bluuebunny/crossref_metadata_2025 huggingface dataset:
The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses
Authors: Garcia Rolando A. G. , Vasudevan Kuzhalini , Buonanno Andres
Published: July 2012

Neuregulins regulate the expression of ligand- and voltage-gated channels in neurons and skeletal muscle by the activation of their cognate tyrosine kinase receptors, ErbB 1–4. The subcellular distribution and mechanisms that regulate the localization of ErbB receptors are unknown. We have found that ErbB receptors are present in brain subcellular fractions enriched for postsynaptic densities (PSD). The ErbB-4 receptor is unique among the ErbB proteins because its C-terminal tail (T-V-V) conforms to a sequence that binds to a protein motif known as the PDZ domain. Using the yeast two-hybrid system, we found that the C-terminal region of ErbB-4 interacts with the three related membrane-associated guanylate kinases (MAGUKs) PSD-95/SAP90, PSD-93/chapsyn-110, and SAP 102, which harbor three PDZ domains, as well as with β
2
-syntrophin, which has a single PDZ domain. As with
N
-methyl-
d
-aspartate (NMDA) receptors, ErbB4 interacts with the first two PDZ domains of PSD-95. Using coimmunoprecipitation assays, we confirmed the direct interactions between ErbB-4 and PSD-95 in transfected heterologous cells, as well as
in vivo
, where both proteins are coimmunoprecipitated from brain lysates. Moreover, evidence for colocalization of these proteins was also observed by immunofluorescence in cultured hippocampal neurons. ErbB-4 colocalizes with PSD-95 and NMDA receptors at a subset of excitatory synapses apposed to synaptophysin-positive presynaptic terminals. The capacity of ErbB receptors to interact with PDZ-domain proteins at cell junctions is conserved from invertebrates to mammals. As discussed, the interactions found between receptor tyrosine kinases and MAGUKs at neuronal synapses may have important implications for activity-dependent plasticity.
A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons
Authors: Millar Julie A. , Barratt Lynne , Southan Andrew P. , Page Karen M. , Fyffe Robert E. W. , Robertson Brian , Mathie Alistair
Published: July 2012

Cerebellar granule neurons (CGNs) are one of the most populous cells in the mammalian brain. They express an outwardly rectifying potassium current, termed a “standing-outward” K
+
current, or IK
SO
, which does not inactivate. It is active at the resting potential of CGNs, and blocking IK
SO
leads to cell depolarization. IK
SO
is blocked by Ba
2+
ions and is regulated by activation of muscarinic M
3
receptors, but it is insensitive to the classical broad-spectrum potassium channel blocking drugs 4-aminopyridine and tetraethylammonium ions. The molecular nature of this important current has yet to be established, but in this study, we provide strong evidence to suggest that IK
SO
is the functional correlate of the recently identified two-pore domain potassium channel TASK-1. We show that IK
SO
has no threshold for activation by voltage and that it is blocked by small extracellular acidifications. Both of these are properties that are diagnostic of TASK-1 channels. In addition, we show that TASK-1 currents expressed in
Xenopus
oocytes are inhibited after activation of endogenous M
3
muscarinic receptors. Finally, we demonstrate that mRNA for TASK-1 is found in CGNs and that TASK-1 protein is expressed in CGN membranes. This description of a functional two-pore domain potassium channel in the mammalian central nervous system indicates its physiological importance in controlling cell excitability and how agents that modify its activity, such as agonists at G protein-coupled receptors and hydrogen ions, can profoundly alter both the neuron's resting potential and its excitability.
Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death
Authors: Grooms Sonja Y. , Opitz Thoralf , Bennett Michael V. L. , Zukin R. Suzanne
Published: July 2012

Kainic acid (KA)-induced status epilepticus in adult rats leads to delayed, selective death of pyramidal neurons in the hippocampal CA1 and CA3. Death is preceded by down-regulation of glutamate receptor 2 (GluR2) mRNA and protein [the subunit that limits Ca
2+
permeability of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] in CA1 and CA3, as indicated by
in situ
hybridization, immunolabeling, and quantitative Western blotting. GluR1 mRNA and protein are unchanged or slightly increased before cell death. These changes could lead to formation of GluR2-lacking, Ca
2+
-permeable AMPA receptors and increased toxicity of endogenous glutamate. GluR2 immunolabeling is unchanged in granule cells of the dentate gyrus, which are resistant to seizure-induced death. Thus, formation of Ca
2+
-permeable AMPA receptors may be a critical mediator of delayed neurodegeneration after status epilepticus.
Castration increases and androgens decrease nitric oxide synthase activity in the brain: Physiologic implications
Authors: Singh Rajan , Pervin Shehla , Shryne James , Gorski Roger , Chaudhuri Gautam
Published: July 2012

Sex differences in nitric oxide synthase (NOS) activity in different regions of the rat brain and effects of testosterone and dihydrotestosterone (DHT) treatment in orchidectomized animals were investigated. Regional but no sex differences in NOS activity were detected in gonadectomized animals. Orchidectomy significantly increased NOS activity in the hypothalamus, “amygdala,” and cerebellum but not in the cortex. In the hypothalamus, the increase in NOS activity after castration and its reversal by androgen treatment was mimicked by changes in neuronal NOS mRNA level. In contrast, androgen receptor (AR) mRNA level in the hypothalamus was slightly reduced by castration and increased by treatment with DHT. Again in the hypothalamus, the increase in NOS activity in castrated rats was accompanied by an increase in the number of neuronal NOS+ cells determined immunohistochemically, whereas androgen treatment prevented this increase. The changes in NOS+ neurons correlated with the changes in the number of AR+ cells to a degree. Overlap of AR in NOS+ cells was not present in the regions of the hypothalamus analyzed. These results indicate that testosterone or, most likely, its metabolite DHT down-regulates NOS activity, mRNA expression or stabilization, and the number of neuronal NOS+ neurons.
Detection of β
2
-adrenergic receptor dimerization in living cells using bioluminescence resonance energy transfer (BRET)
Authors: Angers Stephane , Salahpour Ali , Joly Eric , Hilairet Sandrine , Chelsky Dan , Dennis Michael , Bouvier Michel
Published: July 2012

Heptahelical receptors that interact with heterotrimeric G proteins represent the largest family of proteins involved in signal transduction across biological membranes. Although these receptors generally were believed to be monomeric entities, a growing body of evidence suggests that they may form functionally relevant dimers. However, a definitive demonstration of the existence of G protein-coupled receptor (GPCR) dimers at the surface of living cells is still lacking. Here, using bioluminescence resonance energy transfer (BRET), as a protein–protein interaction assay in whole cells, we unambiguously demonstrate that the human β
2
-adrenergic receptor (β
2
AR) forms constitutive homodimers when expressed in HEK-293 cells. Receptor stimulation with the hydrophilic agonist isoproterenol led to an increase in the transfer of energy between β
2
AR molecules genetically fused to the BRET donor (
Renilla
luciferase) and acceptor (green fluorescent protein), respectively, indicating that the agonist interacts with receptor dimers at the cell surface. Inhibition of receptor internalization did not prevent agonist-promoted BRET, demonstrating that it did not result from clustering of receptors within endosomes. The notion that receptor dimers exist at the cell surface was confirmed further by the observation that BS3, a cell-impermeable cross-linking agent, increased BRET between β
2
AR molecules. The selectivity of the constitutive interaction was documented by demonstrating that no BRET occurred between the β
2
AR and two other unrelated GPCR. In contrast, the well characterized agonist-dependent interaction between the β
2
AR and the regulatory protein β-arrestin could be monitored by BRET. Taken together, the data demonstrate that GPCR exist as functional dimers
in vivo
and that BRET-based assays can be used to study both constitutive and hormone-promoted selective protein–protein interactions.
The
Arabidopsis thaliana SOS2
gene encodes a protein kinase that is required for salt tolerance
Authors: Liu Jiping , Ishitani Manabu , Halfter Ursula , Kim Cheol-Soo , Zhu Jian-Kang
Published: July 2012

In
Arabidopsis thaliana
, the
Salt Overly Sensitive 2
(
SOS2
) gene is required for intracellular Na
+
and K
+
homeostasis. Mutations in
SOS2
cause Na
+
and K
+
imbalance and render plants more sensitive toward growth inhibition by high Na
+
and low K
+
environments. We isolated the
SOS2
gene through positional cloning.
SOS2
is predicted to encode a serine/threonine type protein kinase with an N-terminal catalytic domain similar to that of the yeast SNF1 kinase. Sequence analyses of
sos2
mutant alleles reveal that both the N-terminal catalytic domain and the C-terminal regulatory domain of SOS2 are functionally essential. The steady-state level of
SOS2
transcript is up-regulated by salt stress in the root. Autophosphorylation assays show that SOS2 is an active protein kinase. In the recessive
sos2
-
5
allele, a conserved glycine residue in the kinase catalytic domain is changed to glutamate. This mutation abolishes SOS2 autophosphorylation, indicating that SOS2 protein kinase activity is required for salt tolerance.
Arabidopsis
RelA/SpoT homologs implicate (p)ppGpp in plant signaling
Authors: van der Biezen Erik A. , Sun Jongho , Coleman Mark J. , Bibb Mervyn J. , Jones Jonathan D. G.
Published: July 2012

Arabidopsis RPP5
is a member of a large class of pathogen resistance genes encoding nucleotide-binding sites and leucine-rich repeat domains. Yeast two-hybrid analysis showed that RPP5 specifically interacts with At-RSH1, an
Arabidopsis
RelA/SpoT homolog. In
Escherichia coli
, RelA and SpoT determine the level of guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp), which are the effector nucleotides of the bacterial stringent response. Functional analysis in
E. coli
and in
Streptomyces coelicolor
A3 (2) showed that
At-RSH1
confers phenotypes associated with (p)ppGpp synthesis. We characterized two additional
Arabidopsis
RelA/SpoT homologs,
At-RSH2
and
At-RSH3. At-RSH
genes may regulate a rapid plant (p)ppGpp-mediated response to pathogens and other stresses.
Understanding hippocampal activity by using purposeful behavior: Place navigation induces place cell discharge in both task-relevant and task-irrelevant spatial reference frames
Authors: Zinyuk L. , Kubik S. , Kaminsky Yu. , Fenton A. A. , Bures J.
Published: July 2012

Continuous rotation of an arena in a cue-rich room dissociates the stationary room-bound information from the rotating arena-bound information. This disrupted spatial discharge in the majority of place cells from rats trained to collect randomly scattered food. In contrast, most place cell firing patterns recorded from rats trained to solve a navigation task on the rotating arena were preserved during the rotation. Spatial discharge was preserved in both the task-relevant stationary and the task-irrelevant rotating reference frames, but firing was more organized in the task-relevant frame. It is concluded that, (
i
) the effects of environmental manipulations can be understood with confidence only when the rat's purposeful behavior is used to formulate interpretations of the data, and (
ii
) hippocampal place cell activity is organized in multiple overlapping spatial reference frames.
Peak acceleration during impact with helmet materials: Effects of impactor mass and speed
Authors: Hutchinson Timothy Paul
Published: July 2012

The impact properties of six foam materials used for energy absorption as the liner of children's helmets, reported by Gimbel and Hoshizaki are considered further. In high‐energy impacts, almost complete compression of the energy‐absorbing material (bottoming out) may occur, and the severity of the impact increases greatly. Too soft a material means bottoming out occurs at low speeds, but if it is too stiff, the material itself is injurious. The fitting of equations to results in ‘no bottoming out’ and ‘bottoming out’ conditions may help assessment of what compromise is appropriate. The equations in this article correspond to peak acceleration being proportional to power functions of impactor speed and mass. 1. When there was no bottoming out, peak acceleration was found to be proportional to m ∧(c−1).v ∧(2c), with c being approximately 0.25. 2. For bottoming out, peak acceleration was found to be proportional to m ∧(p).v ∧(q), with p and q being approximately 2 and approximately 3. 3. The constants of proportionality were related to material density in a regular way.
Small optimal Margulis numbers force upper volume bounds
Authors: Shalen Peter
Published: July 2012

If

λ
\lambda

is a positive real number strictly less than

log
⁡
3

\operatorname {log}3

, there is a positive number

V
λ

V_\lambda

such that every orientable hyperbolic

3
3

-manifold of volume greater than

V
λ

V_\lambda

admits

λ
\lambda

as a Margulis number. If

λ
>
(
log
⁡
3
)

/

2

\lambda >(\operatorname {log}3)/2

, such a

V
λ

V_\lambda

can be specified explicitly and is bounded above by
\[

λ

(

6
+

880

log
⁡
3
−
2
λ

log
⁡

1

log
⁡
3
−
2
λ

)

,

\lambda \bigg (6+\frac {880}{\operatorname {log}3-2\lambda } \operatorname {log}{1\over \operatorname {log}3-2\lambda }\bigg ),

\]
where

log
\operatorname {log}

denotes the natural logarithm. These results imply that for

λ
>
log
⁡
3

\lambda >\operatorname {log}3

, an orientable hyperbolic

3
3

-manifold that does not have

λ
\lambda

as a Margulis number has a rank-

2
2

subgroup of bounded index in its fundamental group and in particular has a fundamental group of bounded rank. Again, the bounds in these corollaries can be made explicit if

λ
>
(
log
⁡
3
)

/

2

\lambda >(\operatorname {log}3)/2

.
YAHA: fast and flexible long-read alignment with optimal breakpoint detection
Authors: Faust Gregory G. , Hall Ira M.
Published: July 2012

Motivation: With improved short-read assembly algorithms and the recent development of long-read sequencers, split mapping will soon be the preferred method for structural variant (SV) detection. Yet, current alignment tools are not well suited for this.

Results: We present YAHA, a fast and flexible hash-based aligner. YAHA is as fast and accurate as BWA-SW at finding the single best alignment per query and is dramatically faster and more sensitive than both SSAHA2 and MegaBLAST at finding all possible alignments. Unlike other aligners that report all, or one, alignment per query, or that use simple heuristics to select alignments, YAHA uses a directed acyclic graph to find the optimal set of alignments that cover a query using a biologically relevant breakpoint penalty. YAHA can also report multiple mappings per defined segment of the query. We show that YAHA detects more breakpoints in less time than BWA-SW across all SV classes, and especially excels at complex SVs comprising multiple breakpoints.

Availability: YAHA is currently supported on 64-bit Linux systems. Binaries and sample data are freely available for download from http://faculty.virginia.edu/irahall/YAHA.

Contact:  imh4y@virginia.edu
Nebula—a web-server for advanced ChIP-seq data analysis
Authors: Boeva Valentina , Lermine Alban , Barette Camille , Guillouf Christel , Barillot Emmanuel
Published: July 2012

Motivation: ChIP-seq consists of chromatin immunoprecipitation and deep sequencing of the extracted DNA fragments. It is the technique of choice for accurate characterization of the binding sites of transcription factors and other DNA-associated proteins. We present a web service, Nebula, which allows inexperienced users to perform a complete bioinformatics analysis of ChIP-seq data.

Results: Nebula was designed for both bioinformaticians and biologists. It is based on the Galaxy open source framework. Galaxy already includes a large number of functionalities for mapping reads and peak calling. We added the following to Galaxy: (i) peak calling with FindPeaks and a module for immunoprecipitation quality control, (ii) de novo motif discovery with ChIPMunk, (iii) calculation of the density and the cumulative distribution of peak locations relative to gene transcription start sites, (iv) annotation of peaks with genomic features and (v) annotation of genes with peak information. Nebula generates the graphs and the enrichment statistics at each step of the process. During Steps 3–5, Nebula optionally repeats the analysis on a control dataset and compares these results with those from the main dataset. Nebula can also incorporate gene expression (or gene modulation) data during these steps. In summary, Nebula is an innovative web service that provides an advanced ChIP-seq analysis pipeline providing ready-to-publish results.

Availability: Nebula is available at http://nebula.curie.fr/

Supplementary Information:  Supplementary data are available at Bioinformatics online.
Folding RNA/DNA hybrid duplexes
Authors: Lorenz Ronny , Hofacker Ivo L. , Bernhart Stephan H.
Published: July 2012

Motivation: While there are numerous programs that can predict RNA or DNA secondary structures, a program that predicts RNA/DNA hetero-dimers is still missing. The lack of easy to use tools for predicting their structure may be in part responsible for the small number of reports of biologically relevant RNA/DNA hetero-dimers.

Results: We present here an extension to the widely used ViennaRNAPackage (Lorenz et al., 2011) for the prediction of the structure of RNA/DNA hetero-dimers.

Availability: http://www.tbi.univie.ac.at/~ronny/RNA/vrna2.html

Contact: ronny@tbi.univie.ac.at, berni@bioinf.uni-leipzig.de

Supplementary Information:  Supplementary data are available at Bioinformatics online.
Northward range extension of an endemic soil decomposer with a distinct trophic position
Authors: Melody Carol , Schmidt Olaf
Published: July 2012

Ecological niche theory asserts that invading species become established only if introduced propagules survive stochastic mortality and can exploit resources unconsumed by resident species. Because their transportation is not controlled by plant health or biosecurity regulations, soil macrofauna decomposers, including earthworms are probably introduced frequently into non-native soils. Yet even with climatic change, exotic earthworm species from southern Europe have not been reported to become established in previously glaciated areas of northern Europe that already have trophically differentiated earthworm communities of ‘peregrine’ species. We discovered established populations of the earthworm
Prosellodrilus amplisetosus
(Lumbricidae), a member of a genus endemic to southern France, in six habitats of an urban farm in Dublin, Ireland, about 1000 km north of the genus's endemic range. Not only was
P. amplisetosus
the dominant endogeic (geophagous) earthworm species in two habitats, it also occupied a significantly different trophic position from the resident species, as evinced by stable isotope ratio analysis. The suggested ability of this non-native species to feed on and assimilate isotopically more enriched soil carbon (C) and nitrogen fractions that are inaccessible to resident species portends potential implications of decomposer range expansions for soil functioning including C sequestration.
Challenges in global biodiversity conservation and solutions that cross sociology, politics, economics and ecology
Authors: Hoban Sean , Vernesi Cristiano
Published: July 2012

The study and practice of conservation biology is inherently interdisciplinary, addresses short and long time-scales and occurs within complex human–natural interfaces. Zoos and aquaria, in partnership with researchers, other non-government organizations, government, industry and educators, are combining knowledge of species and ecosystems with economics, psychology and law to create solutions for conserving biodiversity. From 22 to 25 May, the Conservation Forum of the European Association of Zoos and Aquaria was a venue for discussing conservation research, education and interventions, from the scale of villages to global policy.
Do ‘passive’ medical titanium surfaces deteriorate in service in the absence of wear?
Authors: Addison O. , Davenport A. J. , Newport R. J. , Kalra S. , Monir M. , Mosselmans J. F. W. , Proops D. , Martin R. A.
Published: July 2012

Globally, more than 1000 tonnes of titanium (Ti) is implanted into patients in the form of biomedical devices on an annual basis. Ti is perceived to be ‘biocompatible’ owing to the presence of a robust passive oxide film (approx. 4 nm thick) at the metal surface. However, surface deterioration can lead to the release of Ti ions, and particles can arise as the result of wear and/or corrosion processes. This surface deterioration can result in peri-implant inflammation, leading to the premature loss of the implanted device or the requirement for surgical revision. Soft tissues surrounding commercially pure cranial anchorage devices (bone-anchored hearing aid) were investigated using synchrotron X-ray micro-fluorescence spectroscopy and X-ray absorption near edge structure. Here, we present the first experimental evidence that minimal load-bearing Ti implants, which are not subjected to macroscopic wear processes, can release Ti debris into the surrounding soft tissue. As such debris has been shown to be pro-inflammatory, we propose that such distributions of Ti are likely to effect to the service life of the device.
Finished bacterial genomes from shotgun sequence data
Authors: Ribeiro Filipe J. , Przybylski Dariusz , Yin Shuangye , Sharpe Ted , Gnerre Sante , Abouelleil Amr , Berlin Aaron M. , Montmayeur Anna , Shea Terrance P. , Walker Bruce J. , Young Sarah K. , Russ Carsten , Nusbaum Chad , MacCallum Iain , Jaffe David B.
Published: July 2012

Exceptionally accurate genome reference sequences have proven to be of great value to microbial researchers. Thus, to date, about 1800 bacterial genome assemblies have been “finished” at great expense with the aid of manual laboratory and computational processes that typically iterate over a period of months or even years. By applying a new laboratory design and new assembly algorithm to 16 samples, we demonstrate that assemblies exceeding finished quality can be obtained from whole-genome shotgun data and automated computation. Cost and time requirements are thus dramatically reduced.
Photosynthetic Adaptation to Length of Day Is Dependent on S-Sulfocysteine Synthase Activity in the Thylakoid Lumen
Authors: Bermúdez María Ángeles , Galmés Jeroni , Moreno Inmaculada , Mullineaux Philip M. , Gotor Cecilia , Romero Luis C.
Published: July 2012

Arabidopsis (Arabidopsis thaliana) chloroplasts contain two O-acetyl-serine(thiol)lyase (OASTL) homologs, OAS-B, which is an authentic OASTL, and CS26, which has S-sulfocysteine synthase activity. In contrast with OAS-B, the loss of CS26 function resulted in dramatic phenotypic changes, which were dependent on the light treatment. We have performed a detailed characterization of the photosynthetic and chlorophyll fluorescence parameters in cs26 plants compared with those of wild-type plants under short-day growth conditions (SD) and long-day growth conditions (LD). Under LD, the photosynthetic characterization, which was based on substomatal CO2 concentrations and CO2 concentration in the chloroplast curves, revealed significant reductions in most of the photosynthetic parameters for cs26, which were unchanged under SD. These parameters included net CO2 assimilation rate, mesophyll conductance, and mitochondrial respiration at darkness. The analysis also showed that cs26 under LD required more absorbed quanta per driven electron flux and fixed CO2. The nonphotochemical quenching values suggested that in cs26 plants, the excess electrons that are not used in photochemical reactions may form reactive oxygen species. A photoinhibitory effect was confirmed by the background fluorescence signal values under LD and SD, which were higher in young leaves compared with mature ones under SD. To hypothesize the role of CS26 in relation to the photosynthetic machinery, we addressed its location inside of the chloroplast. The activity determination and localization analyses that were performed using immunoblotting indicated the presence of an active CS26 enzyme exclusively in the thylakoid lumen. This finding was reinforced by the observation of marked alterations in many lumenal proteins in the cs26 mutant compared with the wild type.
Photosystem II Photoinactivation, Repair, and Protection in Marine Centric Diatoms
Authors: Wu Hongyan , Roy Suzanne , Alami Meriem , Green Beverley R. , Campbell Douglas A.
Published: July 2012

Revised Version

Diatoms are important contributors to aquatic primary production, and can dominate phytoplankton communities under variable light regimes. We grew two marine diatoms, the small Thalassiosira pseudonana and the large Coscinodiscus radiatus, across a range of temperatures and treated them with a light challenge to understand their exploitation of variable light environments. In the smaller T. pseudonana, photosystem II (PSII) photoinactivation outran the clearance of PSII protein subunits, particularly in cells grown at sub- or supraoptimal temperatures. In turn the absorption cross section serving PSII photochemistry was down-regulated in T. pseudonana through induction of a sustained phase of nonphotochemical quenching that relaxed only slowly over 30 min of subsequent low-light incubation. In contrast, in the larger diatom C. radiatus, PSII subunit turnover was sufficient to counteract a lower intrinsic susceptibility to photoinactivation, and C. radiatus thus did not need to induce sustained nonphotochemical quenching under the high-light treatment. T. pseudonana thus incurs an opportunity cost of sustained photosynthetic down-regulation after the end of an upward light shift, whereas the larger C. radiatus can maintain a balanced PSII repair cycle under comparable conditions.
Processed food consumption and risk of esophageal squamous cell carcinoma: A case‐control study in a high risk area
Authors: Song Qingkun , Wang Xiaorong , Yu Ignatius Tak‐sun , Huang Chengyu , Zhou Xiaoqiao , Li Jun , Wang Dong
Published: July 2012

This study was conducted to investigate the association between consumption of processed foods and esophageal cancer risk. A population‐based case‐control study was designed. For the present study, 254 patients with esophageal squamous cell carcinoma with pathological diagnoses were selected from Yanting during 2008 and 2010 and 254 community‐based controls were selected from the same area, individually matched with cases by age and sex. Data on demographic, lifestyle and dietary factors were collected using food frequency questionnaires. A conditional logistic regression model was used to estimate the odds ratio (OR) with adjustments for potential confounders. Compared to the frequency of <1 time/week, the intake frequency of >3 times/week of preserved vegetables had a significant association with esophageal cancer (OR = 5.01, 95% confidence interval [CI] 2.07, 12.17). In stratified analyses, the OR of increasing intake of preserved vegetables for esophageal cancer were 2.02 in men (95% CI 1.18, 3.48), 3.15 in women (95% CI 1.28, 7.75), 2.41 (95% CI 1.45 4.01) in the persons <65 years old and 1.28 (95% CI 0.35, 4.65) in persons ≥65 years old. Consumption of pickled vegetables was not associated significantly with esophageal cancer risk. Intake of salted meat with a frequency of ≥1 time/week meant that the OR increased to 2.57 (95%CI 1.02, 6.43), but no significant trend or association in subgroup analysis was observed. Preserved vegetable consumption was associated with increased risk of esophageal cancer, while no association was found with pickled vegetables.
Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease
Authors: Anderson J. L. , Edney R. J. , Whelan K.
Published: July 2012

Background

The intestinal microbiota is involved in the pathogenesis of inflammatory bowel disease (IBD). Faecal microbiota transplantation (FMT) has been used for the management of IBD as well as infectious diarrhoea.

Aim

To undertake a systematic review of FMT in patients with IBD.

Methods

The systematic review followed Cochrane and PRISMA recommendations. Nine electronic databases were searched in addition to hand searching and contacting experts. Inclusion criteria were reports (RCT, nonrandomised trials, case series and case reports) of FMT in patients with IBD.

Results

Of the 5320 articles identified, 17 fulfilled the inclusion criteria, none of which were controlled trials. There were nine case series/case reports of patients receiving FMT for management of their IBD, and eight where FMT was for the treatment of infectious diarrhoea in IBD. These 17 articles reported on 41 patients with IBD (27 UC, 12 Crohn's, 2 unclassified) with a follow‐up period of between 2 weeks and 13 years. Where reported, FMT was administered via colonoscopy/enema (26/33) or via enteral tube (7/33). In patients treated for their IBD, the majority experienced a reduction of symptoms (19/25), cessation of IBD medications (13/17) and disease remission (15/24). There was resolution of C. difficile infection in all those treated for such (15/15).

Conclusions

Whilst the available evidence is limited and weak, it suggests that faecal microbiota transplantation has the potential to be an effective and safe treatment for IBD, at least when standard treatments have failed. Well‐designed randomised controlled trials are required to investigate these findings.
Meta‐analysis: sequential therapy for Helicobacter pylori eradication in children
Authors: Horvath A. , Dziechciarz P. , Szajewska H.
Published: July 2012

Background

Problems with the standard triple treatment recommended for
Helicobacter pylori eradication therapy include unsatisfactory (less than 80%) eradication rates among children.

Aim

To assess the evidence for sequential therapy compared with triple therapy on
H. pylori eradication rates in children.

Methods

The Cochrane Library, MEDLINE and EMBASE databases were searched in May 2012, with no language restrictions, as were abstracts from major gastroenterology conferences, for randomised controlled trials (RCTs) comparing sequential therapy with standard triple therapy for
H. pylori eradication. Additional references were obtained from reviewed articles. Authors were contacted for extra information. Dichotomous data were pooled to obtain the relative risk (RR) of the eradication rate, with a 95% CI.

Results

Ten RCTs involving a total of 857 children aged 3–18 years met the inclusion criteria. Of the 409 patients in the sequential therapy group, 318 (78%, 95% CI 73–82) experienced eradication compared with 314 of the 444 patients (71%, 95% CI 66–75) in the standard triple therapy group (RR 1.14, 95% CI 1.06–1.23, number needed to treat 15; fixed‐effects model). Sequential therapy was superior to 7‐day standard triple therapy, but was not significantly better than 10‐day or 14‐day triple therapy. There were no significant differences between groups in the risk of adverse effects.

Conclusions

The pooled evidence suggests that 10‐day sequential therapy compared with standard triple therapy may be considered as an option for increasing the eradication rates in children; however, it is still less than desired.
Effect of diuretic, beta‐adrenoceptor blocking agent and their combination on elevated blood pressure and serum potassium: a cross‐ over study.
Authors: Neuvonen PJ , Pentikainen PJ , Jounela AJ
Published: July 2012

1. The antihypertensive effect of a new beta‐adrenoceptor blocking agent, trimepranol (10–14 mg/twice daily), chlorthalidone (50 mg every second day) and their combination was studied in eighteen patients with mild to moderate essential hypertension. In a controlled randomized cross‐over study the drugs were given for 6 week periods. 2. A significant and equal decrease in blood pressure was achieved both with trimepranol and chlorthalidone, whereas their combination was significantly more effective. 3. Trimepranol significantly antagonized the chlorthalidone‐induced hypokalemia. 4. The results favor the use of diuretic or diuretic‐beta‐adrenoceptor blocker combination over beta‐ adrenoceptor blocker monotherapy in the treatment of mild to moderate hypertension.
Cimetidine: effect on pancreatic and biliary function in man.
Authors: Maudgal DP , Lawrence D , Sanderson FM , Northfield TC
Published: July 2012

1 Pancreatic and biliary function were studied in eight patients taking oral cimetidine (1.6 g/day for 6 weeks) for endoscopically confirmed active peptic ulcer disease. 2 Postprandial jejunal tryptic activity and bile acid concentration were unchanged during cimetidine given for 1 and 6 weeks. 3 Postprandial gallbladder emptying was also unchanged. 4 Direct examination of postprandial upper jejunal aspirate for deconjugated bile acids was negative in all patients; but the more sensitive [14C]‐glycocholate bile acid breath test showed a significant increase in breath 14CO2, indicating increased bacterial deconjugation of bile acids in the gastrointestinal tract.
Initial impressions of dazoxiben in the treatment of the ischaemic limb.
Authors: Raftery AT , Livesey S , Forty J
Published: July 2012

1 Dazoxiben, a selective thromboxane synthetase inhibitor, which is active after oral administration, has been used to treat eight patients with severe peripheral vascular disease associated with ischaemic rest pain. 2 Patients were selected for treatment on the basis that amputation was the only alternative procedure. 3 Three of eight patients are well and pain‐free 1, 7 and 11 months after initially receiving the drug and have not required amputation. 4 Dazoxiben may prove useful in the treatment of peripheral vascular disease.
Hypnotic efficacy and clinical safety of midazolam in shift‐workers.
Authors: Scollo‐Lavizzari G
Published: July 2012

The effect of 15 mg midazolam and 15 mg oxazepam compared with placebo was investigated in 12 shift‐workers in a randomized cross‐over sleep laboratory study with psychometric testing. Sleep latency was normal under all experimental conditions. Midazolam shortened the sleep latency, reduced the frequency of nocturnal awakenings, and increased the length of sleep stages 3 and 4. Both midazolam and oxazepam reduced the total waking time and prolonged the total sleep time. Neither of the two benzodiazepines negatively influenced performance after awakening. On the basis of these findings, midazolam would appear to be suited for the treatment of insomnia in shift‐workers or of other situational sleep disturbances.
Midazolam and sleep in insomniac patients.
Authors: Monti JM , Debellis J , Alterwain P , D'Angelo L
Published: July 2012

The effects of midazolam (15 and 30 mg p.o.) on the sleep of insomniac patients were assessed by means of polysomnographic recordings. As compared with placebo, 15 mg midazolam significantly increased non‐REM sleep while other objective measures of insomnia were only slightly modified. At the 30 mg dose, midazolam significantly decreased total wake time and wake time after sleep onset. On the other hand, total sleep and non‐REM sleep time were increased. No development of tolerance was observed following 2 weeks of drug use.
Midazolam: sleep and performance studies in middle age.
Authors: Nicholson AN , Stone BM
Published: July 2012

Effects of 10, 20 and 30 mg midazolam on sleep and on performance the next day were studied in six healthy adult males aged between 47 and 53 years. The study was double‐blind, placebo‐controlled and included another rapidly eliminated benzodiazepine (brotizolam, 0.25 mg) as an active control. With 10 mg midazolam, sleep‐onset latency was quicker, and the duration and percentage of stage 2 sleep was increased over the first 6 h. Effects of 20 and 30 mg midazolam were similar to each other. Sleep onsets were earlier, total sleep times and stage 2 sleep were increased, and the sleep efficiency indices improved. During the first 6 h there was reduced duration and percentage of drowsy (stage 1) sleep. There was no consistent evidence of delay to the first period of rapid eye movement sleep, but over the dose range the duration was reduced during the first 2 h. Digit symbol substitution did not show any residual decrement 9 h after ingestion of 10, 20 or 30 mg midazolam. Midazolam may prove to be a particularly useful hypnotic for shiftworkers whose rest periods tend to be shorter than in those who have a regular nocturnal sleep pattern.
Midazolam and triazolam in out‐patients: a double‐blind comparison of hypnotic efficacy.
Authors: E Silva JA Costa , Acioli A , Naylor C , Da Silva C Jones , Ferreira I
Published: July 2012

The hypnotic efficacy and the effect on the condition after morning awakening of midazolam 15 mg and of triazolam 0.5 mg were studied in a multicentre, double‐blind cross‐over study in 198 out‐patients with sleeping difficulties of various origin. The subjects received each drug for two consecutive nights, and completed a questionnaire each day on awakening. Both midazolam and triazolam significantly shortened the sleep‐onset latency, reduced the number of awakenings, and increased the total sleep time. The state on awakening was also significantly improved after both compounds for several self‐rated items. There was a difference only with regard to the patients' feeling of being under drug influence, which was reported as being significantly more marked after triazolam. In conclusion, both compounds were effective and well tolerated in the doses used, only a few side‐effects being reported.
Efficacy and tolerance: comparative studies with brotizolam and flunitrazepam.
Authors: Goetzke E , Findeisen P , Welbers IB
Published: July 2012

Efficacy of and tolerance to 0.25 mg brotizolam and 2.0 mg flunitrazepam were compared over a period of 6 days in ambulatory patients complaining of sleep disturbance. The study was double‐blind and randomised with a parallel group design. Both drugs improved sleep. More patients assessed sleep latency as shorter during the first night of ingestion with flunitrazepam than with brotizolam, but assessments were comparable over the next 5 days. The number of patients who considered that the frequency of nocturnal awakenings was less did not differ significantly between drugs. Tolerance to brotizolam (0.25 mg) was assessed more favourably than with flunitrazepam (2.0 mg). The study suggests that brotizolam (0.25 mg) is indicated for patients who have difficulty in falling asleep and staying asleep, and who must preserve their alertness during the early part of the next day. Flunitrazepam (2.0 mg) is equally effective, but at this dose there is a higher incidence of adverse effects.
The effect of ranitidine on the plasma clearance and hepatic extraction of indocyanine green in patients with chronic liver disease.
Authors: Dunk AA , Jenkins WJ , Burroughs AK , Walt RP , Osuafor TO , Sherlock S. , Mackie S. , Dick R.
Published: July 2012

Since hepatic clearance of ICG is reduced by H2‐receptor antagonists in normal subjects, it has been suggested that they reduce liver blood flow. We have studied the effect of intravenous ranitidine on ICG clearance in twelve patients with chronic liver disease. Wedged and free hepatic venous pressure were measured before and after intravenous ranitidine in nine of the patients, and the hepatic extraction of ICG was determined in six patients. ICG clearance fell by 22 +/‐ 11% (s.e. mean) 60 min after ranitidine. In patients in whom ICG clearance fell after intravenous ranitidine the hepatic extraction of ICG was also reduced. There was no significant change in the gradient between wedged and free hepatic venous pressure after ranitidine. It is therefore unlikely that ranitidine lowers liver blood flow.
Changes in blood chemistry in hypertensive patients during propranolol therapy.
Authors: Andreasen F , Jakobsen P , Kornerup HJ , Pedersen EB , Pedersen OL , Weeke J
Published: July 2012

Propranolol induced changes in blood plasma chemistry were followed in thirty hypertensive patients (WHO I‐II) who were seen each week during 14‐15 weeks. The initial 4 weeks were a drug free period and the next 2 weeks were a drug adjustment period. After that the patients were on an unchanged propranolol dose for 8 weeks (40, 80 or 160 mg four times daily). For all observed changes the correlation was studied to (1) dose, (2) free and total simultaneously determined plasma concentration and (3) free and total average plasma concentration of unchanged drug during the preceding 24 h period. Total protein and albumin did not change significantly. After 4 and 8 weeks on the final dose orosomucoid was increased significantly (by 10%) compared with the value from the end of the drug free period. Creatinine rose significantly during the initial 4‐6 weeks therapy to remain at the same level during the last 4 weeks. Urate was increased at the two lowest dose levels. Total cholesterol fell significantly (5%) while triglycerides increased significantly (16%). T4 rose significantly, T3 fell and r‐T3 rose significantly in a dose dependent way. Interindividually r‐T3 was the only biochemical change showing a significant relationship to the propranolol plasma concentration. The relationship reached the highest level of significance to the average 24 h free concentration.
Local anaesthetic effect of antiarrhythmic drugs and human sperm immobilization: mechanism and application of the interrelationship.
Authors: Hong CY , Chiang BN
Published: July 2012

Sperm immobilizing activity of three class I antiarrhythmic drugs, quinidine, procainamide, mexiletine, one adrenoceptor blocking drug, labetalol and one calcium channel blocking drug, diltiazem was measured with a trans‐membrane migration method. All these drugs immobilized human sperm. Local anaesthetic effect is the underlying mechanism for these drugs to inhibit sperm motility. Sperm immobilization could be a screening test for the local anaesthetic effect of antiarrhythmic drugs.
Is circadian variation in theophylline trough serum concentrations determined by time of dosing?
Authors: Jackson SH , Wiffen JK , Smythe MM , Johnston A
Published: July 2012

Ten healthy volunteers were each given two separate courses of eight doses of theophylline 200 mg as a slow release preparation at 12 hourly intervals. In the first course (regimen 1) the dose was given at 11.00 h and 23.00 h and in the second (regimen 2) at 05.00 h and 17.00 h. Sixty hours after the start of each course, four consecutive trough serum theophylline concentrations were measured. On regimen 1 the trough concentration of theophylline was 6.2 +/‐ 2.2 mg/l (mean +/‐ s.d.) at 11.00 h compared with 5.4 +/‐ 1.9 mg/l at 23.00 h (P less than 0.01). This circadian variation was abolished during regimen 2 when the mean theophylline concentrations were identical at 5.2 mg/l. The higher trough concentrations after the evening dose on regimen 1 and the loss of circadian variation on regimen 2 may be due to the change in sleep period in relation to the time of dosing.
Pituitary secretion after administration of a new cerebroactive drug, fipexide.
Authors: Rolandi E , Franceschini R , Marabini A , Messina V , Bongera P , Barreca T
Published: July 2012

The effect of a single oral dose of 400 mg fipexide on pituitary secretion was investigated in 10 elderly non‐endocrine patients. Fipexide induced significant decrease (P less than 0.05) in serum prolactin (PRL) values at 90 and 120 min after drug administration, without affecting serum growth hormone (GH), gonadotropin (LH and FSH), thyrotropin (TSH) and cortisol values. Fipexide was unable to modify metoclopramide‐induced PRL release in five of these patients. Our results show that this drug acts as a mild dopamine (DA) agonist, probably not directly affecting hypothalamic and/or pituitary DA receptors but indirectly via a reduced DA re‐uptake at the pre‐synaptic level.
The protein binding of timegadine determined by equilibrium dialysis.
Authors: George S , McBurney A , Ward J
Published: July 2012

The protein binding of timegadine to albumin, serum, plasma and plasma enriched with the acute phase reactants alpha 1‐acid glycoprotein, alpha 1‐anti‐trypsin and C‐reactive protein was determined by equilibrium dialysis. The effects of other analgesic and anti‐ inflammatories (indomethacin, ketoprofen, paracetamol and sodium salicylate) and other basic drugs (disopyramide, lignocaine, propranolol and quinidine) on the binding of timegadine were also determined. Timegadine binding was concentration‐dependent up to 0.5 micrograms/ml, but independent above this level up to 10.0 micrograms/ml, the mean and standard error being 93.8 +/‐ 0.5%. Albumin accounted for only 32.4% of timegadine bound to plasma. Plasma enrichment with the acute phase reactants led to significant increases in timegadine binding. Simultaneous dialysis with other drugs caused significant decreases in timegadine binding.
Circadian variation in plasma theophylline concentrations during maintenance therapy with a sustained‐release preparation in patients with obstructive airways disease.
Authors: Taylor DR , Duffin D. , Kinney CD , McDevitt DG
Published: July 2012

Circadian variation in plasma theophylline concentrations was studied in eight patients with obstructive airways disease during regular 12‐ hourly dosing at 09.00 and 21.00 h with a sustained‐release theophylline formulation. After regular dosing for a minimum period of 3 days, plasma concentration measurements were made at 09.00, 13.00, 21.00 and 01.00 h on 3 consecutive days and at more regular intervals during a complete 24 h period on day 4. On each day, theophylline concentrations for the first 4 h of the dosing interval were consistently higher during the day than at night. However, the differences were significant only at 13.00/01.00 h on day 2, and for each of the first 4 h on day 4. On day 4, following the dose at 21.00 h the mean peak plasma theophylline concentration occurred 6.9 +/‐ 0.8 h after dosing; in contrast, after the morning dose the mean peak concentration occurred at 4.5 +/‐ 0.8 h. However, the mean 'steady‐ state' concentrations during the two dose intervals were not significantly different. Thus circadian variations in plasma drug concentrations do occur in patients taking maintenance theophylline therapy: differing rates of absorption may account for the observed pattern.
The effects in volunteers of BW12C, a compound designed to left‐shift the blood‐oxygen saturation curve.
Authors: Fitzharris P , McLean AE , Sparks RG , Weatherley BC , White RD , Wootton R
Published: July 2012

BW12C, a potent left‐shifting anti‐sickling compound in vitro, was administered to normal healthy male Caucasian volunteers. Doses of 2‐20 mg kg‐1 given by intravenous infusion over 1 h caused a dose‐dependent left‐shift of the blood‐oxygen saturation curve and at the highest dose some 16% of the haemoglobin existed in a high affinity form. Peak left‐ shift was observed at the end of infusion and decayed thereafter with a mean half‐life of approximately 3 h. There were no adverse systemic effects, either clinical, biochemical or haematological, but there was some local irritation at the intravenous infusion site if the infusion was too concentrated. Pharmacokinetic measurements indicated uptake into erythrocytes, low levels in plasma and a volume of distribution not appreciably greater than the blood volume. A pilot radiolabel study indicated extensive metabolism with elimination into the urine.