bluuebunny/crossref_metadata_2025 huggingface dataset:
An Efficient Synthesis of Some Novel 3‐Cyano‐4‐imino‐2‐(methylthio)4H‐pyrido[1,2‐a]pyrimidine and Their Derivatives
Authors: Vartale Sambhaji P. , Halikar Nilesh K. , Sirsat Shivraj B. , Pawar Yogesh D.
Published: March 2013

Pyrazolo pyrimido pyrimidine (4a–k) was prepared by the reaction of compound 3‐cyano‐4‐imino‐2‐(methylthio)4H‐pyrido[1,2‐a]pyrimidine (3) with hydrazine hydrate, phenyl hydrazine, 2‐hydrazino benzothiazole, and 6‐substituted hydrazine benzothiazole in N,N‐dimethylformamide and anhydrous potassium carbonate. These synthesized compounds were characterized by elemental analysis IR, 1H NMR, and mass spectral data.
Functional improvement in hospitalized older adults is independent of dementia diagnosis: Experience of a specialized delirium management unit
Authors: Bee Gek Tay Laura , Chew Chan Mark Peng , Sian Chong Mei
Published: March 2013

BACKGROUND

Patients with delirium, especially when superimposed on dementia, are at high risk of functional decline.

OBJECTIVE

To examine the influence of a multicomponent delirium management program, the geriatric monitoring unit (GMU), on functional progress of delirious older patients and the impact of underlying dementia on functional recovery.

DESIGN

Prospective cohort study.

SETTING

The GMU is a specialized 5‐bed unit for the care of delirious older adults within an acute tertiary hospital.

PATIENTS

Patients aged 65 years and older with delirium.

INTERVENTION

The GMU is a multifactorial delirium treatment program with core interventions focusing on early mobilization and rehabilitation.

MEASUREMENTS

Baseline measures included delirium severity (Delirium Rating Scale‐98 and Confusion Assessment Method severity), Chinese Mini‐Mental State Examination, functional status (modified Barthel Index [MBI]), comorbidity (Charlson's), and illness severity (modified Severity of Illness Index). Patients with and without dementia were compared for recovery in cognitive scores and functional status.

RESULTS

Of 122 patients with delirium who were admitted to the GMU over a 1‐year period, 82 (67.2%) had underlying dementia. There were no significant differences in age, gender, delirium severity, illness severity, cognitive performance, and functional status at admission to the GMU between groups, although patients with dementia had significantly higher comorbidity (Charlson's 2.27 vs 1.75, P = 0.05). Significant cognitive and functional improvement was observed for the entire GMU cohort, with demented and nondemented groups capable of functional recovery (MBI gain of 20.43 vs 17.35, respectively, P = 0.35).

CONCLUSION

Elderly patients with dementia recovering from delirium have comparable potential for functional recovery as their cognitively intact counterparts in a delirium management unit focused on geriatric nursing care and rehabilitation. Journal of Hospital Medicine 2013;8:321–327. © 2013 Society of Hospital Medicine
Preischemic exercise reduces brain damage by ameliorating metabolic disorder in ischemia/reperfusion injury
Authors: Dornbos David , Zwagerman Nathan , Guo Miao , Ding Jamie Y. , Peng Changya , Esmail Fatema , Sikharam Chaitanya , Geng Xiaokun , Guthikonda Murali , Ding Yuchuan
Published: March 2013

Physical exercise preconditioning is known to ameliorate stroke‐induced injury. In addition to several other mechanisms, the beneficial effect of preischemic exercise following stroke is due to an upregulated capacity to maintain energy supplies. Adult male Sprague‐Dawley rats were used in exercise and control groups. After 1–3 weeks of exercise, several enzymes were analyzed as a gauge of the direct effect of physical exercise on cerebral metabolism. As a measure of metabolic capacity, an ADP/ATP ratio was obtained. Glucose transporters (GLUT1 and GLUT3) were monitored to assess glucose influx, and phosphofructokinase (PFK) was measured to determine the rate of glycolysis. Hypoxia‐induced factor‐1α (HIF‐1α) and 5′AMP‐activated protein kinase (AMPK) levels were also determined. These same analyses were performed on preconditioned and control rats following an ischemic/reperfusion (I/R) insult. Our results show that GLUT1, GLUT3, PFK, AMPK, and HIF‐1α were all increased following 3 weeks of exercise training. In addition, the ADP/ATP ratio was chronically elevated during these 3 weeks. After I/R injury, HIF‐1α and AMPK were significantly higher in exercised rats. The ADP/ATP ratio was reduced in preconditioned rats in the acute phase after stroke, suggesting a lower level of metabolic disorder. GLUT1 and GLUT3 were also increased in the acute phase in exercise rats, indicating that these rats were better able to increase rates of metabolism immediately after ischemic injury. In addition, PFK expression was increased in exercise rats showing an enhanced glycolysis resulting from exercise preconditioning. Altogether, exercise preconditioning increased the rates of glucose metabolism, allowing a more rapid and more substantial increase in ATP production following stroke. © 2013 Wiley Periodicals, Inc.
Reduced extracellular zinc levels facilitate glutamate‐mediated oligodendrocyte death after trauma
Authors: Johnstone Joshua T. , Morton Paul D. , Jayakumar Arumugam R. , Bracchi‐Ricard Valerie , Runko Erik , Liebl Daniel J. , Norenberg Michael D. , Bethea John R.
Published: March 2013

Spinal cord injury results in irreversible paralysis, axonal injury, widespread oligodendrocyte death, and white matter damage. Although the mechanisms underlying these phenomena are poorly understood, previous studies from our laboratory indicate that inhibiting activation of the nuclear factor‐κB transcription factor in astrocytes reduces white matter damage and improves functional recovery following spinal cord injury. In the current study, we demonstrate that activation of the nuclear factor‐κB transcription factor within astrocytes results in a significant increase in oligodendrocyte death following trauma by reducing extracellular zinc levels and inducing glutamate excitotoxicity. By using an ionotropic glutamate receptor antagonist (CNQX), we show that astroglial nuclear factor‐κB‐mediated oligodendrocyte death is dependent on glutamate signaling despite no change in extracellular glutamate concentrations. Further analysis demonstrated a reduction in levels of extracellular zinc in astrocyte cultures with functional nuclear factor‐κB signaling following trauma. Cotreatment of oligodendrocytes with glutamate and zinc showed a significant increase in oligodendrocyte toxicity under low‐zinc conditions, suggesting that the presence of zinc at specific concentrations can prevent glutamate excitotoxicity. These studies demonstrate a novel role for zinc in regulating oligodendrocyte excitotoxicity and identify new therapeutic targets to prevent oligodendrocyte cell death in central nervous system trauma and disease. © 2013 Wiley Periodicals, Inc.
Behavioral and structural effects of unilateral intrastriatal injections of botulinum neurotoxin a in the rat model of Parkinson's disease
Authors: Antipova Veronica , Hawlitschka Alexander , Mix Eilhard , Schmitt Oliver , Dräger Désirée , Benecke Reiner , Wree Andreas
Published: March 2013

Botulinum neurotoxin (BoNT) inhibits the release of acetylcholine from presynaptic vesicles through its proteinase activity cleaving the SNARE complex. Parkinson's disease (PD) is associated with locally increased cholinergic activity in the striatum. Therefore, the present study investigates the effect of unilateral intrastriatal BoNT‐A injection in naïve rats on striatal morphology; i.e., the total number of Nissl‐stained neurons and the volume of caudate‐putamen (CPu) were estimated. Furthermore, stainings for markers of gliosis (glial fibrillary acidic protein) and microglia (Iba1) were performed. In addition, the potential beneficial effects of a unilateral intrastriatal injection of BoNT‐A on motor activity in the rat model of hemi‐PD were evaluated. Hemi‐PD was induced by unilateral injection of 6‐hydroxydopamine (6‐OHDA) into the right medial forebrain bundle. Six weeks later, rats received an ipsilateral intrastriatal injection of BoNT‐A. Behaviorally, motor performance was tested. The total number of CPu neurons and the striatal volume were not significantly different between the BoNT‐A‐injected right and the intact left hemispheres of naïve rats. In hemi‐PD rats, intrastriatal BoNT‐A abolished apomorphine‐induced rotations, increased amphetamine‐induced rotations, and tended to improve left forelimb usage. Forced motor function in the accelerod test was not significantly changed by BoNT‐A, and open field activity was also unaltered compared with sham treatment. Thus, intrastriatal BoNT‐A affects spontaneous motor activity of hemi‐PD rats to a minor degree compared with drug‐induced motor function. In the future, tests assessing the cognitive and emotional performance should be performed to ascertain finally the potential therapeutic usefulness of intrastriatal BoNT‐A for PD. © 2013 Wiley Periodicals, Inc.
Spinal astrocytes stimulated by tumor necrosis factor‐α and/or interferon‐γ attenuate connexin 43‐gap junction via c‐jun terminal kinase activity
Authors: Zhang Fang Fang , Morioka Norimitsu , Nakashima‐Hisaoka Kazue , Nakata Yoshihiro
Published: March 2013

Spinal astrocytes have important mechanistic contributions to the initiation and maintenance of neurodegenerative diseases and chronic pain. Under inflammatory conditions, spinal astrocytes are exposed to cytokines such as tumor necrosis factor‐α (TNF‐α) and interferon‐γ (IFN‐γ), and these cytokines could alter astrocytic function by modulating connexin (Cx43), subunits that form channels that modulate intercellular communication in astrocytes. The current study investigated the alteration of Cx43‐gap junction in rat primary cultured spinal astrocytes stimulated with cytokines by real‐time PCR and Western blotting. The transcriptional and translational levels of Cx43 were significantly but partially reduced 24 and 48 hr treatment with either TNF‐α (10 ng/ml) or IFN‐γ (5 ng/ml). A mixture of TNF‐α and IFN‐γ led to a robust decrease of Cx43 expression and, moreover, a moderate reduction of gap junction intercellular communication (GJIC), which was evaluated by a scrap loading/dye transfer assay. Both the decrease of Cx43 expression and the reduction in GJIC induced by the mixture of TNF‐α and IFN‐γ were prevented by blocking c‐jun terminal kinase (JNK) but not by blocking extracellular signaling molecules ERK and p38 kinase, indicating a specific role of astrocytic JNK in the response to cytokines. In addition, treatment with cytokines potently induced the phosphorylation of JNK and c‐jun in a time‐dependent manner. These results indicate that intercellular communication of astrocytes is significantly disrupted in the inflammatory state and that stimulation of spinal astrocytes with inflammatory cytokines leads to significant inhibition of Cx43‐GJIC through activation of the JNK signaling pathway. © 2013 Wiley Periodicals, Inc.
Hyperglycemia magnifies bupivacaine‐induced cell apoptosis triggered by mitochondria dysfunction and endoplasmic reticulum stress
Authors: Li Le , Ye Xiao‐ping , Lu Ai‐zhu , Zhou Shu‐qin , Liu Hui , Liu Zhong‐jie , Jiang Shan , Xu Shi‐yuan
Published: March 2013

Nerve cell injury associated with apoptosis plays an important role in the development of diabetic peripheral neuropathy (DPN). However, it remains unclear whether preexisting or potential neurocyte damage induced by hyperglycemia increases sensitivity to local anesthetics. SH‐SY5Y cells were pretreated with a high concentration of glucose in vitro, to imitate DPN prior to administration of bupivacaine or placebo. Cell viability and apoptosis were investigated with a CCK‐8 assay and flow cytometry, respectively. In addition, mitochondrial membrane potential, reactive oxygen species (ROS), mitochondrially generated ROS, and activity of mitochondrial complexes I and III were studied to explore the molecular mechanism of bupivacaine‐induced mitochondrial injury. Grp78 and caspase‐12 expression were measured by qRT‐PCR and Western blot, representing endoplasmic reticulum (ER) stress. Cell structure was also assessed via transmission electron microscopy. Incubation with bupivacaine decreased the activity of mitochondrial complexes I and III; increased ROS production at cell and mitochondrial levels, mitochondrial potential depolarization, and Grp78 and caspase‐12 expression at both transcription and translation levels; and affected cell structure, which could be enhanced by glucose pretreatment. These findings indicate that mitochondrial dysfunction and ER stress related to ROS are involved in bupivacaine‐induced apoptosis and may be enhanced by glucose administration. © 2013 Wiley Periodicals, Inc.
Utility of skin biopsy in management of small fiber neuropathy
Authors: Boruchow Scott A. , Gibbons Christopher H.
Published: March 2013

Introduction: We examined the role of skin biopsy in the evaluation and management of patients with suspected small fiber neuropathy (SFN). Methods: A retrospective chart review was performed among all patients who underwent skin biopsy for evaluation of SFN at our institution between March 2008 and March 2011. Change in management was defined as a new diagnosis or change in treatment in response to both positive and negative skin biopsies. Results: Among 69 patients who underwent skin biopsy, 25 had pathological evidence of an SFN, and 9 had evidence of borderline SFN. Change in management or diagnosis occurred in 14 of 25 patients with definite SFN, 6 of 9 patients with borderline SFN, and 16 of 35 biopsy negative patients. Conclusions: Skin biopsy changed management or diagnosis in 52% of patients evaluated for a possible SFN and appears to play a valuable role in the workup of these patients. Muscle Nerve 48: 877–882, 2013
Coloring–decoloring behavior of fluoroalkyl end‐capped 2‐acrylamido‐2‐methylpropanesulfonic acid oligomer/acetone composite in methanol
Authors: Kijima Tetsushi , Nishida Masakazu , Fukaya Haruhiko , Yoshida Masato , Sawada Hideo
Published: March 2013

A reddish‐brown fluoroalkyl end‐capped 2‐acrylamido‐2‐methylpropanesulfonic acid (AMPS) oligomer/acetone composite was prepared by heating the white oligomer powder with acetone at 80 °C for 3 h. The color was not observed in the corresponding non‐fluorinated AMPS oligomer/acetone composite, which was prepared under similar conditions. The coloring was probably caused by the formation of acetone polyaldol condensation products in the fluorinated oligomeric gel network cores. The colored RF‐(AMPS)n‐RF/acetone composite powders were stable and did not exhibit any color change after 2 years in natural light at room temperature. The colored composite powders dissolved in methanol to give a reddish‐brown solution at room temperature. However, the retro‐polyaldol condensation decolored the solution after 1 day at room temperature. This is the first example of the retro‐aldol polycondensation of acetone under mild conditions. The decoloration increased by between 38‐ and 70‐fold under UV irradiation, compared with that in dark conditions. The coloring–decoloring behavior was consistent and repeatable; therefore our fluorinated oligomer/acetone composites are promising candidates for new fluorinated coloring materials. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 2555–2564
One‐pot synthesis of composite microspheres with core‐shell structure
Authors: Gong Yi , Liu Qing Lin , Zhu Ai Mei , Zhang Qiu Gen
Published: March 2013

One‐pot synthesis of thermoresponsive magnetic composite microspheres with a poly(N‐isopropylacrylamide) (PNIPAM) shell and a Fe3O4 core is demonstrated. Temperature sensitivity of PNIPAM was adopted to design the novel synthesis pathway. The as‐prepared composite microspheres have an obvious core‐shell structure with a mean size of approximately 250 nm. The Fe3O4 core is approximately 5 nm and the thickness of the PNIPAM shell is approximately 10 nm. The content of Fe3O4 in the composite microspheres can be controlled by this method. The composite microspheres experience a swelling and shrinking process in water by adjusting the temperature below and above the lower critical solution temperature (LCST) around 32 °C. These microspheres also show fine response to an external magnetic field. This work presents a platform to synthesize organic/inorganic composite microspheres in a facile and efficient approach. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 2702–2708
Liquid crystal functionalization of electrospun polymer fibers
Authors: Kim Dae Kyom , Hwang Minsik , Lagerwall Jan P. F.
Published: March 2013

A recently introduced new branch of applied polymer science is the production of highly functional and responsive fiber mats by means of electrospinning polymers that include liquid crystals. The liquid crystal, which provides the responsiveness, is most often contained inside fibers of core‐sheath geometry, produced via coaxial electrospinning, but it may also be inherent to the polymer itself, for example, in case of liquid crystal elastomers. The first experiments served as proof of concept and to elucidate the basic behavior of the liquid crystal in the fibers, and the field is now ripe for more applied research targeting novel devices, in particular in the realm of wearable technology. In this perspective, we provide a bird's eye view of the current state of the art of liquid crystal electrospinning, as well as of some relevant recent developments in the general electrospinning and liquid crystal research areas, allowing us to sketch a picture of where this young research field and its applications may be heading in the next few years. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part B Polym. Phys. 2013, 51, 855–867
Tracking trade transactions in water resource systems: A node‐arc optimization formulation
Authors: Erfani Tohid , Huskova Ivana , Harou Julien J.
Published: March 2013

Key Points

arc‐path and node‐arc formulations can track transactions in water networks

formulation allows converting existing arc‐node hydro‐economic models

node‐arc formulation builds larger models but with easier data management
Toward a quantitative understanding of the Wnt/β‐catenin pathway through simulation and experiment
Authors: Lloyd‐Lewis Bethan , Fletcher Alexander G. , Dale Trevor C. , Byrne Helen M.
Published: March 2013

Wnt signaling regulates cell survival, proliferation, and differentiation throughout development and is aberrantly regulated in cancer. The pathway is activated when Wnt ligands bind to specific receptors on the cell surface, resulting in the stabilization and nuclear accumulation of the transcriptional co‐activator β‐catenin. Mathematical and computational models have been used to study the spatial and temporal regulation of the Wnt/β‐catenin pathway and to investigate the functional impact of mutations in key components. Such models range in complexity, from time‐dependent, ordinary differential equations that describe the biochemical interactions between key pathway components within a single cell, to complex, multiscale models that incorporate the role of the Wnt/β‐catenin pathway target genes in tissue homeostasis and carcinogenesis. This review aims to summarize recent progress in mathematical modeling of the Wnt pathway and to highlight new biological results that could form the basis for future theoretical investigations designed to increase the utility of theoretical models of Wnt signaling in the biomedical arena. WIREs Syst Biol Med 2013, 5:391–407. doi: 10.1002/wsbm.1221

This article is categorized under:

Biological Mechanisms > Cell Signaling

Developmental Biology > Lineages

Models of Systems Properties and Processes > Mechanistic Models
Slipped capital femoral epiphysis and its association with endocrine, metabolic and chronic diseases: A systematic review of the literature
Authors: Witbreuk M. , van Kemenade F. J. , van der Sluijs J. A. , Jansma E. P. , Rotteveel J. , van Royen B. J.
Published: March 2013

Purpose

Puberty, obesity, endocrine and chronic systemic diseases are known to be associated with slipped capital femoral epiphysis (SCFE). The mechanical insufficiency of the physis in SCFE is thought to be the result of an abnormal weakening of the physis. However, the mechanism at the cellular level has not been unravelled up to now.

Methods

To understand the pathophysiology of endocrine and metabolic factors acting on the physis, we performed a systematic review focussing on published studies reporting on hormonal, morphological and cellular abnormalities of the physis in children with SCFE. In addition, we looked for studies of the effects of endocrinopathies on the human physis which can lead to cause SCFE and focussed in detail on hormonal signalling, hormone receptor expression and extracellular matrix (ECM) composition of the physis. We searched in the PubMed, EMBASE.com and The Cochrane Library (via Wiley) databases from inception to 11th September 2012. The search generated a total of 689 references: 382 in PubMed, 232 in EMBASE.com and 75 in The Cochrane Library. After removing duplicate papers, 525 papers remained. Of these, 119 were selected based on titles and abstracts. After excluding 63 papers not related to the human physis, 56 papers were included in this review.

Results

Activation of the gonadal axis and the subsequent augmentation of the activity of the growth hormone–insulin-like growth factor 1 (GH-IGF-1) axis are important for the pubertal growth spurt, as well as for cessation of the physis at the end of puberty. The effects of leptin, thyroid hormone and corticosteroids on linear growth and on the physis are also discussed. Children with chronic diseases suffer from inflammation, acidosis and malnutrition. These consequences of chronic diseases affect the GH-IGF-1 axis, thereby, increasing the risk of the development of SCFE. The risk of SCFE and avascular necrosis in children with chronic renal insufficiency, growth hormone treatment and renal osteodystrophy remains equivocal.

Conclusions

SCFE is most likely the result of a multi-factorial event during adolescence when height and weight increase dramatically and the delicate balance between the various hormonal equilibria can be disturbed. Up to now, there are no screening or diagnostic tests available to predict patients at risk.
HDAC inhibitors prevent the induction of the immediate‐early gene FOSL1, but do not alter the nucleosome response
Authors: Khan Dilshad H. , Davie James R.
Published: March 2013

Dynamic histone acetylation, catalyzed by lysine acetyltransferases and HDACs, is critical to IEG expression. Expression of IEGs, such as FOSL1, is induced by several signal transduction pathways resulting in activation of the protein kinase MSK and phosphorylation of histone H3 at serine 10 of nucleosomes (the nucleosome response) at the upstream promoter and regulatory region of target genes. HDAC inhibitors prevent FOSL1 gene induction and the association of HDAC1, 2 and 3 with the gene body. However, HDAC inhibitors did not prevent the nucleosome response. Thus HDAC inhibitors perturb events downstream of the nucleosome response required for FOSL1 transcription initiation.
In vitro characterization of the RS motif in N‐terminal head domain of goldfish germinal vesicle lamin B3 necessary for phosphorylation of the p34cdc2 target serine by SRPK1
Authors: Yamaguchi Akihiko , Iwatani Miho , Ogawa Mariko , Kitano Hajime , Matsuyama Michiya
Published: March 2013

The nuclear envelopes surrounding the oocyte germinal vesicles of lower vertebrates (fish and frog) are supported by the lamina, which consists of the protein lamin B3 encoded by a gene found also in birds but lost in the lineage leading to mammals. Like other members of the lamin family, goldfish lamin B3 (gfLB3) contains two putative consensus phosphoacceptor p34cdc2 sites (Ser‐28 and Ser‐398) for the M‐phase kinase to regulate lamin polymerization on the N‐ and C‐terminal regions flanking a central rod domain. Partial phosphorylation of gfLB3 occurs on Ser‐28 in the N‐terminal head domain in immature oocytes prior to germinal vesicle breakdown, which suggests continual rearrangement of lamins by a novel lamin kinase in fish oocytes. We applied the expression‐screening method to isolate lamin kinases by using phosphorylation site Ser‐28‐specific monoclonal antibody and a vector encoding substrate peptides from a goldfish ovarian cDNA library. As a result, SRPK1 was screened as a prominent lamin kinase candidate. The gfLB3 has a short stretch of the RS repeats (9‐SRASTVRSSRRS‐20) upstream of the Ser‐28, within the N‐terminal head. This stretch of repeats is conserved among fish lamin B3 but is not found in other lamins. In vitro phosphorylation studies and GST‐pull down assay revealed that SRPK1 bound to the region of sequential RS repeats (9–20) with affinity and recruited serine into the active site by a grab‐and‐pull manner. These results indicate SRPK1 may phosphorylate the p34cdc2 site in the N‐terminal head of GV‐lamin B3 at the RS motifs, which have the general property of aggregation.
Earth’s land surface temperature trends: A new approach confirms previous results
Authors: Levi Barbara Goss
Published: March 2013

The newcomers to the task looked at many more weather stations and used a geostatistics technique to adjust for data discontinuities.
Neural mechanisms underlying heterogeneity in the presentation of anxious temperament
Authors: Shackman Alexander J. , Fox Andrew S. , Oler Jonathan A. , Shelton Steven E. , Davidson Richard J. , Kalin Ned H.
Published: March 2013

Children with an anxious temperament (AT) are at risk for developing psychiatric disorders along the internalizing spectrum, including anxiety and depression. Like these disorders, AT is a multidimensional phenotype and children with extreme anxiety show varying mixtures of physiological, behavioral, and other symptoms. Using a well-validated juvenile monkey model of AT, we addressed the degree to which this phenotypic heterogeneity reflects fundamental differences or similarities in the underlying neurobiology. The rhesus macaque is optimal for studying AT because children and young monkeys express the anxious phenotype in similar ways and have similar neurobiology. Fluorodeoxyglucose (FDG)-positron emission tomography (FDG-PET) in 238 freely behaving monkeys identified brain regions where metabolism predicted variation in three dimensions of the AT phenotype: hypothalamic-pituitary-adrenal (HPA) activity, freezing behavior, and expressive vocalizations. We distinguished brain regions that predicted all three dimensions of the phenotype from those that selectively predicted a single dimension. Elevated activity in the central nucleus of the amygdala and the anterior hippocampus was consistently found across individuals with different presentations of AT. In contrast, elevated activity in the lateral anterior hippocampus was selective to individuals with high levels of HPA activity, and decreased activity in the motor cortex (M1) was selective to those with high levels of freezing behavior. Furthermore, activity in these phenotype-selective regions mediated relations between amygdala metabolism and different expressions of anxiety. These findings provide a framework for understanding the mechanisms that lead to heterogeneity in the clinical presentation of internalizing disorders and set the stage for developing improved interventions.
Rapid electron exchange between surface-exposed bacterial cytochromes and Fe(III) minerals
Authors: White Gaye F. , Shi Zhi , Shi Liang , Wang Zheming , Dohnalkova Alice C. , Marshall Matthew J. , Fredrickson James K. , Zachara John M. , Butt Julea N. , Richardson David J. , Clarke Thomas A.
Published: March 2013

The mineral-respiring bacterium
Shewanella oneidensis
uses a protein complex, MtrCAB, composed of two decaheme cytochromes, MtrC and MtrA, brought together inside a transmembrane porin, MtrB, to transport electrons across the outer membrane to a variety of mineral-based electron acceptors. A proteoliposome system containing a pool of internalized electron carriers was used to investigate how the topology of the MtrCAB complex relates to its ability to transport electrons across a lipid bilayer to externally located Fe(III) oxides. With MtrA facing the interior and MtrC exposed on the outer surface of the phospholipid bilayer, the established in vivo orientation, electron transfer from the interior electron carrier pool through MtrCAB to solid-phase Fe(III) oxides was demonstrated. The rates were 10
3
times higher than those reported for reduction of goethite, hematite, and lepidocrocite by
S. oneidensis
, and the order of the reaction rates was consistent with those observed in
S. oneidensis
cultures. In contrast, established rates for single turnover reactions between purified MtrC and Fe(III) oxides were 10
3
times lower. By providing a continuous flow of electrons, the proteoliposome experiments demonstrate that conduction through MtrCAB directly to Fe(III) oxides is sufficient to support in vivo, anaerobic, solid-phase iron respiration.
Improved ancestry inference using weights from external reference panels
Authors: Chen Chia-Yen , Pollack Samuela , Hunter David J. , Hirschhorn Joel N. , Kraft Peter , Price Alkes L.
Published: March 2013

Motivation: Inference of ancestry using genetic data is motivated by applications in genetic association studies, population genetics and personal genomics. Here, we provide methods and software for improved ancestry inference using genome-wide single nucleotide polymorphism (SNP) weights from external reference panels. This approach makes it possible to leverage the rich ancestry information that is available from large external reference panels, without the administrative and computational complexities of re-analyzing the raw genotype data from the reference panel in subsequent studies.

Results: We extensively validate our approach in multiple African American, Latino American and European American datasets, making use of genome-wide SNP weights derived from large reference panels, including HapMap 3 populations and 6546 European Americans from the Framingham Heart Study. We show empirically that our approach provides much greater accuracy than either the prevailing ancestry-informative marker (AIM) approach or the analysis of genome-wide target genotypes without a reference panel. For example, in an independent set of 1636 European American genome-wide association study samples, we attained prediction accuracy (R2) of 1.000 and 0.994 for the first two principal components using our method, compared with 0.418 and 0.407 using 150 published AIMs or 0.955 and 0.003 by applying principal component analysis directly to the target samples. We finally show that the higher accuracy in inferring ancestry using our method leads to more effective correction for population stratification in association studies.

Availability: The SNPweights software is available online at http://www.hsph.harvard.edu/faculty/alkes-price/software/.

Contact:  aprice@hsph.harvard.edu or cychen@mail.harvard.edu.

Supplementary information:  Supplementary data are available at Bioinformatics online.
An upper limit to the sodium layer longitudinal and transversal altitude structure function from MCAO data
Authors: Rigaut F. , Neichel B.
Published: March 2013

The Gemini Multi-Conjugate Adaptive Optics System is the first sodium-based Multi-Laser Guide Star (LGS) Adaptive Optics system used for astronomy. It uses five LGSs distributed on a 1 arcmin2 constellation to measure and compensate for atmospheric distortions. In this Letter, we use the LGS wavefront sensor data to derive the amount of differential focus caused by horizontal sodium layer structures, which we call the focus excess (because it comes in addition to the turbulent part). Based on data accumulated at a rate of around 1 week per month during a period of 1 year, we derive an upper limit of the focus excess of 15 ± 60 nm rms for an 8-m telescope over an 85 arcsec baseline. No anisotropy in the spatial distribution of this error is detected.
Treatment outcome in adults with chronic fatigue syndrome: a prospective study in England based on the CFS/ME National Outcomes Database
Authors: Crawley E , Collin S M , White P D , Rimes K , Sterne J A C , May M T ,   CFS/ME National Outcomes Database
Published: March 2013

Background

Chronic fatigue syndrome (CFS) is relatively common and disabling. Over 8000 patients attend adult services each year, yet little is known about the outcome of patients attending NHS services.

Aim

Investigate the outcome of patients with CFS and what factors predict outcome.

Design

Longitudinal patient cohort.

Methods

We used data from six CFS/ME (myalgic encephalomyelitis) specialist services to measure changes in fatigue (Chalder Fatigue Scale), physical function (SF-36), anxiety and depression (Hospital Anxiety and Depression Scale) and pain (visual analogue pain rating scale) between clinical assessment and 8–20 months of follow-up. We used multivariable linear regression to investigate baseline factors associated with outcomes at follow-up.

Results

Baseline data obtained at clinical assessment were available for 1643 patients, of whom 834 (51%) had complete follow-up data. There were improvements in fatigue [mean difference from assessment to outcome: −6.8; 95% confidence interval (CI) −7.4 to −6.2; P < 0.001]; physical function (4.4; 95% CI 3.0–5.8; P < 0.001), anxiety (−0.6; 95% CI −0.9 to −0.3; P < 0.001), depression (−1.6; 95% CI −1.9 to −1.4; P < 0.001) and pain (−5.3; 95% CI −7.0 to −3.6; P < 0.001). Worse fatigue, physical function and pain at clinical assessment predicted a worse outcome for fatigue at follow-up. Older age, increased pain and physical function at assessment were associated with poorer physical function at follow-up.

Conclusions

Patients who attend NHS specialist CFS/ME services can expect similar improvements in fatigue, anxiety and depression to participants receiving cognitive behavioural therapy and graded exercise therapy in a recent trial, but are likely to experience less improvement in physical function. Outcomes were predicted by fatigue, disability and pain at assessment.
SEROUS RETINAL DETACHMENTS ASSOCIATED WITH LIGHT CHAIN DEPOSITION DISEASE
Authors: Shah Ankoor R. , Zaidi Ali , Brucker Alexander J.
Published: March 2013

Purpose:

To report the clinical, fluorescein angiography, spectral-domain optical coherence tomography, and fundus autofluorescence (AF) findings of a 64-year-old woman with systemic light chain deposition disease.

Methods:

Clinical examination, fundus photographs, fundus AF, spectral-domain optical coherence tomography, and fluorescein angiography before and after renal transplantation in a patient with light chain deposition disease.

Results:

The patient presented with decreased visual acuity in her right eye. Fundus examination showed bilateral drusenoid subretinal deposits associated with subretinal fluid. Fluorescein angiography showed staining of the lesions seen on clinical examination. Spectral-domain optical coherence tomography showed hyperreflective material below the neurosensory retina associated with subretinal fluid. Fundus AF showed areas of increased AF corresponding to the lesions. The lesions showed improvement after renal transplantation and initiation of immunosuppressive agents.

Conclusion:

Patients with light chain deposition disease may present with subretinal deposits that can be seen clinically and demonstrated on fluorescein angiography, AF, and optical coherence tomography. They may also present with localized serious retinal detachments. Both these deposits and serous retinal detachments may improve with renal transplantation or immunosuppressive therapy.
HEADACHES SECONDARY TO INTRAVENTRICULAR SILICONE OIL SUCCESSFULLY MANAGED WITH VENTRICULOPERITONEAL SHUNT
Authors: Hruby Paul M. , Poley Preeti R. , Terp Patricia A. , Thorell William E. , Margalit Eyal
Published: March 2013

Purpose:

To describe a case of intravitreal silicone oil (SO) migration into the cerebral ventricles with secondary chronic headaches.

Methods:

Retrospective case report. Chart review. Single patient.

Results:

A 51-year-old man with a history of proliferative diabetic retinopathy underwent surgery for traction retinal detachment using SO. Postoperatively, he developed elevated intraocular pressure, headaches, and a blind painful eye, which was enucleated. Neuroimaging revealed SO within the cerebral ventricles. Five years after the initial retinal detachment surgery, the patient developed chronic headaches. Lumbar puncture revealed an elevated opening pressure. The headaches were initially managed medically. A ventriculoperitoneal shunt was placed after the headaches persisted, which resulted in their complete resolution at 6 weeks after shunt placement.

Conclusion:

Ocular hypertension after intravitreal SO placement may play a role in SO intracranial migration. In the case presented, intraventricular SO was the apparent cause of elevated intracranial pressure and headaches. As all published cases of intraventricular SO migration reporting intraocular pressure to this point have described ocular hypertension, careful monitoring of intraocular pressure and aggressive control of ocular hypertension in the presence of intravitreal SO is recommended.
Safety, Tolerability, and Clinical Response After Fecal Transplantation in Children and Young Adults With Ulcerative Colitis
Authors: Kunde Sachin , Pham Angela , Bonczyk Sarah , Crumb Teri , Duba Meg , Conrad Harold , Cloney Deborah , Kugathasan Subra
Published: March 2013

Background and Objective:

Colonic dysbiosis contributes to the development of colonic inflammation in ulcerative colitis (UC). Fecal microbial transplantation (FMT) is being proposed as a novel treatment for UC because it can eliminate dysbiosis; however, no prospective data exist. We initiated a pilot study to evaluate feasibility and safety of FMT in children with UC.

Methods:

Ten children, 7 to 21 years of age, with mild‐to‐moderate UC (pediatric UC activity index [PUCAI] between 15 and 65) received freshly prepared fecal enemas daily for 5 days. Data on tolerability, adverse events, and disease activity were collected during FMT and weekly for 4 weeks after FMT. Clinical response was defined as decrease in PUCAI by >15, and decrease in PUCAI to <10 was considered clinical remission.

Results:

No serious adverse events were noted. Mild (cramping, fullness, flatulence, bloating, diarrhea, and blood in stool) to moderate (fever) adverse events were self‐limiting. One subject could not retain fecal enemas. Average tolerated enema volume by remaining 9 subjects was 165 mL/day. After FMT, 7 of the 9 (78%) subjects showed clinical response within 1 week, 6 of the 9 (67%) subjects maintained clinical response at 1 month, and 3 of the 9 (33%) subjects achieved clinical remission at 1 week after FMT. Median PUCAI significantly improved after FMT (P = 0.03) compared with the baseline.

Conclusions:

Fecal enemas were feasible and tolerated by children with UC. Adverse events were acceptable, self‐limiting, and manageable by subjects. FMT indicated efficacy in the treatment of UC.
α-Cyclodextrin decreases cholera toxin binding to GM1-gangliosides
Authors: Ermolinsky Boris , Peredelchuk Michael , Provenzano Daniele
Published: March 2013

Cholera toxin (CT), the principal virulence factor secreted byVibrio cholerae, is an A-B5 type exotoxin that binds to host cell GM1-gangliosides and is responsible for cholera diarrhoea. We tested the hypothesis that the cyclic hexasaccharide α-cyclodextrin (α-CD), but not the cyclic heptasaccharides methyl-β-cyclodextrin (MD-β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) inhibit binding of CT to GM1-gangliosides. We report that α-CD decreases CT binding to GM1-ganglioside-coated microtitre plate wells and on the surface of fixed HeLa cells in a concentration-dependent manner, suggesting that this may be a promising lead for the development of compounds with therapeutic properties.
Community spread of extended-spectrum β-lactamase-producing Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis: a long-term study in Japan
Authors: Chong Yong , Shimoda Shinji , Yakushiji Hiroko , Ito Yoshikiyo , Miyamoto Toshihiro , Kamimura Tomohiko , Shimono Nobuyuki , Akashi Koichi
Published: March 2013

Community-acquired infections caused by extended-spectrum β-lactamase (ESBL)-producing bacteria, particularly CTX-M-producing Escherichia coli, are a rising concern worldwide. There are few data from Japan on the acquisition of ESBLs in the community or the influx of these bacteria into hospitals. Therefore, we examined the prevalence of ESBL carriage in outpatients, in order to estimate the spread of ESBLs in community settings. We analysed bacterial isolates from outpatient samples at our institution over a 9-year period from 2003 to 2011, with respect to epidemiological data on ESBL-producing bacteria and their genotypic features. Out of 5137 isolates, 321 (6.3 %) were ESBL producers, including E. coli, Klebsiella pneumoniae and Proteus mirabilis. The detection rates of the ESBL-producing isolates gradually increased and reached 14.3, 8.7 and 19.6 % for E. coli, K. pneumoniae and P. mirabilis strains, respectively, in 2011. Genotyping analysis showed that many of the strains produced multiple β-lactamases, including TEM, SHV and CTX-M, rather than just CTX-M. The CTX-M-9 group was dominant among the CTX-M genotypes; further, the CTX-M-1 and M-2 groups were also detected (~30 %). This is believed to be the first report from Japan showing a definite increase in ESBL detection in outpatients. In addition, our findings suggest the simultaneous community spread of diverse ESBL genotypes, not an expansion of particular ESBL genes.
HCFC1 is a common component of active human CpG-island promoters and coincides with ZNF143, THAP11, YY1, and GABP transcription factor occupancy
Authors: Michaud Joëlle , Praz Viviane , James Faresse Nicole , JnBaptiste Courtney K. , Tyagi Shweta , Schütz Frédéric , Herr Winship
Published: March 2013

In human transcriptional regulation, DNA-sequence-specific factors can associate with intermediaries that orchestrate interactions with a diverse set of chromatin-modifying enzymes. One such intermediary is HCFC1 (also known as HCF-1). HCFC1, first identified in herpes simplex virus transcription, has a poorly defined role in cellular transcriptional regulation. We show here that, in HeLa cells, HCFC1 is observed bound to 5400 generally active CpG-island promoters. Examination of the DNA sequences underlying the HCFC1-binding sites revealed three sequence motifs associated with the binding of (1) ZNF143 and THAP11 (also known as Ronin), (2) GABP, and (3) YY1 sequence-specific transcription factors. Subsequent analysis revealed colocalization of HCFC1 with these four transcription factors at ∼90% of the 5400 HCFC1-bound promoters. These studies suggest that a relatively small number of transcription factors play a major role in HeLa-cell transcriptional regulation in association with HCFC1.
Mutations in the TIR1 Auxin Receptor That Increase Affinity for Auxin/Indole-3-Acetic Acid Proteins Result in Auxin Hypersensitivity
Authors: Yu Hong , Moss Britney L. , Jang Seunghee S. , Prigge Michael , Klavins Eric , Nemhauser Jennifer L. , Estelle Mark
Published: March 2013

The phytohormone auxin regulates virtually every aspect of plant development. The hormone directly mediates the interaction between the two members of the auxin coreceptor complex, a TRANSPORT INHIBITOR RESPONSE (TIR1)/AUXIN SIGNALING F-BOX protein and an AUXIN/INDOLE-3-ACETIC ACID (Aux/IAA) transcriptional repressor. To learn more about the interaction between these proteins, a mutant screen was performed using the yeast (Saccharomyces cerevisiae) two-hybrid system in Arabidopsis (Arabidopsis thaliana). Two tir1 mutations were identified that increased interaction with Aux/IAAs. The D170E and M473L mutations increase affinity between TIR1 and the degron motif of Aux/IAAs and enhance the activity of the SCFTIR1 complex. This resulted in faster degradation of Aux/IAAs and increased transcription of auxin-responsive genes in the plant. Plants carrying the pTIR1:tir1 D170E/M473L-Myc transgene exhibit diverse developmental defects during plant growth and display an auxin-hypersensitive phenotype. This work demonstrates that changes in the leucine-rich repeat domain of the TIR1 auxin coreceptor can alter the properties of SCFTIR1.
Decreased Peripheral Blood CD4+/CD25+ Regulatory T Cells in Patients with Alcoholic Hepatitis
Authors: Almeida Julia , Polvorosa Maria Angeles , Gonzalez‐Quintela Arturo , Marcos Miguel , Pastor Isabel , Hernandez Cerceño Maria Luisa , Orfao Alberto , Laso Francisco‐Javier
Published: March 2013

Background

Development of alcoholic hepatitis (AH) may be favored by the activation of the innate immune response. Recently, decreased numbers of circulating regulatory T cells (Tregs) have been reported in diseases associated with an immune activation status, but no studies have focused so far, in investigating the distribution of Tregs in chronic alcoholism and its potential association with liver disease. Here, we analyzed for the first time the frequency of peripheral blood (PB) Tregs and Treg subsets in AH and its relationship with the production of inflammatory cytokines by PB monocytes and dendritic cells (DCs).

Methods

PB samples from 25 male patients with AH were studied; in parallel, 15 male chronic alcoholic patients without liver disease (AWLD) and 17 male healthy donors were also studied, as controls. The distribution of CD4+CD25hiCD127−/lo Tregs and their maturation subsets (naïve, central memory, and peripheral memory Tregs) was analyzed by flow cytometry. Spontaneous and in vitro‐stimulated production of inflammatory cytokines by PB monocytes and DCs was analyzed by flow cytometry at the cytoplasmic level.

Results

Patients with AH showed decreased (p < 0.05) numbers of PB CD4+CD25hiCD127−/lo Tregs at the expense of all maturation‐associated subsets, while AWLD and healthy subjects showed a similar (p > 0.05) distribution of PB CD4+CD25hiCD127−/lo Tregs. Interestingly, significantly increased amounts of spontaneously produced inflammatory cytokines were found among circulating monocyte‐derived DCs and monocytes from AH (and AWLD) patients in comparison with healthy donors. Conversely, the ability of these cell subsets to produce cytokines after in vitro stimulation was lower (p < 0.05) in AH versus the 2 control groups.

Conclusions

PB CD4+CD25hiCD127−/lo Tregs are significantly decreased in patients with AH when compared to both healthy and AWLD; this may contribute to explain the more pronounced activation of the innate immune response observed in AH, as reflected by an increased secretion of inflammatory cytokines by PB DCs and monocytes, and could facilitate the development of liver disease.