bluuebunny/crossref_metadata_2025 huggingface dataset:
Occupational lung cancer in US women, 1984–1998
Authors: Robinson Cynthia F. , Sullivan Patricia A. , Li Jia , Walker James T.
Published: October 2010

Background

Lung cancer is the leading cause of cancer death in US women, accounting for 72,130 deaths in 2006. In addition to smoking cessation, further reduction of the burden of lung cancer mortality can be made by preventing exposure to occupational lung carcinogens. Data for occupational exposures and health outcomes of US working women are limited.

Methods

Population‐based mortality data for 4,570,711 women who died between 1984 and 1998 in 27 US States were used to evaluate lung cancer proportionate mortality over time by the usual occupation and industry reported on death certificates. Lung cancer proportionate mortality ratios were adjusted for smoking, using data from the National Health Interview Survey (NHIS) and the American Cancer Society's Cancer Prevention Study II.

Results

Analyses revealed that 194,382 white, 18,225 Black and 1,515 Hispanic women died 1984–1998 with lung cancer reported as the underlying cause of death. Following adjustment for smoking, significant excess proportionate lung cancer mortality was observed among US women working in the US manufacturing; transportation; retail trade; agriculture, forestry, and fishing; and nursing/personal care industries. Women employed in precision production, technical, managerial, professional specialty, and administrative occupations experienced some of the highest significantly excess proportionate lung cancer mortality during 1984–1998.

Conclusions

The results of our study point to significantly elevated risks for lung cancer after adjustment for smoking among women in several occupations and industries. Because 6–17% of lung cancer in US males is attributable to known exposures to occupational carcinogens, and since synergistic interactions between cigarette smoke and other occupational lung carcinogens have been noted, it is important to continue research into the effects of occupational exposures on working men and women. Am. J. Ind. Med. 54:102–117, 2011. © 2010 Wiley‐Liss, Inc.
Physical examination has a low yield in screening for carpal tunnel syndrome
Authors: Dale Ann Marie , Descatha Alexis , Coomes Justin , Franzblau Alfred , Evanoff Bradley
Published: October 2010

Background

Physical examination is often used to screen workers for carpal tunnel syndrome (CTS). In a population of newly hired workers, we evaluated the yield of such screening.

Methods

Our study population included 1,108 newly hired workers in diverse industries. Baseline data included a symptom questionnaire, physical exam, and bilateral nerve conduction testing of the median and ulnar nerves; individual results were not shared with the employer. We tested three outcomes: symptoms of CTS, abnormal median nerve conduction, and a case definition of CTS that required both symptoms and median neuropathy.

Results

Of the exam measures used, only Semmes–Weinstein sensory testing had a sensitivity value above 31%. Positive predictive values were low, and likelihood ratios were all under 5.0 for positive testing and over 0.2 for negative testing.

Conclusion

Physical examination maneuvers have a low yield for the diagnosis of CTS in workplace surveillance programs and in post‐offer, pre‐placement screening programs. Am. J. Ind. Med. 54:1–9, 2011. © 2010 Wiley‐Liss, Inc.
A longitudinal assessment of occupation, respiratory symptoms, and blood lead levels among latino day laborers in a non‐agricultural setting
Authors: Rabito Felicia A. , Perry Sara , Salinas Oscar , Hembling John , Schmidt Norine , Parsons Patrick J. , Kissinger Patricia
Published: October 2010

Background

The reliance on Latino migrant day labor in the U.S. is increasing. Prospective data on day laborers' work and health experience in non‐agriculture settings are lacking and outcomes are generally restricted to injury rates.

Methods

An ambidirectional study was conducted to quantify the number of job and job task changes held over 12 months in a cohort of 73 migrant day laborers and assessed the relation between work type, health symptoms, and blood lead level.

Results

On average, participants worked 2.4 different jobs over the past year averaging 41.5 hr per week. Construction work was associated with a twofold increase in sino‐nasal and respiratory symptoms in both adjusted and unadjusted models and was associated with increased blood lead levels.

Conclusions

Despite day labor status, workers had relatively stable employment. Respiratory symptoms were common and often improved when away from work suggesting that workplace irritant exposure is likely. Migrant day laborers working construction are vulnerable to adverse health effects associated with irritant and lead exposure. Am. J. Ind. Med. 54:366–374, 2011. © 2010 Wiley‐Liss, Inc.
Use of guidelines improves the neurological outcome in glutaric aciduria type I
Authors: Heringer Jana , Boy S. P. Nikolas , Ensenauer Regina , Assmann Birgit , Zschocke Johannes , Harting Inga , Lücke Thomas , Maier Esther M. , Mühlhausen Chris , Haege Gisela , Hoffmann Georg F. , Burgard Peter , Kölker Stefan
Published: October 2010

Objective:

To evaluate the effect of treatment according to current evidence‐based recommendations on the neurological outcome of patients with glutaric aciduria type I (GA‐I).

Methods:

Fifty‐two patients identified by newborn screening (NBS) in Germany from 1999 to 2009 were followed prospectively. Neurological outcome was assessed by the occurrence of an acute encephalopathic crisis and the severity of a movement disorder (MD) with predominant dystonia superimposing on axial hypotonia. Outcome was evaluated in relation to therapy and therapy‐independent parameters.

Results:

Outcome was best in GA‐I patients who were treated in full accordance with treatment recommendations (n=37; 5% MD). Deviations from recommended basic metabolic treatment (low‐lysine diet, carnitine) resulted in an intermediate outcome (n=9; 44% MD), whereas disregard of emergency treatment recommendations was associated with a poor outcome (n=6; 100% MD). Treatment regimens deviating from recommendations significantly increased the risk for MD (odds ratio [OR], 35; 95% confidence interval [CI], 5.88–208.39) and acute encephalopathic crises (OR, 51.32; 95% CI, 2.65–993.49). Supervision by a metabolic center improved the outcome (18% vs 57% MD; OR, 6.17; 95% CI, 1.15–33.11), whereas migrational background and biochemical phenotype (high versus low excretor status) had no significant effect.

Interpretation:

Follow‐up of neonatally diagnosed patients with GA‐I in Germany clearly demonstrates that the inclusion of this rare disease in the NBS disease panel has significantly improved the neurological outcome of affected individuals. The establishment of and adherence to evidence‐based treatment recommendations, and supervision by experienced metabolic centers helps to minimize the number of patients who do not benefit from NBS. Ann Neurol 2010;68:743–752
Natural history of incidental world health organization grade II gliomas
Authors: Pallud Johan , Fontaine Denys , Duffau Hugues , Mandonnet Emmanuel , Sanai Nader , Taillandier Luc , Peruzzi Philippe , Guillevin Rémy , Bauchet Luc , Bernier Valérie , Baron Marie‐Hélène , Guyotat Jacques , Capelle Laurent
Published: October 2010

Objective:

Seizure is the presenting symptom in most of World Health Organization grade II gliomas (GIIGs). Rarely, a GIIG is discovered incidentally on imaging. Little is known about the natural course and prognosis of incidental GIIGs. The aim of the present study is to characterize their natural history and to investigate whether their clinical and radiological behaviors differ from those of symptomatic GIIGs.

Methods:

The clinical and radiological findings, treatments, and outcomes of 47 histologically‐proven incidental GIIGs were compared with those of 1249 symptomatic GIIGs.

Results:

Incidental GIIGs differ significantly from symptomatic GIIGs: they have a female predominance (p = 0.05), smaller initial tumor volumes (p < 0.001), lower incidence of contrast enhancement (p = 0.009), and are more likely to undergo gross total surgical removal (p < 0.001). Proliferation rates were similar to that observed among symptomatic GIIGs. Younger age at the time of discovery, frontal lobes, and noneloquent brain regions were associated with incidental GIIGs, as compared to their symptomatic counterparts. When not treated, incidental GIIGs demonstrated radiological growth (median velocity of diametric expansion at 3.5 mm/year), and became symptomatic at a median interval of 48 months after radiological discovery. Overall, incidental discovery was associated with a significant survival benefit (p = 0.04).

Interpretation:

Incidental GIIGs are progressive tumors leading to clinical transformation toward symptomatic GIIGs. They may represent an earlier step in the natural history of a glioma than the symptomatic GIIGs. ANN NEUROL 2010;68:727–733
Intractable vomiting as the initial presentation of neuromyelitis optica
Authors: Apiwattanakul Metha , Popescu Bogdan F. , Matiello Marcelo , Weinshenker Brian G. , Lucchinetti Claudia F. , Lennon Vanda A. , McKeon Andrew , Carpenter Adam F. , Miller Gary M. , Pittock Sean J.
Published: October 2010

We report 12 aquaporin‐4 antibody‐positive patients (12% of seropositive Mayo Clinic patients identified since 2005) whose initial presenting symptom of neuromyelitis optica was intractable vomiting. The initial evaluation in 75% was gastroenterologic. Vomiting lasted a median of 4 weeks (range, 2 days–80 weeks). Optic neuritis or transverse myelitis developed after vomiting onset in 11 patients (median interval, 11 weeks; range, 1–156). At last evaluation (median, 48 months after vomiting onset), 7 patients fulfilled neuromyelitis optica diagnostic criteria. Our clinical, pathologic and neuroimaging observations suggest the aquaporin‐4–rich area postrema may be a first point of attack in neuromyelitis optica. Ann Neurol 2010;68:757–761
Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab
Authors: Gunnarsson Martin , Malmeström Clas , Axelsson Markus , Sundström Peter , Dahle Charlotte , Vrethem Magnus , Olsson Tomas , Piehl Fredrik , Norgren Niklas , Rosengren Lars , Svenningsson Anders , Lycke Jan
Published: October 2010

Objective:

The impact of present disease‐modifying treatments (DMTs) in multiple sclerosis (MS) on nerve injury and reactive astrogliosis is still unclear. Therefore, we studied the effect of natalizumab treatment on the release of 2 brain‐specific tissue damage markers into cerebrospinal fluid (CSF) in MS patients.

Methods:

CSF samples from 92 patients with relapsing forms of MS were collected in a prospective manner prior to natalizumab treatment and after 6 or 12 months. In 86 cases, natalizumab was used as second‐line DMT due to breakthrough of disease activity. The levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were determined using highly sensitive in‐house developed enzyme‐linked immunosorbent assays.

Results:

Natalizumab treatment led to a 3‐fold reduction of NFL levels, from a mean value of 1,300 (standard deviation [SD], 2,200) to 400 (SD, 270) ng/l (p < 0.001). The later value was not significantly different from that found in healthy control subjects (350ng/l; SD, 170; n = 28). Subgroup analysis revealed a consistent effect on NFL release, regardless of previous DMT or whether patients had relapses or were in remission within 3 months prior to natalizumab treatment. No differences between pre‐ and post‐treatment levels of GFAP were detected.

Interpretation:

Our data demonstrate that natalizumab treatment reduces the accumulation of nerve injury in relapsing forms of MS. It is anticipated that highly effective anti‐inflammatory treatment can reduce axonal loss, thereby preventing development of permanent neurological disability. Ann Neurol 2010
Alternative splicing dysregulation secondary to skeletal muscle regeneration
Authors: Orengo James P. , Ward Amanda J. , Cooper Thomas A.
Published: October 2010

Objective

Dysregulation of alternative splicing has become a molecular hallmark of myotonic dystrophy type 1 (DM1), in which neonatal splice variants are expressed in adult skeletal muscle. Splicing dysregulation is induced by RNA containing expanded CUG repeats expressed from the expanded mutant allele by sequestration of muscleblindlike 1 (MBNL1) protein within nuclear RNA foci and increased CUGBP, ELAV‐like family member 1 (CELF1) protein levels. Dysregulated splicing has also been identified in other neuromuscular disorders, suggesting either that diseases with different molecular causes share a common pathogenic mechanism or that dysregulated splicing can also be a common secondary consequence of muscle degeneration and regeneration.

Methods

In this study, we examined regulation of alternative splicing in 4 different mouse models of muscular dystrophy, including DM1, limb‐girdle muscular dystrophy, congenital merosin‐deficient muscular dystrophy, and Duchenne muscular dystrophy, and 2 myotoxin (cardiotoxin and notexin) muscle injury models.

Results

We show that DM1‐like alternative splicing dysregulation and altered expression of MBNL1 and CELF1 occur in non‐DM1 mouse models of muscular dystrophy and muscle injury, most likely due to recapitulation of neonatal splicing patterns in regenerating fibers. In contrast, CELF1 was elevated in nuclei of mature myofibers of the DM1 model, consistent with a primary effect of pathogenic RNA expression.

Interpretation

Splicing dysregulation in DM1 is a primary effect of RNA containing expanded CUG repeats. However, we conclude that splicing changes can also be observed secondary to muscle regeneration, and this possibility must be taken into account when evaluating cause‐effect relationships between dysregulated splicing and disease processes. Ann Neurol 2010;
Age‐specific progression of nigrostriatal dysfunction in Parkinson's disease
Authors: de la Fuente‐Fernández Raúl , Schulzer Michael , Kuramoto Lisa , Cragg Jacquelyn , Ramachandiran Nandhagopal , Au Wing L. , Mak Edwin , McKenzie Jess , McCormick Siobhan , Sossi Vesna , Ruth Thomas J. , Lee Chong S. , Calne Donald B. , Stoessl A. Jon
Published: October 2010

Objective:

To investigate in vivo the impact of age on nigrostriatal dopamine dysfunction in Parkinson's disease (PD).

Methods:

PD patients (n = 78) and healthy control subjects (n = 35) underwent longitudinal positron emission tomography assessments using 3 presynaptic dopamine markers: (1) [11C](±)dihydrotetrabenazine (DTBZ), to estimate the density of the vesicular monoamine transporter type 2; (2) [11C]d‐threo‐methylphenidate, to estimate the density of the plasma membrane dopamine transporter; and (3) 6‐[18F]‐fluoro‐L‐dopa, to estimate the activity of the enzyme dopa‐decarboxylase.

Results:

The study comprised 438 PD scans and 241 control scans (679 scans in total). At symptom onset, the loss of putamen DTBZ binding was substantially greater in younger compared to older PD patients (p = 0.015). Remarkably, however, the rate of progression of DTBZ binding loss was significantly slower in younger patients (p < 0.05). The estimated presymptomatic phase of the disease spanned more than 2 decades in younger patients, compared to 1 decade in older patients.

Interpretation:

Our results suggest that, compared to older patients, younger PD patients progress more slowly and are able to endure more damage to the dopaminergic system before the first motor symptoms appear. These observations suggest that younger PD patients have more efficient compensatory mechanisms. Ann Neurol 2011;
Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis
Authors: Irani Sarosh R. , Michell Andrew W. , Lang Bethan , Pettingill Philippa , Waters Patrick , Johnson Michael R. , Schott Jonathan M. , Armstrong Richard J. E. , S. Zagami Alessandro , Bleasel Andrew , Somerville Ernest R. , Smith Shelagh M. J. , Vincent Angela
Published: October 2010

Objective:

To describe a distinctive seizure semiology that closely associates with voltage‐gated potassium channel (VGKC)‐complex/Lgi1 antibodies and commonly precedes the onset of limbic encephalitis (LE).

Methods:

Twenty‐nine patients were identified by the authors (n = 15) or referring clinicians (n = 14). The temporal progression of clinical features and serum sodium, brain magnetic resonance imaging (MRI), positron emission tomography/single photon emission computed tomography, and VGKC‐complex antibodies was studied.

Results:

Videos and still images showed a distinctive adult‐onset, frequent, brief dystonic seizure semiology that predominantly affected the arm and ipsilateral face. We have termed these faciobrachial dystonic seizures (FBDS). All patients tested during their illness had antibodies to VGKC complexes; the specific antigenic target was Lgi1 in 89%. Whereas 3 patients never developed LE, 20 of the remaining 26 (77%) experienced FBDS prior to the development of the amnesia and confusion that characterize LE. During the prodrome of FBDS alone, patients had normal sodium and brain MRIs, but electroencephalography demonstrated ictal epileptiform activity in 7 patients (24%). Following development of LE, the patients often developed other seizure semiologies, including typical mesial temporal lobe seizures. At this stage, investigations commonly showed hyponatremia and MRI hippocampal high T2 signal; functional brain imaging showed evidence of basal ganglia involvement in 5/8. Antiepileptic drugs (AEDs) were generally ineffective and in 41% were associated with cutaneous reactions that were often severe. By contrast, immunotherapies produced a clear, and often dramatic, reduction in FBDS frequency.

Interpretation:

Recognition of FBDS should prompt testing for VGKC‐complex/Lgi1 antibodies. AEDs often produce adverse effects; treatment with immunotherapies may prevent the development of LE with its potential for cerebral atrophy and cognitive impairment. ANN NEUROL 2010;
SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer's disease risk
Authors: Reitz Christiane , Tokuhiro Shinya , Clark Lorraine N. , Conrad Christopher , Vonsattel Jean‐Paul , Hazrati Lili‐Naz , Palotás András , Lantigua Raphael , Medrano Martin , Z. Jiménez ‐Velázquez Ivonne , Vardarajan Badri , Simkin Irene , Haines Jonathan L. , Pericak ‐Vance Margaret A. , Farrer Lindsay A. , Lee Joseph H. , Rogaeva Ekaterina , George‐ Hyslop Peter St. , Mayeux Richard
Published: October 2010

Objective:

Sorting mechanisms that cause the amyloid precursor protein (APP) and the β‐secretases and γ‐secretases to colocalize in the same compartment play an important role in the regulation of Aβ production in Alzheimer's disease (AD). We and others have reported that genetic variants in the Sortilin‐related receptor (SORL1) increased the risk of AD, that SORL1 is involved in trafficking of APP, and that underexpression of SORL1 leads to overproduction of Aβ. Here we explored the role of one of its homologs, the sortilin‐related VPS10 domain containing receptor 1 (SORCS1), in AD.

Methods:

We analyzed the genetic associations between AD and 16 SORCS1–single nucleotide polymorphisms (SNPs) in 6 independent data sets (2,809 cases and 3,482 controls). In addition, we compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in microarray gene expression and real‐time polymerase chain reaction (RT‐PCR) sets, explored the effects of significant SORCS1‐SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and Aβ generation.

Results:

Inherited variants in SORCS1 were associated with AD in all datasets (0.001 < p
< 0.049). In addition, SorCS1 influenced APP processing. While overexpression of SorCS1 reduced γ‐secretase activity and Aβ levels, the suppression of SorCS1 increased γ‐secretase processing of APP and the levels of Aβ.

Interpretations:

These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD. Ann Neurol 2011;69:47–64.
Cerebrospinal fluid biomarkers for Parkinson disease diagnosis and progression
Authors: Shi Min , Bradner Joshua , Hancock Aneeka M. , Chung Kathryn A. , Quinn Joseph F. , Peskind Elaine R. , Galasko Douglas , Jankovic Joseph , Zabetian Cyrus P. , Kim Hojoong M. , Leverenz James B. , Montine Thomas J. , Ginghina Carmen , Kang Un Jung , Cain Kevin C. , Wang Yu , Aasly Jan , Goldstein David , Zhang Jing
Published: October 2010

Objective:

There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis, differential diagnosis of Parkinsonian disorders, and monitoring disease progression. We and others have demonstrated that a decrease in DJ‐1 and/or α‐synuclein in the cerebrospinal fluid (CSF) is a potential index for Parkinson disease diagnosis, but not for PD severity.

Methods:

Using highly sensitive and quantitative Luminex assays, we measured total tau, phosphorylated tau, amyloid beta peptide 1–42 (Aβ1–42), Flt3 ligand, and fractalkine levels in CSF in a large cohort of PD patients at different stages as well as healthy and diseased controls. The utility of these 5 markers was evaluated for disease diagnosis and severity/progression correlation alone, as well as in combination with DJ‐1 and α‐synuclein. The major results were further validated in an independent cohort of cross‐sectional PD patients as well as in PD cases with CSF samples collected longitudinally.

Results:

The results demonstrated that combinations of these biomarkers could differentiate PD patients not only from normal controls but also from patients with Alzheimer disease (AD) and multiple system atrophy. Particularly, with CSF Flt3 ligand, PD could be clearly differentiated from multiple system atrophy, a disease that overlaps with PD clinically, with excellent sensitivity (99%) and specificity (95%). In addition, we identified CSF fractalkine/Aβ1–42 that positively correlated with PD severity in cross‐sectional samples as well as with PD progression in longitudinal samples.

Interpretation:

We have demonstrated that this panel of 7 CSF proteins could aid in Parkinson disease diagnosis, differential diagnosis, and correlation with disease severity and progression. ANN NEUROL 2010
Autoantibodies to low‐density lipoprotein receptor–related protein 4 in myasthenia gravis
Authors: Higuchi Osamu , Hamuro Johko , Motomura Masakatsu , Yamanashi Yuji
Published: October 2010

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction, where acetylcholine receptor (AChR), muscle‐specific kinase (MuSK), and low‐density lipoprotein (LDL) receptor‐related protein 4 (Lrp4) are essential. About 80% and 0% to 10% of patients with generalized MG have autoantibodies to AChR and MuSK, respectively, but pathogenic factors are elusive in others. Here we show that a proportion of AChR antibody‐negative patients have autoantibodies to Lrp4. These antibodies inhibit binding of Lrp4 to its ligand and predominantly belong to the immunoglobulin G1 (IgG1) subclass, a complement activator. These findings together indicate the involvement of Lrp4 antibodies in the pathogenesis of AChR antibody‐negative MG. Ann Neurol 2011
Increased brain atrophy rates in cognitively normal older adults with low cerebrospinal fluid Aβ1‐42
Authors: Schott Jonathan M. , Bartlett Jonathan W. , Fox Nick C. , Barnes Josephine ,   for the Alzheimer's Disease Neuroimaging Initiative Investigators
Published: October 2010

Objective

To identify cognitively normal individuals at risk of Alzheimer disease (AD) based on cerebrospinal fluid (CSF) Aβ1‐42, and to determine rates of cerebral atrophy.

Methods

Control subjects from the Alzheimer's Disease Neuroimaging Initiative with CSF and serial magnetic resonance imaging (MRI) were dichotomized on CSF Aβ1‐42 (normal control [NC]‐high >192pg/ml; NC‐low ≤192pg/ml). Baseline and 1‐year MRIs were registered, and brain, hippocampal, and ventricular volumes and annualized volume changes were calculated. Baseline characteristics, CSF profiles, neuropsychology, brain volumes and atrophy rates, and APOE, PICALM, CLU, and TOMM40 genotypes were compared. Sample sizes to power presymptomatic clinical trials based on rate of atrophy were calculated.

Results

Forty of 105 (38%) were classified as NC‐low, and 65 (62%) as NC‐high. There were no differences in age (76.3 ± 5.1 vs 74.9 ± 5.1 years), gender, brain volumes, and all but 1 cognitive score (Trails B; p = 0.015). The NC‐low group had higher tau (p = 0.005) and p‐tau (p < 0.001), and was more likely to be APOE4 positive (48% vs 11%, p < 0.001). The NC‐low group had significantly higher whole brain loss (9.3 vs 4.4ml/yr, p < 0.001), ventricular expansion (2.04 vs 0.95ml/yr, p = 0.002), and hippocampal atrophy rate (0.07 vs 0.03ml/yr, p = 0.029). Baseline Aβ1‐42 level was strongly correlated with rate of brain atrophy only in the NC‐low group (p < 0.001). Using 141 (95% confidence interval, 86–287) patients per arm provides 80% power in a 1‐year treatment trial to show 25% slowing of brain atrophy in the NC‐low group.

Interpretation

A significant percentage of healthy older adults have CSF profiles consistent with AD and increased rates of brain atrophy, suggesting that they may be in the earliest stages of neurodegeneration. Brain atrophy may be a feasible outcome measure for AD prevention studies. Ann Neurol 2010.
Glut1/SLC2A1 is crucial for the development of the blood‐brain barrier in vivo
Authors: Zheng Ping‐Pin , Romme Edwin , Spek Peter J. van der , Dirven Clemens M.F. , Willemsen Rob , Kros Johan M.
Published: October 2010

Objective

The overall permeability of the blood‐brain barrier (BBB) is regulated by specialized cerebral endothelial cells and their junctional complexes, consisting of adherens junctions (AJs) and tight junctions (TJs). Among the members of the glucose transporters (Glut), Glut1 is a unique molecule expressed in the cerebral endothelial cells. Glut1 and the junctional proteins are concomitantly downregulated in situations in which breakdown of the BBB has taken place. We hypothesized that the expression of Glut1 may play a significant role in the development of the cerebral microvasculature with BBB properties. To date, there is no information on the role of Glut1 during the development of BBB. In the present study, the in vivo effects of Glut1 knockdown on the cerebral vascular development were investigated.

Methods

Zebrafish was used as a model organism. We confirmed that the structure of the zebrafish homologue of Glut1 is highly similar to the human Glut1 and that the function of the Glut1‐mediated cerebral uptake of glucose is evolutionally conserved.

Results

In the Glut1 knockdown model, we observed loss of the cerebral endothelial cells, with concomitant downregulation of the junctional proteins important for intactness of the AJs/TJs and impaired cerebral circulation. The resulting leaky BBB caused vasogenic brain edema.

Interpretation

The data suggest a crucial role of Glut1 in the development of the cerebral endothelial cells with BBB properties in vivo. The findings suggest that modulation of Glut1 expression and function may open new directions of research for therapeutic strategies to prevent vasogenic brain edema. Ann Neurol 2010;
Independent and joint effects of the MAPT and SNCA genes in Parkinson disease
Authors: Elbaz Alexis , Ross Owen A. , Ioannidis John P. A. , Soto‐Ortolaza Alexandra I. , Moisan Frédéric , Aasly Jan , Annesi Grazia , Bozi Maria , Brighina Laura , Chartier‐Harlin Marie‐Christine , Destée Alain , Ferrarese Carlo , Ferraris Alessandro , Gibson J. Mark , Gispert Suzana , Hadjigeorgiou Georgios M. , Jasinska‐Myga Barbara , Klein Christine , Krüger Rejko , Lambert Jean‐Charles , Lohmann Katja , van de Loo Simone , Loriot Marie‐Anne , Lynch Timothy , Mellick George D. , Mutez Eugénie , Nilsson Christer , Opala Grzegorz , Puschmann Andreas , Quattrone Aldo , Sharma Manu , Silburn Peter A. , Stefanis Leonidas , Uitti Ryan J. , Valente Enza Maria , Vilariño‐Güell Carles , Wirdefeldt Karin , Wszolek Zbigniew K. , Xiromerisiou Georgia , Maraganore Demetrius M. , Farrer Matthew J. ,   on behalf of the Genetic Epidemiology of Parkinson's Disease (GEO‐PD) consortium
Published: October 2010

Objective:

We studied the independent and joint effects of the genes encoding alpha‐synuclein (SNCA) and microtubule‐associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta‐analysis of individual data from case–control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO‐PD) consortium.

Methods:

Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed‐ and random‐effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case–control and case‐only approach.

Results:

Fifteen GEO‐PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1‐haplotype–defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 3′ end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale.

Interpretation:

This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects. ANN NEUROL 2011
Oxetanes as Versatile Elements in Drug Discovery and Synthesis
Authors: Burkhard Johannes A. , Wuitschik Georg , Rogers‐Evans Mark , Müller Klaus , Carreira Erick M.
Published: October 2010

Sizable resources, both financial and human, are invested each year in the development of new pharmaceutical agents. However, despite improved techniques, the new compounds often encounter difficulties in satisfying and overcoming the numerous physicochemical and many pharmacological constraints and hurdles. Oxetanes have been shown to improve key properties when grafted onto molecular scaffolds. Of particular interest are oxetanes that are substituted only in the 3‐position, since such units remain achiral and their introduction into a molecular scaffold does not create a new stereocenter. This Minireview gives an overview of the recent advances made in the preparation and use of 3‐substituted oxetanes. It also includes a discussion of the site‐dependent modifications of various physicochemical and biochemical properties that result from the incorporation of the oxetane unit in molecular architectures.
A Bond by Any Other Name
Authors: Desiraju Gautam R.
Published: October 2010

A hydrogen bond is an interaction wherein a hydrogen atom is attracted to two atoms, rather than just one, and acts like a bridge between them. The strength of this attraction increases with the increasing electronegativity of either of the atoms, and in the classical view, all hydrogen bonds are highly electrostatic and sometimes even partly covalent. Gradually, the concept of a hydrogen bond has become more relaxed to include weaker and more dispersive interactions, provided some electrostatic character remains. A great variety of very strong, strong, moderately strong, weak, and very weak hydrogen bonds are observed in practice. Weak hydrogen bonds are now invoked in several matters in structural chemistry and biology. While strong hydrogen bonds are easily covered by all existing definitions of the phenomenon, the weaker ones may pose a challenge with regard to nomenclature and definitions. Recently, a recommendation has been made to the International Union of Pure and Applied Chemistry (IUPAC) suggesting an updated definition of the term hydrogen bond. This definition will be discussed in greater detail.
A new heterogeneous chiral (salen)manganese(III) system for enantioselective epoxidation of non‐functionalized olefins
Authors: Wei Saili , Tang Yuhai , Xu Xiaoqian , Xu Guojin , Yu Yong , Sun Yang , Zheng Yuansuo
Published: October 2010

This communication describes the design and application of a novel catalytic epoxidation system derived from the initial immobilization of a homogeneous sulfonato (salen)Mn(III) complex on two solid carriers (silica gel and siliceous earth) and subsequent dispersion of the supported manganese complexes into ionic liquid 1‐butyl‐3‐methylimidazolium hexafluorophosphate (BMImPF6) and 1‐butyl‐3‐methylimidazolium tetrafluoroborate (BMImBF4) for recycling. The performance of chiral (salen)Mn(III) system in enantioselective epoxidation of olefins was investigated systematically. Even higher enantioselectivity than that of the homogeneous counterpart was obtained with similar catalytic activity. In particular, the best catalytic result is that the combination of the silica gel‐supported (salen)Mn(III) catalyst and BMImPF6 affords 97–100% ee for epoxidation of α‐methylstyrene, and high ee values were retained even after three cycles. Copyright © 2010 John Wiley & Sons, Ltd.
Ontogenetic Variation in the Bony Labyrinth of Monodelphis domestica (Mammalia: Marsupialia) Following Ossification of the Inner Ear Cavities
Authors: Ekdale Eric G.
Published: October 2010

Ontogeny, or the development of an individual from conception to death, is a major source of variation in vertebrate morphology. All anatomical systems are affected by ontogeny, and knowledge of the ontogenetic history of these systems is important to understand when formulating biological interpretations of evolutionary history and physiology. The present study is focused on how variation affects the bony labyrinth across a growth series of an extant mammal after ossification of the inner ear chambers. Digital endocasts of the bony labyrinth were constructed using CT data across an ontogenetic sequence of Monodelphis domestica, an important experimental animal. Various aspects of the labyrinth were measured, including angles between the semicircular canals, number of turns of the cochlea, volumes of inner ear constituents, as well as linear dimensions of semicircular canals. There is a strong correlation between skull length and age, but from 27 days after birth onward, there is no correlation with age among most of the inner ear measurements. Exceptions are the height of the arc of the lateral semicircular canal, the angular deviation of the lateral canal from planarity, the length of the slender portion of the posterior semicircular canal, and the length of the canaliculus cochleae. Adult dimensions of several of the inner ear structures, such as the arcs of the semicircular canals, are achieved before the inner ear is functional, and the non‐ontogenetic variation in the bony labyrinth serves as an important source for behavioral, physiological, and possibly phylogenetic information. Anat Rec, 2010. © 2010 Wiley‐Liss, Inc.
Light rain events change over North America, Europe, and Asia for 1973–2009
Authors: Qian Yun , Gong Daoyi , Leung Ruby
Published: October 2010

Analysis of daily precipitation data reveals diverse long‐term trends of light rain events in North America (NA), Europe (EU), and Asia (AS), but overall a decreasing trend is found from 1973–2009, especially over East Asia, where a remarkable shift from light to heavy rain events has been observed. Although it has been argued that global warming may lead to a shift from light to heavy rain, regionally little correspondence is found between light rain trends and temperature/precipitable water (PW) trends. This argues for the need to include other factors such as atmospheric circulation and aerosol changes that affect regional rain rates and cloud processes. Copyright © 2010 Royal Meteorological Society
Paraoxonase 1 polymorphisms and haplotypes and the risk for having offspring affected with spina bifida in Southeast Mexico
Authors: Gonzalez‐Herrera Lizbeth , Martín Cerda‐Flores Ricardo , Luna‐Rivero Marianne , Canto‐Herrera Jorge , Pinto‐Escalante Doris , Perez‐Herrera Norma , Quintanilla‐Vega Betzabet
Published: October 2010

BACKGROUND

Spina bifida (SB) is a common congenital malformation in Southeast Mexico. Parents of children with SB reside in areas with frequent pesticide spraying or have agriculture activities, suggesting potential exposure to pesticides. Paraoxonase 1 (PON1) is the responsible enzyme for deactivation of organophosphates (OP) in the central nervous system. Polymorphisms of PON1 genes influence the catalytic activity and plasma protein level of the enzyme, therefore, genotypic characterization of PON1 gene represents a potential predictor for susceptibility to OP‐related effects.

METHODS

The frequency of PON1 haplotypes and polymorphisms (−108CT, L55M, and Q192R) were determined in this study. A case‐control study was performed to evaluate the risk for having offspring affected by SB in 152 cases and 160 control parents. Polymorphisms were determined by PCR amplification and restriction fragment length polymorphism and Real Time‐PCR. Odds ratios and confidence interval 95% were estimated.

RESULTS

Genotype frequencies for the three PON1 polymorphisms were distributed according to Hardy–Weinberg expectations (p > 0.05) and were significantly different between cases and controls (p < 0.05). The heterozygous CT genotype of −108CT polymorphism, the RR genotype of Q192R polymorphism, both LM and MM genotypes of L55M polymorphism, and the haplotypes 221 and 222 (for −108CT, L55M, and Q192R) were associated with the risk for having a child affected by SB (p < 0.02). The heterozygous −108CT genotype was associated only maternally, whereas the heterozygous L55M genotype was relevant only in the fathers. The RR homozygous genotype was relevant both in mothers and fathers, suggesting the importance of this substrate‐specific polymorphism.

CONCLUSION

Results suggest that PON1 polymorphisms are relevant risk factors for having offspring affected with SB in this population from Southeast Mexico. Birth Defects Research (Part A), 2010. © 2010 Wiley‐Liss, Inc.
Zur Krise der westdeutschen Grenzwertpolitik in den 1970er Jahren: Die Verwandlung des Berufskrebses von einem toxikologischen in ein sozioökonomisches Problem
Authors: Bächi Beat
Published: October 2010

Concerning the Crisis of the West German Politics of Limit Values in the 1970s: The Transformation of Cancer at the Workplace from a Toxicological into a Socioeconomic Problem.The paper tackles the changes that occurred in the political culture and the episteme of risk in the Federal Republic of Germany in the 1970s. The objects of observation are limit values for hazardous industrial materials, especially for carcinogens. At the forefront of the production of such values in Germany was the German Research Society's Senate Commission for the Examination of Hazardous Industrial Materials. Limit values bring economy, politics, and science together and they mediate different interests. This makes limit values an ideal object of study to bring together changes in different parts of society. In 1972, a new category of limit values for carcinogenic substances is introduced, the so called „Technische Richtkonzentration”︁ (TRK). This category of values does not assume that complete safety can be reached, as do limit values for hazardous industrial materials, so called “Maximale Arbeitsplatzkonzentrationen” (MAK). This means an important rupture in toxicological thinking. Until the 1970s, Paracelsus' dictum about dosage and poison still served as starting point for toxicologists. The innovation of TRK marks an important rupture in the episteme of regulating dangerous matters. Whereas until the 1970s there existed, at least as an ideal, the myth of “no risk” or “zero tolerance” even in the case of carcinogens, since the beginning of the 1970s, certainty is no more guaranteed by epistemically, but by socially robust knowledge. This also means the return of the risk society at the beginning of the 1970s, whereby cancer at the workplace becomes – in the view of the regulatory bodies – out of a medical problem a socioeconomic illness. The paper argues that these changes are connected to a general feeling of disorientation.
Regulierung des Verhaltens zwischen den Weltkriegen. Robert Musil und Kurt Lewin
Authors: Innerhofer Roland , Rothe Katja
Published: October 2010

Regulation of Behavior in the Period between the World Wars: Robert Musil and Kurt Lewin. The paper attempts to reconstruct the proto‐cybernetic concept of regulation which emerged in early 20th century both in biology and psychology, and was critically reflected in literature. The basic premise is that Kurt Lewin's field‐theoretical psychology played a crucial role in the development of behavioral self‐regulation concepts. The goal is to show (1) that Lewin's early experiments and theories were based on the idea of a dynamic process of self‐regulation determined by the actors and their personal motivation and interaction, (2) that this concept of self‐regulation functioned as a camouflage for power‐strategies that aimed to regulate and optimize the economic production and social reproduction processes, (3) that in Robert Musil's fragmentary, ‘fringing’ novel The Man without Qualities the attempt to optimize the social and economic behavior and to establish a homeostatic state proved to be a complete failure. As a notable result, this ‘literary test’ of behavioral self‐regulation revealed the violence and imbalance of power inherent in this concept of self‐regulation and its practical implementation.
Regulierungswissen und Regulierungskonzepte
Authors: Reinhardt Carsten
Published: October 2010

Regulatory Knowledge and Regulatory Concepts. The article argues for a historical understanding of a specific form of knowledge which is attached to the practices of regulatory science: regulatory knowledge. By definition, regulatory science deals with problems that are thought of not belonging to the normal spectrum of scientific work, i. e., they are ‘trans‐scientific’. In order to bridge science and other social spheres, regulatory science and regulatory knowledge carry certain features deemed to fulfil this task. Using Foucault's concept of governmentality and newer attempts of the sociology of knowledge, the article proposes the study of regulatory concepts as an avenue to explore the history of regulatory knowledge. As a case, the regulation by boundary values of chemicals at the work place in the Federal Republic of Germany is presented. The main advantage of boundary values as a regulatory concept is, arguably, their capacity to carry the necessary ambiguity for connecting different social spheres and for fulfilling specific functions in each social system, respectively. In this respect, the notion of regulatory concept is borrowed from the uses of boundary concepts and boundary objects in science studies.
Synthesis and characterization of a novel high luminescent gold‐2‐mercapto‐1‐methyl‐imidazole complex
Authors: Cardone Giorgio , Carotenuto Gianfranco , Conte Pellegrino , Alonzo Giuseppe
Published: October 2010

Synthesis and characterization of a new gold‐2‐mercapto‐1‐methyl imidazole are reported. This new organic material shows an extraordinary fluorescence activity (superfluorescence) up to 220°C with an unusual quantum yield of 0.2. Both fluorescence and NMR spectroscopy were applied to understand the behavior of the gold‐2‐mercapto‐1‐methylimidazole complex. Results suggest that the superfluorescence activity can be attributed to the shrinking of the HOMO‐LUMO band gap energy following complexation of the organic imidazole system with gold. Copyright © 2010 John Wiley & Sons, Ltd.
Enhancing the enzymatic hydrolysis of lignocellulosic biomass by increasing the carboxylic acid content of the associated lignin
Authors: Nakagame Seiji , Chandra Richard P. , Kadla John F. , Saddler Jack N.
Published: October 2010

To assess the effects that the physical and chemical properties of lignin might have on the enzymatic hydrolysis of pretreated lignocellulosic substrates, protease treated lignin (PTL) and cellulolytic enzyme lignin (CEL) fractions, isolated from steam and organosolv pretreated corn stover, poplar, and lodgepole pine, were prepared and characterized. The adsorption of cellulases to the isolated lignin preparations corresponded to a Langmuir adsorption isotherm. It was apparent that, rather than the physical properties of the isolated lignin, the carboxylic acid functionality of the isolated lignin, as determined by FTIR and NMR spectroscopy, had much more of an influence when lignin was added to typical hydrolysis of pure cellulose (Avicel). An increase in the carboxylic content of the lignin preparation resulted in an increased hydrolysis yield. These results suggested that the carboxylic acids within the lignin partially alleviate non‐productive binding of cellulases to lignin. To try to confirm this possible mechanism, dehydrogenative polymers (DHP) of monolignols were synthesized from coniferyl alcohol (CA) and ferulic acid (FA), and these model compounds were added to a typical enzymatic hydrolysis of Avicel. The DHP from FA, which was enriched in carboxylic acid groups compared with the DHP from CA, adsorbed a lower mount of cellulases and did not decrease hydrolysis yields when compared to the DHP from CA, which decreased the hydrolysis of Avicel by 8.4%. Thus, increasing the carboxylic acid content of the lignin seemed to significantly decrease the non‐productive binding of cellulases and consequently increased the enzymatic hydrolysis of the cellulose. Biotechnol. Bioeng. 2011; 108:538–548. © 2010 Wiley Periodicals, Inc.
Improved product‐per‐glucose yields in P450‐dependent propane biotransformations using engineered Escherichia coli
Authors: Fasan Rudi , Crook Nathan C. , Peters Matthew W. , Meinhold Peter , Buelter Thomas , Landwehr Marco , Cirino Patrick C. , Arnold Frances H.
Published: October 2010

P450‐dependent biotransformations in Escherichia coli are attractive for the selective oxidation of organic molecules using mild and sustainable procedures. The overall efficiency of these processes, however, relies on how effectively the NAD(P)H cofactors derived from oxidation of the carbon source are utilized inside the cell to support the heterologous P450‐catalyzed reaction. In this work, we investigate the use of metabolic and protein engineering to enhance the product‐per‐glucose yield (YPPG) in whole‐cell reactions involving a proficient NADPH‐dependent P450 propane monooxygenase prepared by directed evolution [P450PMOR2; Fasan et al. (2007); Angew Chem Int Ed 46:8414–8418]. Our studies revealed that the metabolism of E. coli (W3110) is able to support only a modest propanol:glucose molar ratio (YPPG ∼ 0.5) under aerobic, non‐growing conditions. By altering key processes involved in NAD(P)H metabolism of the host, considerable improvements of this ratio could be achieved. A metabolically engineered E. coli strain featuring partial inactivation of the endogenous respiratory chain (Δndh) combined with removal of two fermentation pathways (ΔadhE, Δldh) provided the highest YPPG (1.71) among the strains investigated, enabling a 230% more efficient utilization of the energy source (glucose) in the propane biotransformation compared to the native E. coli strain. Using an engineered P450PMOR2 variant which can utilize NADPH and NADH with equal efficiency, we also established that dual cofactor specificity of the P450 enzyme can provide an appreciable improvement in YPPG. Kinetic analyses suggest, however, that much more favorable parameters (KM, kcat) for the NADH‐driven reaction are required to effectively compete with the host's endogenous NADH‐utilizing enzymes. Overall, the metabolic/protein engineering strategies described here can be of general value for improving the performance of NAD(P)H‐dependent whole‐cell biotransformations in E. coli. Biotechnol. Bioeng. 2011; 108:500–510. © 2010 Wiley Periodicals, Inc.