bluuebunny/crossref_metadata_2025 huggingface dataset:
LIDAR technology for measuring trace gases on Mars and Earth
Authors: Riris H. , Numata K. , Li S. , Wu S. , Sun X. , Abshire J.
Published: November 2010

Abstract. Trace gases and their isotopic ratios in planetary atmospheres offer important but subtle clues as to the origins of a planet's atmosphere, hydrology, geology, and potential for biology. Calculations show that an orbiting laser remote sensing instrument is capable of measuring trace gases on a global scale with unprecedented accuracy, and higher spatial resolution that can be obtained by passive instruments. Our proposed lidar uses Integrated Path Differential Absorption technique, Optical Parametric Amplifiers, and a receiver with high sensitivity detector at 1.65 μm to map methane concentrations, a strong greenhouse gas. For Mars we can use the same technique in the 3–4 μm spectral range to map various biogenic gas concentrations and search for the existence of life. Preliminary results demonstrating methane and water vapour detection using a laboratory prototype illustrate the viability of the technique.
Glacier changes in the Pascua-Lama region, Chilean Andes (29° S): recent mass-balance and 50-year surface-area variations
Authors: Rabatel A. , Castebrunet H. , Favier V. , Nicholson L. , Kinnard C.
Published: November 2010

Abstract. Since 2003, a monitoring program has been conducted on several glaciers and glacierets in the Pascua-Lama region of the Chilean Andes (29° S/70° W; 5000 m a.s.l.), permitting the study of glaciological processes on ice-bodies in a subtropical, arid, high-elevation area where no measurements were previously available. In this paper we present: (i) 6 years of glaciological surface mass-balance measurements from 4 ice-bodies in the area, including a discussion of the nature of the studied glaciers and glacierets and characterization of the importance of winter mass-balance to annual mass-balance variability; and (ii) changes in surface-area of 20 ice-bodies in the region since 1955, reconstructed from aerial photographs and satellite images, which show that ice-bodies have lost 44 ± 21% of their 1955 surface-area, and that the rate of surface-area shrinkage increased in the late 20th century. From these datasets we present an interpretation of inter-decadal glacier changes, which appear to be linked to El Niño Southern Oscillation and to the Pacific Decadal Oscillation.
Synthesis of Propiolic Acids via Copper‐Catalyzed Insertion of Carbon Dioxide into the CH Bond of Terminal Alkynes
Authors: Gooßen Lukas J. , Rodríguez Nuria , Manjolinho Filipe , Lange Paul P.
Published: October 2010

A highly effective copper catalyst has been developed that promotes the insertion of carbon dioxide into the CH bond of terminal alkynes under unprecedentedly mild conditions. For the first time, propiolic acids can thus be synthesized in excellent yields from alkynes and carbon dioxide in the presence of the mild base cesium carbonate. The catalyst, (4,7‐diphenyl‐1,10‐phenanthroline)bis[tris(4‐fluorophenyl)phosphine]copper(I) nitrate, is easy accessible and relatively stable against air and water.
Dimethyl Sulfoxide/Potassium Hydroxide: A Superbase for the Transition Metal‐Free Preparation of Cross‐Coupling Products
Authors: Yuan Yu , Thomé Isabelle , Kim Seok Hwan , Chen Duanteng , Beyer Astrid , Bonnamour Julien , Zuidema Erik , Chang Sukbok , Bolm Carsten
Published: October 2010

Potassium hydroxide (KOH) in dimethyl sulfoxide (DMSO) forms a superbasic medium that allows one to access cross‐coupling products from reactions between aryl halides with various sulfur‐, oxygen‐ and nitrogen‐based nucleophiles under transition metal‐free conditions.
Lack of respiratory improvement following remediation of a water‐damaged office building
Authors: Iossifova Yulia Y. , Cox‐Ganser Jean M. , Park Ju‐Hyeong , White Sandra K. , Kreiss Kathleen
Published: October 2010

Background

Damp buildings are commonly remediated without removing employees or ongoing medical surveillance.

Methods

We examined paired pulmonary function and questionnaire data from 2002 and 2005 for 97 employees in a water‐damaged building during ongoing but incomplete remediation.

Results

We observed no overall improvement in respiratory health, as reflected in symptom scores, overall medication use, spirometry abnormalities, or sick leave. Four employees went from borderline bronchial hyperresponsiveness to bronchial hyperresponsiveness; six developed abnormal spirometry; three more reported post‐occupancy current asthma, and four hypersensitivity pneumonitis. The number of participants without lower respiratory symptoms decreased from 27 in 2002 to 20 in 2005. Respiratory cases relocated in the building had a decrease in medication use and sick leave in 2005.

Conclusions

During dampness remediation, relocation may be health protective and prevent incident building‐related respiratory cases. Without relocation of entire workforces, medical surveillance is advisable for secondary prevention of existing building‐related disease. Am. J. Ind. Med. 54:269–277, 2011. © 2010 Wiley‐Liss, Inc.
Risk of beryllium sensitization in a low‐exposed former nuclear weapons cohort from the cold war era
Authors: Mikulski Marek A. , Leonard Stephanie A. , Sanderson Wayne T. , Hartley Patrick G. , Sprince Nancy L. , Fuortes Laurence J.
Published: October 2010

Background

The nuclear weapons industry has long been known as a source of beryllium exposure.

Methods

A total of 1,004 former workers from a nuclear weapons assembly site in the Midwest were screened for sensitization to beryllium (BeS). The screenings were part of the Department of Energy (DOE) Former Worker Program established in 1996.

Results

Twenty‐three (2.3%) workers were found sensitized to beryllium and this prevalence was comparable to other DOE sites. Occasional, direct exposure to beryllium through machining and grinding of copper–beryllium (Cu–Be) 2% alloy tools was found to increase the risk of sensitization compared to background exposure (OR = 3.83; 95% CI: 1.04–14.03) with a statistically significant trend (P = 0.03) revealing that particular jobs are associated with sensitization. Exposure potential in this study was estimated based on job titles and not personal exposure information.

Conclusions

These results confirm the need to screen workers using beryllium alloy tools in other industries and for consideration of altering work practices. Am. J. Ind. Med. 54:194–204, 2011. © 2010 Wiley‐Liss, Inc.
Risk factors for lower extremity fatigue among assembly plant workers
Authors: Gell Nancy , Werner Robert A. , Hartigan Anne , Wiggermann Neal , Keyserling W. Monroe
Published: October 2010

Background

Work‐related fatigue of the lower extremities is a known cause of lost productivity and significant employer costs. Common workplace solutions to reduce fatigue levels include anti‐fatigue matting, shoe orthoses, or sit/stand work stations. However, assessment of these anti‐fatigue measures within the workplace has been limited.

Methods

This was a cross sectional study in an automotive assembly plant on employees with at least 6 months tenure. Subject data were collected via questionnaires including Likert‐scale questions to define fatigue severity. Jobs were evaluated for lower extremity ergonomic exposures via videotaping, pedometers, interviews, and industrial engineering records.

Results

Lower extremity fatigue at the end of the work day was associated with a higher prevalence of smoking, rheumatoid arthritis, job dissatisfaction, use of shoes with firmer outsoles, and increased time on the job spent standing or walking. Supervisor support and increased time spent on carpet were protective. Lower extremity fatigue that interfered with activities outside of work had additional risk factors including higher BMI, prior diagnosis of osteoarthritis, and increased hours per week spent working.

Conclusions

While these results identify carpet as being protective against lower extremity fatigue, no similar relationship was identified for anti‐fatigue mats. No adverse relationship was found between hard surfaces such as concrete and lower extremity fatigue. Given the high costs associated with work‐related fatigue, future areas for potential intervention include smoking cessation, specific shoe recommendations, and enhancing psychosocial aspects of work such as supervisor support. Am. J. Ind. Med. 54:216–223, 2011. © 2010 Wiley‐Liss, Inc.
Intragenic deletions of IL1RAPL1: Report of two cases and review of the literature
Authors: Behnecke Anne , Hinderhofer Katrin , Bartsch Oliver , Nümann Astrid , Ipach Marie‐Luise , Damatova Natalja , Haaf Thomas , Dufke Andreas , Riess Olaf , Moog Ute
Published: October 2010

IL1RAPL1 (interleukin‐1 receptor accessory protein‐like 1) located at Xp21.3‐22.1 has repeatedly been shown to be deleted in patients with a contiguous gene syndrome also affecting neighboring genes, in particular DMD (dystrophin), DAX‐1 (NR0B1, nuclear receptor subfamily 0, group B, member 1), and GK (glycerol kinase). In contrast, intragenic deletions of IL1RAPL1 or other mutations or cytogenetic aberrations affecting IL1RAPL1 have only rarely been identified. Up to date, they have mostly been associated with nonspecific mental retardation (MRX). We report on two nonrelated patients with MR and additional dysmorphic features who both show intragenic deletions of IL1RAPL1, one of them being de novo (exon 2) and the other one being inherited from his mother (exons 3–5). Deletions were identified by microarray‐based chromosome analysis and confirmed by multiplex PCR and FISH, respectively. These data, along with recent functional studies indicating its role in neuronal development, provide further evidence for the relevance of IL1RAPL1 in the pathogenesis of X‐linked MR and add knowledge to the phenotypic spectrum of IL1RAPL1 mutations. © 2010 Wiley‐Liss, Inc.
Brain biopsy in children with primary small‐vessel central nervous system vasculitis
Authors: Elbers Jorina , Halliday William , Hawkins Cynthia , Hutchinson Clare , Benseler Susanne M.
Published: October 2010

Objective::

Primary angiitis of the central nervous system in childhood (cPACNS) is an immune‐mediated inflammatory process directed toward blood vessels in the central nervous system. It has been associated with variable clinical and radiological presentations, and devastating consequences without treatment. Brain biopsy is required for definitive diagnosis. The objective of this study was to characterize the clinical and histopathological features of brain biopsies in small‐vessel cPACNS (SVcPACNS).

Methods::

A single‐center prospective cohort study of children diagnosed with cPACNS from 1998 to 2008 was performed. All patients with negative cerebral angiography and brain biopsy were included. Patient data were reviewed for clinical, laboratory, and radiological characteristics at presentation. Standardized brain biopsy review protocols were established, with independent analysis by 2 neuropathologists. Histopathology was correlated with collected clinical data.

Results::

A total of 13 SVcPACNS patients were included. Ages ranged from 5 to 17 years. Presenting features included seizures (85%), headache (62%), and cognitive decline (54%). Brain biopsy confirmed SVcPACNS in 11 patients with intramural lymphocytic infiltrate. Two had nonspecific perivascular inflammation only. All 6 nonlesional biopsies yielded a diagnosis of SVcPACNS. Lack of specific histological features correlated with prolonged time to biopsy, prior steroid treatment, and inadequate specimen sampling.

Interpretation::

In children presenting with new onset severe headaches, seizures, or cognitive decline, SVcPACNS and brain biopsy should be considered. Lesional biopsies are preferred; however, nonlesional biopsies may succeed in yielding the diagnosis. Steroid treatment prior to biopsy and inadequate biopsy sampling may obscure the diagnosis in true cases of SVcPACNS. ANN NEUROL 2010;68:602–610
Recurrent ischemic events in young adults after first‐ever ischemic stroke
Authors: Putaala Jukka , Haapaniemi Elena , Metso Antti J. , Metso Tiina M. , Artto Ville , Kaste Markku , Tatlisumak Turgut
Published: October 2010

Objective::

Data on recurrence of vascular events and their prognostic factors in young (<50 years of age) stroke patients are not well defined.

Methods::

We assessed the occurrence of arterial thrombotic events in consecutive first‐ever ischemic stroke patients aged 15 to 49 years entered into the Helsinki Young Stroke Registry (January 1994–October 2004) within 5‐year follow‐up. Follow‐up was conducted with a structured telephone interview or letter, and review of all patient records; mortality data came from Statistics Finland. Primary outcomes were (1) nonfatal or fatal recurrent ischemic stroke; (2) nonfatal or fatal myocardial infarct, other arterial thrombotic event, or revascularization procedure; and (3) any combination of these, whichever occurred first (composite endpoint). We used Kaplan‐Meier analysis to estimate cumulative risks and Cox proportional hazard model—adjusted for age, gender, relevant risk factors, and stroke subtype—for identifying predictors of recurrence.

Results::

In the 807 patients followed (mean age, 41.5 ± 7.4 years; 62.9% male), cumulative 5‐year recurrence rate was 9.4% (95% confidence interval [CI], 7.3–11.5%) for nonfatal or fatal ischemic stroke, 2.4% (95% CI, 1.3‐3.5%) for nonfatal or fatal myocardial infarct or other arterial endpoint, and 11.5% (95% CI, 9.2‐13.7%) for the composite endpoint. Independent predictors of the composite endpoint were type 1 diabetes mellitus (hazard ratio [HR], 4.39; 95% CI, 2.28‐8.45), large‐artery atherosclerosis underlying the index stroke (HR, 2.82; 95% CI, 1.36‐5.83), heart failure (HR, 2.96; 95% CI, 1.17‐7.50), previous transient ischemic attack (HR, 2.33; 95% CI, 1.40‐3.88), and increasing age (HR, 1.05; 95% CI, 1.01‐1.10).

Interpretation::

Despite their young age, these individuals were at marked risk of recurrent arterial events, predicted by mostly modifiable baseline factors.ANN NEUROL 2010;68:661–671
Caffeine and brain development in very preterm infants
Authors: Doyle Lex W. , Cheong Jeanie , Hunt Rod W. , Lee Katherine J. , Thompson Deanne K. , Davis Peter G. , Rees Sandra , Anderson Peter J. , Inder Terrie E.
Published: October 2010

Objective:

Caffeine improves neurological outcome in very preterm infants, but the mechanisms responsible for this neurological benefit are unknown. The objective of this study was to assess whether caffeine influenced brain macro‐ or microstructural development in preterm infants.

Methods:

Seventy preterm infants <1,251 g birthweight randomly allocated to either caffeine (n = 33) or placebo (n = 37) underwent brain magnetic resonance imaging (MRI) at term‐equivalent age; white and gray matter abnormalities were qualitatively scored, global and regional brain volumes were measured, and white matter microstructure was evaluated using diffusion‐weighted imaging.

Results:

There were no significant differences between the groups in the extent of white matter or gray matter abnormality, or in global or regional brain volumes. In contrast, although only available in 28 children, caffeine exposure was associated with reductions in the apparent diffusion coefficient, and radial and axial diffusivity with the greatest impact in the superior brain regions. The alterations in diffusion measures were not mediated by lowering the rate of lung injury, known as bronchopulmonary dysplasia.

Interpretation:

These diffusion changes are consistent with improved white matter microstructural development in preterm infants who received caffeine. ANN NEUROL 2010;68:734–742
Recombinant osteopontin in cerebral vasospasm after subarachnoid hemorrhage
Authors: Suzuki Hidenori , Hasegawa Yu , Chen Wanqiu , Kanamaru Kenji , Zhang John H.
Published: October 2010

Objective:

Osteopontin (OPN), a pleiotropic extracellular matrix glycoprotein, has been reported to be protective against ischemic lesions, but effects of OPN on vascular functions have not been investigated. The aim of this study was to assess whether recombinant OPN (r‐OPN) could prevent cerebral vasospasm after subarachnoid hemorrhage (SAH) in rats.

Methods:

r‐OPN was administered intraventricularly to rats undergoing SAH by endovascular perforation, and its protective effects were evaluated by measuring the diameter of cerebral arteries and neurobehavioral testing. Western blotting and immunofluorescence were performed to explore the underlying mechanisms. An integrin receptor antagonist GRGDSP or mitogen‐activated protein kinase (MAPK) phosphatase (MKP)‐1 small interfering RNA (siRNA) was also administered to r‐OPN‐treated SAH rats, and those effects were evaluated.

Results:

Pre‐SAH administration of r‐OPN prevented vasospasm and neurological impairments at 24–72 hours post‐SAH. r‐OPN enhanced an endogenous MAPK inhibitor, MKP‐1, and suppressed the phosphorylation of MAPKs, caldesmon, and heat shock protein 27 in the spastic cerebral arteries at 24 hours post‐SAH. Immunofluorescence revealed that MKP‐1 was induced in the arterial smooth muscle layer. GRGDSP prevented r‐OPN‐induced MKP‐1 upregulation, and MKP‐1 siRNA abolished both MAPK inactivation and anti‐vasospastic effects by r‐OPN. Post‐SAH r‐OPN treatment also prevented vasospasm.

Interpretation:

r‐OPN induced MKP‐1 in the spastic cerebral arteries via binding to L‐arginyl‐glycyl‐L‐aspartate‐dependent integrin receptors and prevented vasospasm after SAH. Therapeutic induction of MKP‐1 may be a novel approach for the prevention and treatment of cerebral vasospasm. ANN NEUROL 2010;68:650–660
Glycogen hyperphosphorylation underlies lafora body formation
Authors: Turnbull Julie , Wang Peixiang , Girard Jean‐Marie , Ruggieri Alessandra , Wang Tony J. , Draginov Arman G. , Kameka Alexander P. , Pencea Nela , Zhao Xiaochu , Ackerley Cameron A. , Minassian Berge A.
Published: October 2010

Objective:

Glycogen, the largest cytosolic macromolecule, acquires solubility, essential to its function, through extreme branching. Lafora bodies are aggregates of polyglucosan, a long, linear, poorly branched, and insoluble form of glycogen. Lafora bodies occupy vast numbers of neuronal dendrites and perikarya in Lafora disease in time‐dependent fashion, leading to intractable and fatal progressive myoclonus epilepsy. Lafora disease is caused by deficiency of either the laforin glycogen phosphatase or the malin E3 ubiquitin ligase. The 2 leading hypotheses of Lafora body formation are: (1) increased glycogen synthase activity extends glycogen strands too rapidly to allow adequate branching, resulting in polyglucosans; and (2) increased glycogen phosphate leads to glycogen conformational change, unfolding, precipitation, and conversion to polyglucosan. Recently, it was shown that in the laforin phosphatase‐deficient form of Lafora disease, there is no increase in glycogen synthase, but there is a dramatic increase in glycogen phosphate, with subsequent conversion of glycogen to polyglucosan. Here, we determine whether Lafora bodies in the malin ubiquitin ligase‐deficient form of the disease are due to increased glycogen synthase or increased glycogen phosphate.

Methods:

We generated malin‐deficient mice and tested the 2 hypotheses.

Results:

Malin‐deficient mice precisely replicate the pathology of Lafora disease with Lafora body formation in skeletal muscle, liver, and brain, and in the latter in the pathognomonic perikaryal and dendritic locations. Glycogen synthase quantity and activity are unchanged. There is a highly significant increase in glycogen phosphate.

Interpretation:

We identify a single common modification, glycogen hyperphosphorylation, as the root cause of Lafora body pathogenesis. ANN NEUROL, 2010
Signatures of cardioembolic and large‐vessel ischemic stroke
Authors: Jickling Glen C. , Xu Huichun , Stamova Boryana , Ander Bradley P. , Zhan Xinhua , Tian Yingfang , Liu Dazhi , Turner Renée J. , Mesias Matthew , Verro Piero , Khoury Jane , Jauch Edward C. , Pancioli Arthur , Broderick Joseph P. , Sharp Frank R.
Published: October 2010

Objective:

The cause of stroke remains unknown or cryptogenic in many patients. We sought to determine whether gene expression signatures in blood can distinguish between cardioembolic and large‐vessel causes of stroke, and whether these profiles can predict stroke etiology in the cryptogenic group.

Methods:

A total of 194 samples from 76 acute ischemic stroke patients were analyzed. RNA was isolated from blood and run on Affymetrix U133 Plus2.0 microarrays. Genes that distinguish large‐vessel from cardioembolic stroke were determined at 3, 5, and 24 hours following stroke onset. Predictors were evaluated using cross‐validation and a separate set of patients with known stroke subtype. The cause of cryptogenic stroke was predicted based on a model developed from strokes of known cause and identified predictors.

Results:

A 40‐gene profile differentiated cardioembolic stroke from large‐vessel stroke with >95% sensitivity and specificity. A separate 37‐gene profile differentiated cardioembolic stroke due to atrial fibrillation from nonatrial fibrillation causes with >90% sensitivity and specificity. The identified genes elucidate differences in inflammation between stroke subtypes. When applied to patients with cryptogenic stroke, 17% are predicted to be large‐vessel and 41% to be cardioembolic stroke. Of the cryptogenic strokes predicted to be cardioembolic, 27% were predicted to have atrial fibrillation.

Interpretation:

Gene expression signatures distinguish cardioembolic from large‐vessel causes of ischemic stroke. These gene profiles may add valuable diagnostic information in the management of patients with stroke of unknown etiology though they need to be validated in future independent, large studies. Ann Neurol 2010;68:681–692
Imaging the future of stroke: II. Hemorrhage
Authors: Liebeskind David S.
Published: October 2010

Bleeding into the brain or adjacent structures is one of the most devastating neurological conditions, incurring tremendous emotional, financial, and societal costs. Imaging is essential to differentiate variants of hemorrhage, as the clinical features may be insufficient. A comprehensive approach to hemorrhage therefore relies on imaging to disclose pathophysiology, elucidate mechanisms, and thereby open further avenues to effective treatment. Hemorrhage patterns from superficial to deep locations in the brain are surveyed in this work, noting myriad potential causes and the influential pathophysiology of arterial ischemia, venous hypertension, and microvascular dysfunction. Recent progress of imaging studies and novel techniques to evaluate hemorrhage are explored. For decades, only computed tomography was available to define a hematoma without corroborating evidence of other pathology whereas multimodal computed tomography and magnetic resonance imaging, including noninvasive imaging of brain tissue, vessels, and perfusion, have now radically altered clinical practice. Imaging of the blood‐brain barrier, cerebral microbleeds, coexistent ischemia, associated vascular lesions, and markers of hemorrhage expansion is possible with routine protocols akin to diagnostic strategies for ischemic stroke. Imaging applications for hemorrhagic transformation, venous thrombosis, and microvascular disorders are considered with a perspective that balances concern for hemorrhage with prevention of ischemia as these processes are often intertwined and clinical conundrums arise. Imminent imaging advances are anticipated with increased use of detailed imaging for hemorrhage and overlap with cerebral ischemia. Numerous questions abound regarding optimal management of hemorrhage and definitive treatments are lacking, yet imaging of pivotal pathophysiology offers tremendous opportunity for future progress in combating this debilitating condition. Ann Neurol 2010;68:581–592
Immune regulation of multiple sclerosis by transdermally applied myelin peptides
Authors: Juryńczyk Maciej , Walczak Agata , Jurewicz Anna , Jesionek‐Kupnicka Dorota , Szczepanik Marian , Selmaj Krzysztof
Published: October 2010

Objective:

Antigen‐specific therapy targeting selective inhibition of autoreactive responses holds promise for controlling multiple sclerosis (MS) without disturbing homeostasis of the whole immune system. Key autoantigens in MS include myelin proteins, such as myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG). In this study, we examined the effect of transdermal therapy with myelin peptides on immune responses in the skin, lymph nodes, and peripheral blood immune cells of MS patients.

Methods:

In a 1‐year placebo‐controlled study, 30 patients with relapsing‐remitting MS were treated transdermally with a mixture of 3 myelin peptides: MBP85‐99, PLP139‐151, and MOG35‐55, or placebo. The phenotype of immune cells in the skin was assessed using immunohistochemistry. Cell populations in lymph nodes were analyzed using flow cytometry. In peripheral blood immune cells, cytokine production was measured by enzyme‐linked immunosorbent assay, and myelin‐specific proliferation was examined by carboxyfluorescein succinimidyl ester‐based assay.

Results:

We found that myelin peptides applied transdermally to MS patients activated dendritic Langerhans cells in the skin at the site of immunization and induced a unique population of granular dendritic cells in local lymph nodes. In the periphery, transdermal immunization with myelin peptides resulted in the generation of type 1, interleukin‐10–producing regulatory T cells, suppression of specific autoreactive proliferative responses, and suppression of interferon‐γ and transforming growth factor‐β production.

Interpretation:

We demonstrate for the first time the immunoregulatory potential of transdermal immunization with myelin peptides in MS patients. Ann Neurol 2010;68:593–601
Elevated plasma YKL‐40 levels and ischemic stroke in the general population
Authors: Kjaergaard Alisa D. , Bojesen Stig E. , Johansen Julia S. , Nordestgaard Børge G.
Published: October 2010

Objective:

We hypothesized that elevated plasma YKL‐40 levels are associated with increased risk of ischemic cardiovascular disease in the general population. In contrast to C‐reactive protein (CRP) produced in the liver in response to inflammation, YKL‐40 is produced by lipid‐laden macrophages inside the vessel wall.

Methods:

We measured plasma YKL‐40 in 8,899 21‐ to 93‐year‐old participants of the Copenhagen City Heart Study 1991–1994 examination, and followed them for up to 18 years. Endpoints were ischemic stroke, ischemic cerebrovascular disease, myocardial infarction, and ischemic heart disease. Hazard ratios were calculated for plasma YKL‐40 levels in 10‐year age percentile categories of 34 to 66%, 67 to 90%, and 91 to 100% versus 0 to 33%.

Results:

Multifactorially and CRP‐adjusted hazard ratios for ischemic stroke were 1.2 (95% confidence interval, 0.9–1.6) for 33 to 66%, 1.8 (1.3–2.4) for 67 to 90%, and 2.3 (1.5–3.3) for 91 to 100% versus the 0 to 33% percentile category (p‐trend < 0.001). Corresponding hazard ratios for ischemic cerebrovascular disease were 1.2 (0.9–1.5), 1.6 (1.2–2.0), and 2.2 (1.6–3.2) (p‐trend < 0.001). Hazard ratios for myocardial infarction were not significant, whereas corresponding hazard ratios for ischemic heart disease were 1.0 (0.8–1.2), 1.2 (1.0–1.5), and 1.3 (1.0–1.6) (p‐trend = 0.01). Stratifying for CRP or other risk factors gave similar results. A doubling in plasma YKL‐40 was associated with multifactorially and CRP‐adjusted increased risk of 20% (95% confidence interval, 11%–30%) for ischemic stroke, 16% (8%–24%) for ischemic cerebrovascular disease, 3% (‐5%–11%) for myocardial infarction, and 7% (1%–12%) for ischemic heart disease.

Interpretation:

In the general population, elevated plasma YKL‐40 levels are associated with increased risk of ischemic stroke and ischemic cerebrovascular disease, independent of plasma CRP levels.Ann Neurol 2010;68:672–680
Sustained alpha‐sarcoglycan gene expression after gene transfer in limb‐girdle muscular dystrophy, type 2D
Authors: Mendell Jerry R. , Rodino‐Klapac Louise R. , Rosales Xiomara Q. , Coley Brian D. , Galloway Gloria , Lewis Sarah , Malik Vinod , Shilling Chris , Byrne Barry J. , Conlon Thomas , Campbell Katherine J. , Bremer William G. , Taylor Laura E. , Flanigan Kevin M. , Gastier‐Foster Julie M. , Astbury Caroline , Kota Janaiah , Sahenk Zarife , Walker Christopher M. , Clark K. Reed
Published: October 2010

Objective:

The aim of this study was to attain long‐lasting alpha‐sarcoglycan gene expression in limb‐girdle muscular dystrophy, type 2D (LGMD2D) subjects mediated by adeno‐associated virus (AAV) gene transfer under control of a muscle specific promoter (tMCK).

Methods:

rAAV1.tMCK.hSGCA (3.25 × 1011 vector genomes) was delivered to the extensor digitorum brevis muscle of 3 subjects with documented SGCA mutations via a double‐blind, randomized, placebo controlled trial. Control sides received saline. The blind was not broken until the study was completed at 6 months and all results were reported to the oversight committee.

Results:

Persistent alpha‐sarcoglycan gene expression was achieved for 6 months in 2 of 3 LGMD2D subjects. Markers for muscle fiber transduction other than alpha‐sarcoglycan included expression of major histocompatibility complex I, increase in muscle fiber size, and restoration of the full sarcoglycan complex. Mononuclear inflammatory cells recruited to the site of gene transfer appeared to undergo programmed cell death, demonstrated by terminal deoxynucleotide transferase–mediated deoxyuridine triphosphate nick‐end labeling and caspase‐3 staining. A patient failing gene transfer demonstrated an early rise in neutralizing antibody titers and T‐cell immunity to AAV, validated by enzyme‐linked immunospot on the second day after gene injection. This was in clear distinction to other participants with satisfactory gene expression.

Interpretation:

The findings of this gene replacement study in LGMD2D subjects have important implications not previously demonstrated in muscular dystrophy. Long‐term, sustainable gene expression of alpha‐sarcoglycan was observed following gene transfer mediated by AAV. The merit of a muscle‐specific tMCK promoter, not previously used in a clinical trial, was evident, and the potential for reversal of disease was displayed. ANN NEUROL 2010;68:629–638
Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration–motor neuron disease
Authors: Luty Agnes A. , Kwok John B.J. , Dobson‐Stone Carol , Loy Clement T. , Coupland Kirsten G. , Karlström Helena , Sobow Tomasz , Tchorzewska Joanna , Maruszak Aleksandra , Barcikowska Maria , Panegyres Peter K. , Zekanowski Cezary , Brooks William S. , Williams Kelly L. , Blair Ian P. , Mather Karen A. , Sachdev Perminder S. , Halliday Glenda M. , Schofield Peter R.
Published: October 2010

Objective:

Frontotemporal lobar degeneration (FTLD) is the most common cause of early‐onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans‐activating response element (TAR) DNA binding protein (TDP‐43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD‐MND pedigree with no mutations in known dementia genes.

Methods:

A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation.

Results:

We identified a nonpolymorphic mutation (c.672*51G>T) in the 3′‐untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected individuals from the FTLD‐MND pedigree. The c.672*51G>T mutation increased gene expression by 1.4‐fold, corresponding with a significant 1.5‐fold to 2‐fold change in the SIGMAR1 transcript or Sigma‐1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP‐43 or FUS but not Sigma‐1. Overexpression of SIGMAR1 shunted TDP‐43 and FUS from the nucleus to the cytoplasm by 2.3‐fold and 5.2‐fold, respectively. Treatment of cells with Sigma‐1 ligands significantly altered translocation of TDP‐43 by up to 2‐fold.

Interpretation:

SIGMAR1 is a causative gene for familial FTLD‐MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma‐1 drugs as potential treatments for the TDP‐43/FUS proteinopathies. Ann Neurol 2010;68:639–649
DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53‐dependent myopathy in vivo
Authors: Wallace Lindsay M. , Garwick Sara E. , Mei Wenyan , Belayew Alexandra , Coppee Frederique , Ladner Katherine J. , Guttridge Denis , Yang Jing , Harper Scott Q.
Published: October 2010

Objective:

Facioscapulohumeral muscular dystrophy (FSHD) is associated with D4Z4 repeat contraction on human chromosome 4q35. This genetic lesion does not result in complete loss or mutation of any gene. Consequently, the pathogenic mechanisms underlying FSHD have been difficult to discern. In leading FSHD pathogenesis models, D4Z4 contractions are proposed to cause epigenetic changes, which ultimately increase expression of genes with myopathic potential. Although no gene has been conclusively linked to FSHD development, recent evidence supports a role for the D4Z4‐encoded DUX4 gene in FSHD. In this study, our objective was to test the in vivo myopathic potential of DUX4.

Methods:

We delivered DUX4 to zebrafish and mouse muscle by transposon‐mediated transgenesis and adeno‐associated viral vectors, respectively.

Results:

Overexpression of DUX4, which encodes a transcription factor, caused abnormalities associated with muscular dystrophy in zebrafish and mice. This toxicity required DNA binding, because a DUX4 DNA binding domain mutant produced no abnormalities. Importantly, we found the myopathic effects of DUX4 were p53 dependent, as p53 inhibition mitigated DUX4 toxicity in vitro, and muscles from p53 null mice were resistant to DUX4‐induced damage.

Interpretation:

Our work demonstrates the myopathic potential of DUX4 in animal muscle. Considering previous studies showed DUX4 was elevated in FSHD patient muscles, our data support the hypothesis that DUX4 overexpression contributes to FSHD development. Moreover, we provide a p53‐dependent mechanism for DUX4 toxicity that is consistent with previous studies showing p53 pathway activation in FSHD muscles. Our work justifies further investigation of DUX4 and the p53 pathway in FSHD pathogenesis. Ann Neurol 2010
More severe white matter changes in the elderly with jugular venous reflux
Authors: Chung Chih‐Ping , Wang Pei‐Ning , Wu Yi‐Hui , Tsao Yu‐Chien , Sheng Wen‐Yung , Lin Ker‐Neng , Lin Shing‐Jong , Hu Han‐Hwa
Published: October 2010

Objective

The etiology of age‐related white matter changes is unclear. Cerebral white matter changes on magnetic resonance imaging (MRI) and progressive dementia have been reported in patients with dural arteriovenous fistulas of the sigmoid sinus. The frequency of jugular venous reflux, which mimics a dural arteriovenous fistula, significantly increases with age. We investigated whether jugular venous reflux was associated with the severity of age‐related white matter changes in 97 persons (aged 55–90 years, mean [standard deviation]: 75.77 [8.19] years; 55 men) from a medical center memory clinic.

Methods

MRI (1.5T) and the semiquantitative Scheltens scale were used to investigate the severity of white matter changes. Subjects were classified into 3 groups (no, mild, and severe jugular venous reflux) by duplex ultrasonography.

Results

Subjects with severe jugular venous reflux had more severe age‐related white matter changes in occipital subcortical, thalamus, pontine, and summed infratentorial regions compared with subjects with no jugular venous reflux (all corrected p
< 0.0166), especially subjects aged ≥75 years (corrected p
< 0.0166 in occipital subcortical; corrected p
< 0.0001 in pontine and summed infratentorial regions). In subjects ≥75 years, we further noted that the whole brain age‐related white matter changes rating scores were higher in the severe jugular venous reflux group than the no and mild jugular venous reflux groups (corrected p
< 0.0166).

Interpretation

People with severe jugular venous reflux exhibit more severe age‐related white matter changes, especially in caudal brain regions. We also demonstrate age‐dependent jugular venous reflux effects on the severity of age‐related white matter changes. These findings may provide new clues into the pathophysiology of age‐related white matter changes. ANN NEUROL 2011
CR1 is associated with amyloid plaque burden and age‐related cognitive decline
Authors: Chibnik Lori B. , Shulman Joshua M. , Leurgans Sue E. , Schneider Julie A. , Wilson Robert S. , Tran Dong , Aubin Cristin , Buchman Aron S. , Heward Christopher B. , Myers Amanda J. , Hardy John A. , Huentelman Matthew J. , Corneveaux Jason J. , Reiman Eric M. , Evans Denis A. , Bennett David A. , De Jager Philip L.
Published: October 2010

Objective

Recently, genome‐wide association studies have identified 3 new susceptibility loci for Alzheimer's disease (AD), CLU, CR1, and PICALM. We leveraged available neuropsychological and autopsy data from 2 cohort studies to investigate whether these loci are associated with cognitive decline and AD neuropathology.

Methods

The Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP) are longitudinal studies that enroll nondemented subjects and include annual clinical evaluations and brain donation at death. We evaluated CR1 (rs6656401), CLU (rs11136000), and PICALM (rs7110631) in 1,666 subjects. We evaluated associations between genotypes and rate of change in cognitive function as well as AD‐related pathology. Lastly, we used pathway analysis to determine whether relationships between single nucleotide polymorphisms and cognitive decline are mediated through AD pathology.

Results

Among our study cohort, the mean years of follow‐up were 7.8 for ROS and 4.3 for MAP. Only the CR1 locus was associated with both global cognitive decline (p = 0.011) and global AD pathology (p = 0.025). More specifically, the locus affects the deposition of neuritic amyloid plaque (p = 0.009). In a mediation analysis, controlling for amyloid pathology strongly attenuated the effect of the CR1 locus on cognitive decline.

Interpretation

We found that common variation at the CR1 locus has a broad impact on cognition and that this effect is largely mediated by an individual's amyloid plaque burden. We therefore highlight 1 functional consequence of the CR1 susceptibility allele and generalize the role of this locus to cognitive aging in the general population. ANN NEUROL 2011
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression
Authors: Eikermann‐Haerter Katharina , Yuzawa Izumi , Dilekoz Ergin , Joutel Anne , Moskowitz Michael A. , Ayata Cenk
Published: October 2010

Migraine with aura is often the first manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome (CADASIL), a disorder caused by NOTCH3 gene mutations expressed predominantly in vascular smooth muscle. Here, we report that cortical spreading depression (CSD), the electrophysiological substrate of migraine aura, is enhanced in mice expressing a vascular Notch 3 CADASIL mutation (R90C) or a Notch 3 knockout mutation. The phenotype was stronger in Notch 3 knockout mice, implicating both loss of function and neomorphic mutations in its pathogenesis. Our results link vascular smooth muscle Notch 3 mutations to enhanced spreading depression susceptibility, implicating the neurovascular unit in the development of migraine aura. Ann Neurol 2011
Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder
Authors: Postuma Ronald B. , Gagnon Jean‐François , Vendette Mélanie , Desjardins Catherine , Montplaisir Jacques Y.
Published: October 2010

Objective:

For development of neuroprotective therapy, neurodegenerative disease must be identified as early as possible. However, current means of identifying “preclinical” neurodegeneration are limited. Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) are at >50% risk of synuclein‐mediated neurodegenerative disease—this provides a unique opportunity to directly observe preclinical synucleinopathy and to test potential markers of preclinical disease.

Methods:

Patients with RBD without neurodegenerative disease were enrolled in a prospective cohort starting in 2004. Olfaction and color vision were tested at baseline, then annually for 5 years. Test results were compared between patients who developed neurodegenerative disease and those who remained disease‐free.

Results:

Out of 64 patients, 62 (97%) participated in annual follow‐up. During follow‐up, 21 developed disease, and 41 remained disease‐free. Out of 21, 16 developed a combination of parkinsonism and dementia, 4 developed isolated parkinsonism (all with tremor), and 1 developed isolated dementia. Compared to those remaining disease‐free, patients destined to develop disease had worse baseline olfaction (University of Pennsylvania Smell Identification Test [UPSIT] = 58.3 ± 27.0% age/sex‐adjusted normal vs 80.2 ± 26.3%; p = 0.003) and color vision (Farnsworth‐Munsell 100‐Hue color test [FM‐100] errors 153.0 ± 82.2% normal vs 120.2 ± 26.5%; p = 0.022). Kaplan‐Meier 5‐year‐disease‐free survival in those with normal olfaction was 86.0%, vs 35.4% with impaired olfaction (p = 0.029). Disease‐free survival with normal color vision was 70.3%, vs 26.0% with impaired vision (p = 0.009). Both olfaction and color vision were reduced as much as 5 years before disease diagnosis, with only slight decline in preclinical stages.

Interpretation:

Olfaction and color vision identify early‐stage synuclein‐mediated neurodegenerative diseases. In most cases, abnormalities are measurable at least 5 years before disease onset, and progress slowly in the preclinical stages. Ann Neurol 2011;
Large genomic deletions: A novel cause of Ullrich congenital muscular dystrophy
Authors: Foley A. Reghan , Hu Ying , Zou Yaqun , Yang Michele , Medne Līvija , Leach Meganne , Conlin Laura K. , Spinner Nancy , Shaikh Tamim H. , Falk Marni , Neumeyer Ann M. , Bliss Laurie , Tseng Brian S. , Winder Thomas L. , Bönnemann Carsten G.
Published: October 2010

Two mutational mechanisms are known to underlie Ullrich congenital muscular dystrophy (UCMD): heterozygous dominant negatively‐acting mutations and recessively‐acting loss‐of‐function mutations. We describe large genomic deletions on chromosome 21q22.3 as a novel type of mutation underlying recessively inherited UCMD in 2 families. Clinically unaffected parents carrying large genomic deletions of COL6A1and COL6A2also provide conclusive evidence that haploinsufficiency for COL6A1and COL6A2is not a disease mechanism for Bethlem myopathy. Our findings have important implications for the genetic evaluation of patients with collagen VI–related myopathies as well as for potential therapeutic interventions for this patient population. Ann Neurol 2011;69:206–211
Evidence for a vascular factor in migraine
Authors: Asghar Mohammad S. , Hansen Adam E. , Amin Faisal M. , van der Geest R. J. , Koning Patrick van der , Larsson Henrik B. W. , Olesen Jes , Ashina Messoud
Published: October 2010

Objective

It has been suggested that migraine is caused by neural dysfunction without involvement of vasodilatation. Because dismissal of vascular mechanisms seemed premature, we examined diameter of extra‐ and intracranial vessels in migraine without aura patients.

Methods

A novel high‐resolution direct magnetic resonance angiography imaging technique was used to measure arterial circumference of the extracranial middle meningeal artery (MMA) and the intracranial middle cerebral artery (MCA). Data were obtained at baseline, during migraine attack, and after treatment with the migraine abortive drug sumatriptan (a 5‐hydroxytryptamine agonist).

Results

We found dilatation of both MMA and MCA during migraine attack (p = 0.001). Sumatriptan administration caused amelioration of headache (p
< 0.001) and contraction of MMA (p < 0.001), but MCA remained unchanged (p = 0.16). Exploratory analysis revealed that in migraine attacks with half‐sided headache, there was only dilatation on the headache side of MMA of 12.49% (95% confidence interval [CI], 4.16–20.83%) and of MCA of 12.88% (95% CI, 3.49–22.27%) and no dilatation on the nonheadache side of MMA (95% CI, −4.27 to 11.53%) and MCA (95% CI, −6.7 to 14.28%). In double‐sided headache we found bilateral vasodilatation of both MMA and MCA (p
< 0.001).

Interpretation

These data show that migraine without aura is associated with dilatation of extra‐ and intracerebral arteries and that the headache location is associated with the location of the vasodilatation. Furthermore, contraction of extracerebral and not intracerebral arteries is associated with amelioration of headache. Collectively, these data suggest that vasodilatation and perivascular release of vasoactive substances is an integral mechanism of migraine pathophysiology. ANN NEUROL 2011
Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia
Authors: Lancaster Eric , Huijbers Maartje G. M. , Bar Vered , Boronat Anna , Wong Andrew , Martinez‐Hernandez Eugenia , Wilson Christina , Jacobs Dina , Lai Meizan , Walker Russell W. , Graus Francesc , Bataller Luis , Illa Isabel , Markx Sander , Strauss Kevin A. , Peles Elior , Scherer Steven S. , Dalmau Josep
Published: October 2010

Objective

To report clinical and immunological investigations of contactin‐associated protein‐like 2 (Caspr2), an autoantigen of encephalitis and peripheral nerve hyperexcitability (PNH) previously attributed to voltage‐gated potassium channels (VGKC).

Methods

Clinical analysis was performed on patients with encephalitis, PNH, or both. Immunoprecipitation and mass spectrometry were used to identify the antigen and to develop an assay with Caspr2‐expressing cells. Immunoabsorption with Caspr2 and comparative immunostaining of brain and peripheral nerve of wild‐type and Caspr2‐null mice were used to assess antibody specificity.

Results

Using Caspr2‐expressing cells, antibodies were identified in 8 patients but not in 140 patients with several types of autoimmune or viral encephalitis, PNH, or mutations of the Caspr2‐encoding gene. Patients' antibodies reacted with brain and peripheral nerve in a pattern that colocalized with Caspr2. This reactivity was abrogated after immunoabsorption with Caspr2 and was absent in tissues from Caspr2‐null mice. Of the 8 patients with Caspr2 antibodies, 7 had encephalopathy or seizures, 5 neuropathy or PNH, and 1 isolated PNH. Three patients also had myasthenia gravis, bulbar weakness, or symptoms that initially suggested motor neuron disease. None of the patients had active cancer; 7 responded to immunotherapy and were healthy or only mildly disabled at last follow‐up (median, 8 months; range, 6–84 months).

Interpretation

Caspr2 is an autoantigen of encephalitis and PNH previously attributed to VGKC antibodies. The occurrence of other autoantibodies may result in a complex syndrome that at presentation could be mistaken for a motor neuron disorder. Recognition of this disorder is important, because it responds to immunotherapy. Ann Neurol 2011