reviews epidemiologic data supporting the concept of cognitive reserve, with a particular focus of its implications for aging and dementia. It then focuses on methodologic issues that are important when attempting to elucidate the neural underpinnings of cognitive reserve using imaging studies, and reviews some of our group's work in order to demonstrate these issues.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Sedation and Delirium in the Intensive Care Unit Reade, Michael C; Finfer, Simon
New England journal of medicine/The New England journal of medicine,
01/2014, Volume:
370, Issue:
5
Journal Article
Peer reviewed
Open access
Patients in ICUs often require pain relief and sedation to treat both the underlying medical condition and the unpleasantness associated with being in an ICU. This review provides guidance on the ...identification and treatment of delirium and sedation.
Patients in intensive care units (ICUs) are treated with many interventions (most notably endotracheal intubation and invasive mechanical ventilation) that are observed or perceived to be distressing. Pain is the most common memory patients have of their ICU stay.
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Agitation can precipitate accidental removal of endotracheal tubes or of intravascular catheters used for monitoring or administration of life-sustaining medications. Consequently, sedatives and analgesics are among the most commonly administered drugs in ICUs.
Early intensive care practice evolved from intraoperative anesthetic care at a time when mechanical ventilation was delivered by rudimentary machines that were not capable of synchronizing with patients' . . .
Summary Background The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and ...safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment. Methods In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18–55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT00548405. Findings 202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 95% CI 0·39–0·65; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 95% CI 0·38–0·87; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 66% of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia. Interpretation For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity. Funding Genzyme (Sanofi) and Bayer Schering Pharma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Emotion, memories and behaviour emerge from the coordinated activities of regions connected by the limbic system. Here, we propose an update of the limbic model based on the seminal work of Papez, ...Yakovlev and MacLean. In the revised model we identify three distinct but partially overlapping networks: (i) the Hippocampal-diencephalic and parahippocampal-retrosplenial network dedicated to memory and spatial orientation; (ii) The temporo-amygdala-orbitofrontal network for the integration of visceral sensation and emotion with semantic memory and behaviour; (iii) the default-mode network involved in autobiographical memories and introspective self-directed thinking. The three networks share cortical nodes that are emerging as principal hubs in connectomic analysis. This revised network model of the limbic system reconciles recent functional imaging findings with anatomical accounts of clinical disorders commonly associated with limbic pathology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to ...assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial. Methods In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18–50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT00530348. Findings 187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 95% CI 0·32–0·63; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 95% CI 0·40–1·23; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma. Interpretation Alemtuzumab's consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here. Funding Genzyme (Sanofi) and Bayer Schering Pharma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Although animal models and early-phase clinical trials suggested that progesterone had beneficial effects in severe traumatic brain injury, this phase 3 clinical trial showed no benefit of ...progesterone as a neuroprotective agent for this condition.
Traumatic brain injury (TBI) is a major cause of death and disability, with large direct and indirect costs to society. In the United States, more than 1.7 million persons have a TBI annually,
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and the annual burden of TBI has been estimated at more than $76 billion.
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Globally, the incidence of TBI is increasing, particularly in developing countries.
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Although in recent years there has been a heightened interest in mild TBI and concussion, the problem of more severe TBI remains substantial, despite improvements in trauma systems and critical care. Mortality rates of approximately 40% have been reported in a review . . .
Changes in memory performance are one of the hallmark symptoms of mild cognitive impairment and are affected by healthy aging as well. Pattern separation, which refers to the process of ...orthogonalizing overlapping inputs into distinct memory representations, may be a sensitive marker of these memory changes. Here, we describe a paradigm, the Behavioral Pattern Separation Task—Object Version (BPS-O task), which reveals age-related changes in pattern separation performance. Specifically, we report an age-related decline in pattern separation in healthy adults, ranging from ages 20 to 89. When we classify those individuals aged 60 and older into two groups, Aged Unimpaired (AU) and Aged Impaired (AI) based on their delayed word recall performance, we observe impairments in pattern separation performance in the Impaired group, but no overall impairment in recognition performance. In contrast, those individuals diagnosed with mild cognitive impairment demonstrate worse performance than age-matched controls in both pattern separation and recognition memory performance. Therefore, the BPS-O task provides a sensitive measure for observing changes in memory performance across the lifespan and may be useful for the early detection of memory impairments that may provide an early signal of later development to mild cognitive impairment.
► Behavioral pattern separation declines in human aging. ► MCI individuals exhibit impairments in both recognition memory and behavioral pattern separation. ► Aged Impaired adults demonstrate pattern separation deficits but normal recognition.
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