bluuebunny/crossref_metadata_2025 huggingface dataset:
“Asleep” deep brain stimulation for essential tremor
Authors: Chen Tsinsue , Mirzadeh Zaman , Chapple Kristina , Lambert Margaret , Dhall Rohit , Ponce Francisco A.
Published: November 2015

OBJECT

Deep brain stimulation (DBS) performed under general anesthesia (“asleep” DBS) has not been previously reported for essential tremor. This is in part due to the inability to visualize the target (the ventral intermediate nucleus [VIM]) on MRI. The authors evaluate the efficacy of this asleep technique in treating essential tremor by indirect VIM targeting.

METHODS

The authors retrospectively reviewed consecutive cases of initial DBS for essential tremor performed by a single surgeon. DBS was performed with patients awake (n = 40, intraoperative test stimulation without microelectrode recording) or asleep (n = 17, under general anesthesia). Targeting proceeded with standardized anatomical coordinates on preoperative MRI. Intraoperative CT was used for stereotactic registration and lead position confirmation. Functional outcomes were evaluated with pre- and postoperative Bain and Findley Tremor Activities of Daily Living scores.

RESULTS

A total of 29 leads were placed in asleep patients, and 60 were placed in awake patients. Bain and Findley Tremor Activities of Daily Living Questionnaire scores were not significantly different preoperatively for awake versus asleep cohorts (p = 0.2). The percentage of postoperative improvement was not significantly different between asleep (48.6%) and awake (45.5%) cohorts (p = 0.35). Euclidean error (mm) was higher for awake versus asleep patients (1.7 ± 0.8 vs 1.2 ± 0.4, p = 0.01), and radial error (mm) trended higherfor awake versus asleep patients (1.3 ± 0.8 vs 0.9 ± 0.5, p = 0.06). There were no perioperative complications.

CONCLUSIONS

In the authors’ initial experience, asleep VIM DBS for essential tremor without intraoperative test stimulation can be performed safely and effectively.
Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer’s Disease Mouse Model
Authors: LeVault Kelsey R. , Tischkau Shelley A. , Brewer Gregory J.
Published: November 2015

It is unclear whether pre-symptomatic Alzheimer’s disease (AD) causes circadian disruption or whether circadian disruption accelerates AD pathogenesis. In order to examine the sensitivity of learning and memory to circadian disruption, we altered normal lighting phases by an 8 h shortening of the dark period every 3 days (jet lag) in the APPSwDI NOS2–/– model of AD (AD-Tg) at a young age (4-5 months), when memory is not yet affected compared to non-transgenic (non-Tg) mice. Analysis of activity in 12-12 h lighting or constant darkness showed only minor differences between AD-Tg and non-Tg mice. Jet lag greatly reduced activity in both genotypes during the normal dark time. Learning on the Morris water maze was significantly impaired only in the AD-Tg mice exposed to jet lag. However, memory 3 days after training was impaired in both genotypes. Jet lag caused a decrease of glutathione (GSH) levels that tended to be more pronounced in AD-Tg than in non-Tg brains and an associated increase in NADH levels in both genotypes. Lower brain GSH levels after jet lag correlated with poor performance on the maze. These data indicate that the combination of the environmental stress of circadian disruption together with latent stress of the mutant amyloid and NOS2 knockout contributes to cognitive deficits that correlate with lower GSH levels.
Future Dementia Severity is Almost Entirely Explained by the Latent Variable δ’s Intercept and Slope
Authors: Palmer Raymond F. , Royall Donald R.
Published: November 2015

Background: Structural equation models (SEM) can explicitly distinguish dementia-relevant variance in cognitive task performance. The resulting latent construct “δ” (for dementia) provides a relatively “error free” continuously varying dementia-specific phenotype. Objective: To estimate δ’s change over time (Δδ) and determine Δδ’s predictive validity using future dementia status as an outcome. Methods: Data from n = 2,191 participants of the Texas Alzheimer’s Research and Care Consortium (TARCC) were used to construct a latent growth curve model of longitudinal change over four years using five cognitive measures and one measure of Instrumental Activities of Daily Living. Four final latent factors, including baseline δ and Δδ, were simultaneously entered as predictors of wave 4 dementia severity, as estimated by the Clinical Dementia Rating Scale “sum of boxes” (CDR). Results: All observed measures exhibited significant change [χ2 = 1,152 (df = 229); CFI = 0.968; RMSEA = 0.043]. The final model demonstrated excellent fit to the data [χ2 = 543 (df = 245); CFI = 0.991; RMSEA = 0.023]. All latent indicator loadings were significant, yielding four distinct factors. After adjustment for demographic covariates and baseline CDR scores, d and Δd were significantly independently associated with CDR4, explaining 25% and 49% of its variance, respectively. The latent variable g’ significantly explained 3% of CDR4 variance independently of d and Δd. Δg’ was not significantly associated with CDR4. Baseline CDR explained 16% of CDR4 variance. Conclusions: Future dementia severity is almost entirely explained by the latent construct δ’s intercept and slope.
The Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment
Authors: Koppara Alexander , Wolfsgruber Steffen , Kleineidam Luca , Schmidtke Klaus , Frölich Lutz , Kurz Alexander , Schulz Stefanie , Hampel Harald , Heuser Isabella , Peters Oliver , Reischies Friedel M. , Jahn Holger , Luckhaus Christian , Hüll Michael , Gertz Hermann-Josef , Schröder Johannes , Pantel Johannes , Rienhoff Otto , Rüther Eckart , Henn Fritz , Wiltfang Jens , Maier Wolfgang , Jessen Frank , Kornhuber Johannes , Wagner Michael
Published: November 2015

Background: The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer’s disease (AD) research and clinical trials. Objective: To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI). Methods: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences. Results: In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aβ42/tau ratio indicative of AD (n = 340, AUC = 0.78, p <  0.001), and predicted incident dementia within 1–3 years of follow-up (n = 525, AUC = 0.84, p <  0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects. Conclusion: These findings support the interpretation of δ as a construct capturing the disease-related “essence” of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research.
White Matter Changes are Associated with Ventricular Expansion in Aging, Mild Cognitive Impairment, and Alzheimer’s Disease
Authors: Coutu Jean-Philippe ,   the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Goldblatt Alison , Rosas H. Diana , Salat David H.
Published: November 2015

White matter lesions are highly prevalent in individuals with Alzheimer’s disease (AD). Although these lesions are presumed to be of vascular origin and linked to small vessel disease in older adults, little information exists about their relationship to markers of classical AD neurodegeneration. Thus, we examined the link between these white matter changes (WMC) segmented on T1-weighted MRI and imaging markers presumed to be altered due to primary AD neurodegenerative processes. Tissue microstructure of WMC was quantified using diffusion tensor imaging and the relationship of WMC properties and volume to neuroimaging markers was examined in 219 cognitively healthy older adults and individuals with mild cognitive impairment and AD using data from the Alzheimer’s Disease Neuroimaging Initiative. No significant group differences in WMC properties were found. However, there were strong associations between diffusivity of WMC and ventricular volume, volume of WMC and total WM volume. In comparison, group differences in parahippocampal white matter microstructure were found for all diffusion metrics and were largely explained by hippocampal volume. Factor analysis on neuroimaging markers suggested two independent sets of covarying degenerative changes, with potentially age- and vascular-mediated tissue damage contributing to one factor and classical neurodegenerative changes associated with AD contributing to a second factor. These data demonstrate two potentially distinct classes of degenerative change in AD, with one factor strongly linked to aging, ventricular expansion, and both volume and tissue properties of white matter lesions, while the other factor related to classical patterns of cortical and hippocampal neurodegeneration in AD.
Age-Dependent Regulation of the Blood-Brain Barrier Influx/Efflux Equilibrium of Amyloid-β Peptide in a Mouse Model of Alzheimer’s Disease (3xTg-AD)
Authors: Do Tuan Minh , Dodacki Agnès , Alata Wael , Calon Frederic , Nicolic Sophie , Scherrmann Jean-Michel , Farinotti Robert , Bourasset Fanchon
Published: November 2015

The involvement of transporters located at the blood-brain barrier (BBB) has been suggested in the control of cerebral Aβ levels, and thereby in Alzheimer’s disease (AD). However, little is known about the regulation of these transporters at the BBB in animal models of AD. In this study, we investigated the BBB expression of Aβ influx (Rage) and efflux (Abcb1-Abcg2-Abcg4-Lrp-1) transporters and cholesterol transporter (Abca1) in 3–18-month-old 3xTg-AD and control mice. The age-dependent effect of BBB transporters regulation on the brain uptake clearance (Clup) of [3H]cholesterol and [3H]Aβ1 - 40 was then evaluated in these mice, using the in situ brain perfusion technique. Our data suggest that transgenes expression led to the BBB increase in Aβ influx receptor (Rage) and decrease in efflux receptor (Lrp-1). Our data also indicate that mice have mechanisms counteracting this increased net influx. Indeed, Abcg4 and Abca1 are up regulated in 3- and 3/6-month-old 3xTg-AD mice, respectively. Our data show that the balance between the BBB influx and efflux of Aβ is maintained in 3 and 6-month-old 3xTg-AD mice, suggesting that Abcg4 and Abca1 control the efflux of Aβ through the BBB by a direct (Abcg4) or indirect (Abca1) mechanism. At 18 months, the BBB Aβ efflux is significantly increased in 3xTg-AD mice compared to controls. This could result from the significant up-regulation of both Abcg2 and Abcb1 in 3xTg-AD mice compared to control mice. Thus, age-dependent regulation of several Aβ and cholesterol transporters at the BBB could ultimately limit the brain accumulation of Aβ.
The Korean Size/Weight Attribute Test: A Semantic Knowledge Test for Korean Older Adults and Brain-Imaging Evidence
Authors: Yoo Yongjoon , Shin Seong A. , Park Soowon , Lee Ji-Hye , Youn Jung-Hae , Kim Yu Kyeong , Lee Jun-Young
Published: November 2015

Background: A standardized tool for evaluating semantic knowledge of the Korean population is needed. Objective: The purpose of this study was to develop a neuropsychological test for the evaluation of semantic knowledge in the Korean elderly population. Methods: The Korean version of the Size/Weight Attribute Test (SWAT-K) was developed in reference to the original version. The diagnostic validity of SWAT-K was evaluated with 95 elderly outpatients [67 normal controls; 18 with Alzheimer’s disease (AD); 10 with semantic-variant progressive aphasia (SV-PPA)]. Voxel-based morphometry (VBM) was employed to examine associations between SWAT-K scores and morphological changes of the brain. Results: SWAT-K could discriminate the three subject groups (normal >AD, p <  0.001; AD >SV-PPA, p = 0.040), whereas Boston Naming Test could not distinguish SV-PPA from AD. ROC curve analysis confirmed high levels of sensitivity (0.90) and specificity (0.93) for SWAT-K. The test’s inter-rater reliability (ICC = 0.827) and test-retest reliability (ICC = 0.666) were assessed as well. VBM found a significant positive correlation (uncorrected p <  0.005, k >  100) between SWAT-K scores and gray matter volume in right inferior frontal cortex (T = 4.08, k = 191) and bilateral temporal cortices (left, T = 4.42, k = 135; right, T = 3.55, k = 253), the areas the most affected in SV-PPA. Conclusions: SWAT-K is a sensitive and reliable test for evaluating semantic knowledge in the Korean elderly population. Strong positive correlations between SWAT-K scores and the brain areas responsible for semantic processing further corroborate the validity of SWAT-K.
Discovery and Subsequent Confirmation of Novel Serum Biomarkers Diagnosing Alzheimer’s Disease
Authors: Shah Dipti Jigar , Rohlfing Frederick , Anand Swati , Johnson W. Evan , Alvarez MeiHwa Tanielle Bench , Cobell Jesse , King Jackson , Young Sydney A. , Kauwe John S.K. , Graves Steven W.
Published: November 2015

Background: Alzheimer’s disease (AD) remains challenging to diagnose, especially early disease. Having serum AD biomarkers would be of significant interest both in the clinical setting and in drug development efforts. Objective: We applied a novel serum proteomic approach to interrogate the low-molecular weight proteome for serum AD biomarkers. Methods: A discovery study used sera from 58 any-stage AD cases and 55 matched controls analyzed by capillary liquid chromatography-electrospray ionization-tandem mass spectrometry. Candidate biomarkers were statistically modeled and promising biomarkers were retested in a second, blinded confirmatory study (AD cases = 68, controls = 57). Biomarkers that replicated in the second study were modeled for the diagnosis of any-stage and very early stage AD. Further, they were chemically identified by tandem MS. Results: The initial discovery study found 59 novel potential AD biomarkers. Thirteen recurred in more than one multi-marker panel. In a second, blinded, confirmatory study, these same biomarkers were retested in separate specimens. In that study, four markers validated comparing controls to patients with any-stage AD and also with very early AD. The four biomarkers with replicable ability to diagnose AD were then chemically identified. Conclusion: These results suggest novel serum AD diagnostic biomarkers can be found using this approach.
MicroRNA and mRNA Expression Changes in Steroid Naïve and Steroid Treated DMD Patients
Authors: Liu Da Zhi , Stamova Boryana , Hu Shengyong , Ander Bradley P. , Jickling Glen C. , Zhan Xinhua , Sharp Frank R. , Wong Brenda
Published: November 2015

Background:

Duchenne Muscular Dystrophy (DMD) is a recessive X-linked form of muscular dystrophy. Steroid therapy has clinical benefits for DMD patients, but the mechanism remains unclear.

Objective:

This study was designed to identify mRNAs and microRNAs regulated in Duchenne Muscular Dystrophy patients prior to and after steroid therapy.

Methods:

Genome wide transcriptome profiling of whole blood was performed to identify mRNAs and microRNAs regulated in DMD patients.

Results:

The data show many regulated mRNAs and some microRNAs, including some muscle-specific microRNAs (e.g., miR-206), that were significantly altered in blood of young (age 3–10) DMD patients compared to young controls. A total of 95 microRNAs, but no mRNAs, were differentially expressed in older DMD patients compared to matched controls (age 11–20). Steroid treatment reversed expression patterns of several microRNAs (miR-206, miR-181a, miR-4538, miR-4539, miR-606, and miR-454) that were altered in the young DMD patients. As an example, the over-expression of miR-206 in young DMD patients is predicted to down-regulate a set of target genes (e.g., RHGAP31, KHSRP, CORO1B, PTBP1, C7orf58, DLG4, and KLF4) that would worsen motor function. Since steroids decreased miR-206 expression to control levels, this could provide one mechanism by which steroids improve motor function.

Conclusions:

These identified microRNA-mRNA alterations will help better understand the pathophysiology of DMD and the response to steroid treatment.
Orthopedic Management of Scoliosis by Garches Brace and Spinal Fusion in SMA Type 2 Children
Authors: Catteruccia Michela , Vuillerot Carole , Vaugier Isabelle , Leclair Danielle , Azzi Viviane , Viollet Louis , Estournet Brigitte , Bertini Enrico , Quijano-Roy Susana
Published: November 2015

Background:

Scoliosis is the most debilitating issue in SMA type 2 patients. No evidence confirms the efficacy of Garches braces (GB) to delay definitive spinal fusion.

Objective:

Compare orthopedic and pulmonary outcomes in children with SMA type 2 function to management.

Method:

We carried out a monocentric retrospective study on 29 SMA type 2 children who had spinal fusion between 1999 and 2009. Patients were divided in 3 groups: group 1-French patients (12 children) with a preventive use of GB; group 2-French patients (10 children) with use of GB after the beginning of the scoliosis curve; and group 3-Italian patients (7 children) with use of GB after the beginning of the scoliosis curve referred to our centre to perform orthopedic preoperative management.

Results:

Mean preoperative and postoperative Cobb angle were significantly lower in the group 1 of proactively braced than in group 2 or 3 (Anova p = 0.03; Kruskal Wallis test p = 0.05). Better surgical results were observed in patients with a minor preoperative Cobb angle ( r = 0.92 p <  0.0001). Fewer patients in the group 1 proactively braced required trunk casts and/or halo traction and an additional anterior fusion in comparison with patients in the group 2 and 3. Moreover, major complications tend to be less in the group 1 proactively braced. No significant differences were found between groups in pulmonary outcome measures.

Conclusions:

A proactive orthotic management may improve orthopedic outcome in SMA type 2. Further prospective studies comparing SMA management are needed to confirm these results.

Level of Evidence:

Therapeutic Level III. See Instructions to Authors on jbjs.org for a complete description of levels of evidence (Retrospective comparative study).
The Impact of Pregnancy on Myotonic Dystrophy: A Registry-Based Study
Authors: Johnson Nicholas E. , Hung Man , Nasser Eriko , Hagerman Katharine A. , Chen Wei , Ciafaloni Emma , Heatwole Chad R.
Published: November 2015

Background:

The rate of symptom progression during pregnancy in myotonic dystrophy (DM) is not currently known. Further, there is little data regarding the rate of pregnancy complications and neonatal outcomes in DM.

Objective:

This study assesses symptom progression and complication rates during pregnancy in women with DM.

Methods:

DM women completed surveys regarding their prior pregnancies. Participants identified complications during their pregnancies and completed the Myotonic Dystrophy Health Index-Short Form (MDHI-SF) to measure their disease burden and identify the severity of select symptoms six-months prior to, during, and six-months after their first pregnancy.

Results:

152 women with DM reported on 375 pregnancies. Among these pregnancies, there was a 32.5% miscarriage rate. Some complications were common including: pre-term labor (27.8%), pre-eclampsia (10.4%), and peripartum hemorrhage (13.9%). Participants’ perception of their mobility and ability to perform activities, as measured by the MDHI-SF, worsened during pregnancy and did not recover during the post-partum period.

Discussion:

Miscarriage, maternal disease progression during pregnancy, and other pregnancy related complications may occur in DM. Women with DM should be counseled on these potential risks prior to considering pregnancy.
Comparison of Experimental Protocols of Physical Exercise for mdx Mice and Duchenne Muscular Dystrophy Patients
Authors: Hyzewicz Janek , Ruegg Urs T. , Takeda Shin’ichi
Published: November 2015

Duchenne Muscular Dystrophy (DMD) is caused by mutations in the gene coding for dystrophin and leads to muscle degeneration, wheelchair dependence and death by cardiac or respiratory failure. Physical exercise has been proposed as a palliative therapy for DMD to maintain muscle strength and prevent contractures for as long as possible. However, its practice remains controversial because the benefits of training may be counteracted by muscle overuse and damage.

The effects of physical exercise have been investigated in muscles of dystrophin-deficient mdx mice and in patients with DMD. However, a lack of uniformity among protocols limits comparability between studies and translatability of results from animals to humans. In the present review, we summarize and discuss published protocols used to investigate the effects of physical exercise on mdx mice and DMD patients, with the objectives of improving comparability between studies and identifying future research directions.
Night Activity Reduction is a Signature Physiological Biomarker for Duchenne Muscular Dystrophy Dogs
Authors: Hakim Chady H. , Peters Austin A. , Feng Feng , Yao Gang , Duan Dongsheng
Published: November 2015

Background:

Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease. Dystrophic dogs are excellent models to test novel therapies for DMD. However, the use of the dog model has been hindered by the lack of an effective method to evaluate whole-body mobility. We recently showed that night activity is a good indicator of dog mobility. However, our published method relies on frame-by-frame manual processing of a 12-hour video for each dog. This labor-intensive and time-consuming approach makes it unrealistic to use this assay as a routine outcome measurement.

Objective:

To solve this problem, we developed an automatic video-capturing/imaging processing system. The new system reduces the data analysis time over 1,000 fold and also provides a more detailed activity profile of the dog.

Methods:

Using the new system, we analyzed more than120 twelve-hour recordings from 12 normal and 22 affected dogs.

Results:

We observed similar activity profiles during repeated recording of the same dog. Throughout the night, normal dogs were in motion 10.4 ± 0.9% of the time while affected dogs were in motion 4.6 ± 0.2% of the time ( p <  0.0001). Further, normal dogs made significantly more movements ( p <  0.0001) while affected dogs rested significantly longer ( p <  0.0001) during the period of recording (from 6 pm to 6 am next day). Importantly, statistical significance persisted irrespective of the coat color, gender and mutation type.

Conclusions:

Our results suggest that night activity reduction is a robust, quantitative physiological biomarker for dystrophic dogs. The new system may be applicable to study mobility in other species.
Mammalian Mss51 is a Skeletal Muscle-Specific Gene Modulating Cellular Metabolism
Authors: Moyer Adam L. , Wagner Kathryn R.
Published: November 2015

Background:

The transforming growth factor β (TGF-β) signaling pathways modulate skeletal muscle growth, regeneration, and cellular metabolism. Several recent gene expression studies have shown that inhibition of myostatin and TGF-β1 signaling consistently leads to a significant reduction in expression of Mss51, also named Zmynd17. The function of mammalian Mss51 is unknown although a putative homolog in yeast is a mitochondrial translational activator.

Objective:

The objective of this work was to characterize mammalian MSS51.

Methods:

Quantitative RT-PCR and immunoblot of subcellular fractionation were used to determine expression patterns and localization of Mss51. The CRISPR/Cas9 system was used to reduce expression of Mss51 in C2C12 myoblasts and the function of Mss51 was evaluated in assays of proliferation, differentiation and cellular metabolism.

Results:

Mss51 was predominantly expressed in skeletal muscle and in those muscles dominated by fast-twitch fibers. In vitro, its expression was upregulated upon differentiation of C2C12 myoblasts into myotubes. Expression of Mss51 was modulated in response to altered TGF-β family signaling. In human muscle, MSS51 localized to the mitochondria. Its genetic disruption resulted in increased levels of cellular ATP, β-oxidation, glycolysis, and oxidative phosphorylation.

Conclusions:

Mss51 is a novel, skeletal muscle-specific gene and a key target of myostatin and TGF-β1 signaling. Unlike myostatin, TGF-β1 and IGF-1, Mss51 does not regulate myoblast proliferation or differentiation. Rather, Mss51 appears to be one of the effectors of these growth factors on metabolic processes including fatty acid oxidation, glycolysis and oxidative phosphorylation.
Adult Onset Leigh Syndrome in the Intensive Care Setting: A Novel Presentation of a C12orf65 Related Mitochondrial Disease
Authors: Wesolowska Maria , Gorman Grainne S. , Alston Charlotte L. , Pajak Aleksandra , Pyle Angela , He Langping , Griffin Helen , Chinnery Patrick F. , Miller James A.L. , Schaefer Andrew M. , Taylor Robert W. , Lightowlers Robert N. , Chrzanowska-Lightowlers Zofia M.
Published: November 2015

Background:

Mitochondrial disease can present at any age, with dysfunction in almost any tissue making diagnosis a challenge. It can result from inherited or sporadic mutations in either the mitochondrial or the nuclear genome, many of which affect intraorganellar gene expression. The estimated prevalence of 1/4300 indicates these to be amongst the commonest inherited neuromuscular disorders, emphasising the importance of recognition of the diagnostic clinical features.

Objective:

Despite major advances in our understanding of the molecular basis of mitochondrial diseases, accurate and early diagnoses are critically dependent on the fastidious clinical and biochemical characterisation of patients. Here we describe a patient harbouring a previously reported homozygous mutation in C12orf65, a mitochondrial protein of unknown function, which does not adhere to the proposed distinct genotype-phenotype relationship.

Methods:

We performed clinical, biochemical and molecular analysis including whole exome sequencing on patient samples and cell lines.

Results:

We report an extremely rare case of an adult presenting with Leigh-like disease, in intensive care, in the 5th decade of life, harbouring a recessively inherited mutation previously reported in children. A global reduction in intra-mitochondrial protein synthesis was observed despite normal or elevated levels of mt-RNA, leading to an isolated complex IV deficiency.

Conclusions:

All the reported C12orf65 mutations have shown an autosomal recessive pattern of inheritance. Mitochondrial disease causing mutations inherited in this manner are usually of early onset and associated with a severe, often fatal clinical phenotype. Presentations in adulthood are usually less severe. This patient’s late adulthood presentation is in sharp contrast emphasising the clinical variability that is characteristic of mitochondrial disease and illustrates why making a definitive diagnosis remains a formidable challenge.
Efficacy and safety of goserelin combined with adjuvant chemotherapy in premenopausal women with breast cancer
Authors: Wang Yang , Zhu Zheng Fei , Pan Wei Jun , Xu Zhe
Published: November 2015

This study aims to evaluate the efficacy and safety of goserelin combined with chemotherapy for premenopausal women with breast cancer. Literatures were extracted from databases including Excerpta Medica Database, Springer, Pubmed, China National Knowledge Infrastructure and Chinese Biological Medicine from their inception up to May 2014. The main efficacy measures were 5 years overall survival (OS), 10 years OS, 5 years disease free survival and 5 years progress free survival. Ten randomized comparison clinical trials were eligible in this study. The result showed that goserelin combined with chemotherapy group can improve the survival rate and decrease the incidence of arthralgia in postmenopausal breast cancer patients, respectively, compared to the control group. However, they can increase the occurrence of vomiting during the chemotherapy process. Compared with the simple chemotherapy, goserelin combined with chemotherapy can provide benefits for premenopausal women with breast cancer on improving the survival rate and reducing arthralgia.

 
Genetic Dissection of Disease Resistance to the Blue Mold Pathogen, Peronospora tabacina, in Tobacco
Authors: Wu Xia , Li Dandan , Bao Yinguang , Zaitlin David , Miller Robert , Yang Shengming
Published: November 2015

Tobacco blue mold, caused by the obligately biotrophic oomycete pathogen Peronospora tabacina D.B. Adam, is a major foliar disease that results in significant losses in tobacco-growing areas. Natural resistance to P. tabacina has not been identified in any variety of common tobacco. Complete resistance, conferred by RBM1, was found in N. debneyi and was transferred into cultivated tobacco by crossing. In the present study, we characterized the RBM1-mediated resistance to blue mold in tobacco and show that the hypersensitive response (HR) plays an important role in the host defense reactions. Genetic mapping indicated that the disease resistance gene locus resides on chromosome 7. The genetic markers linked to this gene and the genetic map we generated will not only benefit tobacco breeders for variety improvement but will also facilitate the positional cloning of RBM1 for biologists.
Early Onset of Laying and Bumblefoot Favor Keel Bone Fractures
Authors: Gebhardt-Henrich Sabine , Fröhlich Ernst
Published: November 2015

Numerous studies have demonstrated influences of hybrid, feed, and housing on prevalence of keel bone fractures, but influences of behavior and production on an individual level are less known. In this longitudinal study, 80 white and brown laying hens were regularly checked for keel bone deviations and fractures while egg production was individually monitored using Radio Frequency Identification (RFID) from production until depopulation at 65 weeks of age. These focal birds were kept in eight pens with 20 hens per pen in total. About 62% of the hens had broken keel bones at depopulation. The occurrence of new fractures was temporally linked to egg laying: more new fractures occurred during the time when laying rates were highest. Hens with fractured keel bones at depopulation had laid their first egg earlier than hens with intact keel bones. However, the total number of eggs was neither correlated with the onset of egg laying nor with keel bone fractures. All birds with bumblefoot on both feet had a fracture at depopulation. Hens stayed in the nest for a longer time during egg laying during the ten days after the fracture than during the ten days before the fracture. In conclusion, a relationship between laying rates and keel bone fractures seems likely.
Enhancement of Spatial Resolution Using a Metamaterial Sensor in Nondestructive Evaluation
Authors: Savin Adriana , Bruma Alina , Steigmann Rozina , Iftimie Nicoleta , Faktorova Dagmar
Published: November 2015

The current stage of non-destructive evaluation techniques imposes the development of new electromagnetic methods that are based on high spatial resolution and increased sensitivity. Printed circuit boards, integrated circuit boards, composite materials with polymeric matrix containing conductive fibers, as well as some types of biosensors are devices of interest in using such evaluation methods. In order to achieve high performance, the work frequencies must be either radiofrequencies or microwaves. At these frequencies, at the dielectric/conductor interface, plasmon polaritons can appear, propagating between conductive regions as evanescent waves. Detection of these waves, containing required information, can be done using sensors with metamaterial lenses. We propose in this paper the enhancement of the spatial resolution using electromagnetic methods, which can be accomplished in this case using evanescent waves that appear in the current study in slits of materials such as the spaces between carbon fibers in Carbon Fibers Reinforced Plastics or in materials of interest in the nondestructive evaluation field with industrial applications, where microscopic cracks are present. We propose herein a unique design of the metamaterials for use in nondestructive evaluation based on Conical Swiss Rolls configurations, which assure the robust concentration/focusing of the incident electromagnetic waves (practically impossible to be focused using classical materials), as well as the robust manipulation of evanescent waves. Applying this testing method, spatial resolution of approximately λ/2000 can be achieved. This testing method can be successfully applied in a variety of applications of paramount importance such as defect/damage detection in materials used in a variety of industrial applications, such as automotive and aviation technologies.
Aberrant GLI1 Activation in DNA Damage Response, Carcinogenesis and Chemoresistance
Authors: Palle Komaraiah , Mani Chinnadurai , Tripathi Kaushlendra , Athar Mohammad
Published: November 2015

The canonical hedgehog (HH) pathway is a multicomponent signaling cascade (HH, protein patched homolog 1 (PTCH1), smoothened (SMO)) that plays a pivotal role during embryonic development through activation of downstream effector molecules, namely glioma-associated oncogene homolog 1 (GLI1), GLI2 and GLI3. Activation of GLIs must be tightly regulated as they modulate target genes which control tissue patterning, stem cell maintenance, and differentiation during development. However, dysregulation or mutations in HH signaling leads to genomic instability (GI) and various cancers, for example, germline mutation in PTCH1 lead to Gorlin syndrome, a condition where patients develop numerous basal cell carcinomas and rarely rhabdomyosarcoma (RMS). Activating mutations in SMO have also been recognized in sporadic cases of medulloblastoma and SMO is overexpressed in many other cancers. Recently, studies in several human cancers have shown that GLI1 expression is independent from HH ligand and canonical intracellular signaling through PTCH and SMO. In fact, this aberrantly regulated GLI1 has been linked to several non-canonical oncogenic growth signals such as Kirsten rat sarcoma viral oncogene homolog (KRAS), avian myelocytomatosis virus oncogene cellular homolog (C-MYC), transforming growth factor β (TGFβ), wingless-type MMTV integration site family (WNT) and β-catenin. Recent studies from our lab and other independent studies demonstrate that aberrantly expressed GLI1 influences the integrity of several DNA damage response and repair signals, and if altered, these networks can contribute to GI and impact tumor response to chemo- and radiation therapies. Furthermore, the ineffectiveness of SMO inhibitors in clinical studies argues for the development of GLI1-specific inhibitors in order to develop effective therapeutic modalities to treat these tumors. In this review, we focus on summarizing current understanding of the molecular, biochemical and cellular basis for aberrant GLI1 expression and discuss GLI1-mediated HH signaling on DNA damage responses, carcinogenesis and chemoresistance.
Species Distribution Model for Management of an Invasive Vine in Forestlands of Eastern Texas
Authors: Wang Hsiao-Hsuan , Koralewski Tomasz , McGrew Erin , Grant William , Byram Thomas
Published: November 2015

Invasive plants decrease biodiversity, modify vegetation structure, and inhibit growth and reproduction of native species. Japanese honeysuckle (Lonicera japonica Thunb.) is the most prevalent invasive vine in the forestlands of eastern Texas. Hence, we aimed to identify potential factors influencing the distribution of the species, quantify the relative importance of each factor, and test possible management strategies. We analyzed an extensive dataset collected as part of the Forest Inventory and Analysis Program of the United States Department of Agriculture (USDA) Forest Service to quantify the range expansion of Japanese honeysuckle in the forestlands of eastern Texas from 2006 to 2011. We then identified potential factors influencing the likelihood of presence of Japanese honeysuckle using boosted regression trees. Our results indicated that the presence of Japanese honeysuckle on sampled plots almost doubled during this period (from 352 to 616 plots), spreading extensively, geographically. The probability of invasion was correlated with variables representing landscape conditions, climatic conditions, forest features, disturbance factors, and forest management activities. Habitats most at risk to invasion under current conditions occurred primarily in northeastern Texas, with a few invasion hotspots in the south. Estimated probabilities of invasion were reduced most by artificial site regeneration, with habitats most at risk again occurring primarily in northeastern Texas.
Performance and Uncertainty Evaluation of Snow Models on Snowmelt Flow Simulations over a Nordic Catchment (Mistassibi, Canada)
Authors: Troin Magali , Arsenault Richard , Brissette François
Published: November 2015

An analysis of hydrological response to a multi-model approach based on an ensemble of seven snow models (SM; degree-day and mixed degree-day/energy balance models) coupled with three hydrological models (HM) is presented for a snowmelt-dominated basin in Canada. The present study aims to compare the performance and the reliability of different types of SM-HM combinations at simulating snowmelt flows over the 1961–2000 historical period. The multi-model approach also allows evaluating the uncertainties associated with the structure of the SM-HM ensemble to better predict river flows in Nordic environments. The 20-year calibration shows a satisfactory performance of the ensemble of 21 SM-HM combinations at simulating daily discharges and snow water equivalents (SWEs), with low streamflow volume biases. The validation of the ensemble of 21 SM-HM combinations is conducted over a 20-year period. Performances are similar to the calibration in simulating the daily discharges and SWEs, again with low model biases for streamflow. The spring-snowmelt-generated peak flow is captured only in timing by the ensemble of 21 SM-HM combinations. The results of specific hydrologic indicators show that the uncertainty related to the choice of the given HM in the SM-HM combinations cannot be neglected in a more quantitative manner in simulating snowmelt flows. The selection of the SM plays a larger role than the choice of the SM approach (degree-day versus mixed degree-day/energy balance) in simulating spring flows. Overall, the snow models provide a low degree of uncertainty to the total uncertainty in hydrological modeling for snow hydrology studies.
Indoor Air Contamination from Hazardous Waste Sites: Improving the Evidence Base for Decision-Making
Authors: Johnston Jill , MacDonald Gibson Jacqueline
Published: November 2015

At hazardous waste sites, volatile chemicals can migrate through groundwater and soil into buildings, a process known as vapor intrusion. Due to increasing recognition of vapor intrusion as a potential indoor air pollution source, in 2015 the U.S. Environmental Protection Agency (EPA) released a new vapor intrusion guidance document. The guidance specifies two conditions for demonstrating that remediation is needed: (1) proof of a vapor intrusion pathway; and (2) evidence that human health risks exceed established thresholds (for example, one excess cancer among 10,000 exposed people). However, the guidance lacks details on methods for demonstrating these conditions. We review current evidence suggesting that monitoring and modeling approaches commonly employed at vapor intrusion sites do not adequately characterize long-term exposure and in many cases may underestimate risks. On the basis of this evidence, we recommend specific approaches to monitoring and modeling to account for these uncertainties. We propose a value of information approach to integrate the lines of evidence at a site and determine if more information is needed before deciding whether the two conditions specified in the vapor intrusion guidance are satisfied. To facilitate data collection and decision-making, we recommend a multi-directional community engagement strategy and consideration of environment justice concerns.
The MARINA Risk Assessment Strategy: A Flexible Strategy for Efficient Information Collection and Risk Assessment of Nanomaterials
Authors: Bos Peter , Gottardo Stefania , Scott-Fordsmand Janeck , Van Tongeren Martie , Semenzin Elena , Fernandes Teresa , Hristozov Danail , Hund-Rinke Kerstin , Hunt Neil , Irfan Muhammad-Adeel , Landsiedel Robert , Peijnenburg Willie , Sánchez Jiménez Araceli , Van Kesteren Petra , Oomen Agnes
Published: November 2015

An engineered nanomaterial (ENM) may actually consist of a population of primary particles, aggregates and agglomerates of various sizes. Furthermore, their physico-chemical characteristics may change during the various life-cycle stages. It will probably not be feasible to test all varieties of all ENMs for possible health and environmental risks. There is therefore a need to further develop the approaches for risk assessment of ENMs. Within the EU FP7 project Managing Risks of Nanoparticles (MARINA) a two-phase risk assessment strategy has been developed. In Phase 1 (Problem framing) a base set of information is considered, relevant exposure scenarios (RESs) are identified and the scope for Phase 2 (Risk assessment) is established. The relevance of an RES is indicated by information on exposure, fate/kinetics and/or hazard; these three domains are included as separate pillars that contain specific tools. Phase 2 consists of an iterative process of risk characterization, identification of data needs and integrated collection and evaluation of data on the three domains, until sufficient information is obtained to conclude on possible risks in a RES. Only data are generated that are considered to be needed for the purpose of risk assessment. A fourth pillar, risk characterization, is defined and it contains risk assessment tools. This strategy describes a flexible and efficient approach for data collection and risk assessment which is essential to ensure safety of ENMs. Further developments are needed to provide guidance and make the MARINA Risk Assessment Strategy operational. Case studies will be needed to refine the strategy.
Weather Conditions, Weather Information and Car Crashes
Authors: Perrels Adriaan , Votsis Athanasios , Nurmi Väinö , Pilli-Sihvola Karoliina
Published: November 2015

Road traffic safety is the result of a complex interaction of factors, and causes behind road vehicle crashes require different measures to reduce their impacts. This study assesses how strongly the variation in daily winter crash rates associates with weather conditions in Finland. This is done by illustrating trends and spatiotemporal variation in the crash rates, by showing how a GIS application can evidence the association between temporary rises in regional crash rates and the occurrence of bad weather, and with a regression model on crash rate sensitivity to adverse weather conditions. The analysis indicates that a base rate of crashes depending on non-weather factors exists, and some combinations of extreme weather conditions are able to substantially push up crash rates on days with bad weather. Some spatial causation factors, such as variation of geophysical characteristics causing systematic differences in the distributions of weather variables, exist. Yet, even in winter, non-spatial factors are normally more significant. GIS data can support optimal deployment of rescue services and enhance in-depth quantitative analysis by helping to identify the most appropriate spatial and temporal resolutions. However, the supportive role of GIS should not be inferred as existence of highly significant spatial causation.
Characterization of Aspartate Kinase from Corynebacterium pekinense and the Critical Site of Arg169
Authors: Min Weihong , Li Huiying , Li Hongmei , Liu Chunlei , Liu Jingsheng
Published: November 2015

Aspartate kinase (AK) is the key enzyme in the biosynthesis of aspartate-derived amino acids. Recombinant AK was efficiently purified and systematically characterized through analysis under optimal conditions combined with steady-state kinetics study. Homogeneous AK was predicted as a decamer with a molecular weight of ~48 kDa and a half-life of 4.5 h. The enzymatic activity was enhanced by ethanol and Ni2+. Moreover, steady-state kinetic study confirmed that AK is an allosteric enzyme, and its activity was inhibited by allosteric inhibitors, such as Lys, Met, and Thr. Theoretical results indicated the binding mode of AK and showed that Arg169 is an important residue in substrate binding, catalytic domain, and inhibitor binding. The values of the kinetic parameter Vmax of R169 mutants, namely, R169Y, R169P, R169D, and R169H AK, with l-aspartate as the substrate, were 4.71-, 2.25-, 2.57-, and 2.13-fold higher, respectively, than that of the wild-type AK. Furthermore, experimental and theoretical data showed that Arg169 formed a hydrogen bond with Glu92, which functions as the entrance gate. This study provides a basis to develop new enzymes and elucidate the corresponding amino acid production.
Metagenomic Analysis of Upwelling-Affected Brazilian Coastal Seawater Reveals Sequence Domains of Type I PKS and Modular NRPS
Authors: Cuadrat Rafael , Cury Juliano , Dávila Alberto
Published: November 2015

Marine environments harbor a wide range of microorganisms from the three domains of life. These microorganisms have great potential to enable discovery of new enzymes and bioactive compounds for industrial use. However, only ~1% of microorganisms from the environment can currently be identified through cultured isolates, limiting the discovery of new compounds. To overcome this limitation, a metagenomics approach has been widely adopted for biodiversity studies on samples from marine environments. In this study, we screened metagenomes in order to estimate the potential for new natural compound synthesis mediated by diversity in the Polyketide Synthase (PKS) and Nonribosomal Peptide Synthetase (NRPS) genes. The samples were collected from the Praia dos Anjos (Angel’s Beach) surface water—Arraial do Cabo (Rio de Janeiro state, Brazil), an environment affected by upwelling. In order to evaluate the potential for screening natural products in Arraial do Cabo samples, we used KS (keto-synthase) and C (condensation) domains (from PKS and NRPS, respectively) to build Hidden Markov Models (HMM) models. From both samples, a total of 84 KS and 46 C novel domain sequences were obtained, showing the potential of this environment for the discovery of new genes of biotechnological interest. These domains were classified by phylogenetic analysis and this was the first study conducted to screen PKS and NRPS genes in an upwelling affected sample