bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of Loss-of-Function FTO Mutations in Lean and Obese Individuals
Authors: Meyre David , Proulx Karine , Kawagoe-Takaki Hiroko , Vatin Vincent , Gutiérrez-Aguilar Ruth , Lyon Debbie , Ma Marcella , Choquet Helene , Horber Fritz , Van Hul Wim , Van Gaal Luc , Balkau Beverley , Visvikis-Siest Sophie , Pattou François , Farooqi I. Sadaf , Saudek Vladimir , O'Rahilly Stephen , Froguel Philippe , Sedgwick Barbara , Yeo Giles S.H.
Published: October 2009

OBJECTIVE

Single nucleotide polymorphisms (SNPs) in intron 1 of fat mass– and obesity-associated gene (FTO) are strongly associated with human adiposity, whereas Fto−/− mice are lean and Fto+/− mice are resistant to diet-induced obesity. We aimed to determine whether FTO mutations are disproportionately represented in lean or obese humans and to use these mutations to understand structure-function relationships within FTO.

RESEARCH DESIGN AND METHODS

We sequenced all coding exons of FTO in 1,433 severely obese and 1,433 lean individuals. We studied the enzymatic activity of selected nonsynonymous variants.

RESULTS

We identified 33 heterozygous nonsynonymous variants in lean (2.3%) and 35 in obese (2.4%) individuals, with 8 mutations unique to the obese and 11 unique to the lean. Two novel mutations replace absolutely conserved residues: R322Q in the catalytic domain and R96H in the predicted substrate recognition lid. R322Q was unable to catalyze the conversion of 2-oxoglutarate to succinate in the presence or absence of 3-methylthymidine. R96H retained some basal activity, which was not enhanced by 3-methylthymidine. However, both were found in lean and obese individuals.

CONCLUSIONS

Heterozygous, loss-of-function mutations in FTO exist but are found in both lean and obese subjects. Although intron 1 SNPs are unequivocally associated with obesity in multiple populations and murine studies strongly suggest that FTO has a role in energy balance, it appears that loss of one functional copy of FTO in humans is compatible with being either lean or obese. Functional analyses of FTO mutations have given novel insights into structure-function relationships in this enzyme.
Absence of p53-Dependent Apoptosis Combined With Nonhomologous End-Joining Deficiency Leads to a Severe Diabetic Phenotype in Mice
Authors: Tavana Omid , Puebla-Osorio Nahum , Sang Mei , Zhu Chengming
Published: October 2009

OBJECTIVE

Regulation of pancreatic β-cell mass is essential to preserve sufficient insulin levels for the maintenance of glucose homeostasis. Previously, we reported that DNA double-strand breaks (DSBs) resulting from nonhomologous end-joining (NHEJ) deficiency induce apoptosis and, when combined with p53 deficiency, progressed rapidly into lymphomagenesis in mice. Combination of NHEJ deficiency with a hypomorphic mutation, p53R172P, leads to the abrogation of apoptosis, upregulation of p21, and senescence in precursor lymphocytes. This was sufficient to prevent tumorigenesis. However, these mutant mice succumb to severe diabetes and die at an early age. The aim of this study was to determine the pathogenesis of diabetes in these mutant mice.

RESEARCH DESIGN AND METHODS

We analyzed the morphology of the pancreatic islets and the function, proliferation rate, and senescence of β-cells. We also profiled DNA damage and p53 and p21 expression in the pancreas.

RESULTS

NHEJ-p53R172P mutant mice succumb to diabetes at 3–5 months of age. These mice show a progressive decrease in pancreatic islet mass that is independent of apoptosis and innate immunity. We observed an accumulation of DNA damage, accompanied with increased levels of p53 and p21, a significant decrease in β-cell proliferation, and cellular senescence in the mutant pancreatic islets.

CONCLUSIONS

Combined DSBs with an absence of p53-dependent apoptosis activate p53-dependent senescence, which leads to a diminished β-cell self-replication, massive depletion of the pancreatic islets, and severe diabetes. This is a model that connects impaired DNA repair and accumulative DNA damage, a common phenotype in aging individuals, to the onset of diabetes.
Hyperglycemia-Induced Reactive Oxygen Species Increase Expression of the Receptor for Advanced Glycation End Products (RAGE) and RAGE Ligands
Authors: Yao Dachun , Brownlee Michael
Published: October 2009

OBJECTIVE

RAGE interacts with the endogenous ligands S100 calgranulins and high mobility group box 1 (HMGB1) to induce inflammation. Since hyperglycemia-induced reactive oxygen species (ROS) activate many pathways of diabetic tissue damage, the effect of these ROS on RAGE and RAGE ligand expression was evaluated.

RESEARCH DESIGN AND METHODS

Expression of RAGE, S100A8, S100A12, and HMGB1 was evaluated in human aortic endothelial cells (HAECs) incubated in normal glucose, high glucose, and high glucose after overexpression of either uncoupling protein 1 (UCP1), superoxide dismutase 2 (SOD2), or glyoxalase 1 (GLO1). Expression was also evaluated in normal glucose after knockdown of GLO1. Expression was next evaluated in high glucose after knockdown of nuclear factor (NF)-κB p65 (RAGE) and after knockdown of activated protein-1 (AP-1) (S100A8, S100A12, and HMGB1), and chromatin immunoprecipitation (ChIP) was performed ± GLO1 overexpression for NFκB p65 (RAGE promoter) and AP-1 (S100A8, S100A12, and HMGB1 promoters). Finally, endothelial cells from nondiabetic mice, STZ diabetic mice, and STZ diabetic mice treated with the superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP) were evaluated.

RESULTS

High glucose increased RAGE, S100A8, S100A12, and HMGB1 expression, which was normalized by overexpression of UCP1, SOD2, or GLO1. GLO1 knockdown mimicked the effect of high glucose, and in high glucose, overexpression of GLO1 normalized increased binding of NFκB p65 and AP-1. Diabetes increased RAGE, S100A8, and HMGB1 expression, and MnTBAP treatment normalized this.

CONCLUSIONS

These results show that hyperglycemia-induced ROS production increases expression of RAGE and RAGE ligands. This effect is mediated by ROS-induced methylglyoxal, the major substrate of glyoxalase 1.
Genetic Heterogeneity in Latent Autoimmune Diabetes Is Linked to Various Degrees of Autoimmune Activity
Authors: Pettersen Elin , Skorpen Frank , Kvaløy Kirsti , Midthjell Kristian , Grill Valdemar
Published: October 2009

OBJECTIVE

Previous studies have indicated that the latent autoimmune diabetes in adults (LADA) phenotype is heterogeneous and that LADA patients share features of type 1 and type 2 diabetes in various proportions. We tested for association of known type 1 and type 2 diabetes susceptibility genes in LADA subjects and analyzed relationships to a marker of autoimmune activity (titers of anti-GAD) and a phenotypic risk factor of type 2 diabetes (BMI).

RESEARCH DESIGN AND METHODS

Data were assembled from the Nord-Trøndelag Health Study (HUNT) study, which comprises the adult population of an entire county in Norway. We genotyped 60 single nucleotide polymorphisms (SNPs) known to be associated with type 1 or type 2 diabetes, including 14 tag SNPs used for HLA haplotyping in 120 type 1 diabetic, 126 LADA, and 1,090 type 2 diabetic patients and 1,503 age- and sex-matched nondiabetic subjects.

RESULTS

The majority of the strongly associated HLA haplotypes for type 1 diabetes were significantly associated with LADA in general, but mainly with high anti-GAD LADA patients. Two distinct HLA haplotypes were associated only with LADA and mainly in low anti-GAD LADA patients. There were no associations of non-HLA type 1 diabetes loci with LADA. Of type 2 diabetes–associated genes, the CC/CT genotypes of rs7961581 (TSPAN8) and the obesity-linked AA/AC genotypes of rs8050136 (FTO) were associated with LADA in general, but mainly in low anti-GAD LADA patients (P = 0.004 and P = 0.004, respectively).

CONCLUSIONS

Genetic heterogeneity in LADA is linked to various degrees of autoimmune activity and may be partly distinct from both type 1 and type 2 diabetes.
Leucine Deprivation Decreases Fat Mass by Stimulation of Lipolysis in White Adipose Tissue and Upregulation of Uncoupling Protein 1 (UCP1) in Brown Adipose Tissue
Authors: Cheng Ying , Meng Qingshu , Wang Chunxia , Li Houkai , Huang Zhiying , Chen Shanghai , Xiao Fei , Guo Feifan
Published: October 2009

OBJECTIVE

White adipose tissue (WAT) and brown adipose tissue (BAT) play distinct roles in adaptation to changes in nutrient availability, with WAT serving as an energy store and BAT regulating thermogenesis. We previously showed that mice maintained on a leucine-deficient diet unexpectedly experienced a dramatic reduction in abdominal fat mass. The cellular mechanisms responsible for this loss, however, are unclear. The goal of current study is to investigate possible mechanisms.

RESEARCH DESIGN AND METHODS

Male C57BL/6J mice were fed either control, leucine-deficient, or pair-fed diets for 7 days. Changes in metabolic parameters and expression of genes and proteins related to lipid metabolism were analyzed in WAT and BAT.

RESULTS

We found that leucine deprivation for 7 days increases oxygen consumption, suggesting increased energy expenditure. We also observed increases in lipolysis and expression of β-oxidation genes and decreases in expression of lipogenic genes and activity of fatty acid synthase in WAT, consistent with increased use and decreased synthesis of fatty acids, respectively. Furthermore, we observed that leucine deprivation increases expression of uncoupling protein (UCP)-1 in BAT, suggesting increased thermogenesis.

CONCLUSIONS

We show for the first time that elimination of dietary leucine produces significant metabolic changes in WAT and BAT. The effect of leucine deprivation on UCP1 expression is a novel and unexpected observation and suggests that the observed increase in energy expenditure may reflect an increase in thermogenesis in BAT. Further investigation will be required to determine the relative contribution of UCP1 upregulation and thermogenesis in BAT to leucine deprivation-stimulated fat loss.
Sympathetic Neural Adaptation to Hypocaloric Diet With or Without Exercise Training in Obese Metabolic Syndrome Subjects
Authors: Straznicky Nora E. , Lambert Elisabeth A. , Nestel Paul J. , McGrane Mariee T. , Dawood Tye , Schlaich Markus P. , Masuo Kazuko , Eikelis Nina , de Courten Barbora , Mariani Justin A. , Esler Murray D. , Socratous Florentia , Chopra Reena , Sari Carolina I. , Paul Eldho , Lambert Gavin W.
Published: October 2009

OBJECTIVE

Sympathetic nervous system (SNS) overactivity contributes to the pathogenesis and target organ complications of obesity. This study was conducted to examine the effects of lifestyle interventions (weight loss alone or together with exercise) on SNS function.

RESEARCH DESIGN AND METHODS

Untreated men and women (mean age 55 ± 1 year; BMI 32.3 ± 0.5 kg/m2) who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated to either dietary weight loss (WL, n = 20), dietary weight loss and moderate-intensity aerobic exercise (WL+EX, n = 20), or no treatment (control, n = 19). Whole-body norepinephrine kinetics, muscle sympathetic nerve activity by microneurography, baroreflex sensitivity, fitness (maximal oxygen consumption), metabolic, and anthropometric measurements were made at baseline and 12 weeks.

RESULTS

Body weight decreased by −7.1 ± 0.6 and −8.4 ± 1.0 kg in the WL and WL+EX groups, respectively (both P < 0.001). Fitness increased by 19 ± 4% (P < 0.001) in the WL+EX group only. Resting SNS activity decreased similarly in the WL and WL+EX groups: norepinephrine spillover by −96 ± 30 and −101 ± 34 ng/min (both P < 0.01) and muscle sympathetic nerve activity by −12 ± 6 and −19 ± 4 bursts/100 heart beats, respectively (both P < 0.01), but remained unchanged in control subjects. Blood pressure, baroreflex sensitivity, and metabolic parameters improved significantly and similarly in the two lifestyle intervention groups.

CONCLUSIONS

The addition of moderate-intensity aerobic exercise training to a weight loss program does not confer additional benefits on resting SNS activity. This suggests that weight loss is the prime mover in sympathetic neural adaptation to a hypocaloric diet.
Adiposity, Cardiometabolic Risk, and Vitamin D Status: The Framingham Heart Study
Authors: Cheng Susan , Massaro Joseph M. , Fox Caroline S. , Larson Martin G. , Keyes Michelle J. , McCabe Elizabeth L. , Robins Sander J. , O'Donnell Christopher J. , Hoffmann Udo , Jacques Paul F. , Booth Sarah L. , Vasan Ramachandran S. , Wolf Myles , Wang Thomas J.
Published: October 2009

OBJECTIVE

Because vitamin D deficiency is associated with a variety of chronic diseases, understanding the characteristics that promote vitamin D deficiency in otherwise healthy adults could have important clinical implications. Few studies relating vitamin D deficiency to obesity have included direct measures of adiposity. Furthermore, the degree to which vitamin D is associated with metabolic traits after adjusting for adiposity measures is unclear.

RESEARCH DESIGN AND METHODS

We investigated the relations of serum 25-hydroxyvitamin D (25[OH]D) concentrations with indexes of cardiometabolic risk in 3,890 nondiabetic individuals; 1,882 had subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes measured by multidetector computed tomography (CT).

RESULTS

In multivariable-adjusted regression models, 25(OH)D was inversely associated with winter season, waist circumference, and serum insulin (P < 0.005 for all). In models further adjusted for CT measures, 25(OH)D was inversely related to SAT (−1.1 ng/ml per SD increment in SAT, P = 0.016) and VAT (−2.3 ng/ml per SD, P < 0.0001). The association of 25(OH)D with insulin resistance measures became nonsignificant after adjustment for VAT. Higher adiposity volumes were correlated with lower 25(OH)D across different categories of BMI, including in lean individuals (BMI <25 kg/m2). The prevalence of vitamin D deficiency (25[OH]D <20 ng/ml) was threefold higher in those with high SAT and high VAT than in those with low SAT and low VAT (P < 0.0001).

CONCLUSIONS

Vitamin D status is strongly associated with variation in subcutaneous and especially visceral adiposity. The mechanisms by which adiposity promotes vitamin D deficiency warrant further study.
Gene Variants in the Novel Type 2 Diabetes Loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B Affect Different Aspects of Pancreatic β-Cell Function
Authors: Simonis-Bik Annemarie M. , Nijpels Giel , van Haeften Timon W. , Houwing-Duistermaat Jeanine J. , Boomsma Dorret I. , Reiling Erwin , van Hove Els C. , Diamant Michaela , Kramer Mark H.H. , Heine Robert J. , Maassen J. Antonie , Slagboom P. Eline , Willemsen Gonneke , Dekker Jacqueline M. , Eekhoff Elisabeth M. , de Geus Eco J. , 't Hart Leen M.
Published: October 2009

OBJECTIVE

Recently, results from a meta-analysis of genome-wide association studies have yielded a number of novel type 2 diabetes loci. However, conflicting results have been published regarding their effects on insulin secretion and insulin sensitivity. In this study we used hyperglycemic clamps with three different stimuli to test associations between these novel loci and various measures of β-cell function.

RESEARCH DESIGN AND METHODS

For this study, 336 participants, 180 normal glucose tolerant and 156 impaired glucose tolerant, underwent a 2-h hyperglycemic clamp. In a subset we also assessed the response to glucagon-like peptide (GLP)-1 and arginine during an extended clamp (n = 123). All subjects were genotyped for gene variants in JAZF1, CDC123/CAMK1D, TSPAN8/LGR5, THADA, ADAMTS9, NOTCH2/ADAMS30, DCD, VEGFA, BCL11A, HNF1B, WFS1, and MTNR1B.

RESULTS

Gene variants in CDC123/CAMK1D, ADAMTS9, BCL11A, and MTNR1B affected various aspects of the insulin response to glucose (all P < 6.9 × 10−3). The THADA gene variant was associated with lower β-cell response to GLP-1 and arginine (both P < 1.6 × 10−3), suggesting lower β-cell mass as a possible pathogenic mechanism. Remarkably, we also noted a trend toward an increased insulin response to GLP-1 in carriers of MTNR1B (P = 0.03), which may offer new therapeutic possibilities. The other seven loci were not detectably associated with β-cell function.

CONCLUSIONS

Diabetes risk alleles in CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B are associated with various specific aspects of β-cell function. These findings point to a clear diversity in the impact that these various gene variants may have on (dys)function of pancreatic β-cells.
Greater Sage‐Grouse Centrocercus urophasianus Use of Threetip Sagebrush Relative to Big Sagebrush in South‐Central Idaho
Authors: Lowe Brad S. , Delehanty David J. , Connelly John W.
Published: October 2009

Disturbances that change sagebrush Artemisia spp.‐steppe communities may have an impact on greater sage‐grouse Centrocercus urophasianus populations. Fire can rapidly alter sagebrush‐steppe communities and may result in an increase in threetip sagebrush A. tripartita because this shrub is one of the few species of sagebrush that will sprout following fire. We examined the use of threetip sagebrush by sage‐grouse as nest cover and compared nest success of grouse using threetip sagebrush to that of grouse using big sagebrush A. tridentata. Sage‐grouse used threetip sagebrush as nest cover less than expected based on the abundance of this shrub. The only other species of sagebrush used as nest cover was big sagebrush, and sage‐grouse used big sagebrush more than expected based on big sagebrush abundance. However, nest site selection was confounded by age of sage‐grouse females. Sage‐grouse that used big sagebrush as nest cover had greater nest success than grouse using threetip sagebrush. Our findings demonstrate another negative, but subtle, effect of fire on sage‐grouse populations and further underscore the need for fire suppression and carefully implemented habitat rehabilitation projects.
Home Range, Daily Movements and Site Fidelity of Male Reeves's Pheasants Syrmaticus reevesii in the Dabie Mountains, Central China
Authors: Xu Ji‐Liang , Zhang Xiao‐Hui , Sun Quan‐Hui , Zheng Guang‐Mei , Wang Yong , Zhang Zheng‐Wang
Published: October 2009

Reeves's pheasant Syrmaticus reevesii is a threatened species endemic to China. During April 2000 ‐ August 2003, we studied home range size, daily movements and site fidelity of 17 male Reeves's pheasants at Dongzhai National Nature Reserve in central China. Average annual home range size was 44.9 ± 24.6 ha (minimum convex polygon) and 23.8 ± 13.7 ha (95% fixed kernel estimation). The average annual core area determined by 60% fixed kernel estimator was 4.2 ± 3.5 ha. Home range size was generally smaller in winter than in spring, whereas the size of the core area remained stable through all seasons. Conifer‐broadleaf mixed forests occupied a very large part of home ranges and core areas. Male pheasants exhibited strong site fidelity among seasons and years. Our results provide baseline data for habitat management, habitat restoration and reintroduction of the Reeves's pheasant.
Capercaillie Tetrao urogallus Nest Loss and Attendance at Abernethy Forest, Scotland
Authors: Summers Ron W. , Willi Johanna , Selvidge Jennifer
Published: October 2009

Improvement of breeding success is key to capercaillie Tetrao urogallus conservation in Scotland. However, factors affecting breeding success are not fully understood, including the cause of nest loss. We monitored 20 capercaillie nests with video or digital cameras at Abernethy Forest, Scotland to measure nest loss, determine causes of losses, and describe nest attendance by females. The mean date for the onset of incubation was 15 May and mean clutch size was 7.25 eggs. During incubation, females usually left the nest twice a day (range: 0–4), on average 28 minutes after sunrise and 2 hours 13 minutes before sunset, for a total of 53 minutes per day. There were no egg losses during egg laying, and the daily loss of clutches during incubation (26 days) was 0.0427 (95% CI = 0.0191–0.0663). However, an experiment with artificial nests suggested that predation rates were higher where video cameras were installed than at nests where they were not. After adjusting for the potential effect of deployment of the video system, the daily loss of the capercaillie nests was 0.0205 (95% CI = 0.0074–0.0554). Thus, the probability of a nest failing was 0.68 (95% CI = 0.39–0.83, unadjusted) or 0.42 (95% CI = 0.18–0.77, adjusted). This adjusted estimate at Abernethy Forest was close to the mid‐range of other studies of capercaillie nest loss in Scotland and elsewhere in Europe. Eleven of the nests were depredated, nine by pine martens Martes martes and two by unknown predators. One nest was abandoned. Based upon unadjusted daily predation rates, predators destroyed 65% of nests (57% known to be by pine martens) or, after adjusting for the potential effect of the video system, 39% of nests (33% known to be by pine martens). A better understanding of factors affecting pine marten (a protected species in the UK) numbers and hunting patterns is required before a habitat management plan can be implemented to reduce pine marten predation on capercaillie nests.
The Effect of Capture on Ranging Behaviour and Activity of the European Roe Deer Capreolus capreolus
Authors: Morellet Nicolas , Verheyden Hélène , Angibault Jean‐Marc , Cargnelutti Bruno , Lourtet Bruno , Hewison Mark A.J.
Published: October 2009

Locating and monitoring animals using tracking devices is a method commonly used for many taxa to study characteristics such as home‐range size, habitat selection, movement patterns and other aspects of ranging behaviour. Fitting such devices requires the capture and handling of the study organism and researchers must then assume that a monitored animal behaves in a ‘normal’ way. We investigated whether the capture and handling of roe deer Capreolus capreolus induced behavioural alterations. In particular, we expected that the roe deer would exhibit a ‘seeking a refuge and waiting before returning’ strategy immediately after release, taking shelter far from the capture scene, in closed habitat, and exhibiting a reduced activity level. We evaluated the effect of capture and handling on 112 roe deer equipped with GPS collars, during a period of 50 days after release. We compared the first 10 days after release with the subsequent days for the following behavioural parameters: distance to the barycentre of their GPS fixes, presence in forest habitat, distance to the nearest forest patch, distance to a source of human disturbance, and activity level. We found pronounced differences in terms of spatial behaviour, habitat use and overall activity level between the two periods in GPS monitored roe deer. We also found differences in terms of spatial displacement between the sexes, with females responding less than males, and among age classes, with yearlings responding most and fawns least, to the capture and handling event. Finally, spatial displacement of roe deer increased with openness of the habitat due, in part, to the scarcity of available shelter in open areas. We conclude that the roe deer exhibited a strategy consisting of seeking a refuge and waiting before returning after capture, handling and fitting of a collar, with displacement towards a refuge habitat, in or near woodland, avoidance of sources of human disturbance and reduced activity levels. From a practical point of view, we recommend removing data during the first days of monitoring as behavioural alterations due to capture and handling may be pronounced.
Resource Selection and Movements by Female Mule Deer Odocoileus hemionus: Effects of Reproductive Stage
Authors: Long Ryan A. , Kie John G. , Terry Bowyer R. , Hurley Mark A.
Published: October 2009

Recent declines of mule deer Odocoileus hemionus, ostensibly a result of low rates of recruitment, highlight the importance of understanding relationships between parturient females and their critical habitats. We estimated timing of parturition for 20 mule deer in northeastern Oregon, USA, using movement data from global positioning system (GPS) collars in 2005 and 2006. We then evaluated patterns of resource selection by female mule deer during late gestation, the week of parturition, and subsequent lactation to determine how different stages of reproduction influenced habitat selection. Movement rates of all but one deer declined sharply between late‐May and mid‐June, when female mule deer give birth in northeastern Oregon. Patterns of resource selection also varied substantially relative to the estimated time of parturition. Prior to parturition, female mule deer selected gentle south‐facing slopes dominated by ponderosa pine Pinus ponderosa and avoided permanent water sources. Parturient females also selected areas used concurrently by elk Cervus elaphus. Following parturition, however, females selected steep north‐facing slopes dominated by fir Abies spp., avoided elk and selected habitat located close to permanent water sources. Stage of reproduction clearly influenced choice of habitat by female mule deer. Mule deer management plans should consider potential seasonal variability in the relative importance of forage, risk of predation and competition.
Treatment of brain arteriovenous malformations with high-flow arteriovenous fistulas: risk and complications associated with endovascular embolization in multimodality treatment
Authors: Yuki Ichiro , Kim Robert H. , Duckwiler Gary , Jahan Reza , Tateshima Satoshi , Gonzalez Nestor , Gorgulho Alessandra , Diaz Jorge Lee , De Salles Antonio A. , Viñuela Fernando
Published: October 2009

Object

High-flow fistulas associated with brain arteriovenous malformations (AVMs) pose a significant challenge to both stereotactic radiosurgery (SRS) and surgical treatment. The purpose of this study was to examine the outcomes of multimodality treatment of AVMs in association with a large arteriovenous fistula (AVF), with a special focus on endovascular embolization and its associated complications.

Methods

One hundred ninety-two patients harboring cerebral AVMs underwent endovascular treatment in the authors' department between 1997 and 2003. Of these, the authors selected 74 patients presenting with an AVM associated with high-flow AVF(s) for a retrospective analysis based on the findings of superselective angiography. After endovascular embolization, 32 patients underwent resection, 33 underwent either SRS or hypofractionated stereotactic radiotherapy (HSRT), and 3 underwent both surgery and SRS. Six patients underwent embolization only. Immediate and midterm treatment outcomes were analyzed.

Results

Fifty-seven (77%) of the 74 patients had AVMs that were Spetzler-Martin Grade III or higher. A complete resection was achieved in all 32 patients. Of patients who underwent SRS/HSRT, 13 patients (39.3%) had either complete or > 90% obliteration of the AVM, and 2 patients (6.1%) had incomplete obliteration. Fourteen patients (42.4%) with residual AVM underwent repeated radiotherapy (and remain under observation). Of the 3 patients who underwent both SRS and resection, resection was complete in 2 and incomplete in one. No follow-up was obtained in 6 patients (8.1%). An endovascular complication was observed in 4 patients (5.4%). Fistula embolization was safely performed in every patient, whereas every endovascular complication was associated with other procedures such as nidus embolization.

Conclusions

Endovascular occlusion of the fistulous component was successfully achieved in every patient; every endovascular complication in this series was related to other procedures such as nidus embolization. The importance of the fistula treatment should be emphasized to minimize the endovascular complications and to maximize the treatment effect when a multimodality therapy is used to treat brain AVMs with large AVF.
Endoscopic treatment of distal choroidal artery aneurysm
Authors: Lévêque Marc , McLaughlin Nancy , Laroche Mathieu , Bojanowski Michel W.
Published: October 2009

Distal choroidal artery aneurysms stemming from the lateral wall of the ventricles are rare and are mostly associated with moyamoya disease. The treatment of these aneurysms is difficult because of their deep location. The authors report the case of a 50-year-old woman followed for moyamoya disease presenting with 2 intraventricular hemorrhages. Cerebral angiography showed an aneurysm located on the left distal choroidal artery. Magnetic resonance imaging also demonstrated that the lesion protruded from the lateral wall of the trigone of the left lateral ventricle. Using MR imaging–guided stereotactic localization, the aneurysm was accurately reached endoscopically and successfully resected from the parent artery. The patient was discharged neurologically intact. To the best of the authors' knowledge, this is the first report of a successfully endoscopically treated distal anterior choroidal artery aneurysm. Endoscopic surgery may be added to the armamentarium of procedures used to treat intraventricular aneurysms.
The small “surgical aneurysm” at the basilar apex
Authors: Hauck Erik Friedrich , White Jonathan Ari , Samson Duke
Published: October 2009

Object

Because the risks are reduced, larger basilar apex aneurysms are usually treated endovascularly instead of with surgery. However, small basilar apex aneurysms are more common and an unfavorable shape may prevent definitive endovascular treatment. The goal of this study was to reevaluate the outcome of traditional surgery for small unruptured basilar apex aneurysms as an alternative to the currently more accepted endovascular treatment.

Methods

The authors reviewed clinical data obtained in 21 patients who underwent surgery between 2000 and 2007 for unruptured basilar apex aneurysms < 7 mm.

Results

The median age of the 21 patients was 52 years (range 29–74 years). All patients experienced a good outcome. Two patients harbored a small residual aneurysm (> 95% occlusion). Eight patients (38%) suffered a temporary third nerve paresis, which resolved in all cases.

Conclusions

Surgical clip ligation remains an excellent treatment for small basilar apex aneurysms. The treatment is definitive and in experienced hands is associated with a low risk.
Schwannoma of the greater superficial petrosal nerve
Authors: Amirjamshidi Abbas , Hashemi Seyyed Mahmood Ramak , Abbassioun Kazem
Published: October 2009

The authors report the clinical features, imaging and surgical findings, and follow-up of 5 rare cases of schwannoma of the middle fossa with possible origin from the greater superficial petrosal nerve (GSPN). All patients presented to a single neurosurgical institution. The study design was a prospective follow-up of 5 cases of schwannomas of the middle fossa that most likely originated from the GSPN. The presenting features were burning pain in the eyes in 2 cases, epilepsy and behavioral changes in 2 cases, and headache in 1 case. Imaging studies showed a subtemporal mass on the anterosuperior aspect of the petrous bone in all cases. An enhancing tail on the MR images was highly suggestive of the origin of the tumor from the GSPN. All tumors were removed through a subtemporal extra- or intradural approach.

Partial to complete peripheral facial nerve palsy was encountered after surgery in 3 cases, which recovered completely. Dry eye was the long-term permanent deficit in all cases. Mid- to long-term follow-up of the cases has not revealed any tumor recurrence. The 5 cases of schwannoma of the middle fossa with possible origin from GSPN were managed successfully, and their clinical presentation, differential diagnosis, and management are discussed.
Heparanase expression of glioma in human and animal models
Authors: Hong Xin , Nelson Kevin K. , deCarvalho Ana C. , Kalkanis Steven N.
Published: October 2009

Object

Mammalian heparanase has been shown to function in tumor progression, invasion, and angiogenesis. However, heparanase expression in gliomas has not been well analyzed. To clarify its expression in gliomas, human glioma tissues and glioma animal models were investigated.

Methods

The expression of heparanase mRNA was determined in 33 resected human glioma tissues by semiquantitative real-time polymerase chain reaction. Heparanase expression was verified with a Western blot assay and immunohistochemistry (IHC) staining. Primary neurospheres from human glioblastoma multiforme (GBM) were developed in vitro. Heparanase expression in murine astrocytoma and human primary neurosphere animal models was examined using IHC.

Results

The authors found that heparanase mRNA is greatly increased in gliomas including oligodendroglioma (9 samples), anaplastic astrocytoma (11 samples), and GBM (13 samples) as compared with healthy brain mRNA (3 samples). Note, however, that no significant difference was observed among the 3 tumor groups. Increased heparanase expression was also found in tumor tissues on Western blotting. Immunohistochemistry staining demonstrated that heparanase was expressed by neovessel endothelial cells, infiltrated neutrophils, and in some cases, by neoplastic cells. Heparanase-expressing cells, including GBM tumor cells and neovessel endothelial cells, exhibited decreased expression of CD44, a cell adhesion molecule on the cell membrane that is important for regulating tumor invasion. In addition, heparanase-expressing tumor cells showed an elevated density of the cell proliferation marker Ki 67, as compared with its density in non–heparanase-expressing tumor cells, suggesting that heparanase expression is correlated with enhanced tumor proliferation. Two animal glioma models were tested for heparanase expression. Both murine astrocytoma cells (Ast11.9-2) and cultured primary human GBM neurospheres expressed heparanase when grown in animal brain tissue.

Conclusions

Glioma tissues contain increased levels of heparanase. Multiple cell types contribute to the expression of heparanase, including neovessel endothelial cells, tumor cells, and infiltrated neutrophils. Heparanase plays an important role in the control of cell proliferation and invasion. Animal models using Ast11.9-2 and primary neurospheres are suitable for antitumor studies targeting heparanase.
The Localized Scleroderma Skin Severity Index and Physician Global Assessment of Disease Activity: A Work in Progress Toward Development of Localized Scleroderma Outcome Measures
Authors: ARKACHAISRI THASCHAWEE , VILAIYUK SOAMARAT , LI SUZANNE , O’NEIL KATHLEEN M. , POPE ELENA , HIGGINS GLORIA C. , PUNARO MARILYNN , RABINOVICH EGLA C. , ROSENKRANZ MARGALIT , KIETZ DANIEL A. , ROSEN PAUL , SPALDING STEVEN J. , HENNON TERESA R. , TOROK KATHRYN S. , CASSIDY ELAINE , MEDSGER THOMAS A.
Published: October 2009

Objective.

To develop and evaluate a Localized Scleroderma (LS) Skin Severity Index (LoSSI) and global assessments’ clinimetric property and effect on quality of life (QOL).

Methods.

A 3-phase study was conducted. The first phase involved 15 patients with LS and 14 examiners who assessed LoSSI [surface area (SA), erythema (ER), skin thickness (ST), and new lesion/extension (N/E)] twice for inter/intrarater reliability. Patient global assessment of disease severity (PtGA-S) and Children’s Dermatology Life Quality Index (CDLQI) were collected for intrarater reliability evaluation. The second phase was aimed to develop clinical determinants for physician global assessment of disease activity (PhysGA-A) and to assess its content validity. The third phase involved 2 examiners assessing LoSSI and PhysGA-A on 27 patients. Effect of training on improving reliability/validity and sensitivity to change of the LoSSI and PhysGA-A was determined.

Results.

Interrater reliability was excellent for ER [intraclass correlation coefficient (ICC) 0.71], ST (ICC 0.70), LoSSI (ICC 0.80), and PhysGA-A (ICC 0.90) but poor for SA (ICC 0.35); thus, LoSSI was modified to mLoSSI. Examiners’ experience did not affect the scores, but training/practice improved reliability. Intrarater reliability was excellent for ER, ST, and LoSSI (Spearman’s rho = 0.71–0.89) and moderate for SA. PtGA-S and CDLQI showed good intrarater agreement (ICC 0.63 and 0.80). mLoSSI correlated moderately with PhysGA-A and PtGA-S. Both mLoSSI and PhysGA-A were sensitive to change following therapy.

Conclusion.

mLoSSI and PhysGA-A are reliable and valid tools for assessing LS disease severity and show high sensitivity to detect change over time. These tools are feasible for use in routine clinical practice. They should be considered for inclusion in a core set of LS outcome measures for clinical trials.
Prevalence of Flare and Influence of Demographic and Serologic Factors on Flare Risk in Systemic Lupus Erythematosus: A Prospective Study
Authors: PETRI MICHELLE , SINGH SUKHMINDER , TESFASYONE HANNA , MALIK ASHIMA
Published: October 2009

Objective.

We determined the prevalence of and risk factors for British Isles Lupus Activity Group (BILAG) flare in patients with systemic lupus erythematosus (SLE).

Methods.

We followed 299 patients for 1 year with the BILAG scores calculated using British Lupus Integrated Prospective System software and confirmed with manual calculation.

Results.

“A” flares occurred at a rate of 0.254/year, “B” flares 1.637/year, and A or B flares 1.765/year. The most common A flares were renal and mucocutaneous. The most common B flares were hematologic, renal, mucocutaneous, and musculoskeletal. Risk factors for a later A or B flare in the hematological system included: low C3 (p < 0.0001), low C4 (p = 0.0004), and positive anti-double-stranded (ds)DNA (p = 0.003); in the mucocutaneous system: low C3 (p = 0.02) and low C4 (p = 0.0004); and in the renal system: low C3 (p = 0.02) and low C4 (p = 0.02). In a stepwise regression model, only ethnicity (p = 0.02) and low C4 (p = 0.0002) remained as independent predictors of later A or 2B flares.

Conclusion.

The organ system distribution of A and B flares is very different, with A flares more common in renal and mucocutaneous, and B flares more common in hematologic and renal systems. A or 2B flares are significantly more common in African Americans and in patients with abnormal serologies (low C3, low C4, or high anti-dsDNA). If flare is an outcome in an SLE clinical trial, these factors must be balanced by taking them into account at baseline in terms of randomization, or by statistical adjustment in final analyses.
Circulating Surfactant Protein D Is Decreased in Systemic Lupus Erythematosus
Authors: HOEGH SILJE VERMEDAL , VOSS ANNE , SORENSEN GRITH LYKKE , HØJ ANETTE , BENDIXEN CHRISTIAN , JUNKER PETER , HOLMSKOV UFFE
Published: October 2009

Objective.

Deficiencies of innate immune molecules like mannan binding lectin (MBL) have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Surfactant protein D (SP-D) and MBL belong to the same family of innate immune molecules — the collectins, which share important structural and functional properties. We aimed to compare concentrations of serum SP-D in patients with SLE and in healthy controls, and to investigate if SP-D is associated with selected disease indicators. We investigated the possible association of the Met11Thr polymorphism with disease, since this polymorphism is an important determinant for serum level, oligomerization pattern, and function of SP-D.

Methods.

Serum SP-D was measured using a 5-layer ELISA in 70 SLE patients and 1476 healthy subjects. DNA was genotyped for the Met11Thr variant.

Results.

Median SP-D level in serum was 911 ng/ml (95% CI 776–1118) in patients and 1068 ng/ml (95% CI 901–1246) in controls (p = 0.0004). Circulating SP-D did not differ significantly in patients with high, intermediate, or low SLE disease activity. Similarly, SP-D did not correlate with C-reactive protein, erythrocyte sedimentation rate, and anti-dsDNA seropositivity. Genetic analysis did not support an association of the Met11Thr genotype with SLE.

Conclusion.

These findings suggest that low SP-D, unrelated to conventional disease indicators, represents an aspect of SLE etiopathogenesis.
Perturbed Insulin-like Growth Factor-1 (IGF-1) and IGF Binding Protein-3 Are Not Associated with Chronic Widespread Pain in Men: Results from the European Male Ageing Study
Authors: McBETH JOHN , TAJAR ABDELOUAHID , O’NEILL TERENCE W. , MACFARLANE GARY J. , PYE STEPHEN R. , BARTFAI GYORGY , BOONEN STEVEN , BOUILLON ROGER , CASANUEVA FELIPE , FINN JOSEPH D. , FORTI GIANNI , GIWERCMAN ALEKSANDER , HAN THANG S. , HUHTANIEMI ILPO T. , KULA KRZYSZTOF , LEAN MICHAEL E.J. , PENDLETON NEIL , PUNAB MARGUS , SILMAN ALAN J. , VANDERSCHUEREN DIRK , WU FREDERICK C.W. ,   and the EMAS Group
Published: October 2009

Objective.

To determine whether perturbations of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) were associated with the presence of chronic widespread pain (CWP) in men.

Methods.

The European Male Ageing Study (EMAS) is an 8-center population-based study of men aged 40–79 years recruited from population registers. A questionnaire asked about the presence and duration of musculoskeletal pain, from which subjects reporting CWP were identified. Subjects also had an interviewer-assisted questionnaire: levels of physical activity and mood were assessed, and height and weight were measured. IGF-1 and IGFBP-3 were assayed from a fasting blood sample. Logistic regression models were used to determine the association between IGF measures and CWP. Results were expressed as odds ratios or relative risk ratios.

Results.

A total of 3206 subjects provided full data. Of those, 1314 (39.0%) reported no pain in the past month and 278 (8.3%) reported pain that satisfied criteria for CWP. IGF-1 concentrations were similar among subjects who reported no pain and those with CWP: 131.5 mg/l and 128.4 mg/l, respectively. This was true also for IGFBP-3 (4.3 and 4.3 mg/l). Obesity was associated with low IGF-1 and a high IGFBP-3/IGF-1 ratio, indicating less bioavailable IGF-1, irrespective of pain status. This relationship persisted after adjustment for comorbidities, depression, smoking, alcohol consumption, and quality of life.

Conclusion.

Overall CWP was not associated with perturbations in IGF-1 and IGFBP-3 concentrations. Hypofunctioning of the axis was noted among subjects who were obese and this was not specific to CWP. These data suggest that IGF-1 is unlikely to be etiologically important in relation to CWP, although the relationship with growth hormone remains to be elucidated.
Which Aspects of Functioning Are Relevant for Patients with Ankylosing Spondylitis: Results of Focus Group Interviews
Authors: BOONEN ANNELIES , van BERKEL MONIQUE , CIEZA ALARCOS , STUCKI GEROLD , van der HEIJDE DÉSIRÉE
Published: October 2009

Objective.

To investigate whether concepts important to patients with ankylosing spondylitis (AS) are covered by disease-specific self-report health status instruments.

Methods.

A qualitative focus group study was conducted with AS patients on problems in daily functioning. Group sessions with 4 to 5 patients each were organized up to the point that no new information was brought forward. Group sessions were tape-recorded, transcribed, and divided into meaning units. Concepts contained in the meaning units were extracted. Self-report instruments on health status specific for AS were identified in a literature search. Using the International Classification of Functioning, Disability and Health (ICF) as a common reference, it was determined whether the concepts identified in the focus groups were covered by the instruments.

Results.

Nineteen patients participated in 4 focus group interviews. In total, 332 unique meaning units were linked to 90 second-level ICF categories, of which 25 referred to body functions, 10 to body structures, 35 to activities and participation and 30 to environmental factors. In addition, several concepts relating to personal factors were identified. Only 47 categories were also covered by one of the self-report instruments in AS. Only a minority of concepts addressed by the AS-specific questionnaires were not revealed as relevant in the interviews.

Conclusion.

Relevant aspects of the influence of AS are not covered by the classic disease-specific instruments. In particular, the influence of AS on socializing and leisure and the relevance of environmental and personal factors are not adequately assessed by available instruments.
Clinical and Serologic Characterization of an Argentine Pediatric Myositis Cohort: Identification of a Novel Autoantibody (anti-MJ) to a 142-kDa Protein
Authors: ESPADA GRACIELA , MALDONADO COCCO JOSE A. , FERTIG NOREEN , ODDIS CHESTER V.
Published: October 2009

Objective.

Autoantibodies are frequently found in adult patients with polymyositis (PM), dermato-myositis (DM), and overlap myositis disorders. They are less common in pediatric patients with myositis. We investigated the autoantibody pattern in a pediatric Argentine Caucasian cohort to characterize novel autoantibodies.

Methods.

Sera from children that satisfied published criteria for idiopathic inflammatory myopathy were analyzed for autoantibodies by RNA and protein immunoprecipitation and immunoblotting techniques. Routine myositis-specific and myositis-associated autoantibodies as well as autoantibody specificities were determined.

Results.

We tested sera from 64 consecutive pediatric myositis patients, including 40 with juvenile DM, 7 with juvenile PM, and 17 with overlap myositis syndromes. Sixteen (25%) patients were found to have anti-MJ autoantibody exclusively, which appears to identify a subset of pediatric myositis patients with severe disease characterized by muscle contractures and atrophy and significant compromise of functional status. Fourteen (22%) patients were found to have an antibody targeting 2 proteins of 155 and 140 kDa. Other myositis-specific autoantibodies were uncommon in this pediatric cohort.

Conclusion.

A newly recognized autoantibody, anti-MJ, was the most common antibody found in this Argentine pediatric cohort. The clinical features indicated that this antibody is distinct from other reported antibodies in pediatric patients with myositis.
Vertical Fragment in Adult Midshaft Clavicle Fractures: An Indicator for Surgical Intervention
Authors: Kirmani Sayyied J. , Pillai Suresh K.G. , Madegowda Babu R. , Shahane Shantanu A.
Published: October 2009

This article describes a retrospective cohort study that investigated whether adult mid-shaft clavicle fractures possessing the radiological sign of a butterfly vertical fragment demonstrate a higher rate of early and delayed surgical intervention when compared to adult midshaft clavicle fractures with no vertical fragment sign. The radiographs of 134 adult midshaft clavicle fractures were divided into 2 cohorts: those with a vertical fragment radiological sign and those without. Within each cohort, the number of cases that underwent early surgical intervention and that underwent delayed surgical intervention was noted.

The vertical fragment group displayed a rate for early surgical intervention, all for skin tenting, of 8.5%, whereas the no vertical fragment group's rate was 1.1%; this proved to be significantly different (
P
=.0464). Furthermore, the vertical fragment group displayed a rate for delayed surgical intervention for symptomatic nonunion of 12.8%, whereas the no vertical fragment group's rate was 5.7%. Despite being twice as likely for the vertical fragment group to have undergone delayed surgical intervention, this did not prove to be statistically significant (
P
=.0965).

This study revealed that midshaft fractures with the radiological sign of an interfragmentary vertical fragment are significantly more likely to require early surgical intervention due to skin tenting. Furthermore, these fractures are twice as likely to go into symptomatic nonunion, and in this area we may be able to improve current management by considering early surgical intervention.