Treatment of cognitive impairment in multiple sclerosis: position paper

Cognitive impairment in multiple sclerosis (MS) is common, debilitating and burdensome. Key evidence from trials was reviewed to enable recommendations to be made to guide clinical practice and research. Behavioural and pharmacological interventions on cognition reported in published studies were reviewed. Most studies evaluating behavioural treatment for impairment in learning and memory, deficits of attention and executive function have demonstrated some improvement. Controlled studies in relapsing remitting MS indicate interferon (IFN) β-1b and IFN β-1a were associated with modest cognitive improvement. The effects of symptomatic therapies such as modafinil and donepezil are inconsistent. Most studies yielding positive findings have significant methodological difficulties limiting the confidence in making any broad treatment recommendations. There are no published reports of glatiramer acetate, natalizumab and fingolimod being effective in improving cognition in controlled trials. The effects of disease modifying therapies in other forms of MS and clinically isolated syndrome have not yielded positive results. Data linking behavioural therapy, symptomatic treatment or disease modifying treatment, to either reducing cognitive decline or improving impaired cognition are limited and inconsistent. The treatment and prevention of cognitive impairment needs to remain a key research focus, identifying new interventions and improving clinical trial methodology.     

Disparities in mammography use among US women aged 40-64 years, by race, ethnicity, income, and health insurance status, 1993 and 2005

OBJECTIVE: To examine current disparities in mammography use, and changes in disparities over time by race, ethnicity, income, insurance, and combinations of these characteristics. RESEARCH DESIGN: Comparison of cross-sectional surveys of mammography use using the 1993 and 2005 National Health Interview Survey. SUBJECTS: Women aged 40-64 (1993, n = 4167; 2005, n = 7434). MEASURES: Mammogram within prior 2 years. RESULTS: In 2005, uninsured women reported the lowest mammography use (38.3%). Though screening increased 6.9 percentage points among low-income, uninsured women, the overall disparity between insured and uninsured women did not change significantly between 1993 and 2005. Screening seems to have declined among middle-income, uninsured women, increasing the gap compared with middle-income, insured women. The lower mammography use in 1993 among American Indian/Alaska Native compared with white women was not present in 2005; however, lower use among Asian compared with white women emerged in 2005. We found no differences between African American and white women. Hispanic women were less likely than non-Hispanic women to report screening in 2005 (58.1% vs. 69.0%). CONCLUSIONS: Although mammography use increased for some groups between 1993 and 2005, low-income, uninsured women continued to have the lowest screening rates in 2005 and the disparity for this group was not reduced. The gap in screening use for middle-income, uninsured women increased, resulting from possible declines in mammography even for uninsured women not in poverty. Asian women became less likely to receive screening in 2005. Continuing efforts are needed to eliminate disparities. Increased efforts are especially needed to address the large persistent disparity for uninsured women, including middle-income uninsured women.     

Relationships between brain and body temperature,clinical and imaging outcomes after ischemic stroke

Pyrexia soon after stroke is associated with severe stroke and poor functional outcome. Few studies have assessed brain temperature after stroke in patients, so little is known of its associations with body temperature, stroke severity, or outcome. We measured temperatures in ischemic and normal-appearing brain using ¹H-magnetic resonance spectroscopy and its correlations with body (tympanic) temperature measured four-hourly, infarct growth by 5 days, early neurologic (National Institute of Health Stroke Scale, NIHSS) and late functional outcome (death or dependency). Among 40 patients (mean age 73 years, median NIHSS 7, imaged at median 17 hours), temperature in ischemic brain was higher than in normal-appearing brain on admission (38.6°C-core, 37.9°C-contralateral hemisphere, P=0.03) but both were equally elevated by 5 days; both were higher than tympanic temperature. Ischemic lesion temperature was not associated with NIHSS or 3-month functional outcome; in contrast, higher contralateral normal-appearing brain temperature was associated with worse NIHSS, infarct expansion and poor functional outcome, similar to associations for tympanic temperature. We conclude that brain temperature is higher than body temperature; that elevated temperature in ischemic brain reflects a local tissue response to ischemia, whereas pyrexia reflects the systemic response to stroke, occurs later, and is associated with adverse outcomes.     

More stressors prior to and during the course of bipolar illness in patients from the United States compared with the Netherlands and Germany

Considerable data suggest that compared to some European countries, in the U.S. there are more childhood onset bipolar disorders, more adverse courses of illness, and greater treatment resistance. Psychosocial variables related to these findings have not been adequately explored. Therefore we analyzed psychosocial stressors in three time domains: childhood; the year prior to illness Onset; and the Last Episode from questionnaires in 968 outpatients (mean age 41) with bipolar I or II disorder; 676 from four sites in the U.S. and 292 from three in the Netherlands and Germany (abbreviated here as Europe). Compared to the Europeans, those from the U.S. had significantly more stressors in childhood and prior to the last episode. Stressors prior to the last episode were related to: childhood stressors; an earlier age at illness onset; anxiety and substance abuse comorbidity; lower income; both parents having an affective illness; and feeling more stigma. These data suggest a greater prevalence of adverse life events in childhood and over the course of bipolar illness in the U.S. compared to the Netherlands and Germany. Clinical, therapeutic, and public health approaches to these illness-relevant stressors require further exploration.     

Evidence for massive methane hydrate destabilization during the penultimate interglacial warming

The stability of widespread methane hydrates in shallow subsurface sediments of the marine continental margins is sensitive to temperature increases experienced by upper intermediate waters. Destabilization of methane hydrates and ensuing release of methane would produce climatic feedbacks amplifying and accelerating global warming. Hence, improved assessment of ongoing intermediate water warming is crucially important, especially that resulting from a weakening of Atlantic meridional overturning circulation (AMOC). Our study provides an independent paleoclimatic perspective by reconstructing the thermal structure and imprint of methane oxidation throughout a water column of 1,300 m. We studied a sediment sequence from the eastern equatorial Atlantic (Gulf of Guinea), a region containing abundant shallow subsurface methane hydrates. We focused on the early part of the penultimate interglacial and present a hitherto undocumented and remarkably large intermediate water warming of 6.8 °C in response to a brief episode of meltwater-induced, modest AMOC weakening centered at 126,000 to 125,000 y ago. The warming of intermediate waters to 14 °C significantly exceeds the stability field of methane hydrates. In conjunction with this warming, our study reveals an anomalously low δ¹³C spike throughout the entire water column, recorded as primary signatures in single and pooled shells of multitaxa foraminifers. This extremely negative δ¹³C excursion was almost certainly the result of massive destabilization of methane hydrates. This study documents and connects a sequence of climatic events and climatic feedback processes associated with and triggered by the penultimate climate warming that can serve as a paleoanalog for modern ongoing warming.

Because ocean intermediate waters impinge on marine sediments that often contain potentially unstable shallow subsurface methane hydrates (1–3), better understanding is crucial about the factors that contribute to intermediate water warming and their potential extent, especially in context with ongoing global warming. Simulation studies have suggested warming of intermediate waters has been limited to ∼1.5 °C to 3 °C, and that such warmings were insufficient to significantly affect the stability of shallow subsurface methane hydrates (2–5). However, the magnitude of intermediate water warming can be significantly amplified by meltwater-induced weakening of atmospheric and ocean circulation (6–11), an amplification not considered in the simulations that examined potential gas hydrate destabilization (2–5). A recent simulation study estimates the contribution of weak Atlantic meridional overturning circulation (AMOC) at 0.3 °C to 0.4 °C to the warming of the intermediate waters for a business-as-usual scenario at the end of the 21st century (12), a modest contribution compared to observations in past climate studies (6–11). An accelerated mass loss of the Greenland ice sheet and the associated freshening of subpolar North Atlantic sea surface waters represents a robust proxy of ongoing rapid global warming (13). Causally linked to this freshening is increasing evidence of a steady weakening of the AMOC (14, 15). Warming of the intermediate waters by 3 °C to 5 °C in response to a meltwater-induced AMOC weakening is a robust feature of the last deglacial (6–11). This corresponds to pockmark formations on the ocean floor and extremely negative foraminiferal δ¹³C values in sediment sequences that reflect methane hydrate dissociation in response to intermediate water warming related to meltwater-induced weakening of AMOC and associated changes in atmospheric circulation during the last deglacial (10, 11, 16–18). A sequence of episodic, extremely low foraminiferal δ¹³C values observed in Late Quaternary sediments of Santa Barbara Basin led to the formulation of the “clathrate gun hypothesis” (10, 11). The hypothesis states that episodic warming of intermediate waters during the last glacial and early deglacial led to dissociation of shallow subsurface methane hydrates and release of methane, contributing to the observed increases of atmosphere methane concentrations, further contributing to climatic warming episodes (10, 11). The key findings of our study add to a growing body of observational findings strongly supporting the “clathrate gun hypothesis” (10, 11). The magnitude of intermediate water warming in response to AMOC weakening most likely is critically dependent on the existing mean climatic state. Importantly, the interval we have studied is marked by a mean climate state comparable to future projections of transient global climate warming of 1.3 °C to 3.0 °C (19). Our findings thus provide insights about major meltwater-induced intermediate water warming during warm episodes like the present with the potential to destabilize structural-type methane hydrates.In this study, we focus on the early part of the Eemian interglacial episode (128,000 to 125,000 y before present [ky BP]), the youngest episode when tropical oceans were warmer than the Holocene by up to 2 °C (20–22). We show that the combination of a warm mean climate state and a relatively brief and modest episode of meltwater-induced AMOC weakening produced an exceptionally large intermediate water warming that significantly exceeds the stability field of methane hydrates. Coincident with this warming, we demonstrate that the dissolved inorganic carbon across the entire 1,300-m water column was marked by an anomalously low carbon isotope ratio (¹³C/¹²C) which we interpret to indicate destabilization of shallow subsurface methane hydrates and ensuing methane oxidation.     

RSV Replication,Transmission, and Disease Are Influenced by the RSV G Protein

It is important to understand the features affecting virus replication, fitness, and transmissibility as they contribute to the outcome of infection and affect disease intervention approaches. Respiratory syncytial virus (RSV) is a major contributor to respiratory disease, particularly in the infant and elderly populations. Although first described over 60 years ago, there are no approved vaccines and there are limited specific antiviral treatments due in part to our incomplete understanding of the features affecting RSV replication, immunity, and disease. RSV studies have typically focused on using continuous cell lines and conventional RSV strains to establish vaccine development and various antiviral countermeasures. This review outlines how the RSV G protein influences viral features, including replication, transmission, and disease, and how understanding the role of the G protein can improve the understanding of preclinical studies.     

Nanomechanical and Vibrational Signature of Chikungunya Viral Particles

Chikungunya virus (CHIKV) belongs to the genus Alphaviridae, with a single-stranded positive-sense RNA genome of 11.8 kbp encoding a polyprotein that generates both non-structural proteins and structural proteins. The virus is transmitted by the Aedes aegypti and A. albopictus mosquitoes, depending on the location. CHIKV infection leads to dengue-like musculoskeletal symptoms and has been responsible for several outbreaks worldwide since its discovery in 1952. Patients often experience fever, headache, muscle pain, joint swelling, and skin rashes. However, the ultrastructural and mechanical properties of CHIKV have not been fully characterized. Thus, this study aims to apply a physical approach to investigate CHIKV′s ultrastructural morphology and mechanical properties, using atomic force microscopy and Raman spectroscopy as the main tools. Using nanomechanical assays of AFM and a gold nanoparticles substrate for Raman signal enhancement, we explored the conformational plasticity, morphology, vibrational signature, and nanomechanical properties of the chikungunya virus, providing new information on its ultrastructure at the nanoscale and offering a novel understanding of the virus’ behavior upon mechanical disruptions besides its molecular composition.