pubmed_id
stringlengths 39
43
| abstract
stringlengths 3
18k
|
|---|---|
http://www.ncbi.nlm.nih.gov/pubmed/215035 | 1. Am J Physiol. 1978 Nov;235(5):C212-9. doi: 10.1152/ajpcell.1978.235.5.C212.
Evaluation of oxidative phosphorylation in hearts from euthyroid, hypothyroid,
and hyperthyroid rats.
Nishiki K, Erecińska M, Wilson DF, Cooper S.
The energy relationships between cytosolic and mitochondrial metabolism were
studied in the hearts from euthyroid, hypothyroid, and hyperthyroid rats.
Isolated mitochondria showed high respiratory control ratios and impermeability
to exogenous NADH. Hypo- and hyperthyroidism, respectively, resulted in lower
and higher contents of both cytochromes per mitochondrion and mitochondrial
protein per gram of wet weight of heart without changes in the ratio of
cytochrome c to cytochrome aa3. In isolated perfused heart, the hyperthyroid
state led to an increase in work rate and thereby an elevation of Vo2, which
resulted in an increase oxidation-reduction turnover number for the cytochromes.
An agreement was found between [ATP]/[ADP][Pi] of cytosolic free adenine
nucleotides and the value calculated from a mathematical model of mitochondrial
respiration. This implies that mitochondrial respiration is controlled at the
cytochrome oxidase reaction and that oxidative phosphorylation in intact tissue
is tightly coupled irrespective of thyroid state. It is concluded that thyroid
hormone causes an increase in the mitochondrial mass, mitochondrial cytochrome
content, and respiratory rate, and consequently expands the capacity of
oxidative metabolism without an uncoupling effect on oxidative phosphorylation.
DOI: 10.1152/ajpcell.1978.235.5.C212
PMID: 215035 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10593671 | 1. Pediatr Neurol. 1999 Nov;21(5):809-13. doi: 10.1016/s0887-8994(99)00100-9.
Jervell and Lange-Nielsen syndrome: neurologic and cardiologic evaluation.
Ilhan A(1), Tuncer C, Komsuoglu SS, Kali S.
Author information:
(1)Department of Neurology, Inonu University Medical Faculty, Turgut Ozal
Medical Center, Malatya, Turkey.
Recurrent syncope, malignant ventricular arrhythmias, and sudden death are
complications of the long QT syndrome (LQTS). Two well-known syndromes with long
QT intervals are known. The Jervell and Lange-Nielsen syndrome (JLNS) is
characterized by prolongation of the QT interval, deafness, and
autosomal-recessive inheritance, and the Romano-Ward syndrome is characterized
by a prolonged QT interval, autosomal-dominant inheritance, and no deafness. In
the present study assessment was performed of the diagnostic importance of the
ventricular derepolarization parameters, clinical features, and prevalence of
JLNS among 132 children with congenital hearing loss (CHL). In the CHL group the
mean QT, QTc, JT, and JTc intervals and the dispersion values (QT-d, JT-d,
QTc-d, and JTc-d) were significantly longer than those of control subjects (n =
96) (P < 0.05). Patients with CHL and JLNS (n = 5) had significantly longer mean
values of QT, QTc, JT, and JTc intervals and dispersion values than those of CHL
without JLNS (n = 127) and control subjects (P < 0.05). The results suggest that
assessment of ventricular derepolarization parameters in children with CHL will
be helpful in the early detection of JLNS because infants with CHL cannot
accurately describe the symptoms of syncope.
DOI: 10.1016/s0887-8994(99)00100-9
PMID: 10593671 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23382946 | 1. PLoS One. 2013;8(1):e54711. doi: 10.1371/journal.pone.0054711. Epub 2013 Jan
30.
Pale body-like inclusion formation and neurodegeneration following depletion of
26S proteasomes in mouse brain neurones are independent of α-synuclein.
Paine SM(1), Anderson G, Bedford K, Lawler K, Mayer RJ, Lowe J, Bedford L.
Author information:
(1)Neural Development Unit, University College London Institute of Child Health,
London, United Kingdom.
Parkinson's disease (PD) is characterized by the progressive degeneration of
substantia nigra pars compacta (SNpc) dopaminergic neurones and the formation of
Lewy bodies (LB) in a proportion of the remaining neurones. α-synuclein is the
main component of LB, but the pathological mechanisms that lead to
neurodegeneration associated with LB formation remain unclear. Three pivotal
elements have emerged in the development of PD: α-synuclein, mitochondria and
protein degradation systems. We previously reported a unique model, created by
conditional genetic depletion of 26S proteasomes in the SNpc of mice, which
mechanistically links these three elements with the neuropathology of PD:
progressive neurodegeneration and intraneuronal inclusion formation. Using this
model, we tested the hypothesis that α-synuclein was essential for the formation
of inclusions and neurodegeneration caused by 26S proteasomal depletion. We
found that both of these processes were independent of α-synuclein. This
provides an important insight into the relationship between the proteasome,
α-synuclein, inclusion formation and neurodegeneration. We also show that the
autophagy-lysosomal pathway is not activated in 26S proteasome-depleted
neurones. This leads us to suggest that the paranuclear accumulation of
mitochondria in inclusions in our model may reflect a role for the ubiquitin
proteasome system in mitochondrial homeostasis and that neurodegeneration may be
mediated through mitochondrial factors linked to inclusion biogenesis.
DOI: 10.1371/journal.pone.0054711
PMCID: PMC3559752
PMID: 23382946 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/21106091 | 1. BMC Genomics. 2010 Nov 24;11:663. doi: 10.1186/1471-2164-11-663.
Rnnotator: an automated de novo transcriptome assembly pipeline from stranded
RNA-Seq reads.
Martin J(1), Bruno VM, Fang Z, Meng X, Blow M, Zhang T, Sherlock G, Snyder M,
Wang Z.
Author information:
(1)Genomics Division, Lawrence Berkeley National Laboratory, Berkeley,
California, USA.
BACKGROUND: Comprehensive annotation and quantification of transcriptomes are
outstanding problems in functional genomics. While high throughput mRNA
sequencing (RNA-Seq) has emerged as a powerful tool for addressing these
problems, its success is dependent upon the availability and quality of
reference genome sequences, thus limiting the organisms to which it can be
applied.
RESULTS: Here, we describe Rnnotator, an automated software pipeline that
generates transcript models by de novo assembly of RNA-Seq data without the need
for a reference genome. We have applied the Rnnotator assembly pipeline to two
yeast transcriptomes and compared the results to the reference gene catalogs of
these organisms. The contigs produced by Rnnotator are highly accurate (95%) and
reconstruct full-length genes for the majority of the existing gene models
(54.3%). Furthermore, our analyses revealed many novel transcribed regions that
are absent from well annotated genomes, suggesting Rnnotator serves as a
complementary approach to analysis based on a reference genome for comprehensive
transcriptomics.
CONCLUSIONS: These results demonstrate that the Rnnotator pipeline is able to
reconstruct full-length transcripts in the absence of a complete reference
genome.
DOI: 10.1186/1471-2164-11-663
PMCID: PMC3152782
PMID: 21106091 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24510189 | 1. Nucleic Acids Res. 2014 Apr;42(8):5217-33. doi: 10.1093/nar/gku129. Epub 2014
Feb 8.
The activation of the decapping enzyme DCP2 by DCP1 occurs on the EDC4 scaffold
and involves a conserved loop in DCP1.
Chang CT(1), Bercovich N, Loh B, Jonas S, Izaurralde E.
Author information:
(1)Department of Biochemistry, Max Planck Institute for Developmental Biology,
Spemannstrasse 35, 72076 Tübingen, Germany.
The removal of the 5'-cap structure by the decapping enzyme DCP2 and its
coactivator DCP1 shuts down translation and exposes the mRNA to 5'-to-3'
exonucleolytic degradation by XRN1. Although yeast DCP1 and DCP2 directly
interact, an additional factor, EDC4, promotes DCP1-DCP2 association in
metazoan. Here, we elucidate how the human proteins interact to assemble an
active decapping complex and how decapped mRNAs are handed over to XRN1. We show
that EDC4 serves as a scaffold for complex assembly, providing binding sites for
DCP1, DCP2 and XRN1. DCP2 and XRN1 bind simultaneously to the EDC4 C-terminal
domain through short linear motifs (SLiMs). Additionally, DCP1 and DCP2 form
direct but weak interactions that are facilitated by EDC4. Mutational and
functional studies indicate that the docking of DCP1 and DCP2 on the EDC4
scaffold is a critical step for mRNA decapping in vivo. They also revealed a
crucial role for a conserved asparagine-arginine containing loop (the NR-loop)
in the DCP1 EVH1 domain in DCP2 activation. Our data indicate that DCP2
activation by DCP1 occurs preferentially on the EDC4 scaffold, which may serve
to couple DCP2 activation by DCP1 with 5'-to-3' mRNA degradation by XRN1 in
human cells.
DOI: 10.1093/nar/gku129
PMCID: PMC4005699
PMID: 24510189 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17663003 | 1. J Neurol Sci. 2007 Dec 15;263(1-2):100-6. doi: 10.1016/j.jns.2007.06.047. Epub
2007 Jul 30.
Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with
predominant hand involvement and Silver syndrome.
Rohkamm B(1), Reilly MM, Lochmüller H, Schlotter-Weigel B, Barisic N, Schöls L,
Nicholson G, Pareyson D, Laurà M, Janecke AR, Miltenberger-Miltenyi G, John E,
Fischer C, Grill F, Wakeling W, Davis M, Pieber TR, Auer-Grumbach M.
Author information:
(1)Institute of Human Genetics, Medical University Graz, Austria.
OBJECTIVE: Distal hereditary motor neuropathy type V (dHMN-V) and
Charcot-Marie-Tooth syndrome (CMT) type 2 presenting with predominant hand
involvement, also known as CMT2D and Silver syndrome (SS) are rare
phenotypically overlapping diseases which can be caused by mutations in the
Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) and in the glycyl-tRNA
synthetase encoding (GARS) genes. Mutations in the heat-shock proteins HSPB1 and
HSPB8 can cause related distal hereditary motor neuropathies (dHMN) and are
considered candidates for dHMN-V, CMT2, and SS.
DESIGN: To define the frequency and distribution of mutations in the GARS,
BSCL2, HSPB1 and HSPB8 genes we screened 33 unrelated sporadic and familial
patients diagnosed as either dHMN-V, CMT2D or SS. Exon 3 of the BSCL2 gene was
screened in further 69 individuals with an unclassified dHMN phenotype or
diagnosed as hereditary spastic paraplegia (HSP) complicated by pure motor
neuropathy.
RESULTS: Four patients diagnosed with dHMN-V or SS carried known heterozygous
BSCL2 mutations (N88S and S90L). In one dHMN-V patient we detected a putative
GARS mutation (A57V). No mutations were detected in HSPB1 and HSPB8. The
diagnostic yield gained in the series of 33 probands was 12% for BSCL2 mutations
and 3% for GARS mutations. In the series of unclassified dHMN and complicated
HSP cases no mutations were found.
CONCLUSIONS: Our data confirm that most likely only two mutations (N88S, S90L)
in exon 3 of BSCL2 may lead to dHMN-V or SS phenotypes. Mutations in GARS, HSPB1
and HSPB8. are not a common cause of dHMN-V, SS and CMT2D. We would therefore
suggest that a genetic testing of dHMN-V and SS patients should begin with
screening of exon 3 of the BSCL2 gene. Screening of the GARS gene is useful in
patients with CMT2 with predominant hand involvement and dHMN-V. The rather low
frequencies of BSCL2, GARS, HSPB1 and HSPB8 mutations in dHMN-V, CMT2D and SS
patients strongly point to further genetic heterogeneity of these related
disorders.
DOI: 10.1016/j.jns.2007.06.047
PMCID: PMC3272403
PMID: 17663003 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23027751 | 1. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Oct 1;68(Pt
10):1217-21. doi: 10.1107/S174430911203607X. Epub 2012 Sep 26.
Purification, crystallization and X-ray diffraction analysis of human
dynamin-related protein 1 GTPase-GED fusion protein.
Klinglmayr E(1), Wenger J, Mayr S, Bossy-Wetzel E, Puehringer S.
Author information:
(1)Department of Molecular Biology, University of Salzburg, 5020 Salzburg,
Austria.
The mechano-enzyme dynamin-related protein 1 plays an important role in
mitochondrial fission and is implicated in cell physiology. Dysregulation of
Drp1 is associated with abnormal mitochondrial dynamics and neuronal damage.
Drp1 shares structural and functional similarities with dynamin 1 with respect
to domain organization, ability to self-assemble into spiral-like oligomers and
GTP-cycle-dependent membrane scission. Structural studies of human dynamin-1
have greatly improved the understanding of this prototypical member of the
dynamin superfamily. However, high-resolution structural information for
full-length human Drp1 covering the GTPase domain, the middle domain and the
GTPase effector domain (GED) is still lacking. In order to obtain mechanistic
insights into the catalytic activity, a nucleotide-free GTPase-GED fusion
protein of human Drp1 was expressed, purified and crystallized. Initial X-ray
diffraction experiments yielded data to 2.67 Å resolution. The hexagonal-shaped
crystals belonged to space group P2(1)2(1)2, with unit-cell parameters a =
53.59, b = 151.65, c = 43.53 Å, one molecule per asymmetric unit and a solvent
content of 42%. Expression of selenomethionine-labelled protein is currently in
progress. Here, the expression, purification, crystallization and X-ray
diffraction analysis of the Drp1 GTPase-GED fusion protein are presented, which
form a basis for more detailed structural and biophysical analysis.
DOI: 10.1107/S174430911203607X
PMCID: PMC3497983
PMID: 23027751 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15893763 | 1. J Mol Cell Cardiol. 2005 Aug;39(2):319-26. doi: 10.1016/j.yjmcc.2005.03.016.
Nuclear-mitochondrial cross-talk in cardiomyocyte T3 signaling: a time-course
analysis.
Goldenthal MJ(1), Ananthakrishnan R, Marín-García J.
Author information:
(1)Molecular Cardiology and Neuromuscular Institute, 75 Raritan Avenue, Highland
Park, NJ 08904, USA.
Thyroid hormone (TH) induces marked changes in the biochemical and physiological
functioning of cardiac muscle affecting its bioenergetics, contractility and
structure. Using a time-course analysis of in vitro treatment of neonatal rat
cardiomyocytes with triiodothyronine (T3), mitochondrial biogenesis, functional
bioenergetics and cardiomyocyte hypertrophic phenotype were assessed. Activity
of respiratory complexes II, IV, V and citrate synthase (CS), levels of
mitochondrial enzyme subunits (e.g. COXI, COXIV) and nuclear-encoded
transcription factors, involved in mitochondrial biogenesis (e.g. PGC-1, mtTFA
and PPAR-alpha), were significantly elevated with 72 h T3 treatment. A
time-course analysis showed an early increase (between 3 and 12 h) in activity
and levels of subunits of complex IV and V, mitochondrial Ca2+ accumulation and
a late increase (at 72 h) in complex II and CS activities, mitochondrial protein
content and mitochondrial respiration. Based on overall protein content and
specific peptide levels (e.g. actin or myosin) only mild cardiomyocyte
hypertrophy was detected. T3 mediates an early stimulation of enzymes containing
mtDNA encoded subunits (e.g. complex IV and V) in contrast to a different
regulatory pattern for the entirely nuclear-encoded enzymes (e.g. CS and complex
II). T3-regulation was similar in both neonatal and young adult cardiomyocytes
(ARCM) but absent in the senescent cardiomyocytes. This model offer an
opportunity to study the rapid timing of events involved in myocardial cell
signaling, bioenergetics and growth dynamics in a timeframe not available with
whole animal studies.
DOI: 10.1016/j.yjmcc.2005.03.016
PMID: 15893763 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20479966 | 1. Mar Drugs. 2010 Mar 31;8(4):1049-58. doi: 10.3390/md8041049.
LC/MS analysis of tetrodotoxin and its deoxy analogs in the marine puffer fish
Fugu niphobles from the southern coast of Korea, and in the brackishwater puffer
fishes Tetraodon nigroviridis and Tetraodon biocellatus from Southeast Asia.
Jang JH(1), Lee JS, Yotsu-Yamashita M.
Author information:
(1)Graduate School of Agricultural Science, Tohoku University, 1-1
Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan.
[email protected]
Tetrodotoxin (TTX) and its deoxy analogs, 5-deoxyTTX, 11-deoxyTTX,
6,11-dideoxyTTX, and 5,6,11-trideoxyTTX, were quantified in the tissues of three
female and three male specimens of the marine puffer fish, Fugu niphobles, from
the southern coast of Korea, and in the whole body of the brackishwater puffer
fishes, Tetraodon nigroviridis (12 specimens) and Tetrodon biocellatus (three
specimens) from Southeast Asia using LC/MS in single ion mode (SIM).
Identification of these four deoxy analogs in the ovarian tissue of F. niphobles
were further confirmed by LC/MS/MS. TTX and 5,6,11-trideoxyTTX were detected in
all three puffer fish species as the major TTX analogs, similar to Japanese Fugu
pardalis. While 6,11-dideoxyTTX was also found to be a major analog in almost
all tissues of Korean F. niphobles, this analog was minor in the two Tetraodon
species and Japanese F. pardalis. Among the tissues of F. niphobles, the
concentrations of TTXs were highest in the ovaries (female) and skin (female and
male).
DOI: 10.3390/md8041049
PMCID: PMC2866474
PMID: 20479966 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23980025 | 1. Bioinformatics. 2013 Oct 15;29(20):2529-38. doi:
10.1093/bioinformatics/btt442. Epub 2013 Aug 25.
MITIE: Simultaneous RNA-Seq-based transcript identification and quantification
in multiple samples.
Behr J(1), Kahles A, Zhong Y, Sreedharan VT, Drewe P, Rätsch G.
Author information:
(1)Computational Biology Center, Sloan-Kettering Institute, 1275 York Avenue,
New York, NY 10065, USA and Friedrich Miescher Laboratory, Max Planck Society,
Spemannstr. 39, 72076 Tübingen, Germany.
MOTIVATION: High-throughput sequencing of mRNA (RNA-Seq) has led to tremendous
improvements in the detection of expressed genes and reconstruction of RNA
transcripts. However, the extensive dynamic range of gene expression, technical
limitations and biases, as well as the observed complexity of the
transcriptional landscape, pose profound computational challenges for
transcriptome reconstruction.
RESULTS: We present the novel framework MITIE (Mixed Integer Transcript
IdEntification) for simultaneous transcript reconstruction and quantification.
We define a likelihood function based on the negative binomial distribution, use
a regularization approach to select a few transcripts collectively explaining
the observed read data and show how to find the optimal solution using Mixed
Integer Programming. MITIE can (i) take advantage of known transcripts, (ii)
reconstruct and quantify transcripts simultaneously in multiple samples, and
(iii) resolve the location of multi-mapping reads. It is designed for genome-
and assembly-based transcriptome reconstruction. We present an extensive study
based on realistic simulated RNA-Seq data. When compared with state-of-the-art
approaches, MITIE proves to be significantly more sensitive and overall more
accurate. Moreover, MITIE yields substantial performance gains when used with
multiple samples. We applied our system to 38 Drosophila melanogaster modENCODE
RNA-Seq libraries and estimated the sensitivity of reconstructing omitted
transcript annotations and the specificity with respect to annotated
transcripts. Our results corroborate that a well-motivated objective paired with
appropriate optimization techniques lead to significant improvements over the
state-of-the-art in transcriptome reconstruction.
AVAILABILITY: MITIE is implemented in C++ and is available from
http://bioweb.me/mitie under the GPL license.
DOI: 10.1093/bioinformatics/btt442
PMCID: PMC3789545
PMID: 23980025 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21094621 | 1. Mol Genet Metab. 2011 Feb;102(2):134-8. doi: 10.1016/j.ymgme.2010.10.013. Epub
2010 Nov 5.
Overexpression of adapted U1snRNA in patients' cells to correct a 5' splice site
mutation in propionic acidemia.
Sánchez-Alcudia R(1), Pérez B, Pérez-Cerdá C, Ugarte M, Desviat LR.
Author information:
(1)Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología
Molecular Severo Ochoa, UAM-CSIC, Universidad Autónoma de Madrid, Madrid, Spain.
Splicing defects account for 16% of the mutant alleles in the PCCA and PCCB
genes, encoding both subunits of the propionyl-CoA carboxylase (PCC) enzyme,
defective in propionic acidemia, one of the most frequent organic acidemias
causing variable neurological impairment. Most of the splicing mutations
identified affect the conserved 3' splice (3' ss) or 5' splice (5' ss) sites,
the latter predictably through lowering the strength of base pairing with
U1snRNA. Among the 5' ss mutations we have focused on the c.1209+3A>G
(IVS13+3A>G) mutation in the PCCA gene, identified in four patients (three
homozygous and one heterozygous) of common geographical origin and causing exon
13 skipping. To study the potential of splicing modulation to restore PCC
function, we analyzed the effect of transient transfections in patients' cells
with modified U1snRNA adapted to compensate the mutant change and other
mismatches at different positions of the 5' ss. Using this strategy normal
transcript could be efficiently recovered with the concomitant disappearance of
the aberrant exon skipping transcript, as observed after standard RT-PCR and
sequence analysis or using fluorescent primers and semiquantitative RT-PCR.
Different efficiencies with up to 100% exon inclusion were observed depending on
the transfection conditions and specifically on the adapted U1snRNA used,
confirming previously reported dependencies between nucleotides at the 5' ss for
its correct recognition by the spliceosome. The reversal of the splicing defect
did not result in a significant increase in enzyme activity, suggesting other
factors must be taken into account for the application of overexpression of
splice factors such as U1 as therapeutic strategy for splice defects.
Copyright © 2010 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ymgme.2010.10.013
PMID: 21094621 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15464417 | 1. Mol Genet Metab. 2004 Sep-Oct;83(1-2):28-37. doi: 10.1016/j.ymgme.2004.08.001.
Propionic acidemia: mutation update and functional and structural effects of the
variant alleles.
Desviat LR(1), Pérez B, Pérez-Cerdá C, Rodríguez-Pombo P, Clavero S, Ugarte M.
Author information:
(1)Centro de Biología Molecular "Severo Ochoa" CSIC-UAM, Universidad Autónoma de
Madrid, Cantoblanco, 28049 Madrid, Spain.
Mutations in the PCCA or PCCB genes, encoding both subunits of propionyl-CoA
carboxylase, result in propionic acidemia, a life-threatening inborn error of
metabolism with autosomal recessive inheritance. To date, 41 mutations in the
PCCA gene and 54 in the PCCB gene have been reported, most of them single base
substitutions causing amino acid replacements, and a variety of small insertions
and deletions and splicing defects. A greater heterogeneity is observed in the
PCCA gene, specially in Caucasians, with no prevalent mutations, while in the
Japanese population three mutations account for more than half of the alleles
studied. For the PCCB gene a limited number of mutations is responsible for the
majority of the alleles characterized in both Caucasian and Oriental
populations. These two populations show a different mutational spectrum, only
sharing some involving CpG dinucleotides probably as recurrent mutational
events. Functional characterization of the mutant missense alleles has been
accomplished using different prokaryotic and eukaryotic systems, and the
structural consequences have been analyzed in the available crystal models. For
the PCCA gene, the main molecular effect of the expressed mutations is related
to protein instability, except two mutations in the active site predictably
affecting ATP binding. In the PCCB gene the majority of the analyzed mutations
are predicted to alter the active site conformation resulting in diminished
activity. A few carboxy-terminal PCCB mutations affect the interaction between
subunits and the assembly with PCCA to form a functional PCC oligomer. The
amount of normal transcripts resulting from some PCCA and PCCB splicing
mutations has also been analyzed. Overall, the data generated from the
expression analysis reveal potential genotype-phenotype correlations for this
clinically heterogeneous disorder.
DOI: 10.1016/j.ymgme.2004.08.001
PMID: 15464417 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11245989 | 1. Gene. 2001 Feb 7;264(1):147-52. doi: 10.1016/s0378-1119(00)00586-2.
cDNA cloning, mapping and expression of the mouse propionyl CoA carboxylase beta
(pccb), the gene for human type II propionic acidaemia.
Schrick JJ(1), Lingrel JB.
Author information:
(1)Department of Molecular Genetics, Microbiology and Biochemistry, University
of Cincinnati, Cincinnati OH 45267, USA. [email protected]
Propionyl CoA carboxylase (PCC) is a mitochondrial, biotin-dependent enzyme
involved in the catabolism of amino acids, odd-chained fatty acids and other
metabolites. PCC is composed of two equal subunits, alpha and beta, which are
encoded by two separate genes at two distinct human loci. Mutations of either
gene in humans results in propionic acidemia (PA). To identify the mouse cDNA
for the propionyl CoA carboxylase beta-subunit (pccb), we have screened the
mouse EST database using the human sequence. The murine mRNA transcript is
approximately 2.3 kb, nearly 500 bps larger than the human approximately 1.8 kb
transcript. A PAC genomic DNA clone from the mouse was also isolated and used to
generate probes and PCR primers for mapping the pccb locus in the mouse. Both
the C57Bl/6JEi and Spret/Ei alleles for regions flanking the pccb gene were
sequenced to identify RFLPs. The Jackson Laboratory BSS and BSB backcross panel
DNAs were then analyzed using a DdeI polymorphism placing the pccb locus on
mouse chromosome 9. Northern blots of adult tissue show that the pccb gene is
broadly expressed in the mouse. The approximately 2.3 kb transcript is most
abundantly expressed in the kidney, liver, small intestine and stomach tissues.
DOI: 10.1016/s0378-1119(00)00586-2
PMID: 11245989 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23128392 | 1. Oncogene. 2013 Oct;32(40):4814-24. doi: 10.1038/onc.2012.494. Epub 2012 Nov 5.
Mitochondrial dynamics regulates migration and invasion of breast cancer cells.
Zhao J(1), Zhang J, Yu M, Xie Y, Huang Y, Wolff DW, Abel PW, Tu Y.
Author information:
(1)1] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese
Academy of Sciences, Beijing, China [2] Department of Pharmacology, Creighton
University School of Medicine, Omaha, NE, USA.
Mitochondria are highly dynamic and undergo constant fusion and fission that are
essential for maintaining physiological functions of cells. Although dysfunction
of mitochondria has been implicated in tumorigenesis, little is known about the
roles of mitochondrial dynamics in metastasis, the major cause of cancer death.
In the present study, we found a marked upregulation of mitochondrial fission
protein dynamin-related protein 1 (Drp1) expression in human invasive breast
carcinoma and metastases to lymph nodes. Compared with non-metastatic breast
cancer cells, mitochondria also were more fragmented in metastatic breast cancer
cells that express higher levels of total and active Drp1 and less mitochondrial
fusion protein 1 (Mfn1). Silencing Drp1 or overexpression of Mfn1 resulted in
mitochondria elongation or clusters, respectively, and significantly suppressed
metastatic abilities of breast cancer cells. In contrast, silencing Mfn proteins
led to mitochondrial fragmentation and enhanced metastatic abilities of breast
cancer cells. Interestingly, these manipulations of mitochondrial dynamics
altered the subcellular distribution of mitochondria in breast cancer cells. For
example, silencing Drp1 or overexpression of Mfn1 inhibited lamellipodia
formation, a key step for cancer metastasis, and suppressed
chemoattractant-induced recruitment of mitochondria to lamellipodial regions.
Conversely, silencing Mfn proteins resulted in more cell spreading and
lamellipodia formation, causing accumulation of more mitochondria in
lamellipodia regions. More importantly, treatment with a mitochondrial
uncoupling agent or adenosine triphosphate synthesis inhibitor reduced
lamellipodia formation and decreased breast cancer cell migration and invasion,
suggesting a functional importance of mitochondria in breast cancer metastasis.
Together, our findings show a new role and mechanism for regulation of cancer
cell migration and invasion by mitochondrial dynamics. Thus targeting
dysregulated Drp1-dependent mitochondrial fission may provide a novel strategy
for suppressing breast cancer metastasis.
DOI: 10.1038/onc.2012.494
PMCID: PMC3911914
PMID: 23128392 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest The authors declare no
conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/16049199 | 1. Stroke. 2005 Aug;36(8):1627-32. doi: 10.1161/01.STR.0000176743.67564.5d.
Effects of acute treatment with pravastatin on cerebral vasospasm,
autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid
hemorrhage: a phase II randomized placebo-controlled trial.
Tseng MY(1), Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ.
Author information:
(1)Department of Neurosurgery, Addenbrooke's Hospital, University of Cambridge,
Cambridge CB2 2QQ, United Kingdom.
Comment in
Stroke. 2006 Feb;37(2):335; author reply 335. doi:
10.1161/01.STR.0000199666.44942.41.
BACKGROUND AND PURPOSE: Statins may improve cerebral vasomotor reactivity
through cholesterol-dependent and -independent mechanisms. A phase II randomized
controlled trial was conducted to examine the hypothesis that acute pravastatin
treatment could improve cerebrovascular autoregulation and reduce
vasospasm-related complications after aneurysmal subarachnoid hemorrhage (SAH).
METHODS: A total of 80 aneurysmal SAH (aSAH) patients (18 to 84 years of age)
within 72 hours from the ictus were randomized equally to receive either oral
pravastatin (40 mg) or placebo daily for up to 14 days. Primary end points were
the incidence, duration, and severity of cerebral vasospasm, and duration of
impaired autoregulation estimated from transcranial Doppler ultrasonography.
Secondary end points were the incidence of vasospasm-related delayed ischemic
deficits (DIDs) and disability at discharge.
RESULTS: Prerandomization characteristics were balanced between the 2 groups. No
treatment-related complication was observed. The incidences of vasospasm and
severe vasospasm were reduced by 32% (P=0.006) and 42% (P=0.044), respectively,
and the duration of severe vasospasm was shortened by 0.8 days (P=0.068) in the
pravastatin group. These measurements were maximal on the ipsilateral side of
ruptured aneurysms. The duration of impaired autoregulation was shortened
bilaterally (P< or =0.01), and the incidence of vasospasm-related DIDs and
mortality were decreased by 83% (P<0.001) and 75% (P=0.037), respectively, in
the pravastatin group.
CONCLUSIONS: Acute treatment with pravastatin after aSAH is safe and ameliorates
cerebral vasospasm, improves cerebral autoregulation, and reduces
vasospasm-related DID. Unfavorable outcome at discharge was reduced primarily
because of a reduction in overall mortality. This is the first demonstration of
clinical benefits with immediate statin therapy for an acute cerebrovascular
disorder.
DOI: 10.1161/01.STR.0000176743.67564.5d
PMID: 16049199 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12399470 | 1. J Biol Chem. 2003 Jan 3;278(1):556-66. doi: 10.1074/jbc.M207515200. Epub 2002
Oct 23.
p105.Ikappa Bgamma and prototypical Ikappa Bs use a similar mechanism to bind
but a different mechanism to regulate the subcellular localization of NF-kappa
B.
Moorthy AK(1), Ghosh G.
Author information:
(1)Department of Chemistry & Biochemistry, University of California at San
Diego, La Jolla, California 92093-0359, USA.
p105, also known as NF-kappaB1, is an atypical IkappaB molecule with a
multi-domain organization distinct from other prototypical IkappaBs, like
IkappaBalpha and IkappaBbeta. To understand the mechanism by which p105 binds
and inhibits NF-kappaB, we have used both p105 and its C-terminal inhibitory
segment known as IkappaBgamma for our study. We show here that one IkappaBgamma
molecule binds to NF-kappaB dimers wherein at least one NF-kappaB subunit is
p50. We suggest that the obligatory p50 subunit in IkappaBgamma.NF-kappaB
complexes is equivalent to the N-terminal p50 segment in all p105.NF-kappaB
complexes. The nuclear localization signal (NLS) of the obligatory p50 subunit
is masked by IkappaBgamma, whereas the NLS of the nonobligatory NF-kappaB
subunit is exposed. Thus, the global binding mode of all IkappaB.NF-kappaB
complexes seems to be similar where one obligatory (or specific) NF-kappaB
subunit makes intimate contact with IkappaB and the nonobligatory (or
nonspecific) subunit is bound primarily through its ability to dimerize. In the
case of IkappaBalpha and IkappaBbeta, the specific NF-kappaB subunit in the
complex is p65. In contrast to IkappaBalpha.NF-kappaB complexes, where the
exposed NLS of the nonspecific subunit imports the complex to the nucleus,
p105.NF-kappaB and IkappaBgamma.NF-kappaB complexes are cytoplasmic. We show
that the death domain of p105 (also of IkappaBgamma) is essential for the
cytoplasmic sequestration of NF-kappaB by p105 and IkappaBgamma. However, the
death domain does not mask the exposed NLS of the complex. We also demonstrate
that the death domain alone is not sufficient for cytoplasmic retention and
instead functions only in conjunction with other parts in the three-dimensional
scaffold formed by the association of the ankyrin repeat domain (ARD) and
NF-kappaB dimer. We speculate that additional cytoplasmic protein(s) may
sequester the entire p105.NF-kappaB complex by binding through the death domain
and other segments, including the exposed NLS.
DOI: 10.1074/jbc.M207515200
PMID: 12399470 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/842709 | 1. Am J Psychiatry. 1977 Mar;134(3):302-4. doi: 10.1176/ajp.134.3.302.
Weight reduction in schizophrenics by molindone.
Gardos G, Cole JO.
The weight-reducing property of molindone, a recently introduced antipsychotic
drug, was tested in 9 hospitalized chronic schizophrenic patients. There was an
average weight loss of 7.6 kg after 3 months on molindone; most of the loss
occurred during the first month. The mechanism producing this weight loss is
uncertain, but a central anorexigenic effect may be an important factor.
DOI: 10.1176/ajp.134.3.302
PMID: 842709 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25526884 | 1. BMC Bioinformatics. 2014 Dec 20;15(1):388. doi: 10.1186/s12859-014-0388-9.
Linear-time computation of minimal absent words using suffix array.
Barton C(1), Heliou A(2)(3), Mouchard L(4), Pissis SP(5).
Author information:
(1)Department of Informatics, King's College London, The Strand, WC2R 2LS,
London, UK. [email protected].
(2)Inria Saclay-Île de France, AMIB, Bâtiment Alan Turing, Palaiseau, France.
[email protected].
(3)Laboratoire d'Informatique de l'École Polytechnique (LIX), CNRS UMR 7161,
Palaiseau, France. [email protected].
(4)University of Rouen, LITIS EA 4108, TIBS, Rouen, France.
[email protected].
(5)Department of Informatics, King's College London, The Strand, WC2R 2LS,
London, UK. [email protected].
BACKGROUND: An absent word of a word y of length n is a word that does not occur
in y. It is a minimal absent word if all its proper factors occur in y. Minimal
absent words have been computed in genomes of organisms from all domains of
life; their computation also provides a fast alternative for measuring
approximation in sequence comparison. There exists an [Formula: see text]-time
and [Formula: see text]-space algorithm for computing all minimal absent words
on a fixed-sized alphabet based on the construction of suffix automata
(Crochemore et al., 1998). No implementation of this algorithm is publicly
available. There also exists an [Formula: see text]-time and [Formula: see
text]-space algorithm for the same problem based on the construction of suffix
arrays (Pinho et al., 2009). An implementation of this algorithm was also
provided by the authors and is currently the fastest available.
RESULTS: Our contribution in this article is twofold: first, we bridge this
unpleasant gap by presenting an [Formula: see text]-time and [Formula: see
text]-space algorithm for computing all minimal absent words based on the
construction of suffix arrays; and second, we provide the respective
implementation of this algorithm. Experimental results, using real and synthetic
data, show that this implementation outperforms the one by Pinho et al. The
open-source code of our implementation is freely available at
http://github.com/solonas13/maw .
CONCLUSIONS: Classical notions for sequence comparison are increasingly being
replaced by other similarity measures that refer to the composition of sequences
in terms of their constituent patterns. One such measure is the minimal absent
words. In this article, we present a new linear-time and linear-space algorithm
for the computation of minimal absent words based on the suffix array.
DOI: 10.1186/s12859-014-0388-9
PMCID: PMC4297395
PMID: 25526884 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15059621 | 1. Mol Genet Metab. 2004 Apr;81(4):335-42. doi: 10.1016/j.ymgme.2004.01.003.
Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic
acidemia.
Yang X(1), Sakamoto O, Matsubara Y, Kure S, Suzuki Y, Aoki Y, Yamaguchi S,
Takahashi Y, Nishikubo T, Kawaguchi C, Yoshioka A, Kimura T, Hayasaka K, Kohno
Y, Iinuma K, Ohura T.
Author information:
(1)Department of Medical Genetics, Tohoku University School of Medicine, 1-1
Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Propionic acidemia (PA) is an inborn error of organic acid metabolism caused by
a deficiency of propionyl-CoA carboxylase. This enzyme is composed of two
non-identical subunits, alpha and beta, which are encoded by the PCCA and PCCB
genes, respectively. An enzyme deficiency can result from mutations in either
PCCA or PCCB. To elucidate the mutation spectrum in Japanese patients, we have
performed a mutation analysis of 30 patients with PA, which included nine
previously reported patients. The study revealed that 15 patients were
alpha-subunit deficient and 15 patients were beta-subunit deficient. Seven novel
mutations were found (IVS18-6C >G, 1746G >A, C398R, G197E and IVS18+1G >A in the
PCCA; A153P and IVS9+1G >T in the PCCB). Among these Japanese patients with
alpha-subunit deficiencies, 923-924insT, IVS18-6C >G, and R399Q mutations were
frequent and the total allelic frequency of these three mutations combined was
56% (17/30). This is in sharp contrast to the mutation spectrum found in
Caucasian patients, where no prevalent mutations have been identified. Among the
beta-subunit deficiencies, there were three frequent mutations; R410W, T428I,
and A153P, whose allelic frequencies were 30, 26.7, and 13.3%, respectively. In
conclusion, a limited number of mutations are predominant in both PCCA and PCCB
genes among Japanese patients with propionic acidemia.
DOI: 10.1016/j.ymgme.2004.01.003
PMID: 15059621 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15457700 | 1. Stud Health Technol Inform. 2002;91:86-9.
Positional cloning strategies for idiopathic scoliosis.
Bashiardes S(1), Veile R, Wise CA, Szappanos L, Lovett M.
Author information:
(1)Department of Genetics, Washington University School of-Iedicine, St. Louis,
AIO, USA.
AIM: Idiopathic scoliosis (IS) affects approximately 1-2% of the population and
has a heritable component. It is clear that in general IS displays the features
of a complex genetic disorder; however families displaying a Mendelian
inheritance pattern have been described. Our aim is to identify families
segregating rare, highly penetrant loci. In the case described here the disorder
appears to cosegregate with a chromosomal rearrangement.
METHODS AND MATERIALS: We have studied a family in which a pericentric inversion
of chromosome 8 appears to cosegregate with idiopathic scoliosis in three
generations. We have used fluorescent in situ hybridization (FISH) to identify
cloned DNAs that span the breakpoints on the two arms of the chromosome. These
clones allow the recovery of sequence information from the breakpoint region and
identification of candidate genes.
RESULTS: We have identified a YAC of 1190kb that spans the p arm breakpoint and
from this a cosmid of 35kb that also identifies the break. We have derived DNA
sequence information on this region. We have identified a BAC of 150kb that
crosses the q arm breakpoint. The complete genomic DNA sequence of this BAC is
being analyzed to identify candidate genes and to further localize the precise
breakpoint.
CONCLUSION: We have sublocalized within two small genomic regions the position
of a possible locus for idiopathic scoliosis.
PMID: 15457700 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19036942 | 1. Am J Physiol Cell Physiol. 2009 Feb;296(2):C355-62. doi:
10.1152/ajpcell.00415.2007. Epub 2008 Nov 26.
Effect of thyroid hormone on mitochondrial properties and oxidative stress in
cells from patients with mtDNA defects.
Menzies KJ(1), Robinson BH, Hood DA.
Author information:
(1)School of Kinesiology and Health Science, Farqhuarson Life Science Bldg., Rm.
302, York Univ., Toronto, ON M3JIP3, Canada.
Mitochondrial (mt)DNA mutations contribute to various disease states
characterized by low ATP production. In contrast, thyroid hormone
[3,3',5-triiodothyronine (T(3))] induces mitochondrial biogenesis and enhances
ATP generation within cells. To evaluate the role of T(3)-mediated mitochondrial
biogenesis in patients with mtDNA mutations, three fibroblast cell lines with
mtDNA mutations were evaluated, including two patients with Leigh's syndrome and
one with hypertrophic cardiomyopathy. Compared with control cells, patient
fibroblasts displayed similar levels of mitochondrial mass, peroxisome
proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha),
mitochondrial transcription factor A (Tfam), and uncoupling protein 2 (UCP2)
protein expression. However, patient cells exhibited a 1.6-fold elevation in ROS
production, a 1.7-fold elevation in cytoplasmic Ca2+ levels, a 1.2-fold
elevation in mitochondrial membrane potential, and 30% less complex V activity
compared with control cells. Patient cells also displayed 20-25% reductions in
both cytochrome c oxidase (COX) activity and MnSOD protein levels compared with
control cells. After T(3) treatment of patient cells, ROS production was
decreased by 40%, cytoplasmic Ca2+ was reduced by 20%, COX activity was
increased by 1.3-fold, and ATP levels were elevated by 1.6-fold, despite the
absence of a change in mitochondrial mass. There were no significant alterations
in the protein expression of PGC-1alpha, Tfam, or UCP2 in either T(3)-treated
patient or control cells. However, T(3) restored the mitochondrial membrane
potential, complex V activity, and levels of MnSOD to normal values in patient
cells and elevated MnSOD levels by 21% in control cells. These results suggest
that T(3) acts to reduce cellular oxidative stress, which may help attenuate
ROS-mediated damage, along with improving mitochondrial function and energy
status in cells with mtDNA defects.
DOI: 10.1152/ajpcell.00415.2007
PMID: 19036942 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21865384 | 1. J Virol. 2011 Nov;85(21):11146-58. doi: 10.1128/JVI.05499-11. Epub 2011 Aug
24.
Systems analysis of immune responses in Marek's disease virus-infected chickens
identifies a gene involved in susceptibility and highlights a possible novel
pathogenicity mechanism.
Smith J(1), Sadeyen JR, Paton IR, Hocking PM, Salmon N, Fife M, Nair V, Burt DW,
Kaiser P.
Author information:
(1)The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush,
Midlothian EH25 9RG, United Kingdom. [email protected]
Marek's disease virus (MDV) is a highly contagious oncogenic alphaherpesvirus
that causes disease that is both a cancer model and a continuing threat to the
world's poultry industry. This comprehensive gene expression study analyzes the
host response to infection in both resistant and susceptible lines of chickens
and inherent expression differences between the two lines following the
infection of the host. A novel pathogenicity mechanism, involving the
downregulation of genes containing HIC1 transcription factor binding sites as
early as 4 days postinfection, was suggested from this analysis. HIC1 drives
antitumor mechanisms, suggesting that MDV infection switches off genes involved
in antitumor regulation several days before the expression of the MDV oncogene
meq. The comparison of the gene expression data to previous QTL data identified
several genes as candidates for involvement in resistance to MD. One of these
genes, IRG1, was confirmed by single nucleotide polymorphism analysis to be
involved in susceptibility. Its precise mechanism remains to be elucidated,
although the analysis of gene expression data suggests it has a role in
apoptosis. Understanding which genes are involved in susceptibility/resistance
to MD and defining the pathological mechanisms of the disease gives us a much
greater ability to try to reduce the incidence of this virus, which is costly to
the poultry industry in terms of both animal welfare and economics.
DOI: 10.1128/JVI.05499-11
PMCID: PMC3194948
PMID: 21865384 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9385377 | 1. Hum Genet. 1997 Nov;101(1):93-6. doi: 10.1007/s004390050593.
Three novel splice mutations in the PCCA gene causing identical exon skipping in
propionic acidemia patients.
Richard E(1), Desviat LR, Pérez B, Pérez-Cerdá C, Ugarte M.
Author information:
(1)Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Facultad de Ciencias,
Universidad Autónoma de Madrid, Spain.
Propionyl-CoA carboxylase (PCC) is a mitochondrial, biotin-dependent enzyme
involved in the catabolism of branched chain amino acids, odd chain fatty acids,
and other metabolites. PCC consists of non-identical subunits, alpha and beta,
encoded by the PCCA and PCCB genes, respectively. Inherited deficiency of PCC
due to mutations in either the PCCA or the PCCB gene results in propionic
acidemia (PA), a clinically heterogeneous disorder with a severe, often lethal,
neonatal form, and a mild, later onset form. To characterize PCCA gene mutations
responsible for PCC deficiency, we analyzed RT-PCR products obtained from
cultured fibroblasts from Spanish PCC-alpha deficient patients. In three
patients, smaller than normal PCR products were observed, and sequence analysis
revealed the deletion of a 54-bp exon in the cDNA. Sequencing of genomic DNA
from these three patients led to the identification of three novel mutations in
the PCCA gene, two short deletions and one small insertion, adjacent to short
direct repeats, and all of them affecting the consensus splice sites of the
skipped exon. These mutations, 1771IVS-2del9, 1824IVS+3del4, and 1824IVS+3insCT,
are the cause of the aberrant splicing of the PCCA pre-mRNA and result in an
in-frame deletion of 54 nucleotides in the cDNA, probably leading to an unstable
protein structure which is responsible for the lack of activity leading to PCC
deficiency in these patients.
DOI: 10.1007/s004390050593
PMID: 9385377 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12121623 | 1. Curr Biol. 2002 Jul 9;12(13):1138-44. doi: 10.1016/s0960-9822(02)00925-9.
Role of the arabidopsis DRM methyltransferases in de novo DNA methylation and
gene silencing.
Cao X(1), Jacobsen SE.
Author information:
(1)Department of Molecular, Cell, and Developmental Biology, University of
California, Los Angeles 90095, USA.
Proper DNA methylation patterning requires the complementary processes of de
novo methylation (the initial methylation of unmethylated DNA sequences) and
maintenance methylation (the faithful replication of preexisting methylation).
Arabidopsis has two types of methyltransferases with demonstrated maintenance
activity: MET1, which maintains CpG methylation and is homologous to mammalian
DNMT1, and CHROMOMETHYLASE 3 (CMT3), which maintains CpNpG (N = A, T, C, or G)
methylation and is unique to the plant kingdom. Here we describe
loss-of-function mutations in the Arabidopsis DOMAINS REARRANGED METHYLASE (DRM)
genes and provide evidence that they encode de novo methyltransferases. drm1
drm2 double mutants retained preexisting CpG methylation at the endogenous FWA
locus but blocked de novo CpG methylation that is normally associated with FWA
transgene silencing. Furthermore, drm1 drm2 double mutants blocked de novo CpNpG
and asymmetric methylation and gene silencing of the endogenous SUPERMAN (SUP)
gene, which is normally triggered by an inverted SUP repeat. However, drm1 drm2
double mutants did not show reactivation of previously established SUPERMAN
epigenetic silenced alleles. Thus, drm mutants prevent the establishment but not
the maintenance of gene silencing at FWA and SUP, suggesting that the DRMs
encode the major de novo methylation enzymes affecting these genes.
DOI: 10.1016/s0960-9822(02)00925-9
PMID: 12121623 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19661920 | 1. EMBO J. 2009 Oct 7;28(19):2992-3004. doi: 10.1038/emboj.2009.226. Epub 2009
Aug 6.
A key role for Ctf4 in coupling the MCM2-7 helicase to DNA polymerase alpha
within the eukaryotic replisome.
Gambus A(1), van Deursen F, Polychronopoulos D, Foltman M, Jones RC, Edmondson
RD, Calzada A, Labib K.
Author information:
(1)Cancer Research UK, Paterson Institute for Cancer Research, University of
Manchester, Manchester, UK.
The eukaryotic replisome is a crucial determinant of genome stability, but its
structure is still poorly understood. We found previously that many regulatory
proteins assemble around the MCM2-7 helicase at yeast replication forks to form
the replisome progression complex (RPC), which might link MCM2-7 to other
replisome components. Here, we show that the RPC associates with DNA polymerase
alpha that primes each Okazaki fragment during lagging strand synthesis. Our
data indicate that a complex of the GINS and Ctf4 components of the RPC is
crucial to couple MCM2-7 to DNA polymerase alpha. Others have found recently
that the Mrc1 subunit of RPCs binds DNA polymerase epsilon, which synthesises
the leading strand at DNA replication forks. We show that cells lacking both
Ctf4 and Mrc1 experience chronic activation of the DNA damage checkpoint during
chromosome replication and do not complete the cell cycle. These findings
indicate that coupling MCM2-7 to replicative polymerases is an important feature
of the regulation of chromosome replication in eukaryotes, and highlight a key
role for Ctf4 in this process.
DOI: 10.1038/emboj.2009.226
PMCID: PMC2760104
PMID: 19661920 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/10080697 | 1. Plant Mol Biol. 1999 Jan;39(2):309-23. doi: 10.1023/a:1006135100760.
The role of protein surface charge in catalytic activity and chloroplast
membrane association of the pea NADPH: protochlorophyllide oxidoreductase (POR)
as revealed by alanine scanning mutagenesis.
Dahlin C(1), Aronsson H, Wilks HM, Lebedev N, Sundqvist C, Timko MP.
Author information:
(1)Department of Plant Physiology, Göteborg University, Sweden.
NADPH:protochlorophyllide oxidoreductase (POR) catalyzes the light-dependent
reduction of protochlorophyllide (pchlide) to chlorophyllide (chlide) in the
biosynthesis of chlorophyll. POR is a peripheral membrane protein that
accumulates to high levels in the prolamellar bodies of vascular plant
etioplasts and is present at low levels in the thylakoid membranes of developing
and mature plastids. Clustered charged-to-alanine scanning mutagenesis of the
pea (Pisum sativum L.) POR was carried out and the resulting mutant enzymes
analyzed for their ability to catalyze pchlide photoconversion in vivo and to
associate properly with thylakoid membrane preparations in vitro. Of 37 mutant
enzymes examined, 5 retained wild-type levels of activity, 14 were catalytically
inactive, and the remaining 18 exhibited altered levels of function. Several of
the mutant enzymes showed temperature-dependent enzymatic activity, being
inactive at 32 degrees C, but partially active at 24 degrees C. Mutations in
predicted alpha-helical regions of the protein showed the least effect on enzyme
activity, whereas mutations in predicted beta-sheet regions of the protein
showed a consistent adverse affect on enzyme function. In the absence of added
NADPH, neither wild-type POR nor any of the mutant PORs resisted proteolysis by
thermolysin following assembly onto the thylakoid membranes. In contrast, when
NADPH was present in the assay mixture, 13 of the 37 mutant PORs examined were
found to be resistant to thermolysin upon treatment, suggesting that the
mutations did not affect their ability to be properly attached to the thylakoid
membrane. In general, the replacement of charged amino acids by alanine in the
most N- and C-terminal regions of the mature protein did not significantly
affect POR assembly, whereas mutations within the central core of the protein
(between residues 86 and 342) were incapable of proper attachment to the
thylakoid. Failure to properly associate with the thylakoid membrane in a
protease resistant manner was only weakly correlated to loss of catalytic
function. These studies are a first step towards defining structural
determinants crucial to POR function and intraorganellar localization.
DOI: 10.1023/a:1006135100760
PMID: 10080697 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19496828 | 1. Genes Cells. 2009 Jul;14(7):807-20. doi: 10.1111/j.1365-2443.2009.01310.x.
Epub 2009 Jun 3.
Ctf4 coordinates the progression of helicase and DNA polymerase alpha.
Tanaka H(1), Katou Y, Yagura M, Saitoh K, Itoh T, Araki H, Bando M, Shirahige K.
Author information:
(1)Laboratory of Chromosome Structure and Function, Department of Biological
Science, Graduate School of Bioscience and Biotechnology, Tokyo Institute of
Technology, Yokohama City, Kanagawa, Japan.
Ctf4 is a protein conserved in eukaryotes and a constituent of the replisome
progression complex. It also plays a role in the establishment of sister
chromatid cohesion. In our current study, we demonstrate that the replication
checkpoint is activated in the absence of Ctf4, and that the interaction between
the MCM helicase-go ichi ni san (GINS) complex and DNA polymerase alpha (Pol
alpha)-primase is destabilized specifically in a ctf4Delta mutant. An in vitro
interaction between GINS and DNA Pol alpha was also found to be mediated by
Ctf4. The same interaction was not affected in the absence of the replication
checkpoint mediators Tof1 or Mrc1. In ctf4Delta cells, DNA pol alpha became
significantly unstable and was barely detectable at the replication forks in HU.
In contrast, the quantities of helicase and DNA pol epsilon bound to replication
forks were almost unchanged but their localizations were widely and abnormally
dispersed in the mutant cells compared with wild type. These results lead us to
propose that Ctf4 is a key connector between DNA helicase and Pol alpha and is
required for the coordinated progression of the replisome.
DOI: 10.1111/j.1365-2443.2009.01310.x
PMID: 19496828 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22499815 | 1. Can Fam Physician. 2012 Apr;58(4):398-401.
Cranberry juice for urinary tract infection in children.
Goldman RD(1).
Author information:
(1)BC Children's Hospital, Department of Pediatrics, Room K4-226, Ambulatory
Care Bldg, 4480 Oak St, Vancouver, BC. [email protected]
QUESTION: Several children in my clinic are recovering from urinary tract
infections (UTI). A mother of one of the children asked me if I recommended
cranberry juice for children to prevent future episodes of UTI. She was given
cranberry juice after she suffered from a UTI several months ago.
ANSWER: Cranberry juice has been shown to be effective in preventing adhesion of
bacteria such as Escherichia coli to the bladder epithelium. Current evidence
supports the use of cranberry juice for prevention of UTI in adult women, but no
such evidence exists at this time for the prevention of UTI in children. While
cranberry juice is very safe for most children, its acidity reduces palatability
among children. The dose of cranberry juice to prevent UTI in children has also
yet to be determined.
Question Plusieurs enfants de ma clinique se rétablissent d’une infection des
voies urinaires (IVU). La mère de l’un d’eux m’a demandé si je recommandais le
jus de canneberge pour prévenir de futurs épisodes d’IVU. On lui avait
recommandé d’en boire lorsqu’elle a souffert d’une IVU il y a quelques mois.
Réponse Il a été démontré que le jus de canneberge était efficace pour prévenir
l’adhésion de bactéries comme l’Escherichia coli à l’épithélium de la vessie.
Les données scientifiques actuelles appuient l’utilisation du jus de canneberge
pour la prévention des IVU chez les femmes adultes, mais il n’en existe pas pour
le moment sur la prévention des IVU chez l’enfant. Si le jus de canneberge est
très sécuritaire pour la plupart des enfants, son acidité fait que son goût est
moins apprécié des enfants. Il reste aussi à déterminer la quantité de jus de
canneberge nécessaire pour prévenir les IVU chez les enfants.
PMCID: PMC3325451
PMID: 22499815 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20307337 | 1. Cardiol Young. 2010 Aug;20(4):459-61. doi: 10.1017/S1047951110000260. Epub
2010 Mar 22.
Progressively worsening hypertrophic cardiomyopathy in a child with newly
diagnosed Costello syndrome while receiving growth hormone therapy.
Kobayashi D(1), Cook AL, Williams DA.
Author information:
(1)Division of Pediatric Cardiology, Department of Pediatrics, Wake Forest
University School of Medicine, Winston-Salem, NC 27157, USA. [email protected]
We describe a 6-year-old boy with newly diagnosed Costello syndrome after the
diagnosis of severe hypertrophic cardiomyopathy. His neonatal asymmetric septal
cardiomyopathy resolved by 9 months of age but reappeared at 6 years of age.
This report highlights two important concepts: the association of genetic
syndromes with hypertrophic cardiomyopathy and the possibility of worsening
severity of hypertrophic cardiomyopathy linked to growth hormone therapy.
DOI: 10.1017/S1047951110000260
PMID: 20307337 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22887473 | 1. Am J Med Genet A. 2012 Nov;158A(11):2692-9. doi: 10.1002/ajmg.a.35534. Epub
2012 Aug 7.
Normative growth charts for individuals with Costello syndrome.
Sammon MR(1), Doyle D, Hopkins E, Sol-Church K, Stabley DL, McGready J, Schulze
K, Alade Y, Hoover-Fong J, Gripp KW.
Author information:
(1)Division of General Pediatrics, A. I. duPont Hospital for Children,
Wilmington, Delaware 19803, USA.
Costello syndrome is a rare condition due to heterozygous germline mutations in
the proto-oncogene HRAS. It affects multiple organ systems and includes severe
failure-to-thrive, short stature, and macrocephaly. The goal of this study was
to develop Costello syndrome-specific growth curves. We collected height,
weight, and head circumference (OFC) measurements from 94 individuals (45 males
and 49 females). Their HRAS mutation spectrum reflects previously published
cohorts, with p.G12S in 77.7%. Participants received medical care, therefore our
data does not reflect natural history per se, but rather growth with nutritional
support. Due to limited cohort size, we analyzed data from males and females
together. Weight-for-age data included 417 separate measurements from 80
individuals age 0-36 months, and 585 measurements from 82 individuals for age
0-10 years. Height-for-age data were derived from 391 measurements from 77
individuals age 0-36 months, and 591 measurements from 90 individuals age 0-10
years. Measurements obtained after growth hormone exposure in 15 individuals
were excluded in this analysis. The OFC curve was derived from 221 measurements
from 55 individuals age 0-36 months. Centiles (5th, 50th, and 95th) were
estimated across the age continuum for each growth parameter, and compared to
gender-specific curves for average stature individuals. The resulting curves
demonstrate very slow weight gain in the first 2 years. Short stature is seen in
many, but after age 4 years the 95th centile for height falls within the low
normal range for average stature children. Head circumference curves largely
overlap those for average stature, reflecting relative macrocephaly.
Copyright © 2012 Wiley Periodicals, Inc.
DOI: 10.1002/ajmg.a.35534
PMID: 22887473 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25422900 | 1. CNS Spectr. 2014 Dec;19(6):475-8. doi: 10.1017/S1092852914000637.
Mechanism of action of tasimelteon in non-24 sleep-wake syndrome: treatment for
a circadian rhythm disorder in blind patients.
Stahl SM.
Many individuals with total blindness can develop a circadian rhythm
disorder-called non-24 sleep wake syndrome-because they cannot detect light to
resynchronize their sleep-wake cycles. A new melatonin 1 and melatonin 2 agonist
tasimelteon improves sleep in these patients, resetting their circadian
sleep-wake clocks.
DOI: 10.1017/S1092852914000637
PMID: 25422900 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20380529 | 1. J Neurosurg. 2010 Nov;113(5):1029-35. doi: 10.3171/2010.3.JNS091971. Epub 2010
Apr 9.
The relevance of Simpson Grade I and II resection in modern neurosurgical
treatment of World Health Organization Grade I meningiomas.
Sughrue ME(1), Kane AJ, Shangari G, Rutkowski MJ, McDermott MW, Berger MS, Parsa
AT.
Author information:
(1)Brain Tumor Research Center, Department of Neurological Surgery, University
of California, San Francisco, California 94143, USA.
Comment in
J Neurosurg. 2010 Nov;113(5):1026-7; discussion 1027-8. doi:
10.3171/2010.2.JNS10280.
J Neurosurg. 2017 Jan;126(1):201-211. doi: 10.3171/2016.1.JNS151842.
OBJECT: In 1957, Simpson published a seminal paper defining the risk factors for
recurrence following surgical treatment of intracranial meningiomas. Given that
Simpson's study was published more than 50 years ago, preceding image guidance
technology and MR imaging, the authors reviewed their own experience with
surgical treatment of Grade I meningiomas to determine if Simpson's grading
scale is still relevant to modern neurosurgical practice.
METHODS: From this cohort, the authors evaluated all patients undergoing
craniotomy for resection of a histologically proven WHO Grade I meningioma as
their initial therapy. Clinical information was retrospectively reconstructed
using patient medical records and radiological data. Recurrence analysis was
performed using the Kaplan-Meier method.
RESULTS: The 5-year recurrence/progression-free survival for all patients
receiving a Simpson Grade I, II, III, or IV resection was 95, 85, 88, and 81%,
respectively (p = not significant, log-rank test). Kaplan-Meier analysis
revealed no significant difference in recurrence-free survival between patients
receiving a Simpson Grade I, II, III, or IV resection. Analysis limited to
meningiomas arising from the skull base (excluding the cavernous sinus)
similarly found no significant benefit to Simpson Grade I or II resection, and
the survival curves were nearly superimposed.
CONCLUSIONS: In this study of a cohort of patients undergoing surgery for WHO
Grade I meningiomas, the authors demonstrate that the benefit of more aggressive
attempts to resect the tumor with dura and underlying bone was negligible
compared with simply removing the entire tumor, or even leaving small amounts of
tumor attached to critical structures. The authors believe that these data
reflect an evolution in the nature of meningioma surgery over the past 2
decades, and bring into question the relevance of using Simpson's grading system
as the sole predictor of recurrence.
DOI: 10.3171/2010.3.JNS091971
PMID: 20380529 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23610393 | 1. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7820-5. doi:
10.1073/pnas.1218599110. Epub 2013 Apr 22.
Immune-responsive gene 1 protein links metabolism to immunity by catalyzing
itaconic acid production.
Michelucci A(1), Cordes T, Ghelfi J, Pailot A, Reiling N, Goldmann O, Binz T,
Wegner A, Tallam A, Rausell A, Buttini M, Linster CL, Medina E, Balling R,
Hiller K.
Author information:
(1)Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362
Esch-Belval, Luxembourg.
Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages
during inflammation, but its biological function has not yet been elucidated.
Here, we identify Irg1 as the gene coding for an enzyme producing itaconic acid
(also known as methylenesuccinic acid) through the decarboxylation of
cis-aconitate, a tricarboxylic acid cycle intermediate. Using a
gain-and-loss-of-function approach in both mouse and human immune cells, we
found Irg1 expression levels correlating with the amounts of itaconic acid, a
metabolite previously proposed to have an antimicrobial effect. We purified IRG1
protein and identified its cis-aconitate decarboxylating activity in an
enzymatic assay. Itaconic acid is an organic compound that inhibits isocitrate
lyase, the key enzyme of the glyoxylate shunt, a pathway essential for bacterial
growth under specific conditions. Here we show that itaconic acid inhibits the
growth of bacteria expressing isocitrate lyase, such as Salmonella enterica and
Mycobacterium tuberculosis. Furthermore, Irg1 gene silencing in macrophages
resulted in significantly decreased intracellular itaconic acid levels as well
as significantly reduced antimicrobial activity during bacterial infections.
Taken together, our results demonstrate that IRG1 links cellular metabolism with
immune defense by catalyzing itaconic acid production.
DOI: 10.1073/pnas.1218599110
PMCID: PMC3651434
PMID: 23610393 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/24241345 | 1. Acta Pharmacol Sin. 2013 Dec;34(12):1485-90. doi: 10.1038/aps.2013.160. Epub
2013 Nov 18.
The neuroprotective effects of progesterone on traumatic brain injury: current
status and future prospects.
Wei J(1), Xiao GM.
Author information:
(1)Medical Center, The Affiliated Hospital of Hangzhou Normal University,
Hangzhou 310015, China.
Traumatic brain injury is the leading cause of morbidity and mortality in young
adults. The secondary injury in traumatic brain injury consists of a complex
cascade of processes that simultaneously react to the primary injury to the
brain. This cascade has been the target of numerous therapeutic agents
investigated over the last 30 years, but no neuroprotective treatment option is
currently available that improve neurological outcome after traumatic brain
injury. Progesterone has long been considered merely a female reproductive
hormone. Numerous studies, however, show that progesterone has substantial
pleiotropic properties as a neuroprotective agent in both animal models and
humans. Here, we review the increasing evidence that progesterone can act as a
neuroprotective agent to treat traumatic brain injury and the mechanisms
underlying these effects. Additionally, we discuss the current progress of
clinical studies on the application of progesterone in the treatment of
traumatic brain injuries.
DOI: 10.1038/aps.2013.160
PMCID: PMC3854945
PMID: 24241345 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14581621 | 1. Plant Cell Physiol. 2003 Oct;44(10):963-74. doi: 10.1093/pcp/pcg128.
Functional analysis of isoforms of NADPH: protochlorophyllide oxidoreductase
(POR), PORB and PORC, in Arabidopsis thaliana.
Masuda T(1), Fusada N, Oosawa N, Takamatsu K, Yamamoto YY, Ohto M, Nakamura K,
Goto K, Shibata D, Shirano Y, Hayashi H, Kato T, Tabata S, Shimada H, Ohta H,
Takamiya K.
Author information:
(1)Graduate School of Bioscience and Biotechnology, Tokyo Institute of
Technology, 4259 Nagatsuta, Midori-ku, Yokohama, 226-8501 Japan.
[email protected]
NADPH:protochlorophyllide oxidoreductase (POR) catalyzes the light-dependent
reduction of protochlorophyllide. To elucidate the physiological function of
three differentially regulated POR isoforms (PORA, PORB and PORC) in Arabidopsis
thaliana, we isolated T-DNA tagged null mutants of porB and porC. The mature
seedlings of the mutants had normal photosynthetic competencies, showing that
PORB and PORC are interchangeable and functionally redundant in developed
plants. In etiolated seedlings, only porB showed a reduction in the photoactive
protochlorophyllide and the size of prolamellar bodies (PLBs), indicating that
PORB, as well as PORA, functioned in PLB assembly and photoactive
protochlorophyllide formation in etiolated seedlings. When illuminated, the
etiolated porB seedling was able to green to a similar extent as the wild type,
whereas the greening was significantly reduced under low light conditions.
During greening, high light irradiation increased the level of PORC protein, and
the greening of porC was repressed under high light conditions. The porB, but
not porC, etiolated seedling was more sensitive to the far-red block of greening
than the wild type, which is caused by depletion of endogenous POR proteins
resulting in photo-oxidative damage. These results suggest that, at the onset of
greening, PLBs are important for efficient capture of light energy for
photoconversion under various light conditions, and PORC, which is induced by
high light irradiation, contributes to photoprotection during greening of the
etiolated seedlings.
DOI: 10.1093/pcp/pcg128
PMID: 14581621 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12973153 | 1. Spine (Phila Pa 1976). 2003 Sep 1;28(17):2025-8; discussion 2029. doi:
10.1097/01.BRS.0000083235.74593.49.
Allelic variants of human melatonin 1A receptor in patients with familial
adolescent idiopathic scoliosis.
Morcuende JA(1), Minhas R, Dolan L, Stevens J, Beck J, Wang K, Weinstein SL,
Sheffield V.
Author information:
(1)Department of Orthopaedic Surgery, University of Iowa, Iowa City, Iowa, USA.
[email protected]
STUDY DESIGN: A genetic study of patients with familial adolescent idiopathic
scoliosis.
OBJECTIVES: The purpose of this study was to evaluate the evidence for linkage
on chromosome 4q and determine whether mutations in the gene coding for
melatonin receptor are present.
SUMMARY OF BACKGROUND DATA: Adolescent idiopathic scoliosis is the most common
spine deformity arising during childhood, but its cause remains unknown. The
fact that adolescent idiopathic scoliosis is often seen in several members of
the same family strongly suggests a genetic factor. Recent work by Wise et al
provides evidence for linkage of adolescent idiopathic scoliosis at several
different chromosome sites, including 4q. In addition, there is some evidence
that adolescent idiopathic scoliosis may be related to a disturbance in
melatonin metabolism, and the human melatonin-1A receptor is known to be located
on chromosome 4q.
METHODS: Probands having clinically relevant idiopathic scoliosis (Cobb angle
>30 degrees) and their relatives were identified. Radiographic confirmation was
required for a positive diagnosis. Linkage analysis was performed with 15
microsatellite markers of chromosome 4q spaced at approximately 10-cM resolution
and 5 microsatellite markers surrounding the site for human melatonin receptor.
The gene for human melatonin receptor was screened for mutations in the coding
region using genomic DNA samples by single-strand conformational polymorphism
analysis. Amplimers showing a band shift were reamplified and sequenced
bidirectionally.
RESULTS: There was no evidence for linkage at chromosome 4q in this study
population. Twenty-nine individuals demonstrated aberrant single-strand
conformation polymorphism band patterns, and sequence evaluation demonstrated
six genetic polymorphisms for the gene for human melatonin receptor. These
genetic variations were found in both affected and nonaffected individuals, and
there was no correlation between gene variants and the phenotype for adolescent
idiopathic scoliosis.
CONCLUSIONS: The results of this study demonstrated no evidence of linkage to
chromosome 4q and no mutations in the coding region of the gene for human
melatonin receptor. The identification of variants in the human melatonin
receptor could provide a useful tool for testing the gene in the predisposition
to various other melatonin-related disorders and for clarifying the role of
melatonin in adolescent idiopathic scoliosis.
DOI: 10.1097/01.BRS.0000083235.74593.49
PMID: 12973153 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17375888 | 1. Acta Cardiol. 2007 Feb;62(1):19-24. doi: 10.2143/AC.62.1.2019366.
Relationship between low T3 syndrome and NT-proBNP levels in non-cardiac
patients.
Pinelli M(1), Bindi M, Cassetti G, Moroni F, Pandolfo C, Rosada J, Castiglioni
M.
Author information:
(1)Department of Internal Medicine IV, Azienda Ospedaliera-Universitaria Pisana,
Pisa, Italy.
OBJECTIVES: A low T3 syndrome was described in patients with heart failure (HF),
and it appears to be associated with adverse outcome, representing an
independent predictor of mortality. However, it is not known if low T3 levels
contribute to the pathophysiology of HF. On the other hand, it has been seen
that an elevation of brain natriuretic peptides (BNP and NT-proBNP) may
represent a warning signal for future cardiovascular disease and may be an early
marker of diastolic dysfunction. Therefore we tested the hypothesis that low
levels of free-triiodothyronine (FT3) are sufficient to determine an increased
concentration of the amino-terminal fragment of pro-brain natriuretic peptide
(NT-proBNP), as the result of an initial and asymptomatic cardiac impairment.
METHODS: A total of 52 consecutive non-cardiac patients underwent thyroid
function profile evaluation and NT-proBNP determination. On the basis of FT3
values they were divided in two subgroups: a low T3 group (19 patients) and a
normal T3 group (33 patients).
RESULTS: The median NT-proBNP concentration of patients with low T3 syndrome was
significantly higher than in those with normal FT3 (370 vs. 120 pg/ml, P =
0.002). There is a strong and inverse correlation between FT3 and Log NT-proBNP
(R = -0.47, P < 0.001); this relation persists in a multivariable regression
analysis, after adjustment for other potentially confounding variables (P =
0.008).
CONCLUSION: In absence of overt cardiovascular disease, patients with low T3
syndrome present an increased concentration of NT-proBNP. These data suggest
that low FT3 levels may be a contributing factor for the development of cardiac
dysfunction.
DOI: 10.2143/AC.62.1.2019366
PMID: 17375888 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20182024 | 1. J Alzheimers Dis. 2010;20 Suppl 1:S205-20. doi: 10.3233/JAD-2010-091459.
Effects of caffeine in Parkinson's disease: from neuroprotection to the
management of motor and non-motor symptoms.
Prediger RD(1).
Author information:
(1)Departamento de Farmacologia, Centro de Ciências Biológicas, Hospital
Universitário, Universidade Federal de Santa Catarina, UFSC, Florianópolis-SC,
Brazil. [email protected]
Parkinson's disease (PD) is the second most common neurodegenerative disorder
affecting approximately 1% of the population older than 60 years. Classically,
PD is considered to be a motor system disease and its diagnosis is based on the
presence of a set of cardinal motor signs (rigidity, bradykinesia, rest tremor)
that are consequence of a pronounced death of dopaminergic neurons in the
substantia nigra pars compacta. Nowadays there is considerable evidence showing
that non-dopaminergic degeneration also occurs in other brain areas which seems
to be responsible for the deficits in olfactory, emotional and memory functions
that precede the classical motor symptoms in PD. The present review attempts to
examine results reported in epidemiological, clinical and animal studies to
provide a comprehensive picture of the antiparkinsonian potential of caffeine.
Convergent epidemiological and pre-clinical data suggest that caffeine may
confer neuroprotection against the underlying dopaminergic neuron degeneration,
and influence the onset and progression of PD. The available data also suggest
that caffeine can improve the motor deficits of PD and that adenosine A2A
receptor antagonists such as istradefylline reduces OFF time and dyskinesia
associated with standard 'dopamine replacement' treatments. Finally, recent
experimental findings have indicated the potential of caffeine in the management
of non-motor symptoms of PD, which do not improve with the current dopaminergic
drugs. Altogether, the studies reviewed provide strong evidence that caffeine
may represent a promising therapeutic tool in PD, thus being the first compound
to restore both motor and non-motor early symptoms of PD together with its
neuroprotective potential.
DOI: 10.3233/JAD-2010-091459
PMID: 20182024 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24687255 | 1. CNS Drugs. 2014 May;28(5):455-74. doi: 10.1007/s40263-014-0161-7.
Adenosine A2A receptor antagonists in Parkinson's disease: progress in clinical
trials from the newly approved istradefylline to drugs in early development and
those already discontinued.
Pinna A(1).
Author information:
(1)National Research Council of Italy (CNR), Neuroscience Institute-Cagliari,
National Research Council of Italy (CNR), Via Ospedale, 72, 09124, Cagliari,
Italy, [email protected].
Neurotransmitters other than dopamine, such as norepinephrine,
5-hydroxytryptamine, glutamate, adenosine and acetylcholine, are involved in
Parkinson's disease (PD) and contribute to its symptomatology. Thus, the
progress of non-dopaminergic therapies for PD has attracted much interest in
recent years. Among new classes of drugs, adenosine A2A antagonists have emerged
as promising candidates. The development of new highly selective adenosine A2A
receptor antagonists, and their encouraging anti-parkinsonian responses in
animal models of PD, has provided a rationale for clinical trials to evaluate
the therapeutic potential and the safety of these agents in patients with PD. To
date, the clinical research regarding A2A antagonists and their potential
utilization in PD therapy continues to evolve between drugs just or previously
discontinued (preladenant and vipadenant), new derivatives in development
(tozadenant, PBF-509, ST1535, ST4206 and V81444) and the relatively old drug
istradefylline, which has finally been licensed as an anti-parkinsonian drug in
Japan. All these compounds have been shown to have a good safety profile and be
well tolerated. Moreover, results from phase II and III trials also demonstrate
that A2A antagonists are effective in reducing off-time, without worsening
troublesome dyskinesia, and in increasing on-time with a mild increase of
non-troublesome dyskinesia, in patients at an advanced stage of PD treated with
L-DOPA. In addition, early findings suggest that A2A antagonists might also be
efficacious as monotherapy in patients at an early stage of PD. This review
summarizes pharmacological and clinical data available on istradefylline,
tozadenant, PBF-509, ST1535, ST4206, V81444, preladenant and vipadenant.
DOI: 10.1007/s40263-014-0161-7
PMID: 24687255 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21571763 | 1. Clin Child Psychol Psychiatry. 2011 Apr;16(2):203-14. doi:
10.1177/1359104511404749.
Anxiety problems in young people with autism spectrum disorder: a case series.
Ozsivadjian A(1), Knott F.
Author information:
(1)Guy's and St Thomas' NHS Foundation Trust, London, UK.
[email protected]
It is now well established that the prevalence of mental health difficulties in
individuals with autism spectrum disorders (ASD) is considerably higher than in
the general population. With recent estimates of the prevalence of autism
spectrum disorders being as high as one percent, increasing numbers of children
and young people are presenting to local and specialist services with mental
health problems in addition to a diagnosis of ASD. Many families report that the
impact of the mental health problems can be as or more impairing than the autism
spectrum difficulties themselves. Clinical services are frequently called upon
to treat these difficulties; however, there is limited evidence for the
effectiveness of treatments in this population. This paper reports a case series
of children and adolescents with ASD and an anxiety disorder who were treated
with a standard cognitive behaviour therapy (CBT) rationale adapted to take
account of the neuropsychological features of ASD. Common features of the
presentation of the disorders and also treatment processes are discussed.
DOI: 10.1177/1359104511404749
PMID: 21571763 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16619249 | 1. Int J Cancer. 2006 Sep 15;119(6):1291-7. doi: 10.1002/ijc.21995.
In vivo expression of survivin and its splice variant survivin-2B: impact on
clinical outcome in acute myeloid leukemia.
Wagner M(1), Schmelz K, Wuchter C, Ludwig WD, Dörken B, Tamm I.
Author information:
(1)Department of Hematology and Oncology, Campus Virchow, Universitätsmedizin
Berlin, Berlin, Germany.
Survivin, a member of the inhibitor of apoptosis protein family, is expressed in
most human cancers, but undetectable in normal differentiated adult tissue in
vivo. Because of this cancer-related expression, survivin is a promising target
for cancer therapy. To determine the expression and prognostic role of survivin
in acute myeloid leukemia (AML), we investigated the mRNA expression pattern of
survivin and of the splice variants survivin-2B and survivin-DeltaEx3 in adult
(n = 74) and children (n = 31) with de novo AML using RT-PCR. Survivin was the
predominant transcript variant in AML cells, whereas significantly lower levels
of survivin-2B and survivin-DeltaEx3 were observed (p < or = 0.0001). Neither
expression of survivin nor of any splice variant correlated with maturation
stage (FAB subtypes, immunophenotype) or cytogenetic risk groups. For AML cases
treated according to AMLCG92 (adult) and AML-BFM93 (children) protocols,
respectively, expression patterns were correlated with clinical data: in adult
AML (n = 51), low expression of survivin-2B correlated with a better overall
survival (p = 0.05; mean survival time 19 months vs. 9 months) and a better
eventfree survival (p < or = 0.01; 27 months vs. 10 months). In childhood AML (n
= 31), high survivin-DeltaEx3 expression was associated with a shorter overall
survival (p < or = 0.05; 24 months vs. 43 months). We conclude that certain
survivin splice variants have potential prognostic impact for long-term therapy
outcome in adult as well as childhood de novo AML.
DOI: 10.1002/ijc.21995
PMID: 16619249 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23213374 | 1. Biol Open. 2012 Oct 15;1(10):965-76. doi: 10.1242/bio.20122337. Epub 2012 Aug
8.
3D-structured illumination microscopy provides novel insight into architecture
of human centrosomes.
Sonnen KF(1), Schermelleh L, Leonhardt H, Nigg EA.
Author information:
(1)Biozentrum, University of Basel , Klingelbergstrasse 50/70, CH-4056 Basel ,
Switzerland.
Comment in
Nat Rev Mol Cell Biol. 2012 Dec;13(12):749. doi: 10.1038/nrm3471.
Centrioles are essential for the formation of cilia and flagella. They also form
the core of the centrosome, which organizes microtubule arrays important for
cell shape, polarity, motility and division. Here, we have used super-resolution
3D-structured illumination microscopy to analyse the spatial relationship of 18
centriole and pericentriolar matrix (PCM) components of human centrosomes at
different cell cycle stages. During mitosis, PCM proteins formed extended
networks with interspersed γ-Tubulin. During interphase, most proteins were
arranged at specific distances from the walls of centrioles, resulting in ring
staining, often with discernible density masses. Through use of site-specific
antibodies, we found the C-terminus of Cep152 to be closer to centrioles than
the N-terminus, illustrating the power of 3D-SIM to study protein disposition.
Appendage proteins showed rings with multiple density masses, and the number of
these masses was strongly reduced during mitosis. At the proximal end of
centrioles, Sas-6 formed a dot at the site of daughter centriole assembly,
consistent with its role in cartwheel formation. Plk4 and STIL co-localized with
Sas-6, but Cep135 was associated mostly with mother centrioles. Remarkably, Plk4
formed a dot on the surface of the mother centriole before Sas-6 staining became
detectable, indicating that Plk4 constitutes an early marker for the site of
nascent centriole formation. Our study provides novel insights into the
architecture of human centrosomes and illustrates the power of super-resolution
microscopy in revealing the relative localization of centriole and PCM proteins
in unprecedented detail.
DOI: 10.1242/bio.20122337
PMCID: PMC3507176
PMID: 23213374
Conflict of interest statement: Competing interests: The authors have no
competing interests to declare. |
http://www.ncbi.nlm.nih.gov/pubmed/16663945 | 1. Plant Physiol. 1984 Dec;76(4):1036-40. doi: 10.1104/pp.76.4.1036.
A Comparison between Prolamellar Bodies and Prothylakoid Membranes of Etioplasts
of Dark-Grown Wheat Concerning Lipid and Polypeptide Composition.
Selstam E(1), Sandelius AS.
Author information:
(1)Department of Plant Physiology, University of Umeå, S-901 87 Umeå, Sweden.
The aim of the present investigation was to find factors critical for the
co-existence of prolamellar bodies and prothylakoids in etioplasts of wheat
(Triticum aestivum L. cv Starke II). The lipid composition of the prolamellar
body and prothylakoid fractions was qualitatively similar. However, the molar
ratio of monogalactosyl diacylglycerol to digalactosyl diacylglycerol was higher
in the prolamellar body fraction (1.6 +/- 0.1), as was the lipid content on a
protein basis. Protochlorophyllide was present in both fractions. The dominating
protein of the prolamellar body fraction was protochlorophyllide oxidoreductase.
This protein was present also in prothylakoid fractions. The other major protein
of the prothylakoid fraction was the coupling factor 1, subunit of the
chloroplast ATPase. From the lipid and protein data, we conclude that
prolamellar bodies are formed when monogalactosyl diacylglycerol is present in
larger amounts than can be stabilized into planar bilayer prothylakoid membranes
by lamellar lipids or proteins.
DOI: 10.1104/pp.76.4.1036
PMCID: PMC1064430
PMID: 16663945 |
http://www.ncbi.nlm.nih.gov/pubmed/24551838 | 1. Biomed Res Int. 2014;2014:168106. doi: 10.1155/2014/168106. Epub 2014 Jan 16.
The association study of calmodulin 1 gene polymorphisms with susceptibility to
adolescent idiopathic scoliosis.
Zhang Y(1), Gu Z(2), Qiu G(3).
Author information:
(1)Department of Orthopaedics, Peking Union Medical College Hospital, Beijing
100005, China ; Department of Orthopaedics, The First People's Hospital of
Chengdu, Sichuan 610071, China.
(2)Department of Orthopaedics, The First People's Hospital of Chengdu, Sichuan
610071, China.
(3)Department of Orthopaedics, Peking Union Medical College Hospital, Beijing
100005, China.
OBJECTIVE: Idiopathic scoliosis is the most common pediatric spinal deformity
affecting 1% to 3% of the population, and adolescent idiopathic scoliosis (AIS)
accounts for approximately 80% of these cases; however, the etiology and
pathogenesis of AIS are still uncertain. The current study aims to identify the
relationship between calmodulin 1 (CALM1) gene and AIS predisposition, to
identify the relationship between the genotypes of the SNPs and the clinical
phenotypes of AIS.
METHODS: 146 AIS patients and 146 healthy controls were enrolled into this
case-control study. 12 single nucleotide polymorphisms (SNPs) candidates in
CALM1 gene were selected to determine the relationship between CALM1 gene and
AIS predisposition. Case-only study was performed to determine the effects of
these variants on the severity of the condition.
RESULTS: Three SNPs from 12 candidates were found to be associated with AIS
predisposition. The ORs were observed as 0.549 (95% CI 0.3519-0.8579, P =
0.0079), 0.549 (95% CI 0.3519-0.8579, P = 0.0079), and 1.6139 (95% CI
1.0576-2.4634, P = 0.0257) for rs2300496, rs2300500, and rs3231718,
respectively. There was no statistical difference between main curve, severity,
and genotype distributions of all of 12 SNPs.
CONCLUSION: Genetic variants of CALM1 gene are associated with AIS
susceptibility.
DOI: 10.1155/2014/168106
PMCID: PMC3914287
PMID: 24551838 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23904108 | 1. Am J Physiol Regul Integr Comp Physiol. 2013 Oct 15;305(8):R927-38. doi:
10.1152/ajpregu.00502.2012. Epub 2013 Jul 31.
Inhibition of Drp1-dependent mitochondrial division impairs myogenic
differentiation.
Kim B(1), Kim JS, Yoon Y, Santiago MC, Brown MD, Park JY.
Author information:
(1)Department of Kinesiology, College of Health Professions and Social Work,
Temple University, Philadelphia, Pennsylvania;
Mitochondria are dynamic organelles forming a tubular network that is
continuously fusing and dividing to control their morphology and functions.
Recent literature has shed new light on a potential link between the dynamic
behavior of mitochondria and muscle development. In this study, we investigate
the role of mitochondrial fission factor dynamin-related protein 1 (Drp1) in
myogenic differentiation. We found that differentiation of C2C12 myoblasts
induced by serum starvation was accompanied by a gradual increase in Drp1
protein expression (to ∼350% up to 3 days) and a fast reduction of Drp1
phosphorylation at Ser-637 (to ∼30%) resulting in translocation of Drp1 protein
from the cytosol to mitochondria. During differentiation, treatment of myoblasts
with mitochondrial division inhibitor (mdivi-1), a specific inhibitor of Drp1
GTPase activity, caused extensive formation of elongated mitochondria, which
coincided with increased apoptosis evidenced by both enhanced caspase-3 activity
and increased number of terminal deoxynucleotidyl transferase-mediated dUTP
nick-end labeling (TUNEL)-positive cells. Furthermore, the mdivi-1-treated
myotubes (day 3 in differentiation media) showed a reduction in mitochondrial
DNA content, mitochondrial mass, and membrane potential in a dose-dependent
manner indicating defects in mitochondrial biogenesis during myogenic
differentiation. Most interestingly, mdivi-1 treatment significantly suppressed
myotube formation in both C2C12 cells and primary myoblasts. Likewise, stable
overexpression of a dominant negative mutant Drp1 (K38A) dramatically reduced
myogenic differentiation. These data suggest that Drp-1-dependent mitochondrial
division is a necessary step for successful myogenic differentiation, and
perturbation of mitochondrial dynamics hinders normal mitochondrial adaptations
during muscle development. Therefore, in the present study, we report a novel
physiological role of mitochondrial dynamics in myogenic differentiation.
DOI: 10.1152/ajpregu.00502.2012
PMID: 23904108 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23945108 | 1. J Mol Diagn. 2013 Sep;15(5):695-705. doi: 10.1016/j.jmoldx.2013.05.008. Epub
2013 Aug 12.
miRNA profiling identifies candidate mirnas for bladder cancer diagnosis and
clinical outcome.
Ratert N(1), Meyer HA, Jung M, Lioudmer P, Mollenkopf HJ, Wagner I, Miller K,
Kilic E, Erbersdobler A, Weikert S, Jung K.
Author information:
(1)Department of Urology, University Hospital Charité, Berlin, Germany.
Bladder cancer is a common cancer in the Western world. The current
prognosticators such as tumor grade, stage, size, and multifocality do not
accurately reflect the clinical outcome. It is of clinical interest to identify
biomarkers that could improve diagnostic and/or prognostic predictions. The
objectives of this study were to identify deregulated miRNAs in bladder cancer
samples and evaluate their potential as diagnostic and prognostic biomarkers. We
screened 723 miRNAs by microarray and selected a subset of 15 distinctively
deregulated miRNAs for further validation by real-time quantitative RT-(q)PCR.
Seven miRNAs (miR-20a, miR-106b, miR-130b, miR-141, miR-200a, miR-200a*, and
miR-205) were found to be up-regulated and eight miRNAs (miR-100, miR-125b,
miR-130a, miR-139-5p, miR-145*, miR-199a-3p, miR-214, and miR-222) were found to
be down-regulated in malignant bladder tissue samples compared to healthy
tissue. Four miRNAs that have already been described in the literature (miR-141,
miR-199a-3p, miR-205, and miR-214) were significantly differentially expressed
between nonmuscle-invasive and muscle-invasive bladder cancer. Furthermore,
real-time RT-qPCR of all miRNAs provided high overall correct classification
(>75%) of bladder cancer diagnosis. Two miRNAs (miR-141 and miR-205) were
associated with overall survival time. The verification of tumor-specific miRNA
expression profile, together with the observed association of miR-141 and
miR-205 expression with overall survival, underline the potential of miRNAs to
function as diagnostic and/or prognostic markers of bladder cancer.
Copyright © 2013 American Society for Investigative Pathology and the
Association for Molecular Pathology. Published by Elsevier Inc. All rights
reserved.
DOI: 10.1016/j.jmoldx.2013.05.008
PMID: 23945108 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12176838 | 1. Bioinformatics. 2002 Aug;18(8):1135-6. doi: 10.1093/bioinformatics/18.8.1135.
TFBS: Computational framework for transcription factor binding site analysis.
Lenhard B(1), Wasserman WW.
Author information:
(1)Bioinformatics Unit, Center for Genomics and Bioinformatics, Karolinska
Institutet, Stockholm, Sweden. [email protected]
MOTIVATION: TFBS is a set of integrated, object-oriented Perl modules for
transcription factor binding site detection and analysis. It implements objects
representing specificity profile matrices, binding sites and sets thereof,
pattern generators, and pattern database interfaces. The modules are
interoperable with the BioPerl open source system.
AVAILABILITY AND SUPPLEMENTARY INFORMATION: The module package with
documentation and example scripts are available at
http://forkhead.cgb.ki.se/TFBS/
DOI: 10.1093/bioinformatics/18.8.1135
PMID: 12176838 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23097569 | 1. Lab Anim. 2012 Oct;46(4):341-4. doi: 10.1258/la.2012.011065.
Estimation of glomerular filtration rate in rabbits by a single-sample method
using iodixanol.
Michigoshi Y(1), Katayama R, Yamagishi N, Kato M, Saito J, Satoh H, Furuhama K.
Author information:
(1)Department of Veterinary Basic Medicine, Iwate University, Morioka 020-8550,
Japan.
To estimate the glomerular filtration rate (GFR) in conscious rabbits, a
single-sample method using the non-ionic contrast medium iodixanol was compared
with a three-sample method using the standard agent inulin. Iodixanol and inulin
were co-administered intravenously to male New Zealand White rabbits at 60 mg
I/kg and 40 mg/kg, respectively, and blood was collected 30, 60, 90 and 120 min
later. Serum iodixanol and inulin concentrations were separately determined by
high performance liquid chromatography and colorimetry, respectively. Serum urea
nitrogen (UN) and creatinine concentrations were also determined. Based on the
data from healthy and cisplatin-treated rabbits, the GFR estimated by iodixanol
was well consistent with that by inulin. Further, when the GFR decreased to more
than 60% of the reference value, serum creatinine concentrations became
elevated. However, serum UN concentrations exhibited wide fluctuations,
presumably due to a difference in renal handlings. The single-sample method
using iodixanol was considered to be an expedient tool in both clinical and
research settings, because the stress due to a multi-sample method was reduced.
DOI: 10.1258/la.2012.011065
PMID: 23097569 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16329102 | 1. Med Res Rev. 2006 Mar;26(2):160-80. doi: 10.1002/med.20049.
Molecular activity of sirolimus and its possible application in tuberous
sclerosis treatment.
Jozwiak J(1), Jozwiak S, Oldak M.
Author information:
(1)Department of Histology and Embryology, Center for Biostructure Research,
Medical University of Warsaw, Warsaw, Poland. [email protected]
Sirolimus is one of the intensively investigated drugs with pluripotent
activities. It binds to its intracellular receptor FKBP12 (FK506-binding protein
12), a member of the family of FK506-binding proteins, and inhibits the activity
of mTOR, a serine/threonine kinase involved in numerous cell processes linked to
cell growth control. The drug is currently registered for the prophylaxis of
organ rejection and for use in coronary stents. However, unique characteristics
of sirolimus make it a good candidate for anti-cancer therapy. Indeed, phase II
and III clinical studies in humans with several types of neoplasms are already
under way. The review describes molecular activity of sirolimus and its analogs,
characteristic for specific applications, in view of very recent advances
involving tuberous sclerosis complex (TSC)-mediated signaling pathways. Current
studies with sirolimus performed in tuberous sclerosis animal models are
presented. Possible application of sirolimus for treating tuberous sclerosis,
disease caused by mutations of TSC proteins, is discussed.
(c) 2005 Wiley Periodicals, Inc. Med Res Rev.
DOI: 10.1002/med.20049
PMID: 16329102 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18729306 | 1. Yonsei Med J. 2008 Aug 30;49(4):625-31. doi: 10.3349/ymj.2008.49.4.625.
N-terminal pro B-type natriuretic peptide and the evaluation of cardiac
dysfunction and severity of disease in cirrhotic patients.
Woo JJ(1), Koh YY, Kim HJ, Chung JW, Chang KS, Hong SP.
Author information:
(1)Department of Radiology, Eulji Hospital, Eulji University School of Medicine,
Seoul, Korea.
PURPOSE: Cardiac dysfunction and hyperdynamic systemic circulation may be
present in patients with cirrhosis. The purpose of this study was to identify
relations between plasma levels of N-terminal-proBNP (NT-proBNP), reflecting
early ventricular dysfunction, and the severity of liver disease and cardiac
dysfunction in cirrhotic patients.
MATERIALS AND METHODS: Sixty-three cirrhotic patients and 15 controls (group 1)
were enrolled in this study. Plasma levels of NT-proBNP were determined in
echocardiographically examined patients, which were allocated to 1 of 3 groups
according to Child-Pugh classification or into 2 groups, i.e., a compensated
group without ascites (group 2) and decompensated group with ascites (group 3).
RESULTS: Plasma NT-proBNP levels were significantly higher in cirrhotic patients
(groups 2 and 3) than in age-matched controls (155.9 and 198.3 vs. 40.3 pg/mL,
respectively, p < 0.05). NT-proBNP levels were significantly increased in Child
class C patients than in classes B and A (250.0 vs. 168.6 and 119.6 pg/mL,
respectively, p < 0.05). Left atrial dimension, wall thickness of left
ventricle, and EF or E/E' were significantly increased, and EDT was prolonged in
cirrhotic patients than in controls. Increased LVMI and decreased E/A ratio were
noted in the group of patients with ascites as compared with the other groups.
CONCLUSION: Plasma NT-proBNP levels were high in cirrhotic patients and are
likely to be related to the severity of disease. Advanced cirrhosis is
associated with advanced cardiac dysfunction, and NT-proBNP levels has
predictive value for concomitant cardiac dysfunction and cirrhosis progression.
DOI: 10.3349/ymj.2008.49.4.625
PMCID: PMC2615290
PMID: 18729306 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17646607 | 1. Arch Intern Med. 2007 Jul 23;167(14):1526-32. doi:
10.1001/archinte.167.14.1526.
Association between increased mortality and mild thyroid dysfunction in cardiac
patients.
Iervasi G(1), Molinaro S, Landi P, Taddei MC, Galli E, Mariani F, L'Abbate A,
Pingitore A.
Author information:
(1)Clinical Physiology Institute, National Council of Research, Via Moruzzi 1,
56124 Pisa, Italy. [email protected]
BACKGROUND: The effects of subclinical thyroid dysfunction on cardiac outcome
are not well defined.
METHODS: To assess the relationship between mild thyroid dysfunction and the
incidence of death in cardiac patients, we evaluated 3121 cardiac patients.
Cardiac and overall deaths were considered. Four groups were defined:
euthyroidism, subclinical hypothyroidism (SCH), subclinical hyperthyroidism
(SCT), and low triiodothyronine syndrome (low T3).
RESULTS: After mean follow-up of 32 months, there were 65 and 140 cardiac and
overall deaths (3.4% and 7.3%), respectively, in euthyroidism, 15 and 27 (7.2%
and 13.0%) in SCH, 8 and 9 (8.2% and 9.2%) in SCT, and 59 and 119 (6.5% and
13.1%) in low T3. Survival rates for cardiac death were lower in SCH, SCT, and
low T3 than in euthyroidism (log-rank test; chi2 = 19.46; P < .001). Survival
rates for overall death were lower in SCH and low T3 than in euthyroidism
(log-rank test; chi2 = 26.67; P < .001). After adjustment for several risk
factors, hazard ratios (HRs) for cardiac death were higher in SCH (HR, 2.40; 95%
confidence interval [CI], 1.36-4.21; P = .02), SCT (HR, 2.32; 95% CI, 1.11-4.85;
P = .02), and low T(3) (HR, 1.63; 95% CI, 1.14-2.33; P = .007) than in
euthyroidism; HRs for overall death were higher in SCH (HR, 2.01; 95% CI,
1.33-3.04; P < .001) and low T3 (HR, 1.57; 95% CI, 1.22-2.01; P < .001) but not
in SCT.
CONCLUSION: A mildly altered thyroid status is associated with an increased risk
of mortality in patients with cardiac disease.
DOI: 10.1001/archinte.167.14.1526
PMID: 17646607 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11781336 | 1. J Cell Biol. 2002 Jan 7;156(1):87-99. doi: 10.1083/jcb.200108088. Epub 2002
Jan 7.
Characterization of Cep135, a novel coiled-coil centrosomal protein involved in
microtubule organization in mammalian cells.
Ohta T(1), Essner R, Ryu JH, Palazzo RE, Uetake Y, Kuriyama R.
Author information:
(1)Department of Genetics, Cell Biology, and Development, University of
Minnesota, Minneapolis, MN 55455, USA.
By using monoclonal antibodies raised against isolated clam centrosomes, we have
identified a novel 135-kD centrosomal protein (Cep135), present in a wide range
of organisms. Cep135 is located at the centrosome throughout the cell cycle, and
localization is independent of the microtubule network. It distributes
throughout the centrosomal area in association with the electron-dense material
surrounding centrioles. Sequence analysis of cDNA isolated from CHO cells
predicted a protein of 1,145-amino acid residues with extensive alpha-helical
domains. Expression of a series of deletion constructs revealed the presence of
three independent centrosome-targeting domains. Overexpression of Cep135
resulted in the accumulation of unique whorl-like particles in both the
centrosome and the cytoplasm. Although their size, shape, and number varied
according to the level of protein expression, these whorls were composed of
parallel dense lines arranged in a 6-nm space. Altered levels of Cep135 by
protein overexpression and/or suppression of endogenous Cep135 by RNA
interference caused disorganization of interphase and mitotic spindle
microtubules. Thus, Cep135 may play an important role in the centrosomal
function of organizing microtubules in mammalian cells.
DOI: 10.1083/jcb.200108088
PMCID: PMC2173569
PMID: 11781336 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8375445 | 1. Eur Urol. 1993;24(2):239-43. doi: 10.1159/000474301.
Value of routine sonography in the diagnosis and conservative management of
renal angiomyolipoma.
Höbarth K(1), Klingler HC, Kuber W, Kratzik C.
Author information:
(1)Department of Urology, University of Vienna Medical School, Austria.
A prospective study was undertaken to assess the value of ultrasonography in the
clinical monitoring of angiomyolipomas. 26 patients with angiomyolipomas as
diagnosed by sonography and verified by computerized tomography (CT) were
followed up by sonographic monitoring over a mean period of 45 months. One case
was associated with tuberous sclerosis. Inclusion criteria for conservative
management had been clinically asymptomatic angiomyolipomas smaller than 5 cm.
Significant tumor growth and a change of the sonographic pattern during
follow-up was seen in 2 patients. After renewed follow-up CT scanning failed to
reveal negative density values, both patients were nephrectomized. Histologic
examination showed hemorrhage in the tumor. The remaining 24 patients (92%)
showed no changes in the sonographic patterns. Minor tumor growth of 0.5 cm on
average was seen in 6 patients over a mean follow-up period of 52 months.
Surgical intervention was refrained from in these 24 patients due to the
consistent sonographic pattern and the absence of clinical symptoms. Once the
angiomyolipoma is verified by CT, sonographic monitoring suffices if the
sonostructure remains unchanged. Minor asymptomatic angiomyolipomas today no
longer require surgical intervention as this benign tumor has a pathognomonic
sonographic appearance.
DOI: 10.1159/000474301
PMID: 8375445 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23407992 | 1. Mol Neurobiol. 2013 Aug;48(1):180-5. doi: 10.1007/s12035-013-8424-8. Epub 2013
Feb 14.
TREM2 in Alzheimer's disease.
Jiang T(1), Yu JT, Zhu XC, Tan L.
Author information:
(1)Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical
University, Nanjing, China.
Recent works have demonstrated a rare functional variant (R47H) in triggering
receptor expressed on myeloid cells (TREM) 2 gene, encoding TREM2 protein,
increase susceptibility to late-onset Alzheimer's disease (AD), with an odds
ratio similar to that of the apolipoprotein E ε4 allele. The reduced function of
TREM2 was speculated to be the main cause in the pathogenic effects of this risk
variant, and TREM2 is highly expressed in white matter, as well as in the
hippocampus and neocortex, which is partly consistent with the pathological
features reported in AD brain, indicating the possible involvement of TREM2 in
AD pathogenesis. Emerging evidence has demonstrated that TREM2 could suppress
inflammatory response by repression of microglia-mediated cytokine production
and secretion, which may prevent inflammation-induced bystander damage of
neurons. TREM2 also participates in the regulation of phagocytic pathways that
are responsible for the removal of neuronal debris. In this article, we review
the recent epidemiological findings of TREM2 that related with late-onset AD and
speculate the possible roles of TREM2 in progression of this disease. Based on
the potential protective actions of TREM2 in AD pathogenesis, targeting TREM2
might provide new opportunities for AD treatment.
DOI: 10.1007/s12035-013-8424-8
PMID: 23407992 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20716772 | 1. Blood. 2010 Dec 2;116(23):4894-905. doi: 10.1182/blood-2010-03-275180. Epub
2010 Aug 17.
The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Eμ-
TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor
signaling.
Suljagic M(1), Longo PG, Bennardo S, Perlas E, Leone G, Laurenti L, Efremov DG.
Author information:
(1)International Centre for Genetic Engineering and Biotechnology Molecular
Hematology Group, Campus A. Buzzati-Traverso, Rome, Italy.
Inhibition of antigen-dependent B-cell receptor (BCR) signaling is considered a
promising therapeutic approach in chronic lymphocytic leukemia (CLL), but
experimental in vivo evidence to support this view is still lacking. We have now
investigated whether inhibition of BCR signaling with the selective Syk
inhibitor fostamatinib disodium (R788) will affect the growth of the leukemias
that develop in the Eμ-TCL1 transgenic mouse model of CLL. Similarly to human
CLL, these leukemias express stereotyped BCRs that react with autoantigens
exposed on the surface of senescent or apoptotic cells, suggesting that they are
antigen driven. We show that R788 effectively inhibits BCR signaling in vivo,
resulting in reduced proliferation and survival of the malignant B cells and
significantly prolonged survival of the treated animals. The growth-inhibitory
effect of R788 occurs despite the relatively modest cytotoxic effect in vitro
and is independent of basal Syk activity, suggesting that R788 functions
primarily by inhibiting antigen-dependent BCR signals. Importantly, the effect
of R788 was found to be selective for the malignant clones, as no disturbance in
the production of normal B lymphocytes was observed. Collectively, these data
provide further rationale for clinical trials with R788 in CLL and establish the
BCR-signaling pathway as an important therapeutic target in this disease.
DOI: 10.1182/blood-2010-03-275180
PMID: 20716772 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11262416 | 1. J Biol Chem. 2001 Jun 1;276(22):19126-31. doi: 10.1074/jbc.M101777200. Epub
2001 Mar 21.
A mechanism regulating proteolysis of specific proteins during renal tubular
cell growth.
Franch HA(1), Sooparb S, Du J, Brown NS.
Author information:
(1)Renal Division, Department of Medicine, Emory University School of Medicine,
Atlanta, Georgia, USA.
Growth factors suppress the degradation of cellular proteins in lysosomes in
renal epithelial cells. Whether this process also involves specific classes of
proteins that influence growth processes is unknown. We investigated
chaperone-mediated autophagy, a lysosomal import pathway that depends on the
73-kDa heat shock cognate protein and allows the degradation of proteins
containing a specific lysosomal import consensus sequence (KFERQ motif).
Epidermal growth factor (EGF) or ammonia, but not transforming growth factor
beta1, suppresses total protein breakdown in cultured NRK-52E renal epithelial
cells. EGF or ammonia prolonged the half-life of glyceraldehyde-3-phosphate
dehydrogenase, a classic substrate for chaperone-mediated autophagy, by more
than 90%, whereas transforming growth factor beta1 did not. EGF caused a similar
increase in the half-life of the KFERQ-containing paired box-related
transcription factor, Pax2. The increase in half-life was accompanied by an
increased accumulation of proteins with a KFERQ motif including
glyceraldehyde-3-phosphate dehydrogenase and Pax2. Ammonia also increased the
level of the Pax2 protein. Lysosomal import of KFERQ proteins depends on the
abundance of the 96-kDa lysosomal glycoprotein protein (lgp96), and we found
that EGF caused a significant decrease in lgp96 in cellular homogenates and
associated with lysosomes. We conclude that EGF in cultured renal cells
regulates the breakdown of proteins targeted for destruction by
chaperone-mediated autophagy. Because suppression of this pathway results in an
increase in Pax2, these results suggest a novel mechanism for the regulation of
cell growth.
DOI: 10.1074/jbc.M101777200
PMID: 11262416 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22257305 | 1. Nephrology (Carlton). 2012 May;17(4):407-14. doi:
10.1111/j.1440-1797.2012.01568.x.
Is the Chronic Kidney Disease Epidemiology Collaboration four-level race
equation better than the cystatin C equation?
DU X(1), Liu L, Hu B, Wang F, Wan X, Jiang L, Zhang R, Cao C.
Author information:
(1)Department of Nephrology, Nanjing First Hospital Affiliated to Nanjing
Medical University, Nanjing, China.
AIM: To evaluate the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
four-level race equation in the assessment of glomerular filtration rate (GFR)
in Chinese people with chronic kidney disease (CKD), which was published in
2011, compared with the cystatin C-based GFR estimation equation (CysC GFR) and
the combination of CysC and serum creatinine equation (CysC-Scr GFR).
METHODS: The CKD-EPI four-level race equation estimated GFR (CKD-EPI GFR) was
compared with the CysC GFR and CysC-Scr GFR. Three equations were compared with
body surface area (BSA) standardized GFR (sGFR), which was measured by (99m)
Tc-DTPA renal dynamic imaging method in 111 CKD cases.
RESULTS: A statistically significant correlation was found between sGFR and
CKD-EPI GFR, CysC GFR and CysC-Scr GFR. Three estimated GFR (eGFR) equations of
30% accuracy were 58.6%, 56.8% and 63.5%, respectively. Average deviations of
eGFR from sGFR were 2.34, 1.19, and 1.32 (mL/min per 1.73 m(2)) (P > 0.05),
respectively. There was no significant deviation in the CKD from stages 1 to 5
in CKD-EPI GFR and CysC-Scr GFR. However, when estimated by CysC GFR, the
deviation was increased, with the value of 12.41 mL/min per 1.73 m(2) (P= 0.002)
in CKD stage 5.
CONCLUSION: Our results showed that in a Chinese population with CKD, CKD-EPI
GFR, CysC GFR and CysC-Scr GFR of bias and overall accuracy of 30% were very
similar. There was little advantage in adding Asian coefficient to modifying the
CKD-EPI equation. CysC GFR overestimated GFR in patients with CKD stages 4 and
5.
© 2012 The Authors. Nephrology © 2012 Asian Pacific Society of Nephrology.
DOI: 10.1111/j.1440-1797.2012.01568.x
PMID: 22257305 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22589170 | 1. Prenat Diagn. 2012 Aug;32(8):758-64. doi: 10.1002/pd.3898. Epub 2012 May 15.
Perinatal outcomes of fetal echogenic bowel.
Saha E(1), Mullins EW, Paramasivam G, Kumar S, Lakasing L.
Author information:
(1)Department of Fetal Medicine, St. Mary's Hospital, Imperial College
Healthcare NHS Trust, London, UK.
OBJECTIVE: To investigate perinatal outcomes of fetal echogenic bowel (FEB).
METHOD: This is a retrospective observational study of FEB cases from Jan
2005-Dec 2010. Data from ultrasound and fetal medicine investigations, uterine
artery Doppler (UAD), intra-partum care and neonatal outcome were obtained from
Fetal Medicine, Obstetric and Neonatal Databases.
RESULTS: There were 139 cases presenting at 21(+5) (15(+1) -35(+5) ) weeks
gestation. Overall, 106/139 (76.2%) were live born (LB), 8/139 (5.8%) were
complicated by intra-uterine deaths (IUD), 11/139 (7.9%) had termination of
pregnancy (TOP) and 14/139 (10.1%) were lost to follow-up after 28 weeks
gestation. Six had chromosomal/genetic abnormalities, two had congenital
cytomegalovirus, none had cystic fibrosis.Uterine artery Doppler was normal in
106/130 (81.5%) cases. In this group, there were no cases of fetal growth
restriction (FGR), 95/106 (89.6%) were LB, 1/106 (0.94%) had an IUD. In the
abnormal UAD group, 17/24 (70.1%) developed FGR, 11/24 (45.8%) were LB, 4/24
(16.7%) had TOP, 7/24 (29.2%) had IUD.In total, 20/106 (18.9%) live births were
admitted for specialist neonatal care, 12/20 (60%) for prematurity. Only one had
primary bowel pathology.
CONCLUSION: Pregnancies with FEB and screen positive UAD are at risk of adverse
perinatal outcome. Primary bowel pathology is rare following the finding of FEB.
© 2012 John Wiley & Sons, Ltd.
DOI: 10.1002/pd.3898
PMID: 22589170 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23627915 | 1. Curr Drug Targets. 2013 Nov;14(12):1385-91. doi: 10.2174/13894501113149990160.
Janus kinase inhibition with tofacitinib: changing the face of inflammatory
bowel disease treatment.
Vuitton L(1), Koch S, Peyrin-Biroulet L.
Author information:
(1)Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of
Nancy-Brabois, Université Henri Poincaré 1 Allée du Morvan, 54511
Vandoeuvre-lès-Nancy, France. [email protected].
The advent of anti-Tumor Necrosis Factor (TNF) therapy has changed the way of
treating inflammatory bowel disease (IBD). However, primary and secondary
failure are relatively frequent with all anti-TNF agents, which are available
only as parenteral agents. Tofacitinib is an oral janus kinase (JAK) inhibitor
that inhibits JAK family kinase members, in particular JAK1 and JAK3, achieving
a broad limitation of inflammation by interfering with several cytokine
receptors. It first proved its efficacy as an immunosuppressive regimen after
renal transplantation, and was recently approved by the FDA for rheumatoid
arthritis. First data in IBD are promising, especially in ulcerative colitis.
Ongoing clinical trials in both UC and Crohn's disease (CD) are needed to
further explore its efficacy in CD and to better assess its safety profile.
DOI: 10.2174/13894501113149990160
PMID: 23627915 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19622120 | 1. Genes Cells. 2009 Aug;14(8):949-63. doi: 10.1111/j.1365-2443.2009.01322.x.
Epub 2009 Jul 19.
Replisome progression complex links DNA replication to sister chromatid cohesion
in Xenopus egg extracts.
Tanaka H(1), Kubota Y, Tsujimura T, Kumano M, Masai H, Takisawa H.
Author information:
(1)Department of Biological Sciences, Graduate School of Science, Osaka
University, Toyonaka, Osaka 560-0043, Japan.
Cohesin-mediated sister chromatid cohesion is established during the S-phase,
and recent studies demonstrate that a cohesin protein ring concatenates sister
DNA molecules. However, little is known about how DNA replication is linked to
the establishment of sister chromatid cohesion. Here, we used Xenopus egg
extracts to show that AND-1 and Tim1-Tipin, homologues of Saccharomyces
cerevisiae Ctf4 and Tof1-Csm3, respectively, are associated with the replisome
and are required for proper establishment of the cohesion observed in the
M-phase extracts. Immunodepletion of both AND-1 and Tim1-Tipin from the extracts
leads to aberrant sister chromatid cohesion, which is similarly induced by the
depletion of cohesin. These results demonstrate that AND-1 and Tim1-Tipin are
key factors linking DNA replication and establishment of sister chromatid
cohesion. On the basis of the physical interactions between AND-1 and DNA
polymerases, we discuss a model to describe how replisome progression complex
establishes sister chromatid cohesion.
DOI: 10.1111/j.1365-2443.2009.01322.x
PMID: 19622120 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15874888 | 1. Med Sci Monit. 2005 May;11(5):CR230-234. Epub 2005 Apr 28.
Clinical symptoms of tuberous sclerosis complex in patients with an identical
TSC2 mutation.
Rok P(1), Kasprzyk-Obara J, Domańska-Pakieła D, Jóźwiak S.
Author information:
(1)Department of Child Neurology and Epileptology, The Children's Memorial
Health Institute, Warsaw, Poland.
BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal, dominantly
inherited neurocutaneous syndrome characterized by a wide range of neurological
abnormalities, tumors of different organs, and variable clinical symtomatology
and severity. TSC is caused by mutations in either of two tumor suppressor
genes: TSC1 or TSC2. The aim of this study was to analyze the clinical picture
of TSC in patients with an identical TSC2 mutation. We tried to discover to what
extent we may expect variability in the clinical set of symptoms in patients
with identical mutation of TSC2 gene.
MATERIAL/METHODS: Mutations were identified in 100 of 170 cases. There were only
4 patients with the same type of TSC2 mutation: 5238-5255 del 18bp, del 1746
HIKRLR. Their ages were 1.5, 9, 9, and 10 years. A standardized clinical
assessment of TSC symptoms was used.
RESULTS: Epilepsy, depigmented spots, and periventricular calcification and
cortical tubers were diagnosed in all the 4 patients, cardiac rhabdomyoma and
angiomyolipoma of the kidneys in 3, and mental retardation and forehead fibroma
in 2. Other symptoms occurred rarely or were absent. There was variability in
TSC symptoms in patients with the identical type of TSC2 mutation. The main
symptoms were present in all or in the majority of patients. Clinical picture
also differed with the age of patient.
CONCLUSIONS: There are many influencing factors contributing to the diversity of
the clinical picture and pathology of TSC. Obviously, a greater number of cases
are needed for further analysis and more precise conclusions.
PMID: 15874888 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23852707 | 1. Curr Treat Options Neurol. 2013 Oct;15(5):618-33. doi:
10.1007/s11940-013-0249-2.
Management of CNS-related Disease Manifestations in Patients With Tuberous
Sclerosis Complex.
Krueger DA(1).
Author information:
(1)Departments of Pediatrics and Neurology, University of Cincinnati College of
Medicine and Division of Child Neurology, Cincinnati Children's Hospital Medical
Center, 3333 Burnet Avenue ML #2015, Cincinnati, OH, 45229, USA,
[email protected].
Historically, before the advent of modern imaging and genetic testing, Tuberous
Sclerosis Complex (TSC) was more of a diagnostic challenge and less of a
treatment challenge. This is because the natural history of TSC was poorly
understood and TSC-specific treatments were non-existent. In the current era,
diagnosis is more straightforward but management is much more complex. Disease
manifestations vary by age, severity, and organ system. Management issues in the
first few months of life, including neurologic manifestations, are very
different than late childhood, adolescence, and adulthood. With increasing
numbers of TSC diagnoses being made prenatally or shortly after birth, the
opportunity for interventions that may improve long-term developmental and
epilepsy outcomes now may precede the onset of neurological clinical symptoms.
Familiarity and anticipation of these neurologic complications and rapid
response to their emergence is crucial. Periodic imaging surveillance for
development of subependymal giant cell astrocytoma (SEGA), preferably by
magnetic resonance imaging (MRI) every 1-3 years, is now standard of care. Early
SEGA detection provides opportunity to initiate pharmacologic treatment with
everolimus if appropriate, thereby negating the need for invasive surgery.
Routine electroencephalography (EEG) in asymptomatic infants for the first year
or two of life is becoming increasingly accepted, with treatment initiation of
vigabatrin dependent on concerning EEG findings instead of waiting until onset
of clinical seizures, the traditional approach. Effective SEGA treatment and
optimal seizure control remain principal during the first few decades of life
for the clinical neurologist involved in the management of TSC. However, during
the same period and extending through adulthood, assessment of TSC-associated
neuropsychiatric disorder (TAND) is also key to the best clinical outcome and
quality of life for affected individuals and their surrounding family and
caregivers.
DOI: 10.1007/s11940-013-0249-2
PMID: 23852707 |
http://www.ncbi.nlm.nih.gov/pubmed/17222391 | 1. Biochem Biophys Res Commun. 2007 Mar 2;354(1):222-6. doi:
10.1016/j.bbrc.2006.12.185. Epub 2007 Jan 2.
Chl1 and Ctf4 are required for damage-induced recombinations.
Ogiwara H(1), Ui A, Lai MS, Enomoto T, Seki M.
Author information:
(1)Molecular Cell Biology Laboratory, Graduate School of Pharmaceutical
Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
Deletion mutants of CHL1 or CTF4, which are required for sister chromatid
cohesion, showed higher sensitivity to the DNA damaging agents methyl
methanesulfonate (MMS), hydroxyurea (HU), phleomycin, and camptothecin, similar
to the phenotype of mutants of RAD52, which is essential for recombination
repair. The levels of Chl1 and Ctf4 associated with chromatin increased
considerably after exposure of the cells to MMS and phleomycin. Although the
activation of DNA damage checkpoint did not affected in chl1 and ctf4 mutants,
the repair of damaged chromosome was inefficient, suggesting that Chl1 and Ctf4
act in DNA repair. In addition, MMS-induced sister chromatid recombination in
haploid cells, and, more importantly, MMS-induced recombination between
homologous chromosomes in diploid cells were impaired in these mutants. Our
results suggest that Chl1 and Ctf4 are directly involved in homologous
recombination repair rather than acting indirectly via the establishment of
sister chromatid cohesion.
DOI: 10.1016/j.bbrc.2006.12.185
PMID: 17222391 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10063835 | 1. Neuromuscul Disord. 1999 Jan;9(1):41-9. doi: 10.1016/s0960-8966(98)00090-x.
Characterization of 34 novel and six known MTM1 gene mutations in 47 unrelated
X-linked myotubular myopathy patients.
Tanner SM(1), Schneider V, Thomas NS, Clarke A, Lazarou L, Liechti-Gallati S.
Author information:
(1)Human Molecular Genetics, Department of Clinical Research, Children's
Hospital, University of Berne, Switzerland. [email protected]
X-linked myotubular myopathy (XLMTM) is a congenital muscle disorder mainly
affecting newborn males. Neonatal muscle weakness and hypotonia usually leads to
a rapid demise. The responsible gene, MTM1, was isolated in 1996, and mutational
data derived from 90 patients have been published. We report on our findings in
a further 53 patients, using genomic DNA and mRNA screening protocols.
Thirty-four novel mutations were identified in 37 cases, and six known mutations
found in 10 other patients. The 34 new mutations include five large deletions,
eight nonsense, six frameshift, five missense, and eight splice-site mutations,
whereas two intronic variants causing partial exon skipping represent the first
report on such a mechanism in MTM1. Two deletions, one involving exon 1, and the
second exon 15, are the first defects to be identified in these exons. The
heterogeneity of the mutations, their mutational origins, and the varied ethnic
backgrounds of the patients, indicate that the majority of XLMTM families are
affected by unique MTM1 mutations.
DOI: 10.1016/s0960-8966(98)00090-x
PMID: 10063835 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25786784 | 1. Muscle Nerve. 2015 Jun;51(6):884-9. doi: 10.1002/mus.24653. Epub 2015 Apr 2.
Should patients with asymptomatic pompe disease be treated? A nationwide study
in France.
Echaniz-Laguna A(1), Carlier RY(2), Laloui K(3), Carlier P(3), Salort-Campana
E(4), Pouget J(4), Laforet P(3).
Author information:
(1)Centre de Référence des Maladies Neuromusculaires, Département de Neurologie,
Hôpital de Hautepierre 1, Avenue Molière, 67098, Strasbourg, France.
(2)Assistance Publique-Hôpitaux de Paris (APHP), Service d'imagerie médicale,
CIC-IT handicap, Hôpital Poincaré, Garches, France.
(3)Centre de Référence Neuromusculaire Paris-Est, Hôpital Pitié-Salpêtrière, and
U974, Université Pierre et Marie Curie, Paris, France.
(4)Centre de Référence des Maladies Neuromusculaires, Aix-Marseille Université,
APHP, Marseille, France.
INTRODUCTION: Acid α-glucosidase deficiency, that is, Pompe disease, is a
glycogenosis for which enzyme replacement therapy (ERT) is available. It is not
known whether patients diagnosed at an asymptomatic stage should be treated to
prevent progression of the disease.
METHODS: We investigated 7 patients with asymptomatic Pompe disease identified
from the French Pompe registry.
RESULTS: The patients had a mean age of 45 (range 24-75) years, a median
follow-up duration of 2 (range 1-22) years, and normal clinical examination,
pulmonary function tests (PFTs), and echocardiography. All presented with at
least 1 subclinical abnormality, including hyperCKemia, vacuolar myopathy, and
muscle MRI abnormalities, suggesting that subclinical myopathy was present in
all cases.
CONCLUSIONS: Asymptomatic Pompe disease may remain clinically silent for
decades, and affected patients should be monitored closely for overt myopathy
using clinical examination, PFTs, and muscle MRI to determine when to start ERT.
© 2015 Wiley Periodicals, Inc.
DOI: 10.1002/mus.24653
PMID: 25786784 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20434914 | 1. Neuromuscul Disord. 2010 Jun;20(6):375-81. doi: 10.1016/j.nmd.2010.03.015.
Novel molecular diagnostic approaches for X-linked centronuclear (myotubular)
myopathy reveal intronic mutations.
Tosch V(1), Vasli N, Kretz C, Nicot AS, Gasnier C, Dondaine N, Oriot D, Barth M,
Puissant H, Romero NB, Bönnemann CG, Heller B, Duval G, Biancalana V, Laporte J.
Author information:
(1)Department of Neurobiology and Genetics, Institut de Génétique et de Biologie
Moléculaire et Cellulaire, Illkirch, France.
X-linked centronuclear myopathy (XLMTM), also called myotubular myopathy, is a
severe congenital myopathy characterized by generalized hypotonia and weakness
at birth and the typical histological finding of centralization of myo-nuclei.
It is caused by mutations in the MTM1 gene encoding the 3-phosphoinositides
phosphatase myotubularin. Mutations in dynamin 2 and amphiphysin 2 genes lead to
autosomal forms of centronuclear myopathy (CNM). While XLMTM is the most
frequent and severe form of CNM, no mutations are found in about 30% of patients
by sequencing all MTM1 exons. Moreover, the impact of MTM1 sequence variants is
sometimes difficult to assess. It is thus important to devise a complete
molecular diagnostic strategy that includes analysis of the myotubularin
transcript and protein expression. We therefore developed novel antibodies
against human myotubularin and showed that they are able to detect the
endogenous protein by direct Western blot from muscle samples and from cultured
cells. In conjunction with RT-PCR analysis we validated the consequences of
missense and splice mutations on transcript integrity and protein level. We also
detected and characterized a novel deep intronic mutation consisting of a single
nucleotide change that induces exonisation of a conserved intronic sequence.
Patients with centronuclear myopathy and no molecular diagnosis should be
investigated for MTM1 defects at the cDNA and protein level.
DOI: 10.1016/j.nmd.2010.03.015
PMID: 20434914 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24094931 | 1. Trends Cell Biol. 2014 Mar;24(3):161-70. doi: 10.1016/j.tcb.2013.09.002. Epub
2013 Oct 3.
Proteostasis and aging of stem cells.
Vilchez D(1), Simic MS(2), Dillin A(3).
Author information:
(1)Molecular and Cell Biology Department, The University of California,
Berkeley, Li Ka Shing Center For Biomedical and Health Sciences, Berkeley, CA
94720, USA; Cologne Excellence Cluster for Cellular Stress Responses in
Aging-Associated Diseases (CECAD), Institute for Genetics, University of
Cologne, Zülpicher Strasse 47a, 50674 Cologne, Germany.
(2)Molecular and Cell Biology Department, The University of California,
Berkeley, Li Ka Shing Center For Biomedical and Health Sciences, Berkeley, CA
94720, USA; Université Pierre and Marie Curie, Paris, France.
(3)Molecular and Cell Biology Department, The University of California,
Berkeley, Li Ka Shing Center For Biomedical and Health Sciences, Berkeley, CA
94720, USA; Howard Hughes Medical Institute, The University of California,
Berkeley, CA 94720, USA. Electronic address: [email protected].
The accumulation of misfolded or damaged proteins is an important determinant of
the aging process. Mechanisms that promote the homeostasis of the proteome, or
proteostasis, can slow aging and decrease the incidence of age-related diseases.
Adult stem cell function declines during the aging process of an organism. This
demise of somatic stem cell function could contribute to tissue degeneration and
organismal aging. Accumulation of damaged proteins in embryonic stem cells
(ESCs) may also have an impact on the aging process, because the passage of
these proteins to progenitor cells during asymmetric division could compromise
development and aging. Therefore, proteostasis maintenance in stem cells might
have an important role in organismal aging. In this review, we discuss exciting
new insights into stem cell aging and proteostasis and the questions raised by
these findings.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tcb.2013.09.002
PMID: 24094931 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1411323 | 1. Scand J Infect Dis. 1992;24(4):549-52. doi: 10.3109/00365549209052643.
Early detection of circulating anodic antigen (CAA) in a case of acute
schistosomiasis mansoni with Katayama fever.
Gundersen SG(1), Ravn J, Haagensen I.
Author information:
(1)Department of Infectious Diseases, Ullevaal Hospital, Oslo University,
Norway.
A 34-year-old male developed acute Katayama fever with fever, diarrhoea, joint
pains, headache, urticarial rash and eosinophilia 18 days after falling into and
spending 15 min in the water during water-skiing in the outlet of the Volta
river. Low anti-schistosomal antibody titres were found by the
immunofluorescence assay after 4 weeks, and the first Schistosoma mansoni eggs
were found in faeces after 6 weeks. Both symptoms and eosinophilia increased the
first days after treatment with oxamniquine, after which he improved gradually.
Examination of frozen sera by the newly developed Magnetic Beads Antigen
Capture-EIA (MBAC-EIA) later demonstrated a peak in schistosomal circulating
anodic antigen (CAA) levels of diagnostic significance already 4 weeks after he
was infected.
DOI: 10.3109/00365549209052643
PMID: 1411323 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24916752 | 1. Acta Clin Belg. 2014 Aug;69(4):267-72. doi: 10.1179/2295333714Y.0000000039.
Epub 2014 Jun 10.
Laboratory diagnosis of schistosomiasis and Katayama syndrome in returning
travellers.
Van Meensel B, Van Wijngaerden E, Verhaegen J, Peetermans WE, Lontie ML, Ripert
C.
The gold standard for laboratory diagnosis of schistosomiasis is the presence of
typical eggs in stool or urine. The laboratory diagnosis of schistosomiasis and
Katayama syndrome in returning travellers is difficult because the number of
excreted eggs is often very limited. In early infections and in patients with
only a few contacts with contaminated water, the total number of parasites,
migrating larvae or schistosomulae, and adult worms, is very low. Eggs can only
be found in faeces or urine when there is at least one pair of adult worms at
the final location. The number of parasites increases as a function of the
number of contacts with infected water. The exact latency between contamination
and egg production is unknown. It is estimated that excretion of eggs starts
after 40-50 days. The specific diagnosis of early schistosomiasis and Katayama
fever relies essentially on serologic tests or preferably on PCR (if available).
These assays are much more sensitive (up to four times) in the early phase of
schistosomiasis than microscopic examination for typical eggs. Eosinophilia
(sometimes exceeding 50%) is often present in patients with acute
schistosomiasis (Katayama fever), but may be limited or absent in late fibrotic
manifestations of the disease.
DOI: 10.1179/2295333714Y.0000000039
PMID: 24916752 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20482298 | 1. Clin Chem Lab Med. 2010 Aug;48(8):1121-6. doi: 10.1515/CCLM.2010.234.
Non-invasive fetal RHD genotyping in the first trimester of pregnancy.
Cardo L(1), García BP, Alvarez FV.
Author information:
(1)Hospital Universitario Central de Asturias, Servicio de Bioquímica, Oviedo,
Spain.
BACKGROUND: Hemolytic disease of the fetus and newborn (HDN) is caused primarily
by feto-maternal RhD incompatibility. Although all RhD negative pregnant women
undergo routine antenatal RhD prophylaxis at 28 weeks of gestation, and
following delivery if the newborn is RhD positive, HDN has not been eradicated.
Here, we investigated fetal Rhesus D (RHD) genotype in maternal plasma during
the first trimester of pregnancy in our area.
METHODS: Plasma samples were obtained from 111 RhD negative pregnant women,
between 9 and 13 weeks of gestation. DNA from maternal plasma containing
cell-free fetal DNA (cffDNA) was analyzed by quantitative PCR (qPCR) to detect
RHD exons 5 and 7. A beta-globin (HBB) sequence was quantified to estimate total
DNA concentration. qPCR results were compared with newborn RhD determined in
cord blood serum. The influence of several gestational parameters on DNA
concentration was also analyzed.
RESULTS: The specificity and sensitivity of the assay was 93% and 100%,
respectively, with 97% diagnostic accuracy. Cell-free DNA concentrations during
the first trimester of pregnancy were not affected by the gestational parameters
studied (free-beta fraction of human chorionic gonadotropin and
pregnancy-associated plasma protein A concentrations, fetal sex, materno-fetal
ABO blood group incompatibility, maternal weight and gestational age).
CONCLUSIONS: Non-invasive fetal RHD genotyping during the first trimester of
pregnancy can be determined with a high specificity, thus representing a
valuable tool for improving the management of RhD negative pregnant women. As a
high percentage of pregnant women participate in the routine first trimester
combined screening program for aneuploidies, the fetal RHD study could be of
immediate implementation, since the same blood collection could be used.
DOI: 10.1515/CCLM.2010.234
PMID: 20482298 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24068903 | 1. PLoS Comput Biol. 2013;9(9):e1003220. doi: 10.1371/journal.pcbi.1003220. Epub
2013 Sep 12.
Computational optogenetics: empirically-derived voltage- and light-sensitive
channelrhodopsin-2 model.
Williams JC(1), Xu J, Lu Z, Klimas A, Chen X, Ambrosi CM, Cohen IS, Entcheva E.
Author information:
(1)Department of Biomedical Engineering, Stony Brook University, Stony Brook,
New York, United States of America.
Channelrhodospin-2 (ChR2), a light-sensitive ion channel, and its variants have
emerged as new excitatory optogenetic tools not only in neuroscience, but also
in other areas, including cardiac electrophysiology. An accurate quantitative
model of ChR2 is necessary for in silico prediction of the response to optical
stimulation in realistic tissue/organ settings. Such a model can guide the
rational design of new ion channel functionality tailored to different cell
types/tissues. Focusing on one of the most widely used ChR2 mutants (H134R) with
enhanced current, we collected a comprehensive experimental data set of the
response of this ion channel to different irradiances and voltages, and used
these data to develop a model of ChR2 with empirically-derived voltage- and
irradiance- dependence, where parameters were fine-tuned via simulated annealing
optimization. This ChR2 model offers: 1) accurate inward rectification in the
current-voltage response across irradiances; 2) empirically-derived voltage- and
light-dependent kinetics (activation, deactivation and recovery from
inactivation); and 3) accurate amplitude and morphology of the response across
voltage and irradiance settings. Temperature-scaling factors (Q10) were derived
and model kinetics was adjusted to physiological temperatures. Using optical
action potential clamp, we experimentally validated model-predicted ChR2
behavior in guinea pig ventricular myocytes. The model was then incorporated in
a variety of cardiac myocytes, including human ventricular, atrial and Purkinje
cell models. We demonstrate the ability of ChR2 to trigger action potentials in
human cardiomyocytes at relatively low light levels, as well as the differential
response of these cells to light, with the Purkinje cells being most easily
excitable and ventricular cells requiring the highest irradiance at all pulse
durations. This new experimentally-validated ChR2 model will facilitate virtual
experimentation in neural and cardiac optogenetics at the cell and organ level
and provide guidance for the development of in vivo tools.
DOI: 10.1371/journal.pcbi.1003220
PMCID: PMC3772068
PMID: 24068903 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/23894139 | 1. Bioinformatics. 2013 Oct 1;29(19):2517-8. doi: 10.1093/bioinformatics/btt427.
Epub 2013 Jul 26.
mpMoRFsDB: a database of molecular recognition features in membrane proteins.
Gypas F(1), Tsaousis GN, Hamodrakas SJ.
Author information:
(1)Faculty of Biology, Department of Cell Biology and Biophysics, University of
Athens, Panepistimiopolis, Athens 157 01, Greece.
SUMMARY: Molecular recognition features (MoRFs) are small, intrinsically
disordered regions in proteins that undergo a disorder-to-order transition on
binding to their partners. MoRFs are involved in protein-protein interactions
and may function as the initial step in molecular recognition. The aim of this
work was to collect, organize and store all membrane proteins that contain
MoRFs. Membrane proteins constitute ∼30% of fully sequenced proteomes and are
responsible for a wide variety of cellular functions. MoRFs were classified
according to their secondary structure, after interacting with their partners.
We identified MoRFs in transmembrane and peripheral membrane proteins. The
position of transmembrane protein MoRFs was determined in relation to a
protein's topology. All information was stored in a publicly available mySQL
database with a user-friendly web interface. A Jmol applet is integrated for
visualization of the structures. mpMoRFsDB provides valuable information related
to disorder-based protein-protein interactions in membrane proteins.
AVAILABILITY: http://bioinformatics.biol.uoa.gr/mpMoRFsDB
DOI: 10.1093/bioinformatics/btt427
PMID: 23894139 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21501383 | 1. J Dtsch Dermatol Ges. 2011 Nov;9(11):897-902. doi:
10.1111/j.1610-0387.2011.07683.x. Epub 2011 Apr 19.
Psoriasin: key molecule of the cutaneous barrier?
[Article in English, German]
Gläser R(1), Köten B, Wittersheim M, Harder J.
Author information:
(1)Department of Dermatology, Venereology and Allergy, University Clinic
Schleswig-Holstein, Campus Kiel, Germany. [email protected]
Psoriasin (S100 A7) was discovered two decades ago as a protein abundantly
expressed in psoriatic keratinocytes. Even though much scientific research has
been carried out on the characterization of psoriasin, only recent studies point
to an important role of psoriasin as an antimicrobial and immunomodulatory
protein in skin and other epithelia. In this review, we provide an overview of
the major findings in psoriasin research and discuss novel studies highlighting
the role of psoriasin as an important effector molecule of the cutaneous
barrier.
© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.
DOI: 10.1111/j.1610-0387.2011.07683.x
PMID: 21501383 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16844234 | 1. J Neuroimmunol. 2006 Aug;177(1-2):201-8. doi: 10.1016/j.jneuroim.2006.04.005.
Epub 2006 Jul 14.
Spectrum of neurological diseases associated with antibodies to minor
gangliosides GM1b and GalNAc-GD1a.
Tatsumoto M(1), Koga M, Gilbert M, Odaka M, Hirata K, Kuwabara S, Yuki N.
Author information:
(1)Department of Neurology, Dokkyo Medical University School of Medicine,
Kitakobayashi 880, Mibu, Shimotsuga, Tochigi 321-0293, Japan.
The authors reported the neurological disease spectrum associated with
autoantibodies against minor gangliosides GM1b and GalNAc-GD1a. IgG and IgM
antibody reactivity against gangliosides GM1, GM2, GM1b, GD1a, GalNAc-GD1a and
GQ1b was investigated in sera from 7000 consecutive patients who had various
neurological conditions. The clinical diagnoses for 456 anti-GM1b-positive
patients were Guillain-Barré syndrome (GBS, 71%), atypical GBS with preserved
deep tendon reflexes (12%), Fisher syndrome (10%), Bickerstaff's brainstem
encephalitis (2%), ataxic GBS (2%) and acute ophthalmoparesis (1%). For 193
anti-GalNAc-GD1a-positive patients, the diagnoses were GBS (70%), atypical GBS
(16%), Fisher syndrome (10%) and Bickerstaff's brainstem encephalitis (3%). Of
the patients with GBS or atypical GBS, 28% of 381 anti-GM1b-positive and 31% of
166 anti-GalNAc-GD1a-positive patients had neither anti-GM1 nor anti-GD1a
antibodies. Of those patients with Fisher syndrome, Bickerstaff's brainstem
encephalitis, ataxic GBS or acute ophthalmoparesis, 33% of 67
anti-GM1b-positive, and 52% of 25 anti-GalNAc-GD1a-positive patients had no
anti-GQ1b antibodies. Autoantibodies against GM1b and GalNAc-GD1a are associated
with GBS, Fisher syndrome and related conditions. These antibodies should
provide useful serological markers for identifying patients who have atypical
GBS with preserved deep tendon reflexes, ataxic GBS, Bickerstaff's brainstem
encephalitis or acute ophthalmoparesis, especially for those who have no
antibodies to GM1, GD1a or GQ1b. A method to prepare GM1b was developed.
DOI: 10.1016/j.jneuroim.2006.04.005
PMID: 16844234 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22496245 | 1. Am J Physiol Cell Physiol. 2012 Jun 15;302(12):C1762-71. doi:
10.1152/ajpcell.00425.2011. Epub 2012 Apr 11.
Ablation of sarcolipin results in atrial remodeling.
Xie LH(1), Shanmugam M, Park JY, Zhao Z, Wen H, Tian B, Periasamy M, Babu GJ.
Author information:
(1)Department of Cell Biology and Molecular Medicine, University of Medicine and
Dentistry of New Jersey-New Jersey Medical School, Newark, 07103, USA.
Sarcolipin (SLN) is a key regulator of sarco(endo)plasmic reticulum (SR)
Ca(2+)-ATPase (SERCA), and its expression is altered in diseased atrial
myocardium. To determine the precise role of SLN in atrial Ca(2+) homeostasis,
we developed a SLN knockout (sln-/-) mouse model and demonstrated that ablation
of SLN enhances atrial SERCA pump activity. The present study is designed to
determine the long-term effects of enhanced SERCA activity on atrial remodeling
in the sln-/- mice. Calcium transient measurements show an increase in atrial SR
Ca(2+) load and twitch Ca(2+) transients. Patch-clamping experiments demonstrate
activation of the forward mode of sodium/calcium exchanger, increased L-type
Ca(2+) channel activity, and prolongation of action potential duration at 90%
repolarization in the atrial myocytes of sln-/- mice. Spontaneous Ca(2+) waves,
delayed afterdepolarization, and triggered activities are frequent in the atrial
myocytes of sln-/- mice. Furthermore, loss of SLN in atria is associated with
increased interstitial fibrosis and altered expression of genes encoding
collagen and other extracellular matrix proteins. Our results also show that the
sln-/- mice are susceptible to atrial arrhythmias upon aging. Together, these
findings indicate that ablation of SLN results in increased SERCA activity and
SR Ca(2+) load, which, in turn, could cause abnormal intracellular Ca(2+)
handling and atrial remodeling.
DOI: 10.1152/ajpcell.00425.2011
PMCID: PMC3378074
PMID: 22496245 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24833660 | 1. Circ Res. 2014 Jul 18;115(3):354-63. doi: 10.1161/CIRCRESAHA.115.303632. Epub
2014 May 15.
Cardiac-specific YAP activation improves cardiac function and survival in an
experimental murine MI model.
Lin Z(1), von Gise A(1), Zhou P(1), Gu F(1), Ma Q(1), Jiang J(1), Yau AL(1),
Buck JN(1), Gouin KA(1), van Gorp PR(1), Zhou B(1), Chen J(1), Seidman JG(1),
Wang DZ(1), Pu WT(2).
Author information:
(1)From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G.,
P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W.,
W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA;
Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical
School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University
Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell
Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key
Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
Shanghai, China (B.Z.).
(2)From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G.,
P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W.,
W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA;
Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical
School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University
Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell
Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key
Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
Shanghai, China (B.Z.). [email protected].
Comment in
Circ Res. 2014 Jul 18;115(3):332-4. doi: 10.1161/CIRCRESAHA.114.304389.
RATIONALE: Yes-associated protein (YAP), the terminal effector of the Hippo
signaling pathway, is crucial for regulating embryonic cardiomyocyte
proliferation.
OBJECTIVE: We hypothesized that YAP activation after myocardial infarction (MI)
would preserve cardiac function and improve survival.
METHODS AND RESULTS: We used a cardiac-specific, inducible expression system to
activate YAP in adult mouse heart. Activation of YAP in adult heart promoted
cardiomyocyte proliferation and did not deleteriously affect heart function.
Furthermore, YAP activation after MI preserved heart function and reduced
infarct size. Using adeno-associated virus subtype 9 (AAV9) as a delivery
vector, we expressed human YAP (hYAP) in the adult murine myocardium immediately
after MI. We found that AAV9:hYAP significantly improved cardiac function and
mouse survival. AAV9:hYAP did not exert its salutary effects by reducing
cardiomyocyte apoptosis. Rather, AAV9:hYAP stimulated adult cardiomyocyte
proliferation. Gene expression profiling indicated that AAV9:hYAP stimulated
expression of cell cycle genes and promoted a less mature cardiac gene
expression signature.
CONCLUSIONS: Cardiac-specific YAP activation after MI mitigated myocardial
injury, improved cardiac function, and enhanced survival. These findings suggest
that therapeutic activation of YAP or its downstream targets, potentially
through AAV-mediated gene therapy, may be a strategy to improve outcome after
MI.
© 2014 American Heart Association, Inc.
DOI: 10.1161/CIRCRESAHA.115.303632
PMCID: PMC4104149
PMID: 24833660 [Indexed for MEDLINE]
Conflict of interest statement: DISCLOSURES The authors have no conflicts of
interest to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/23986815 | 1. Commun Integr Biol. 2013 Jul 1;6(4):e24925. doi: 10.4161/cib.24925. Epub 2013
Jun 11.
Chaperone-assisted proteostasis is essential for mechanotransduction in
mammalian cells.
Ulbricht A(1), Arndt V, Höhfeld J.
Author information:
(1)Institute for Cell Biology; University of Bonn; Bonn, Germany.
Maintaining the dynamic proteome of a living cell in the face of an
ever-changing environment depends on a fine-tuned balance of protein synthesis
and protein degradation. Molecular chaperones exert key functions during protein
homeostasis (proteostasis). They associate with nonnative client proteins
following synthesis or damage and facilitate client sorting and folding. When
client proteins are terminally misfolded, chaperones cooperate with protein
degradation systems to dispose of such clients. This dual proteostasis activity
of chaperones is essential for maintaining cell function under normal growth
conditions and becomes even more important under stress conditions such as heat
and oxidative stress. The recent identification of chaperone-assisted selective
autophagy (CASA) as a tension-induced autophagy pathway highlights the critical
role of molecular chaperones in mechanically strained cells and tissues. The
CASA complex, assembled by the cochaperone BAG3, coordinates protein degradation
and protein synthesis in response to mechanical force. Here we describe the
composition and function of this chaperone complex in mammals and discuss its
relevance for tissue homeostasis and the regulation of cell adhesion, migration
and proliferation. We provide a unifying concept for the function of BAG3, which
integrates its involvement in muscle maintenance, tumor formation and virus
infection.
DOI: 10.4161/cib.24925
PMCID: PMC3737759
PMID: 23986815 |
http://www.ncbi.nlm.nih.gov/pubmed/24320032 | 1. Curr Pharm Des. 2014;20(31):5010-24. doi: 10.2174/1381612819666131206111352.
The metabolic syndrome and chronic liver disease.
Rosselli M, Lotersztajn S, Vizzutti F, Arena U, Pinzani M, Marra F(1).
Author information:
(1)Dipartimento di Medicina Sperimentale e Clinica, Largo Brambilla, 3, I-50134
Florence, Italy. [email protected].
The prevalence of the metabolic syndrome (MetS), a cluster of cardiovascular
risk factors associated with obesity and insulin resistance, is dramatically
increasing in Western and developing countries. This disorder is not only
associated with a higher risk of appearance of type 2 diabetes and
cardiovascular events, but impacts on the liver in different ways. Nonalcoholic
fatty liver disease (NAFLD) is considered the hepatic manifestation of MetS, and
is characterized by triglyceride accumulation and a variable degree of hepatic
injury, inflammation, and repair. In the presence of significant hepatocellular
injury and inflammation, the picture is defined 'nonalcoholic steatohepatitis'
(NASH), that has the potential to progress to advanced fibrosis and cirrhosis.
Diagnosis of NASH is based on a liver biopsy, and active search for noninvasive
tests is ongoing. Progression of steatohepatitis to advanced fibrosis or
cirrhosis has been shown in at least one third of patients followed with paired
biopsies. Presence of NASH is associated with lower life expectancy, both due to
liver-related death and to an increase in cardiovascular events. The appearance
of NAFLD is mainly dependent on increased flow of fatty acids derived from an
excess of lipolysis from insulin-resistant adipose tissue. Development of NASH
is based on lipotoxicity and is influenced by signals derived from outside the
liver and from intrahepatic activation of inflammatory and fibrogenic pathways.
The presence of the MetS is also associated with worse outcomes in patients with
cirrhosis due to any causes, and has complex interactions with hepatitis C virus
infection. Moreover, MetS poses a higher risk of development of hepatocellular
carcinoma, not necessarily through the development of NASH-related cirrhosis. In
conclusion, the presence of metabolic alterations has a severe and multifaceted
impact on the liver, and is responsible for a higher risk of liver-dependent and
-independent mortality.
DOI: 10.2174/1381612819666131206111352
PMID: 24320032 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22362515 | 1. Eur Heart J. 2012 May;33(9):1067-75. doi: 10.1093/eurheartj/ehs043. Epub 2012
Feb 23.
SERCA2a gene therapy restores microRNA-1 expression in heart failure via an
Akt/FoxO3A-dependent pathway.
Kumarswamy R(1), Lyon AR, Volkmann I, Mills AM, Bretthauer J, Pahuja A,
Geers-Knörr C, Kraft T, Hajjar RJ, Macleod KT, Harding SE, Thum T.
Author information:
(1)Institute of Molecular and Translational Therapeutic Strategies, Hannover
Medical School, Carl-Neuberg-Str 1, 30625 Hannover, Germany.
AIMS: Impaired myocardial sarcoplasmic reticulum calcium ATPase 2a (SERCA2a)
activity is a hallmark of failing hearts, and SERCA2a gene therapy improves
cardiac function in animals and patients with heart failure (HF). Deregulation
of microRNAs has been demonstrated in HF pathophysiology. We studied the effects
of therapeutic AAV9.SERCA2a gene therapy on cardiac miRNome expression and
focused on regulation, expression, and function of miR-1 in reverse remodelled
failing hearts.
METHODS AND RESULTS: We studied a chronic post-myocardial infarction HF model
treated with AAV9.SERCA2a gene therapy. Heart failure resulted in a strong
deregulation of the cardiac miRNome. miR-1 expression was decreased in failing
hearts, but normalized in reverse remodelled hearts after AAV9.SERCA2a gene
delivery. Increased Akt activation in cultured cardiomyocytes led to
phosphorylation of FoxO3A and subsequent exclusion from the nucleus, resulting
in miR-1 gene silencing. In vitro SERCA2a expression also rescued miR-1 in
failing cardiomyocytes, whereas SERCA2a inhibition reduced miR-1 levels. In
vivo, Akt and FoxO3A were highly phosphorylated in failing hearts, but reversed
to normal by AAV9.SERCA2a, leading to cardiac miR-1 restoration. Likewise,
enhanced sodium-calcium exchanger 1 (NCX1) expression during HF was normalized
by SERCA2a gene therapy. Validation experiments identified NCX1 as a novel
functional miR-1 target.
CONCLUSION: SERCA2a gene therapy of failing hearts restores miR-1 expression by
an Akt/FoxO3A-dependent pathway, which is associated with normalized NCX1
expression and improved cardiac function.
DOI: 10.1093/eurheartj/ehs043
PMCID: PMC3341631
PMID: 22362515 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8068955 | 1. Blood. 1994 Sep 1;84(5):1650-5.
Hematologic abnormalities in Fanconi anemia: an International Fanconi Anemia
Registry study.
Butturini A(1), Gale RP, Verlander PC, Adler-Brecher B, Gillio AP, Auerbach AD.
Author information:
(1)Laboratory for Investigative Dermatology, Rockefeller University, New York,
NY.
Comment in
Blood. 1995 Feb 15;85(4):1148-9.
We analyzed data from 388 subjects with Fanconi anemia reported to the
International Fanconi Anemia Registry (IFAR). Of those, 332 developed
hematologic abnormalities at a median age of 7 years (range, birth to 31 years).
Actuarial risk of developing hematopoietic abnormalities was 98% (95% confidence
interval, 93% to 99%) by 40 years of age. Common hematologic abnormalities were
thrombocytopenia and pancytopenia. These were often associated with decreased
bone marrow (BM) cellularity (75% of cases studied). Clonal cytogenetic
abnormalities developed in 23 of 68 persons with BM failure who had adequate
studies. Actuarial risk of clonal cytogenetic abnormalities during BM failure
was 67% (47% to 87%) by 30 years of age. Fifty-nine subjects developed
myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Actuarial
risk of MDS or AML was 52% (37% to 67%) by 40 years of age. Risk was higher in
persons with than in those without a prior clonal cytogenetic abnormality (3%
[0% to 9%] v 35% [0% to 79%]; P = .006). One hundred twenty persons died of
hematologic causes including BM failure, MDS or AML and treatment related
complications. Actuarial risk of death from hematologic causes was 81% (67% to
90%) by 40 years of age.
PMID: 8068955 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23341466 | 1. J Biol Chem. 2013 Mar 8;288(10):6881-9. doi: 10.1074/jbc.M112.436915. Epub
2013 Jan 22.
Sarcolipin protein interaction with sarco(endo)plasmic reticulum Ca2+ ATPase
(SERCA) is distinct from phospholamban protein, and only sarcolipin can promote
uncoupling of the SERCA pump.
Sahoo SK(1), Shaikh SA, Sopariwala DH, Bal NC, Periasamy M.
Author information:
(1)Department of Physiology and Cell Biology, College of Medicine, The Ohio
State University, Columbus, Ohio 43210, USA.
Sarco(endo)plasmic reticulum Ca(2+)ATPase (SERCA) pump activity is modulated by
phospholamban (PLB) and sarcolipin (SLN) in cardiac and skeletal muscle. Recent
data suggest that SLN could play a role in muscle thermogenesis by promoting
uncoupling of the SERCA pump (Lee, A.G. (2002) Curr. Opin. Struct. Biol. 12,
547-554 and Bal, N. C., Maurya, S. K., Sopariwala, D. H., Sahoo, S. K., Gupta,
S. C., Shaikh, S. A., Pant, M., Rowland, L. A., Bombardier, E., Goonasekera, S.
A., Tupling, A. R., Molkentin, J. D., and Periasamy, M. (2012) Nat. Med. 18,
1575-1579), but the mechanistic details are unknown. To better define how
binding of SLN to SERCA promotes uncoupling of SERCA, we compared SLN and SERCA1
interaction with that of PLB in detail. The homo-bifunctional cross-linker
(1,6-bismaleimidohexane) was employed to detect dynamic protein interaction
during the SERCA cycle. Our studies reveal that SLN differs significantly from
PLB: 1) SLN primarily affects the Vmax of SERCA-mediated Ca(2+) uptake but not
the pump affinity for Ca(2+); 2) SLN can bind to SERCA in the presence of high
Ca(2+), but PLB can only interact to the ATP-bound Ca(2+)-free E2 state; and 3)
unlike PLB, SLN interacts with SERCA throughout the kinetic cycle and promotes
uncoupling of the SERCA pump. Using SERCA transmembrane mutants, we additionally
show that PLB and SLN can bind to the same groove but interact with a different
set of residues on SERCA. These data collectively suggest that SLN is
functionally distinct from PLB; its ability to interact with SERCA in the
presence of Ca(2+) causes uncoupling of the SERCA pump and increased heat
production.
DOI: 10.1074/jbc.M112.436915
PMCID: PMC3591597
PMID: 23341466 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23434623 | 1. Comput Biol Chem. 2013 Jun;44:1-8. doi: 10.1016/j.compbiolchem.2013.01.001.
Epub 2013 Jan 26.
Neighbor-favoring weight reinforcement to improve random walk-based disease gene
prioritization.
Le DH(1), Kwon YK.
Author information:
(1)School of Electrical Engineering, University of Ulsan, 93 Daehak-ro, Nam-gu,
Ulsan 680-749, Republic of Korea. [email protected]
BACKGROUND: Finding candidate genes associated with a disease is an important
issue in biomedical research. Recently, many network-based methods have been
proposed that implicitly utilize the modularity principle, which states that
genes causing the same or similar diseases tend to form physical or functional
modules in gene/protein relationship networks. Of these methods, the random walk
with restart (RWR) algorithm is considered to be a state-of-the-art approach,
but the modularity principle has not been fully considered in traditional RWR
approaches. Therefore, we propose a novel method called ORIENT
(neighbor-favoring weight reinforcement) to improve the performance of RWR
through proper intensification of the weights of interactions close to the known
disease genes.
RESULTS: Through extensive simulations over hundreds of diseases, we observed
that our approach performs better than the traditional RWR algorithm. In
particular, our method worked best when the weights of interactions involving
only the nearest neighbor genes of the disease genes were intensified.
Interestingly, the performance of our approach was negatively related to the
probability with which the random walk will restart, whereas the performance of
RWR without the weight-reinforcement was positively related in dense
gene/protein relationship networks. We further found that the density of the
disease gene-projected sub-graph and the number of paths between the disease
genes in a gene/protein relationship network may be explanatory variables for
the RWR performance. Finally, a comparison with other well-known gene
prioritization tools including Endeavour, ToppGene, and BioGraph, revealed that
our approach shows significantly better performance.
CONCLUSION: Taken together, these findings provide insight to efficiently guide
RWR in disease gene prioritization.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.compbiolchem.2013.01.001
PMID: 23434623 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22984203 | 1. J Neurol Neurosurg Psychiatry. 2013 May;84(5):576-83. doi:
10.1136/jnnp-2012-302824. Epub 2012 Sep 15.
Bickerstaff brainstem encephalitis and Fisher syndrome: anti-GQ1b antibody
syndrome.
Shahrizaila N(1), Yuki N.
Author information:
(1)Division of Neurology, Department of Medicine, Faculty of Medicine,
University of Malaya, Malaysia.
In the 1950s, Bickerstaff and Fisher independently described cases with a unique
presentation of ophthalmoplegia and ataxia. The neurological features were
typically preceded by an antecedent infection and the majority of patients made
a spontaneous recovery. In the cases with Bickerstaff brainstem encephalitis,
there was associated altered consciousness and in some, hyperreflexia, in
support of a central pathology whereas in Fisher syndrome, patients were
areflexic in keeping with a peripheral aetiology. However, both authors
recognised certain similarities to Guillain-Barré syndrome such as the presence
of peripheral neuropathy and cerebrospinal fluid albuminocytological
dissociation. The discovery of immunoglobulin G anti-GQ1b antibodies in patients
with Fisher syndrome and later in Bickerstaff brainstem encephalitis was crucial
in providing the necessary evidence to conclude that both conditions were in
fact part of the same spectrum of disease by virtue of their common clinical and
immunological profiles. Following this, other neurological presentations that
share anti-GQ1b antibodies emerged in the literature. These include acute
ophthalmoparesis and acute ataxic neuropathy, which represent the less extensive
spectrum of the disease whereas pharyngeal-cervical-brachial weakness and Fisher
syndrome overlap with Guillain-Barré syndrome represent the more extensive end
of the spectrum. The conditions can be referred to as the 'anti-GQ1b antibody
syndrome'. In this review, we look back at the historical descriptions and
describe how our understanding of Fisher syndrome and Bickerstaff brainstem
encephalitis has evolved from their initial descriptions more than half a
century ago.
DOI: 10.1136/jnnp-2012-302824
PMID: 22984203 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23072857 | 1. Clin Chem Lab Med. 2013 Jan;51(1):197-204. doi: 10.1515/cclm-2012-0601.
Clinical applications of maternal plasma fetal DNA analysis: translating the
fruits of 15 years of research.
Chiu RW(1), Lo YM.
Author information:
(1)Department of Chemical Pathology, The Chinese University of Hong Kong, Prince
of Wales Hospital, Shatin, New Territories, Hong Kong SAR, P.R. China.
[email protected]
The collection of fetal genetic materials is required for the prenatal diagnosis
of fetal genetic diseases. The conventional methods for sampling fetal genetic
materials, such as amniocentesis and chorionic villus sampling, are invasive in
nature and are associated with a risk of fetal miscarriage. For decades,
scientists had been pursuing studies with goals to develop non-invasive methods
for prenatal diagnosis. In 1997, the existence of fetal derived cell-free DNA
molecules in plasma of pregnant women was first demonstrated. This finding
provided a new source of fetal genetic material that could be obtained safely
through the collection of a maternal blood sample and provided a new avenue for
the development of non-invasive prenatal diagnostic tests. Now 15 years later,
the diagnostic potential of circulating fetal DNA analysis has been realized.
Fruitful research efforts have resulted in the clinical implementation of a
number of non-invasive prenatal tests based on maternal plasma DNA analysis and
included tests for fetal sex assessment, fetal rhesus D blood group genotyping
and fetal chromosomal aneuploidy detection. Most recently, research groups have
succeeded in decoding the entire fetal genome from maternal plasma DNA analysis
which paved the way for the achievement of non-invasive prenatal diagnosis of
many single gene diseases. A paradigm shift in the practice of prenatal
diagnosis has begun.
DOI: 10.1515/cclm-2012-0601
PMID: 23072857 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22918043 | 1. J Pharmacol Exp Ther. 2012 Dec;343(3):547-55. doi: 10.1124/jpet.112.197152.
Epub 2012 Aug 23.
Differential effects of Selexipag [corrected] and prostacyclin analogs in rat
pulmonary artery.
Morrison K(1), Studer R, Ernst R, Haag F, Kauser K, Clozel M.
Author information:
(1)Drug Discovery Department, Actelion Pharmaceuticals Ltd., Switzerland.
[email protected]
Erratum in
J Pharmacol Exp Ther. 2013 Jan;344(1):317.
{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679)
is the main metabolite of the selective prostacyclin (PGI(2)) receptor (IP
receptor) agonist selexipag. The goal of this study was to determine the
influence of IP receptor selectivity on the vasorelaxant efficacy of ACT-333679
and the PGI(2) analog treprostinil in pulmonary artery under conditions
associated with pulmonary arterial hypertension (PAH). Selexipag and ACT-333679
evoked full relaxation of pulmonary artery from control and monocrotaline
(MCT)-PAH rats, and ACT-333679 relaxed normal pulmonary artery contracted with
either endothelin-1 (ET-1) or phenylephrine. In contrast, treprostinil evoked
weaker relaxation than ACT-333679 of control pulmonary artery and failed to
induce relaxation of pulmonary artery from MCT-PAH rats. Treprostinil did not
evoke relaxation of normal pulmonary artery contracted with either ET-1 or
phenylephrine. Expression of prostaglandin E(3) (EP(3)) receptor mRNA was
increased in pulmonary artery from MCT-PAH rats. In contraction experiments, the
selective EP(3) receptor agonist sulprostone evoked significantly greater
contraction of pulmonary artery from MCT-PAH rats compared with control rats.
The presence of a threshold concentration of ET-1 significantly augmented the
contractile response to sulprostone in normal pulmonary artery. ACT-333679 did
not evoke direct contraction of rat pulmonary artery, whereas treprostinil
evoked concentration-dependent contraction that was inhibited by the EP(3)
receptor antagonist
(2E)-3-(3',4'-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism
of EP(3) receptors also revealed a relaxant response to treprostinil in normal
pulmonary artery contracted with ET-1. These data demonstrate that the relaxant
efficacy of the selective IP receptor agonist selexipag and its metabolite
ACT-333679 is not modified under conditions associated with PAH, whereas
relaxation to treprostinil may be limited in the presence of mediators of
disease.
DOI: 10.1124/jpet.112.197152
PMID: 22918043 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25059018 | 1. Genet Couns. 2014;25(2):189-95.
Left cerebral hemisphere and ventricular system abnormalities in a Mexican Meier
Gorlin syndrome patient: widening the clinical spectrum.
Martínez-Barrera LE, García-Delgado C, Manzano-Sierra C, Morán-Barroso VF.
The Meier-Gorlin syndrome (MGS) or ear, patella, short stature syndrome (MIM
#224690) is a rare disorder with bilateral microtia, aplasia or hypoplasia of
the patellae and severe intra-uterine and post-natal growth retardation. We
report the case of a 10-year-old male with MGS diagnosis, his parents were
related, he also showed conductive hearing loss and maloclussion and long upper
central incisors, more importantly he had asymmetry of the left cerebral
hemisphere and ventricular system, his intelligence was normal. As far as we
know, these abnormalities have not been previously described in patients with
MGS and the present report corresponds to the first Mexican case described so
far.
PMID: 25059018 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23028459 | 1. PLoS One. 2012;7(9):e43557. doi: 10.1371/journal.pone.0043557. Epub 2012 Sep
21.
Exploiting protein-protein interaction networks for genome-wide disease-gene
prioritization.
Guney E(1), Oliva B.
Author information:
(1)Structural Bioinformatics Group, GRIB, Universitat Pompeu Fabra, Barcelona
Research Park of Biomedicine, Barcelona, Catalonia, Spain.
Complex genetic disorders often involve products of multiple genes acting
cooperatively. Hence, the pathophenotype is the outcome of the perturbations in
the underlying pathways, where gene products cooperate through various
mechanisms such as protein-protein interactions. Pinpointing the decisive
elements of such disease pathways is still challenging. Over the last years,
computational approaches exploiting interaction network topology have been
successfully applied to prioritize individual genes involved in diseases.
Although linkage intervals provide a list of disease-gene candidates, recent
genome-wide studies demonstrate that genes not associated with any known linkage
interval may also contribute to the disease phenotype. Network based
prioritization methods help highlighting such associations. Still, there is a
need for robust methods that capture the interplay among disease-associated
genes mediated by the topology of the network. Here, we propose a genome-wide
network-based prioritization framework named GUILD. This framework implements
four network-based disease-gene prioritization algorithms. We analyze the
performance of these algorithms in dozens of disease phenotypes. The algorithms
in GUILD are compared to state-of-the-art network topology based algorithms for
prioritization of genes. As a proof of principle, we investigate top-ranking
genes in Alzheimer's disease (AD), diabetes and AIDS using disease-gene
associations from various sources. We show that GUILD is able to significantly
highlight disease-gene associations that are not used a priori. Our findings
suggest that GUILD helps to identify genes implicated in the pathology of human
disorders independent of the loci associated with the disorders.
DOI: 10.1371/journal.pone.0043557
PMCID: PMC3448640
PMID: 23028459 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/21278326 | 1. Am J Respir Cell Mol Biol. 2011 Oct;45(4):692-703. doi:
10.1165/rcmb.2010-0240OC. Epub 2011 Jan 28.
Treprostinil inhibits the adhesion and differentiation of fibrocytes via the
cyclic adenosine monophosphate-dependent and Ras-proximate protein-dependent
inactivation of extracellular regulated kinase.
Nikam VS(1), Wecker G, Schermuly R, Rapp U, Szelepusa K, Seeger W, Voswinckel R.
Author information:
(1)Department of Lung Development and Remodeling, Max Planck Institute for Heart
and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany.
Fibrocytes comprise a recently described cell type of blood-derived,
fibroblast-like cells that are recruited from the circulation to sites of wound
repair, vascular remodeling, or fibrotic tissue remodeling. We recently showed
that the stable prostacyclin analogue treprostinil, a clinically approved drug
for pulmonary arterial hypertension (PAH), significantly reduced the recruitment
of fibrocytes to sites of vascular remodeling in experimental hypoxic pulmonary
hypertension. Here we report on the molecular mechanism underlying the
inhibitory action of treprostinil on the adhesion and differentiation of human
fibrocytes. Human fibrocytes expressed the prostanoid receptors, prostaglandin I
(IP) receptors and prostaglandin E subtype receptors (EP2 and EP4). The
generation of intracellular cyclic adenosine monophosphate (cAMP) by
treprostinil reduced the expression of the integrins CD49 and CD29 when freshly
isolated human peripheral blood mononuclear cells were treated with
treprostinil. Cell-matrix adhesion was significantly impaired by treatment with
treprostinil. We present evidence for a treprostinil/cAMP-induced downstream
suppression of extracellular regulated kinase (ERK) that is transmitted via a
protein kinase A-independent pathway through Rap proteins, which sequester Ras.
The resulting dephosphorylated state of c-Raf limits the activity of ERK. The
cell-matrix adhesion assay with the ERK inhibitor further confirmed that the
adhesion of fibrocytes was impaired. Thus our data suggest that treprostinil
inhibits the adhesion and differentiation of fibrocytes by limiting the activity
of ERK via the cAMP-Rap axis.
DOI: 10.1165/rcmb.2010-0240OC
PMID: 21278326 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22177763 | 1. J Mal Vasc. 2011 Dec;36 Suppl 1:S10-5. doi: 10.1016/S0398-0499(11)70002-6.
[Pharmacologic heterogeneity of new anticoagulants].
[Article in French]
Samamaa MM(1), Conard J, Flaujac C, Combe S, Horellou MH.
Author information:
(1)Groupe Hospitalier Cochin-Broca-Hôtel-Dieu, 27, rue du Faubourg
Saint-Jacques, 75679 Paris cedex 14, France. [email protected]
Amongst numerous promising anticoagulant molecules, rivaroxaban (Xarelto(®)),
dabigatran (Pradaxa(®)) and apixaban (Eliquis(®)) have been registered outside
the USA in the prevention of thromboembolic events in patients undergoing total
hip or knee prosthetic replacement. Rivaroxaban however has been granted
authorisation by the FDA for the thromboprophylaxis after surgery for total hip
or knee surgery. Dabigatran has been granted authorisation by the FDA in
non-valvular atrial fibrillation (RE-LY trial) while rivaroxaban is expecting
approval in this same indication (ROCKET trial). Phase III results in the
treatment and in the secondary prevention of established venous thrombosis and
pulmonary embolism are encouraging. These small molecules are obtained by
chemical synthesis, their molecular weight is lower than 500 daltons. Many
coagulation tests may be affected by these molecules. Those modifications should
be known in order to avoid misinterpretation of the tests but could also be used
to measure plasma concentrations of these products. The choice of a non specific
global and readily available test has been documented (Quick time for
rivaroxaban and aPTT for dabigatran). Anti-Xa (for rivaroxaban) and anti-IIa
(for dabigatran) activities should however be preferred, expressed in ng/ml with
calibrated plasmas (containing predetermined concentration of the tested drug).
The half-life is around 8 to 12 hours, with a peak activity 2 to 4 hours after
ingestion. Dabigatran is mainly eliminated via the kidney, hence requiring
dose-adjustment in case of moderate renal insufficiency, and contra-indicated in
case of severe renal insufficiency. Rivaroxaban being excreted via kidney and
liver, some precautions should apply in case of liver insufficiency. No data are
available in pregnancy or pediatrics, clinical trials are ongoing. There are few
interactions with concomitant drugs, which should not be ignored. The short
half-life of these new agents compensates for the lack of any specific antidote
in many instances. Their oral administration, without the need for dose
adjustment, and without requirement for a laboratory monitoring will increase
their use in a large number of patients, in those indications for which an
approval has been granted by health authorities.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/S0398-0499(11)70002-6
PMID: 22177763 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21431325 | 1. J Mol Med (Berl). 2011 Jul;89(7):667-76. doi: 10.1007/s00109-011-0748-0. Epub
2011 Mar 23.
AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact
on healthspan and lifespan.
Salminen A(1), Hyttinen JM, Kaarniranta K.
Author information:
(1)Department of Neurology, Institute of Clinical Medicine, University of
Eastern Finland, Kuopio, Finland. [email protected]
Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator
of energy metabolic homeostasis and thus a major survival factor in a variety of
metabolic stresses and also in the aging process. Metabolic syndrome is
associated with a low-grade, chronic inflammation, primarily in adipose tissue.
A low-level of inflammation is also present in the aging process. There are
emerging results indicating that AMPK signaling can inhibit the inflammatory
responses induced by the nuclear factor-κB (NF-κB) system. The NF-κB subunits
are not direct phosphorylation targets of AMPK, but the inhibition of NF-κB
signaling is mediated by several downstream targets of AMPK, e.g., SIRT1,
PGC-1α, p53, and Forkhead box O (FoxO) factors. AMPK signaling seems to enhance
energy metabolism while it can repress inflammatory responses linked to chronic
stress, e.g., in nutritional overload and during the aging process. AMPK can
inhibit endoplasmic reticulum and oxidative stresses which are involved in
metabolic disorders and the aging process. Interestingly, many target proteins
of AMPK are so-called longevity factors, e.g., SIRT1, p53, and FoxOs, which not
only can increase the stress resistance and extend the lifespan of many
organisms but also inhibit the inflammatory responses. The activation capacity
of AMPK declines in metabolic stress and with aging which could augment the
metabolic diseases and accelerate the aging process. We will review the AMPK
pathways involved in the inhibition of NF-κB signaling and suppression of
inflammation. We also emphasize that the capacity of AMPK to repress
inflammatory responses can have a significant impact on both healthspan and
lifespan.
DOI: 10.1007/s00109-011-0748-0
PMCID: PMC3111671
PMID: 21431325 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24435274 | 1. Photosynth Res. 1986 Jan;10(1-2):7-35. doi: 10.1007/BF00024183.
Phycobilisome structure and function.
Zilinskas BA(1), Greenwald LS.
Author information:
(1)Department of Biochemistry and Microbiology, Cook College, Rutgers
University, 08903, New Brunswick, NJ, USA.
Phycobilisomes are aggregates of light-harvesting proteins attached to the
stroma side of the thylakoid membranes of the cyanobacteria (blue-green algae)
and red algae. The water-soluble phycobiliproteins, of which there are three
major groups, tetrapyrrole chromophores covalently bound to apoprotein. Several
additional protiens are found within the phycobilisome and serve to link the
phycobiliproteins to each other in an ordered fashion and also to attach the
phycobilisome to the thylakoid membrane. Excitation energy absorbed by
phycoerythrin is transferred through phycocyanin to allophycocyanin with an
efficiency approximating 100%. This pathway of excitation energy transfer,
directly confirmed by time-resolved spectroscopic measurements, has been
incorporated into models describing the ultrastructure of the phycobilisome. The
model for the most typical type of phycobilisome describes an
allophycocyanin-containing core composed of three cylinders arranged so that
their longitudinal axes are parallel and their ends form a triangle. Attached to
this core are six rod structures which contain phycocyanin proximal to the core
and phycoerythrin distal to the core. The axes of these rods are perpendicular
to the longitudinal axis of the core. This arrangement ensures a very efficient
transfer of energy. The association of phycoerythrin and phycocyanin within the
rods and the attachment of the rods to the core and the core to the thylakoid
require the presence of several 'linker' polypeptides. It is recently possible
to assemble functionally and structurally intact phycobilisomes in vitro from
separated components as well as to reassociate phycobilisomes with stripped
thylakoids. Understanding of the biosynthesis and in vivo assembly of
phycobilisomes will be greatly aided by the current advances in molecular
genetics, as exemplified by recent identification of several genes encoding
phycobilisome components.Combined ultrastructural, biochemical and biophysical
approaches to the study of cyanobacterial and red algal cells and isolated
phycobilisome-thylakoid fractions are leading to a clearer understanding of the
phycobilisome-thylakoid structural interactions, energy transfer to the reaction
centers and regulation of excitation energy distribution. However, compared to
our current knowledge concerning the structural and functional organization of
the isolated phycobilisome, this research area is relatively unexplored.
DOI: 10.1007/BF00024183
PMID: 24435274 |
http://www.ncbi.nlm.nih.gov/pubmed/3729752 | 1. Arch Neurol. 1986 Jul;43(7):734-5. doi: 10.1001/archneur.1986.00520070088026.
Autosomal dominant humeroperoneal myopathy.
Gilchrist JM, Leshner RT.
Emery-Dreifuss muscular dystrophy is a syndrome with five salient features:
early and unusual contractures; humeroperoneal muscle wasting; the slow
progression of weakness, beginning in childhood; cardiac conduction defects; and
X-linked inheritance. We present two cases and detail other reports with a
similar constellation of findings with apparent autosomal dominant inheritance.
We postulate separate genetic disorders with similar phenotypic expression.
DOI: 10.1001/archneur.1986.00520070088026
PMID: 3729752 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15226261 | 1. Development. 2004 Jul;131(14):3457-67. doi: 10.1242/dev.01189.
Orpk mouse model of polycystic kidney disease reveals essential role of primary
cilia in pancreatic tissue organization.
Cano DA(1), Murcia NS, Pazour GJ, Hebrok M.
Author information:
(1)Diabetes Center, Department of Medicine, University of California, San
Francisco, CA 94143, USA.
Polycystic kidney disease (PKD) includes a group of disorders that are
characterized by the presence of cysts in the kidney and other organs, including
the pancreas. Here we show that in orpk mice, a model system for PKD that
harbors a mutation in the gene that encodes the polaris protein, pancreatic
defects start to occur at the end of gestation, with an initial expansion of the
developing pancreatic ducts. Ductal dilation continues rapidly after birth and
results in the formation of large, interconnected cysts. Expansion of pancreatic
ducts is accompanied by apoptosis of neighboring acinar cells, whereas endocrine
cell differentiation and islet formation appears to be unaffected. Polaris has
been shown to co-localize with primary cilia, and these structures have been
implicated in the formation of renal cysts. In the orpk pancreas, cilia numbers
are reduced and cilia length is decreased. Expression of polycystin-2, a protein
involved in PKD, is mislocalized in orpk mice. Furthermore, the cellular
localization of beta-catenin, a protein involved in cell adhesion and Wnt
signaling, is altered. Thus, polaris and primary cilia function are required for
the maturation and maintenance of proper tissue organization in the pancreas.
DOI: 10.1242/dev.01189
PMID: 15226261 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23631188 | 1. Nihon Rinsho. 2013 Jan;71(1):153-60.
[Atrial fibrillation in the elderly].
[Article in Japanese]
Watanabe N(1), Kobayashi Y.
Author information:
(1)Division of Cardiology, Department of Medicine, Showa University School of
Medicine.
Elderly people more than 70 years develop atrial fibrillation that causes stroke
and heart failure. Furthermore, the elderly people who have atrial fibrillation
accompany many risk factor, and develop cerebral infarction easily. Therefore,
it is very important to prevent cerebral infarction using anticoagulant drugs.
So far we usually use warfarin, which has many limitations, especially cerebral
bleeding. Now new anticoagulant drugs(dabigatran and rivaroxaban) can become
available. Therefore, we have to learn how to use those drugs. They have to
carefully be used because they discharge from kidney and old aged patients have
potential renal dysfunction. We mainly explain anticoagulant therapy in old aged
patients.
PMID: 23631188 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18425569 | 1. J Interv Card Electrophysiol. 2008 Aug;22(2):129-37. doi:
10.1007/s10840-008-9210-9. Epub 2008 Apr 17.
Advancement in antithrombotics for stroke prevention in atrial fibrillation.
Umer Usman MH(1), Raza S, Raza S, Ezekowitz M.
Author information:
(1)Lankenau Institute for Medical Research, Wynnewood, PA 19096-3425, USA.
The focus of this review is the evolving field of antithrombotic drug therapy
for stroke prevention in patients with atrial fibrillation (AF). The current
standard of therapy includes warfarin, acenocoumarol and phenprocoumon which
have proven efficacy by reducing stroke by 68% against placebo. However, a
narrow therapeutic index, wide variation in metabolism, and numerous food and
drug interactions have limited their clinical application to only 50% of the
indicated population. Newer agents such as direct thrombin inhibitors, factor Xa
inhibitors, factor IX inhibitors, tissue factor inhibitors and a novel vitamin K
antagonist are being developed to overcome the limitations of current agents.
The direct thrombin inhibitor dabigatran is farthest along in development.
Further clinical trial testing, and eventual incorporation into clinical
practice will depend on safety, efficacy and cost. Development of a novel
vitamin K antagonist with better INR control will challenge the newer
mechanistic agents in their quest to replace the existing vitamin K antagonists.
Till then, the large unfilled gap to replace conventional agents remains open.
This review will assess all these agents, and compare their mechanism of action,
stage of development and pharmacologic profile.
DOI: 10.1007/s10840-008-9210-9
PMID: 18425569 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19470175 | 1. BMC Bioinformatics. 2009 May 26;10:159. doi: 10.1186/1471-2105-10-159.
Transmembrane protein topology prediction using support vector machines.
Nugent T(1), Jones DT.
Author information:
(1)Bioinformatics Group, Department of Computer Science, University College
London, Gower Street, London, WC1E 6BT, UK. [email protected]
BACKGROUND: Alpha-helical transmembrane (TM) proteins are involved in a wide
range of important biological processes such as cell signaling, transport of
membrane-impermeable molecules, cell-cell communication, cell recognition and
cell adhesion. Many are also prime drug targets, and it has been estimated that
more than half of all drugs currently on the market target membrane proteins.
However, due to the experimental difficulties involved in obtaining high quality
crystals, this class of protein is severely under-represented in structural
databases. In the absence of structural data, sequence-based prediction methods
allow TM protein topology to be investigated.
RESULTS: We present a support vector machine-based (SVM) TM protein topology
predictor that integrates both signal peptide and re-entrant helix prediction,
benchmarked with full cross-validation on a novel data set of 131 sequences with
known crystal structures. The method achieves topology prediction accuracy of
89%, while signal peptides and re-entrant helices are predicted with 93% and 44%
accuracy respectively. An additional SVM trained to discriminate between
globular and TM proteins detected zero false positives, with a low false
negative rate of 0.4%. We present the results of applying these tools to a
number of complete genomes. Source code, data sets and a web server are freely
available from http://bioinf.cs.ucl.ac.uk/psipred/.
CONCLUSION: The high accuracy of TM topology prediction which includes detection
of both signal peptides and re-entrant helices, combined with the ability to
effectively discriminate between TM and globular proteins, make this method
ideally suited to whole genome annotation of alpha-helical transmembrane
proteins.
DOI: 10.1186/1471-2105-10-159
PMCID: PMC2700806
PMID: 19470175 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16251196 | 1. Hum Mol Genet. 2005 Dec 1;14(23):3759-73. doi: 10.1093/hmg/ddi406. Epub 2005
Oct 26.
Defective lysosomal arginine transport in juvenile Batten disease.
Ramirez-Montealegre D(1), Pearce DA.
Author information:
(1)Center for Aging and Developmental Biology, Aab Institute of Biomedical
Sciences, Rochester, NY 14642, USA.
Mutations in the CLN3 gene, which encodes a lysosomal membrane protein, are
responsible for the neurodegenerative disorder juvenile Batten disease. A
previous study on the yeast homolog to CLN3, designated Btn1p, revealed a
potential role for CLN3 in the transport of arginine into the yeast vacuole, the
equivalent organelle to the mammalian lysosome. Lysosomes isolated from
lymphoblast cell lines, established from individuals with juvenile Batten
disease-bearing mutations in CLN3, but not age-matched controls, demonstrate
defective transport of arginine. Furthermore, we show that there is a depletion
of arginine in cells derived from individuals with juvenile Batten disease. We
have, therefore, characterized lysosomal arginine transport in normal lysosomes
and show that it is ATP-, v-ATPase- and cationic-dependent. This and previous
studies have shown that both arginine and lysine are transported by the same
transport system, designated system c. However, we report that lysosomes
isolated from juvenile Batten disease lymphoblasts are only defective for
arginine transport. These results suggest that the CLN3 defect in juvenile
Batten disease may affect how intracellular levels of arginine are regulated or
distributed throughout the cell. This assertion is supported by two other
experimental approaches. First, an antibody to CLN3 can block lysosomal arginine
transport and second, expression of CLN3 in JNCL cells using a lentiviral vector
can restore lysosomal arginine transport. CLN3 may have a role in regulating
intracellular levels of arginine possibly through control of the transport of
this amino acid into lysosomes.
DOI: 10.1093/hmg/ddi406
PMID: 16251196 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22654636 | 1. ScientificWorldJournal. 2012;2012:842727. doi: 10.1100/2012/842727. Epub 2012
May 2.
Biomarker identification for prostate cancer and lymph node metastasis from
microarray data and protein interaction network using gene prioritization
method.
Arias CR(1), Yeh HY, Soo VW.
Author information:
(1)Institute of Information Systems and Applications, National Tsing Hua
University, Hsinchu 30013, Taiwan. [email protected]
Finding a genetic disease-related gene is not a trivial task. Therefore,
computational methods are needed to present clues to the biomedical community to
explore genes that are more likely to be related to a specific disease as
biomarker. We present biomarker identification problem using gene prioritization
method called gene prioritization from microarray data based on shortest paths,
extended with structural and biological properties and edge flux using voting
scheme (GP-MIDAS-VXEF). The method is based on finding relevant interactions on
protein interaction networks, then scoring the genes using shortest paths and
topological analysis, integrating the results using a voting scheme and a
biological boosting. We applied two experiments, one is prostate primary and
normal samples and the other is prostate primary tumor with and without lymph
nodes metastasis. We used 137 truly prostate cancer genes as benchmark. In the
first experiment, GP-MIDAS-VXEF outperforms all the other state-of-the-art
methods in the benchmark by retrieving the truest related genes from the
candidate set in the top 50 scores found. We applied the same technique to infer
the significant biomarkers in prostate cancer with lymph nodes metastasis which
is not established well.
DOI: 10.1100/2012/842727
PMCID: PMC3354662
PMID: 22654636 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16253609 | 1. Am J Cardiol. 2005 Nov 1;96(9):1334-6. doi: 10.1016/j.amjcard.2005.06.083.
Epub 2005 Sep 16.
Efficacy and safety of sildenafil added to treprostinil in pulmonary
hypertension.
Gomberg-Maitland M(1), McLaughlin V, Gulati M, Rich S.
Author information:
(1)University of Chicago Hospitals, Chicago, Illinois, USA.
[email protected]
Pulmonary arterial hypertension (PAH) is characterized by abnormalities in
endothelial and smooth muscle cell function. Prostacyclin released by
endothelial cells is a potent vasodilator by increasing cyclic adenosine
monophosphate. Sildenafil, an inhibitor of phosphodiesterase-5, increases cyclic
guanosine monophosphate in the lungs, producing vasodilation. To test for a
therapeutic benefit of the combination of a prostacyclin analogue, subcutaneous
treprostinil, and sildenafil, a proof-of-concept, open-label investigational
trial was initiated. Subjects with PAH in World Health Organization (WHO)
functional classes II to IV receiving subcutaneous treprostinil for > or =6
months were evaluated with an exercise treadmill test using the Naughton-Balke
protocol at baseline and after 12 weeks. Sildenafil 50 mg 3 times daily was
added to the treprostinil. Mean treadmill times in seconds were compared before
and after 12 weeks of therapy. Nine subjects enrolled in the trial; 7 were women
(mean age 35 years). At baseline, 3 subjects were in WHO functional class II and
6 subjects were in WHO functional class III. The mean treadmill time at baseline
was 465 +/- 167 seconds and at 12 weeks was 656 +/- 205 seconds (42%
improvement, p = 0.049). All patients had symptomatic improvement. In
conclusion, this pilot study of subcutaneous treprostinil with sildenafil for
PAH suggests additive beneficial effects.
DOI: 10.1016/j.amjcard.2005.06.083
PMID: 16253609 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12412377 | 1. Bull Acad Natl Med. 2002;186(5):851-61; discussion 861-3.
[French results of enzyme replacement therapy in Gaucher's disease].
[Article in French]
Schaison G(1), Caubel I, Belmatoug N, Billette de Villemeur T, Saudubray JM.
Author information:
(1)Service de Pédiatrie à Orientation hématologique-Hôpital Saint Louis-1,
avenue Claude Vellefaux-75475 Paris.
Gaucher disease is an inborn recessive autosomal disease due to a partial
deficiency of the lysosomal enzyme beta glucocerebrosidase. The deficient
activity leads to accumulation of the lipid glucocerebroside in the liver, the
spleen and bone marrow with concomitant anemia and thrombocytopenia. Patients
with Gaucher disease have been classified in three types: type I is the more
common, neurological manifestations occur in types II and III. Enzyme
replacement therapy (ERT) with modified placental human glucocerebrosidase
(ceredase) or recombinant glucocerebrosidase (cerezyme) is effective in most
type I Gaucher disease and has become the current standard care administered to
thousand of patients worldwide. ERT has obviated the need for bone marrow
transplantation and virtually eliminated the need for splenectomy. We report
here the French study including adults and children. ERT of 30 to 60 U/K every
two weeks as starting dose was administrated to 108 patients with severe type I
Gaucher disease. ERT fully reverse many of the manifestations of the disease.
ERT regimen alleviated fatigue, and hematological and visceral signs and
symptoms in nearly all severely-ill patients. Skeletal responses to treatment
develop much more slowly than hematological or visceral responses. Studies in
pediatrics show that the disease is more severe in children. These children
should be treated early in the course of their disease to avoid irreparable
damage. Hematological manifestation in type II cannot be reversed with enzyme
replacement. In type III treatment can rarely reverse neurological deficit.
Gaucher disease is also an excellent candidate for gene therapy.
PMID: 12412377 [Indexed for MEDLINE] |