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http://www.ncbi.nlm.nih.gov/pubmed/21052952 | 1. Cancer Treat Res. 2011;157:97-108. doi: 10.1007/978-1-4419-7073-2_6.
Cyclic and chronic neutropenia.
Dale DC(1), Welte K.
Author information:
(1)Department of Medicine, University of Washington, Seattle, WA 98195, USA.
[email protected]
Patients with severe chronic neutropenia have blood neutrophil level <0.5 ×
10(9)/L, predisposing them to increased susceptibility to life-threatening
bacterial infections. This chapter focuses on cyclic and congenital neutropenia,
two very interesting and rare hematological conditions causing severe chronic
neutropenia. Both disorders respond well to treatment with the myeloid growth
factor, granulocyte colony-stimulating factor (G-CSF). This chapter describes
the basic features of these diseases and addresses several current clinical
issues regarding their diagnosis and management. Cyclic neutropenia is a rare,
inherited autosomal dominant disorder due to mutations in the gene for
neutrophil elastase (ELA-2 or ELANE). Usually these patients have regular
oscillation of blood neutrophil counts with periods of severe neutropenia
occurring every 21 days. During these periods, they have painful mouth ulcers,
fevers, and bacterial infections. The most severe consequences are gangrene,
bacteremia, and septic shock. Cyclic neutropenia patients respond well to
treatment with granulocyte colony-stimulating factor (G-CSF) given by
subcutaneous injections on a daily or alternate-day basis. Severe congenital
neutropenia is also a rare hematological disease, but it is probably more common
than cyclic neutropenia. Blood neutrophils are extremely low on a continuing
basis; the levels may be <0.2 × 10(9)/L, and the risk of severe bacterial
infections is even greater than in cyclic neutropenia. The majority of cases are
due to autosomal dominant inheritance of mutations in the ELA-2 or ELANE gene.
Less commonly, mutations in HAX-1, G6PC3, and other genes cause this disorder.
Treatment with G-CSF is usually effective, but the dose of G-CSF required to
normalize blood neutrophils varies greatly. Ten to thirty percent of severe
congenital neutropenia patients evolve to develop acute myeloid leukemia,
necessitating careful clinical monitoring.
DOI: 10.1007/978-1-4419-7073-2_6
PMID: 21052952 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14598350 | 1. Am J Med Genet A. 2003 Dec 1;123A(2):204-7. doi: 10.1002/ajmg.a.20289.
Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome.
Faivre L(1), Dollfus H, Lyonnet S, Alembik Y, Mégarbané A, Samples J, Gorlin RJ,
Alswaid A, Feingold J, Le Merrer M, Munnich A, Cormier-Daire V.
Author information:
(1)Département de Génétique et INSERM U393, Hôpital Necker Enfants Malades, 149
rue de Sèvres, 75015 Paris, France.
Weill-Marchesani syndrome (WMS) is a rare condition characterized by short
stature, brachydactyly, joint stiffness, and characteristic eye abnormalities
including microspherophakia, ectopia of lens, severe myopia, and glaucoma. Both
autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have
been described for WMS. A locus for AR WMS has recently been mapped to
chromosome 19p13.3-p13.2 while mutation within the fibrillin-1 gene (15q21.1)
was found in one AD WMS family. In order to answer the question of whether or
not genetic heterogeneity could be related to a clinical heterogeneity, we
reviewed 128 WMS patients from the literature (including 57 AR, 50 AD, and 21
sporadic cases), with a particular attention to clinical features. Statistical
analyses using Fischer exact test were used to compare the proportions of 12
clinical parameters between AR and AD patients. There was no significant
difference between both groups for myopia, glaucoma, cataract, short stature,
brachydactyly, thick skin, muscular build, and mental retardation. Significant
results were found for microspherophakia (94% in AR, 74% in AD, Fischer 0.007),
ectopia lentis (64% in AR, 84% in AD, Fischer 0.016), joint limitations (49% in
AR, 77% in AD, Fischer 0.010), and cardiac anomalies (39% in AR, 13% in AD,
Fischer 0.004). Nevertheless, we failed to distinguish AR from AD inheritance in
individual cases. These results support the clinical homogeneity but the genetic
heterogeneity of WMS.
Copyright 2003 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.a.20289
PMID: 14598350 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23123071 | 1. Lancet Neurol. 2012 Dec;11(12):1029-38. doi: 10.1016/S1474-4422(12)70257-0.
Epub 2012 Nov 1.
Pallidal deep brain stimulation in patients with primary generalised or
segmental dystonia: 5-year follow-up of a randomised trial.
Volkmann J(1), Wolters A, Kupsch A, Müller J, Kühn AA, Schneider GH, Poewe W,
Hering S, Eisner W, Müller JU, Deuschl G, Pinsker MO, Skogseid IM, Roeste GK,
Krause M, Tronnier V, Schnitzler A, Voges J, Nikkhah G, Vesper J, Classen J,
Naumann M, Benecke R; DBS study group for dystonia.
Collaborators: Benecke R, Volkmann J, Gierl L, Gierl L, Benecke R, Deuschl G,
Müller J, Pinsker MO, Poewe W, Volkmann J, Wolters A, Mehdorn MH, Gruber D, Kivi
A, Kühn AA, Kupsch A, Müller B, Schneider GH, Trottenberg T, Schnitzler A, Sturm
V, Timmermann L, Voges J, Wojtecki L, Nikkah G, Pinsker M, Prokop T, Vesper J,
Kloss M, Krause M, Eisner W, Fiegele T, Müller J, Hering S, Poewe W, Deuschl G,
Herzog J, Mehdorn MM, Pinsker MO, Pötter M, Steigerwald F, Volkmann J, Boothe
HW, Brentrup A, Vollmer-Haase J, Roeste GK, Skogseid IM, Benecke R, Müller JU,
Wittstock M, Wolters A, Classen J, Naumann M, Schramm A.
Author information:
(1)Department of Neurology, Christian-Albrechts-University, Kiel, Germany.
[email protected]
Comment in
Lancet Neurol. 2012 Dec;11(12):1014-5. doi: 10.1016/S1474-4422(12)70263-6.
BACKGROUND: Severe forms of primary dystonia are difficult to manage medically.
We assessed the safety and efficacy of pallidal neurostimulation in patients
with primary generalised or segmental dystonia prospectively followed up for 5
years in a controlled multicentre trial.
METHODS: In the parent trial, 40 patients were randomly assigned to either sham
neurostimulation or neurostimulation of the internal globus pallidus for a
period of 3 months and thereafter all patients completed 6 months of active
neurostimulation. 38 patients agreed to be followed up annually after the
activation of neurostimulation, including assessments of dystonia severity,
pain, disability, and quality of life. The primary endpoint of the 5-year
follow-up study extension was the change in dystonia severity at 3 years and 5
years as assessed by open-label ratings of the Burke-Fahn-Marsden dystonia
rating scale (BFMDRS) motor score compared with the preoperative baseline and
the 6-month visit. The primary endpoint was analysed on an intention-to-treat
basis. The original trial is registered with ClinicalTrials.gov (NCT00142259).
FINDINGS: An intention-to-treat analysis including all patients from the parent
trial showed significant improvements in dystonia severity at 3 years and 5
years compared with baseline, which corresponded to -20·8 points (SD 17·1;
-47·9%; n=40) at 6 months; -26·5 points (19·7; -61·1%; n=31) at 3 years; and
-25·1 points (21·3; -57·8%; n=32). The improvement from 6 months to 3 years
(-5·7 points [SD 8·4]; -34%) was significant and sustained at the 5-year
follow-up (-4·3 [10·4]). 49 new adverse events occurred between 6 months and 5
years. Dysarthria and transient worsening of dystonia were the most common
non-serious adverse events. 21 adverse events were rated serious and were almost
exclusively device related. One patient attempted suicide shortly after the
6-month visit during a depressive episode. All serious adverse events resolved
without permanent sequelae.
INTERPRETATION: 3 years and 5 years after surgery, pallidal neurostimulation
continues to be an effective and relatively safe treatment option for patients
with severe idiopathic dystonia. This long-term observation provides further
evidence in favour of pallidal neurostimulation as a first-line treatment for
patients with medically intractable, segmental, or generalised dystonia.
FUNDING: Medtronic.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1474-4422(12)70257-0
PMID: 23123071 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12525539 | 1. J Med Genet. 2003 Jan;40(1):34-6. doi: 10.1136/jmg.40.1.34.
In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani
syndrome.
Faivre L(1), Gorlin RJ, Wirtz MK, Godfrey M, Dagoneau N, Samples JR, Le Merrer
M, Collod-Beroud G, Boileau C, Munnich A, Cormier-Daire V.
Author information:
(1)Département de Génétique et INSERM U393, Hôpital Necker Enfants Malades,
Paris, France.
Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterised by
short stature, brachydactyly, joint stiffness, and characteristic eye anomalies
including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma.
Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance
have been described and a gene for AR WMS has recently been mapped to chromosome
19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a
large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS
are genetically heterogeneous entities. Because two AD WMS families were
consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was
sequenced and a 24 nt in frame deletion within a latent transforming growth
factor-beta1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a
AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with
the disease and was not found in 186 controls. This study strongly suggests that
AD WMS and Marfan syndrome are allelic conditions at the fibrillin-1 locus and
adds to the remarkable clinical heterogeneity of type I fibrillinopathies.
DOI: 10.1136/jmg.40.1.34
PMCID: PMC1735272
PMID: 12525539 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22451857 | 1. World J Cardiol. 2012 Mar 26;4(3):84-6. doi: 10.4330/wjc.v4.i3.84.
Brugada electrocardiographic pattern induced by fever.
Lamelas P(1), Labadet C, Spernanzoni F, Saubidet CL, Alvarez PA.
Author information:
(1)Pablo Lamelas, Cardiology Resident, Instituto Cardiovascular Buenos Aires,
Buenos Aires C1428ART, Argentina.
Brugada syndrome is a major cause of sudden death in young adults. Fever has
been described to induce a Brugada-type electrocardiogram in asymptomatic
patients with a negative family history, to disclose Brugada syndrome and to
increase the risk of death and induce T wave alternans in patients with
diagnosed Brugada syndrome. Risk stratification is challenging and demands a
careful evaluation. Here we present 2 case reports and review the literature.
DOI: 10.4330/wjc.v4.i3.84
PMCID: PMC3312236
PMID: 22451857 |
http://www.ncbi.nlm.nih.gov/pubmed/23985272 | 1. Cell Biosci. 2013 Aug 28;3(1):31. doi: 10.1186/2045-3701-3-31.
Mst1 and Mst2 kinases: regulations and diseases.
Qin F(#)(1), Tian J(#)(1), Zhou D(1), Chen L(1).
Author information:
(1)State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen
University, Xiang'An South Road, Xiang'An District, Xiamen, Fujian 361102,
China.
(#)Contributed equally
The Hippo signaling pathway has emerged as a critical regulator for organ size
control. The serine/threonine protein kinases Mst1 and Mst2, mammalian homologs
of the Hippo kinase from Drosophila, play the central roles in the Hippo pathway
controlling the cell proliferation, differentiation, and apoptosis during
development. Mst1/2 can be activated by cellular stressors and the activation of
Mst1/2 might enforce a feedback stimulation system to regulate oxidant levels
through several mechanisms, in which regulation of cellular redox state might
represent a tumor suppressor function of Mst1/2. As in Drosophila, murine
Mst1/Mst2, in a redundant manner, negatively regulate the Yorkie ortholog YAP in
multiple organs, although considerable diversification in the pathway
composition and regulation is observed in some of them. Generally, loss of both
Mst1 and Mst2 results in hyperproliferation and tumorigenesis that can be
largely negated by the reduction or elimination of YAP. The Hippo pathway
integrates with other signaling pathways e.g. Wnt and Notch pathways and
coordinates with them to impact on the tumor pathogenesis and development.
Furthermore, Mst1/2 kinases also act as an important regulator in immune cell
activation, adhesion, migration, growth, and apoptosis. This review will focus
on the recent updates on those aspects for the roles of Mst1/2 kinases.
DOI: 10.1186/2045-3701-3-31
PMCID: PMC3849747
PMID: 23985272 |
http://www.ncbi.nlm.nih.gov/pubmed/12970845 | 1. Am J Hum Genet. 2003 Oct;73(4):835-48. doi: 10.1086/378566. Epub 2003 Sep 10.
Confirmation of the type 2 myotonic dystrophy (CCTG)n expansion mutation in
patients with proximal myotonic myopathy/proximal myotonic dystrophy of
different European origins: a single shared haplotype indicates an ancestral
founder effect.
Bachinski LL(1), Udd B, Meola G, Sansone V, Bassez G, Eymard B, Thornton CA,
Moxley RT, Harper PS, Rogers MT, Jurkat-Rott K, Lehmann-Horn F, Wieser T, Gamez
J, Navarro C, Bottani A, Kohler A, Shriver MD, Sallinen R, Wessman M, Zhang S,
Wright FA, Krahe R.
Author information:
(1)Section of Cancer Genetics, Department of Molecular Genetics, University of
Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults,
is a clinically and genetically heterogeneous neuromuscular disorder. DM is
characterized by autosomal dominant inheritance, muscular dystrophy, myotonia,
and multisystem involvement. Type 1 DM (DM1) is caused by a (CTG)(n) expansion
in the 3' untranslated region of DMPK in 19q13.3. Multiple families,
predominantly of German descent and with clinically variable presentation that
included proximal myotonic myopathy (PROMM) and type 2 DM (DM2) but without the
DM1 mutation, showed linkage to the 3q21 region and were recently shown to
segregate a (CCTG)(n) expansion mutation in intron 1 of ZNF9. Here, we present
linkage to 3q21 and mutational confirmation in 17 kindreds of European origin
with PROMM and proximal myotonic dystrophy, from geographically distinct
populations. All patients have the DM2 (CCTG)(n) expansion. To study the
evolution of this mutation, we constructed a comprehensive physical map of the
DM2 region around ZNF9. High-resolution haplotype analysis of disease
chromosomes with five microsatellite and 22 single-nucleotide polymorphism
markers around the DM2 mutation identified extensive linkage disequilibrium and
a single shared haplotype of at least 132 kb among patients from the different
populations. With the exception of the (CCTG)(n) expansion, the available
markers indicate that the DM2 haplotype is identical to the most common
haplotype in normal individuals. This situation is reminiscent of that seen in
DM1. Taken together, these data suggest a single founding mutation in DM2
patients of European origin. We estimate the age of the founding haplotype and
of the DM2 (CCTG) expansion mutation to be approximately 200-540 generations.
DOI: 10.1086/378566
PMCID: PMC1180606
PMID: 12970845 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20515651 | 1. Biochem Biophys Res Commun. 2010 Jul 2;397(3):548-52. doi:
10.1016/j.bbrc.2010.05.154. Epub 2010 May 31.
Evidence of a bigenomic regulation of mitochondrial gene expression by thyroid
hormone during rat brain development.
Sinha RA(1), Pathak A, Mohan V, Babu S, Pal A, Khare D, Godbole MM.
Author information:
(1)Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical
Sciences, Lucknow 226014, India.
Hypothyroidism during early mammalian brain development is associated with
decreased expression of various mitochondrial encoded genes along with evidence
for mitochondrial dysfunction. However, in-spite of the similarities between
neurological disorders caused by perinatal hypothyroidism and those caused by
various genetic mitochondrial defects we still do not know as to how thyroid
hormone (TH) regulates mitochondrial transcription during development and
whether this regulation by TH is nuclear mediated or through mitochondrial TH
receptors? We here in rat cerebellum show that hypothyroidism causes reduction
in expression of nuclear encoded genes controlling mitochondrial biogenesis like
PGC-1alpha, NRF-1alpha and Tfam. Also, we for the first time demonstrate a
mitochondrial localization of thyroid hormone receptor (mTR) isoform in
developing brain capable of binding a TH response element (DR2) present in
D-loop region of mitochondrial DNA. These results thus indicate an integrated
nuclear-mitochondrial cross talk in regulation of mitochondrial transcription by
TH during brain development.
Copyright 2010 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bbrc.2010.05.154
PMID: 20515651 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22422768 | 1. Hum Mol Genet. 2012 Jun 15;21(12):2759-67. doi: 10.1093/hmg/dds104. Epub 2012
Mar 14.
Absence of triadin, a protein of the calcium release complex, is responsible for
cardiac arrhythmia with sudden death in human.
Roux-Buisson N(1), Cacheux M, Fourest-Lieuvin A, Fauconnier J, Brocard J, Denjoy
I, Durand P, Guicheney P, Kyndt F, Leenhardt A, Le Marec H, Lucet V, Mabo P,
Probst V, Monnier N, Ray PF, Santoni E, Trémeaux P, Lacampagne A, Fauré J,
Lunardi J, Marty I.
Author information:
(1)INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et
Pathologies, Grenoble, France.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited
arrhythmogenic disease so far related to mutations in the cardiac ryanodine
receptor (RYR2) or the cardiac calsequestrin (CASQ2) genes. Because mutations in
RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations
in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT
patients with no detected mutation in these two genes. Based on a candidate gene
approach, we focused our investigations on triadin and junctin, two proteins
that link RyR2 and CSQ2. Mutations in the triadin (TRDN) and in the junctin
(ASPH) genes were searched in a cohort of 97 CPVT patients. We identified three
mutations in triadin which cosegregated with the disease on a recessive mode of
transmission in two families, but no mutation was found in junctin. Two TRDN
mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop
codons; the third mutation, a p.T59R missense mutation, was further studied.
Expression of the p.T59R mutant in COS-7 cells resulted in intracellular
retention and degradation of the mutant protein. This was confirmed after in
vivo expression of the mutant triadin in triadin knock-out mice by viral
transduction. In this work, we identified TRDN as a new gene responsible for an
autosomal recessive form of CPVT. The mutations identified in the two families
lead to the absence of the protein, thereby demonstrating the importance of
triadin for the normal function of the cardiac calcium release complex in
humans.
DOI: 10.1093/hmg/dds104
PMCID: PMC3363337
PMID: 22422768 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18316578 | 1. Clin Cancer Res. 2008 Mar 1;14(5):1529-39. doi: 10.1158/1078-0432.CCR-07-4126.
Tumor escape from endogenous, extracellular matrix-associated angiogenesis
inhibitors by up-regulation of multiple proangiogenic factors.
Fernando NT(1), Koch M, Rothrock C, Gollogly LK, D'Amore PA, Ryeom S, Yoon SS.
Author information:
(1)Division of Surgical Oncology, Department of Surgery, Massachusetts General
Hospital and Harvard Medical School, Boston, MA 02114, USA.
PURPOSE: Thrombospondin-1 (Tsp1), endostatin, and tumstatin are extracellular
matrix-associated proteins that inhibit angiogenesis. We examined the mechanisms
by which tumor cells may bypass the antiangiogenic effects of these endogenous
regulators.
EXPERIMENTAL DESIGN: CT26 colon and RenCa renal carcinoma cells were stably
transfected with Tsp1, endostatin, or tumstatin cDNA. Subcutaneous and
metastatic tumor growth in syngeneic mice was analyzed. Expression of
proangiogenic factors in resulting tumors was measured by quantitative real-time
PCR. The combination of Tsp1 and vascular endothelial growth factor (VEGF)
receptor-2 inhibition was also examined.
RESULTS: There was significant suppression of angiogenesis in flank tumors and
liver metastases formed from cells overexpressing Tsp1, endostatin, or
tumstatin. However, all tumors ultimately escaped angiogenesis inhibition. The
combination of all three angiogenesis inhibitors had no additive effect beyond
overexpression of a single inhibitor. Using quantitative real-time PCR, we found
that VEGF and platelet-derived growth factor (PDGF)-A levels were routinely
up-regulated at least 5-fold in all CT26 tumors overexpressing any
antiangiogenic protein, and there were variable increases in angiopoietin 2
(Ang2), basic fibroblast growth factor, and PDGF-B. In contrast, RenCa tumors,
which have high baseline levels of VEGF and PDGF-B, relied on basic fibroblast
growth factor, Ang1, and PDGF-A up-regulation to counteract Tsp1 overexpression.
Growth of CT26 cells with Tsp1 overexpression was suppressed when anti-VEGFR-2
treatment was added.
CONCLUSIONS: Cancer cells with overexpression of three different endogenous
angiogenesis inhibitor eventually escape angiogenesis inhibition by
up-regulation of various proangiogenic factors. Tsp1, endostatin, and tumstatin
may be functionally redundant in this system. These endogenous angiogenesis
inhibitors are likely best used in combination with the blockade of
proangiogenic pathways or with traditional chemotherapy or radiation therapy.
DOI: 10.1158/1078-0432.CCR-07-4126
PMID: 18316578 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20845110 | 1. Curr Top Microbiol Immunol. 2011;349:197-244. doi: 10.1007/82_2010_108.
NF-κB as a target for oncogenic viruses.
Sun SC(1), Cesarman E.
Author information:
(1)Department of Immunology, The University of Texas MD Anderson Cancer Center,
USA. [email protected]
NF-κB is a pivotal transcription factor that controls cell survival and
proliferation in diverse physiological processes. The activity of NF-κB is
tightly controlled through its cytoplasmic sequestration by specific inhibitors,
IκBs. Various cellular stimuli induce the activation of an IκB kinase, which
phosphorylates IκBs and triggers their proteasomal degradation, causing nuclear
translocation of activated NF-κB. Under normal conditions, the activation of
NF-κB occurs transiently, thus ensuring rapid but temporary induction of target
genes. Deregulated NF-κB activation contributes to the development of various
diseases, including cancers and immunological disorders. Accumulated studies
demonstrate that the NF-κB signaling pathway is a target of several human
oncogenic viruses, including the human T cell leukemia virus type 1, the Kaposi
sarcoma-associated herpesvirus, and the Epstein-Bar virus. These viruses encode
specific oncoproteins that target different signaling components of the NF-κB
pathway, leading to persistent activation of NF-κB. This chapter will discuss
the molecular mechanisms by which NF-κB is activated by the viral oncoproteins.
DOI: 10.1007/82_2010_108
PMCID: PMC3855473
PMID: 20845110 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19430531 | 1. PLoS One. 2009;4(5):e5497. doi: 10.1371/journal.pone.0005497. Epub 2009 May
11.
The ELG1 clamp loader plays a role in sister chromatid cohesion.
Parnas O(1), Zipin-Roitman A, Mazor Y, Liefshitz B, Ben-Aroya S, Kupiec M.
Author information:
(1)Department of Molecular Microbiology and Biotechnology, Tel Aviv University,
Ramat Aviv, Israel.
Mutations in the ELG1 gene of yeast lead to genomic instability, manifested in
high levels of genetic recombination, chromosome loss, and gross chromosomal
rearrangements. Elg1 shows similarity to the large subunit of the Replication
Factor C clamp loader, and forms a RFC-like (RLC) complex in conjunction with
the 4 small RFC subunits. Two additional RLCs exist in yeast: in one of them the
large subunit is Ctf18, and in the other, Rad24. Ctf18 has been characterized as
the RLC that functions in sister chromatid cohesion. Here we present evidence
that the Elg1 RLC (but not Rad24) also plays an important role in this process.
A genetic screen identified the cohesin subunit Mcd1/Scc1 and its loader Scc2 as
suppressors of the synthetic lethality between elg1 and ctf4. We describe
genetic interactions between ELG1 and genes encoding cohesin subunits and their
accessory proteins. We also show that defects in Elg1 lead to higher precocious
sister chromatid separation, and that Ctf18 and Elg1 affect cohesion via a joint
pathway. Finally, we localize both Ctf18 and Elg1 to chromatin and show that
Elg1 plays a role in the recruitment of Ctf18. Our results suggest that Elg1,
Ctf4, and Ctf18 may coordinate the relative movement of the replication fork
with respect to the cohesin ring.
DOI: 10.1371/journal.pone.0005497
PMCID: PMC2676507
PMID: 19430531 [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/21470422 | 1. BMC Mol Biol. 2011 Apr 6;12:13. doi: 10.1186/1471-2199-12-13.
Drosophila Ctf4 is essential for efficient DNA replication and normal cell cycle
progression.
Gosnell JA(1), Christensen TW.
Author information:
(1)Department of Biology, East Carolina University, Greenville, NC 27858, USA.
BACKGROUND: Proper coordination of the functions at the DNA replication fork is
vital to the normal functioning of a cell. Specifically the precise coordination
of helicase and polymerase activity is crucial for efficient passage though S
phase. The Ctf4 protein has been shown to be a central member of the replication
fork and links the replicative MCM helicase and DNA polymerase α primase. In
addition, it has been implicated as a member of a complex that promotes
replication fork stability, the Fork Protection Complex (FPC), and as being
important for sister chromatid cohesion. As such, understanding the role of Ctf4
within the context of a multicellular organism will be integral to our
understanding of its potential role in developmental and disease processes.
RESULTS: We find that Drosophila Ctf4 is a conserved protein that interacts with
members of the GINS complex, Mcm2, and Polymerase α primase. Using in vivo RNAi
knockdown of CTF4 in Drosophila we show that Ctf4 is required for viability, S
phase progression, sister chromatid cohesion, endoreplication, and coping with
replication stress.
CONCLUSIONS: Ctf4 remains a central player in DNA replication. Our findings are
consistent with what has been previously reported for CTF4 function in yeast,
Xenopus extracts, and human tissue culture. We show that Ctf4 function is
conserved and that Drosophila can be effectively used as a model to further
probe the precise function of Ctf4 as a member of the replication fork and
possible roles in development.
DOI: 10.1186/1471-2199-12-13
PMCID: PMC3082215
PMID: 21470422 [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/22975329 | 1. Dev Cell. 2012 Sep 11;23(3):611-23. doi: 10.1016/j.devcel.2012.07.013.
Sef is an inhibitor of proinflammatory cytokine signaling, acting by cytoplasmic
sequestration of NF-κB.
Fuchs Y(1), Brunwasser M, Haif S, Haddad J, Shneyer B, Goldshmidt-Tran O,
Korsensky L, Abed M, Zisman-Rozen S, Koren L, Carmi Y, Apte R, Yang RB, Orian A,
Bejar J, Ron D.
Author information:
(1)Department of Biology, Technion, Israel Institute of Technology, Haifa 32000,
Israel.
Erratum in
Dev Cell. 2020 Nov 23;55(4):514. doi: 10.1016/j.devcel.2020.10.022.
The NF-κB transcription factor controls diverse biological processes. According
to the classical model, NF-κB is retained in the cytoplasm of resting cells via
binding to inhibitory, IκB proteins and translocates into the nucleus upon their
ligand-induced degradation. Here we reveal that Sef, a known tumor suppressor
and inhibitor of growth factor signaling, is a spatial regulator of NF-κB. Sef
expression is regulated by the proinflammatory cytokines tumor necrosis factor
and interleukin-1, and Sef specifically inhibits "classical" NF-κB (p50:p65)
activation by these ligands. Like IκBs, Sef sequesters NF-κB in the cytoplasm of
resting cells. However, contrary to IκBs, Sef continues to constrain NF-κB
nuclear entry upon ligand stimulation. Accordingly, endogenous Sef knockdown
markedly enhances stimulus-induced NF-κB nuclear translocation and consequent
activity. This study establishes Sef as a feedback antagonist of proinflammatory
cytokines and highlights its potential to regulate the crosstalk between
proinflammatory cytokine receptors and receptor tyrosine kinases.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.devcel.2012.07.013
PMID: 22975329 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23053474 | 1. J Inherit Metab Dis. 2013 Sep;36(5):731-40. doi: 10.1007/s10545-012-9545-3.
Epub 2012 Oct 3.
Functional characterization of novel genotypes and cellular oxidative stress
studies in propionic acidemia.
Gallego-Villar L(1), Pérez-Cerdá C, Pérez B, Abia D, Ugarte M, Richard E,
Desviat LR.
Author information:
(1)Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología
Molecular Severo Ochoa, UAM-CSIC, Centro de Investigación Biomédica en Red de
Enfermedades Raras (CIBERER), IdiPAZ, Madrid, Spain.
Propionic acidemia (PA), caused by a deficiency of the mitochondrial biotin
dependent enzyme propionyl-CoA carboxylase (PCC) is one of the most frequent
organic acidurias in humans. PA is caused by mutations in either the PCCA or
PCCB genes encoding the α- and β-subunits of the PCC enzyme which are assembled
as an α6β6 dodecamer. In this study we have investigated the molecular basis of
the defect in ten fibroblast samples from PA patients. Using homology modeling
with the recently solved crystal structure of the PCC holoenzyme and a
eukaryotic expression system we have analyzed the structural and functional
effect of novel point mutations, also revealing a novel splice defect by
minigene analysis. In addition, we have investigated the contribution of
oxidative stress to cellular damage measuring reactive oxygen species (ROS)
levels and apoptosis parameters in patient fibroblasts, as recent studies point
to a secondary mitochondrial dysfunction as pathophysiological mechanism in this
disorder. The results show an increase in intracellular ROS content compared to
controls, correlating with the activation of the JNK and p38 signaling pathways.
Highest ROS levels were present in cells harboring functionally null mutations,
including one severe missense mutation. This work provides molecular insight
into the pathogenicity of PA variants and indicates that oxidative stress may be
a major contributing factor to the cellular damage, supporting the proposal of
antioxidant strategies as novel supplementary therapy in this rare disease.
DOI: 10.1007/s10545-012-9545-3
PMID: 23053474 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12518268 | 1. Pharmacopsychiatry. 2002 Nov;35(6):205-19. doi: 10.1055/s-2002-36391.
Obesity and related metabolic abnormalities during antipsychotic drug
administration: mechanisms, management and research perspectives.
Baptista T(1), Kin NM, Beaulieu S, de Baptista EA.
Author information:
(1)Los Andes University School of Medicine, Department of Physiology, Mèrida,
Venezuela. [email protected]
Excessive body weight gain (BWG) is a common side effect of some typical and
atypical antipsychotic drugs (APs). Convergent evidence suggests a hierarchy in
the magnitude of BWG that may be induced by diverse agents, being very high for
clozapine and olanzapine; high for quetiapine, zotepin, chlorpromazine, and
thioridazine; moderate for risperidone and sertindole; and low for ziprazidone,
amisulpiride, haloperidol, fluphenazine, pimozide, and molindone. BWG may be
related to increased appetite that is due to drug interaction with the brain
monoaminergic and cholinergic systems and to the metabolic/endocrine effects of
hyperprolactinemia. Subjects with schizophrenia and bipolar disorders manifested
a significantly high prevalence of diabetes, even before the introduction of
atypical APs. However, clozapine and olanzapine appear to display a high
propensity to induce glucose dysregulation and dyslipidemia. Sudden BWG, insulin
resistance, increased appetite, and related endocrine changes also may be
involved in the development of glucose intolerance and dyslipidemia in
predisposed individuals. Patients should be informed of these side effects in
order to prevent excessive BWG, and their blood glucose and lipids should be
monitored before treatment and then at regular intervals. Nutritional advice
must be given and regular physical exercise recommended. An appropriate
selection of APs ought to be based on drug efficacy for specific patients and
assessment of relevant risk factors such as propensity to gain weight; family or
personal history of diabetes or hyperlipidemia; and elevated fasting serum
glucose, lipid, or insulin levels. At present, there is no standardized
pharmacological treatment for AP-induced BWG. Some studies have assessed the
effects of agents such as amantadine, orlistat, metformin, nizatidine, and
topiramate on AP-induced BWG. Further studies will provide tools to identify
patients at high risk for obesity and metabolic abnormalities during AP
administration. Excessive body weight gain (BWG), glucose intolerance, and
dyslipidemia during treatment with antipsychotic drugs (APs) were reported in
the late 1950s [14,101]. However, after 1990, interest in these problems
increased noticeably, mainly because of the high propensity of some new atypical
APs to induce these side effects (Fig.1). The APs are currently used in diverse
mental disorders. Hence, excessive BWG and metabolic dysfunction are not
exclusive of subjects with schizophrenia. In the case of bipolar disorders,
AP-induced BWG may be additive to that induced by mood stabilizers [14,48,101].
The clinical features [2,14,24,133,139,140] and mechanisms
[14,34,68,87,93,101,130] of BWG and metabolic dysfunction have been previously
reviewed. In this article, we focus on a unified theory to explain these side
effects, based on the interaction of APs with brain neurotransmitters involved
in appetite regulation. This review comprises the following sections: 1) the
clinical features of AP-induced BWG; 2) the effects of APs on carbohydrate and
lipid metabolism in humans and experimental animals; 3) mechanisms involved in
BWG, glucose, and lipid dysregulation; 4) strategies for prevention and
treatment of these side effects; and 5) research perspectives in the field. The
following sources were consulted: MEDLINE, Cochrane database system, and
PsychINFO. Numerous articles referred to in leading articles also were
consulted. The literature on this subject has increased so rapidly that it was
impossible to include all the data recently published. For the first two
sections, references that illustrate current controversies in the field were
selected.
DOI: 10.1055/s-2002-36391
PMID: 12518268 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24878071 | 1. Biochim Biophys Acta. 2014 Sep;1843(9):2012-26. doi:
10.1016/j.bbamcr.2014.05.012. Epub 2014 May 27.
Functional interplay between Parkin and Drp1 in mitochondrial fission and
clearance.
Buhlman L(1), Damiano M(2), Bertolin G(2), Ferrando-Miguel R(2), Lombès A(3),
Brice A(2), Corti O(4).
Author information:
(1)Inserm, U 1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France;
Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France;
Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France;
Department of Biomedical Sciences, Midwestern University, 19555N 59th Avenue,
Glendale, Arizona 85308, United States.
(2)Inserm, U 1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France;
Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France;
Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
(3)Inserm U 1016, Institut Cochin, F-75014, Paris, France; CNRS UMR 8104,
F-75014 Paris, France; Université Paris 05, UMR_S1016 F-75014, Paris, France.
(4)Inserm, U 1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France;
Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France;
Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
Electronic address: [email protected].
Autosomal recessive early-onset Parkinson's disease is most often caused by
mutations in the genes encoding the cytosolic E3 ubiquitin ligase Parkin and the
mitochondrial serine/threonine kinase PINK1. Studies in Drosophila models and
mammalian cells have demonstrated that these proteins regulate various aspects
of mitochondrial physiology, including organelle transport, dynamics and
turnover. How PINK1 and Parkin orchestrate these processes, and whether they
always do so within a common pathway remain to be clarified. We have revisited
the role of PINK1 and Parkin in mitochondrial dynamics, and explored its
relation to the mitochondrial clearance program controlled by these proteins. We
show that PINK1 and Parkin promote Drp1-dependent mitochondrial fission by
mechanisms that are at least in part independent. Parkin-mediated mitochondrial
fragmentation was abolished by treatments interfering with the
calcium/calmodulin/calcineurin signaling pathway, suggesting that it requires
dephosphorylation of serine 637 of Drp1. Parkinson's disease-causing mutations
with differential impact on mitochondrial morphology and organelle degradation
demonstrated that the pro-fission effect of Parkin is not required for efficient
mitochondrial clearance. In contrast, the use of Förster energy transfer imaging
microscopy revealed that Drp1 and Parkin are co-recruited to mitochondria in
proximity of PINK1 following mitochondrial depolarization, indicating spatial
coordination between these events in mitochondrial degradation. Our results also
hint at a major role of the outer mitochondrial adaptor MiD51 in Drp1
recruitment and Parkin-dependent mitophagy. Altogether, our observations provide
new insight into the mechanisms underlying the regulation of mitochondrial
dynamics by Parkin and its relation to the mitochondrial clearance program
mediated by the PINK1/Parkin pathway.
Copyright © 2014 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbamcr.2014.05.012
PMID: 24878071 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8023851 | 1. Am J Hum Genet. 1994 Jul;55(1):51-8.
Mutations participating in interallelic complementation in propionic acidemia.
Gravel RA(1), Akerman BR, Lamhonwah AM, Loyer M, Léon-del-Rio A, Italiano I.
Author information:
(1)McGill University-Montreal Children's Hospital Research Institute, Quebec,
Canada.
Deficiency of propionyl-CoA carboxylase (PCC; alpha 4 beta 4) results in the
rare, autosomal recessive disease propionic acidemia. Cell fusion experiments
have revealed two complementation groups, pccA and pccB, corresponding to
defects of the PCCA (alpha-subunit) and PCCB (beta-subunit) genes, respectively.
The pccBCC group includes subgroups, pccB and pccC, which are thought to reflect
interallelic complementation between certain mutations of the PCCB gene. In this
study, we have identified the mutations in two pccB, one pccC, and two pccBC
cell lines and have deduced those alleles participating in interallelic
complementation. One pccB line was a compound heterozygote of Pro228Leu and
Asn536Asp. The latter mutation was also detected in a noncomplementing pccBC
line. This leaves Pro228Leu responsible for complementation in the pccB cells.
The second pccB line contained an insertional duplication, dupKICK140-143, and a
splice mutation IVS + 1 G-->T, located after Lys466. We suggest that the dupKICK
mutation is the complementing allele, since the second allele is incompatible
with normal splicing. The pccC line studied was homozygous for Arg410Trp, which
is necessarily the complementing allele in that line. For a second pccC line, we
previously had proposed that delta Ile408 was the complementing allele. We now
show that its second allele, "Ins.Del," a 14-bp deletion replaced by a 12-bp
insertion beginning at codon 407, fails to complement in homozygous form. We
conclude that the interallelic complementation results from mutations in domains
that can interact between beta-subunits in the PCC heteromer to restore
enzymatic function. On the basis of sequence homology with the Propionibacterium
shermanii transcarboxylase 12S subunit, we suggest that the pccC domain, defined
by Ile408 and Arg410, may involve the propionyl-CoA binding site.
PMCID: PMC1918217
PMID: 8023851 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18386809 | 1. Am J Med Genet A. 2008 May 1;146A(9):1117-27. doi: 10.1002/ajmg.a.32178.
Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes
scoliosis.
Kulkarni S(1), Nagarajan P, Wall J, Donovan DJ, Donell RL, Ligon AH,
Venkatachalam S, Quade BJ.
Author information:
(1)Division of Women's and Perinatal Pathology and Clinical Cytogenetics
Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA,
USA.
Herein we characterize an apparently balanced de novo translocation,
t(X;15)(p22.2;q26.1)dn, in a female patient with scoliosis, hirsutism, learning
problems, and developmental delay (DGAP025). Other clinical findings include a
high-arched palate, 2-3 syndactyly of the toes, and mildly elevated serum
testosterone. No known or predicted genes are disrupted by the Xp22.2
breakpoint. The 15q26.1 breakpoint disrupts chromodomain helicase DNA binding
protein 2 (CHD2). Another member of the chromatin-remodeling gene family, CHD7,
has been associated with a defined constellation of congenital anomalies known
as coloboma, heart anomaly, choanal atresia, mental retardation, genital and ear
anomalies syndrome (CHARGE) and idiopathic scoliosis. Monosomy of 15q26 also has
been associated with a spectrum of congenital abnormalities and growth
retardation that overlaps with those of DGAP025. To provide a biological
correlate, we characterized a mutant mouse model with Chd2 disruption that is
associated with embryonic and perinatal lethality. Expression analysis indicated
that Chd2 is expressed in the heart, forebrain, extremities, facial and dorsal
regions during specific times of embryonic development. Chd2(+/m) mice showed
pronounced lordokyphosis, reduced body fat, postnatal runting, and growth
retardation. These data suggest that haploinsufficiency for CHD2 could result in
a complex of abnormal human phenotypes that includes scoliosis and possibly
features similar to CHARGE syndrome.
(c) 2008 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.a.32178
PMCID: PMC2834558
PMID: 18386809 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7875314 | 1. FEBS Lett. 1995 Feb 27;360(2):115-20. doi: 10.1016/0014-5793(95)00068-k.
Transcriptional silencing of human Alu sequences and inhibition of protein
binding in the box B regulatory elements by 5'-CG-3' methylation.
Kochanek S(1), Renz D, Doerfler W.
Author information:
(1)Institut für Genetik, Universität zu Köln, Germany.
In earlier work, we demonstrated that 5'-CG-3' methylation inhibits the
transcriptional activity of human Alu elements associated with the alpha
1-globin and the angiogenin genes in a cell-free transcription system from HeLa
nuclear extracts. These studies have been extended to different Alu sequences
and to investigations on the mechanism involved in transcriptional silencing by
methylation. By comparing the results of DNase I and dimethyl sulfate (DMS) in
vitro footprinting on a consensus sequence in the RNA polymerase III promoter
control B region between the unmethylated and the 5'-CG-3' methylated B box,
evidence has been adduced for effects of 5'-CG-3' methylation on the interaction
of specific nuclear proteins with DNA sequences in the B control region of the
Alu elements. These results are consistent with the interpretation that the
5'-CG-3' methylation interferes with the binding of proteins that are essential
for the function of the B control region in these RNA polymerase III-transcribed
elements, and that promoter methylation thus inhibits transcription.
DOI: 10.1016/0014-5793(95)00068-k
PMID: 7875314 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23659897 | 1. Neurobiol Dis. 2013 Oct;58:49-56. doi: 10.1016/j.nbd.2013.04.019. Epub 2013
May 6.
Ataxin-3 protein modification as a treatment strategy for spinocerebellar ataxia
type 3: removal of the CAG containing exon.
Evers MM(1), Tran HD, Zalachoras I, Pepers BA, Meijer OC, den Dunnen JT, van
Ommen GJ, Aartsma-Rus A, van Roon-Mom WM.
Author information:
(1)Department of Human Genetics, Leiden University Medical Center, The
Netherlands. [email protected]
Spinocerebellar ataxia type 3 is caused by a polyglutamine expansion in the
ataxin-3 protein, resulting in gain of toxic function of the mutant protein. The
expanded glutamine stretch in the protein is the result of a CAG triplet repeat
expansion in the penultimate exon of the ATXN3 gene. Several gene silencing
approaches to reduce mutant ataxin-3 toxicity in this disease aim to lower
ataxin-3 protein levels, but since this protein is involved in deubiquitination
and proteasomal protein degradation, its long-term silencing might not be
desirable. Here, we propose a novel protein modification approach to reduce
mutant ataxin-3 toxicity by removing the toxic polyglutamine repeat from the
ataxin-3 protein through antisense oligonucleotide-mediated exon skipping while
maintaining important wild type functions of the protein. In vitro studies
showed that exon skipping did not negatively impact the ubiquitin binding
capacity of ataxin-3. Our in vivo studies showed no toxic properties of the
novel truncated ataxin-3 protein. These results suggest that exon skipping may
be a novel therapeutic approach to reduce polyglutamine-induced toxicity in
spinocerebellar ataxia type 3.
Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nbd.2013.04.019
PMID: 23659897 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23440506 | 1. J Infect Chemother. 2013 Oct;19(5):812-7. doi: 10.1007/s10156-013-0565-1. Epub
2013 Feb 26.
Urine post equivalent daily cranberry juice consumption may opsonize
uropathogenicity of Escherichia coli.
Chen CS(1), Ho DR, Chang PJ, Lin WY, Huang YC.
Author information:
(1)Division of Urology, Department of Surgery, Chang Gung Memorial Hospital,
Chia-Yi, No. 6, Chiapu West Road, Pu-Z City, Chia-Yi County, Taiwan 613,
Republic of China, [email protected].
Basic studies have proven that cranberries may prevent urinary tract infections
through changing the adhesiveness of Escherichia coli (E. coli) to urothelial
cells. Various cranberry preparations, including extract powder, capsules, and
juice, have been shown to be effective in clinical and epidemiological research.
Because cranberries are most commonly consumed as juice in a diluted
concentration, the aim of this study was to investigate whether the equivalent
daily dose of cranberry juice is sufficient to modify host urine to change the
uropathogenicity of E. coli. Urine from rats taking an equivalent daily dose of
cranberry juice has been shown to decrease the capability of E. coli in
hemagglutination, urothelium adhesion, nematode killing, and biofilm formation.
All these changes occurred after E. coli was incubated in cranberry
metabolite-containing urine, defined as urine opsonization. Urine opsonization
of E. coli resulted in 40.9% (p = 0.0038) decrease in hemagglutination ability,
66.7% (p = 0.0181) decrease in urothelium adhesiveness, 16.7% (p = 0.0004)
increase in the 50% lethal time in killing nematodes, and 53.9% (p = 5.9 ×
10(-4)) decrease in biofilm formation. Thus, an equivalent daily dose of
cranberry juice should be considered sufficiently potent to demonstrate urine
opsonization in E. coli.
DOI: 10.1007/s10156-013-0565-1
PMID: 23440506 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25219681 | 1. Exp Dermatol. 2015 Jan;24(1):5-9. doi: 10.1111/exd.12540. Epub 2014 Nov 11.
Variants of the melanocortin-1 receptor: do they matter clinically?
Haddadeen C(1), Lai C, Cho SY, Healy E.
Author information:
(1)Dermatopharmacology, Sir Henry Wellcome Laboratories, Faculty of Medicine,
University of Southampton, Southampton, UK; Dermatology, University Hospital
Southampton NHS Foundation Trust, Southampton, UK.
The melanocortin 1 receptor (MC1R) gene encodes for a seven-pass transmembrane
receptor primarily expressed on melanocytes and melanoma cells. Single
nucleotide polymorphisms (SNPs, also termed variants) in MC1R frequently cause
red hair, fair skin and are associated with melanoma and keratinocyte-derived
skin cancer development. Activation of wild-type (WT) MC1R in skin assists
cutaneous photoprotection whereas reduced MC1R signalling, seen with MC1R
variants, impairs ultraviolet radiation (UVR)-protective responses. As ancestral
humans migrated out of Africa, the evolutionary advantage of MC1R variants may
have related to improved cutaneous vitamin D synthesis and higher birthweight
reported with certain MC1R variants. Reduced photoprotection secondary to MC1R
dysfunction involves pigmentary and non-pigmentary mechanisms (reduced DNA
repair, effects on cell proliferation and possibly immunological parameters),
leading to clonal expansion of mutated cells within skin and subsequent
carcinogenesis. Recent investigations suggest an association between MC1R
genotype and vitiligo, with preliminary evidence that a MC1R agonist,
[Nle4-D-Phe7]-alpha-MSH, in combination with UVB, assists repigmentation. Future
development of compounds to correct defective MC1R responses secondary to MC1R
variants could result in photoprotective benefits for fair-skinned individuals
and reduce their skin cancer risk.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
DOI: 10.1111/exd.12540
PMID: 25219681 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21181203 | 1. Surg Endosc. 2011 Jun;25(6):1939-44. doi: 10.1007/s00464-010-1491-2. Epub 2010
Dec 22.
Plasma levels of angiostatin and endostatin remain unchanged for the first
3 weeks after colorectal cancer surgery.
Shantha Kumara HM(1), Tohme ST, Yan X, Nasar A, Senagore AJ, Kalady MF, Hyman N,
Kim IY, Whelan RL.
Author information:
(1)Division of Colon and Rectal Surgery, Department of Surgery, St.
Luke-Roosevelt Hospital Center, Suite 7B, 425 West, 59th Street, New York, NY
10019, USA.
INTRODUCTION: Angiostatin and endostatin are endogenous inhibitors of
angiogenesis with anticancer effects. After minimally invasive colorectal
resection (MICR), blood levels of the proangiogenic factors vascular endothelial
growth factor (VEGF) and angiopoetin 2 (Ang-2) are elevated for 2-4 weeks. Also,
postoperative human plasma from weeks 2 and 3 after MICR has been shown to
stimulate endothelial cell proliferation and migration, which are critical to
angiogenesis. This proangiogenic state may stimulate tumor growth early after
MICR. Surgery's impact on angiostatin and endostatin is unknown. This study's
purpose is to determine perioperative plasma levels of these two proteins in
colorectal cancer (CRC) patients undergoing MICR.
METHODS: Endostatin levels were assessed in 34 CRC patients and angiostatin
levels in 30 CRC patients. Blood samples were taken preoperatively and on
postoperative day (POD) 1 and 3 in all patients; in a subset, samples were taken
between POD 7 and 20. The late samples were bundled into 7-day blocks (POD 7-13,
POD 14-20) and considered as single time points. Angiostatin and endostatin
plasma levels were determined via enzyme-linked immunosorbent assay (ELISA) in
duplicate. Wilcoxon signed-rank test and Student's t test were used to analyze
endostatin and angiostatin data, respectively. Significance was set at P<0.0125
(after Bonferroni correction).
RESULTS: There was a significant decrease in median plasma endostatin levels on
POD 1, which returned to the preoperative level by POD 3. There was no
significant difference between pre- and postoperative plasma angiostatin levels.
CONCLUSIONS: MICR has a very transient impact on plasma levels of endostatin and
no impact on angiostatin during the first 21 days following surgery. Thus,
angiostatin and endostatin do not likely contribute to or inhibit the persistent
proangiogenic changes noted after MICR.
DOI: 10.1007/s00464-010-1491-2
PMID: 21181203 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25213867 | 1. Semin Oncol. 2014 Oct;41 Suppl 6:S35-41. doi:
10.1053/j.seminoncol.2014.09.006. Epub 2014 Sep 8.
Alternating electric fields (tumor-treating fields therapy) can improve
chemotherapy treatment efficacy in non-small cell lung cancer both in vitro and
in vivo.
Giladi M(1), Weinberg U(2), Schneiderman RS(2), Porat Y(2), Munster M(2),
Voloshin T(2), Blatt R(2), Cahal S(2), Itzhaki A(2), Onn A(3), Kirson ED(2),
Palti Y(2).
Author information:
(1)Novocure Ltd., Haifa, Israel. Electronic address: [email protected].
(2)Novocure Ltd., Haifa, Israel.
(3)Sheba Medical Center, Tel Hashomer, Israel.
Non-small cell lung cancer (NSCLC) is one of the leading causes of
cancer-related deaths worldwide. Common treatment modalities for NSCLC include
surgery, radiotherapy, chemotherapy, and, in recent years, the clinical
management paradigm has evolved with the advent of targeted therapies. Despite
such advances, the impact of systemic therapies for advanced disease remains
modest, and as such, the prognosis for patients with NSCLC remains poor.
Standard modalities are not without their respective toxicities and there is a
clear need to improve both efficacy and safety for current management
approaches. Tumor-treating fields (TTFields) are low-intensity,
intermediate-frequency alternating electric fields that disrupt proper spindle
microtubule arrangement, thereby leading to mitotic arrest and ultimately to
cell death. We evaluated the effects of combining TTFields with standard
chemotherapeutic agents on several NSCLC cell lines, both in vitro and in vivo.
Frequency titration curves demonstrated that the inhibitory effects of TTFields
were maximal at 150 kHz for all NSCLC cell lines tested, and that the addition
of TTFields to chemotherapy resulted in enhanced treatment efficacy across all
cell lines. We investigated the response of Lewis lung carcinoma and KLN205
squamous cell carcinoma in mice treated with TTFields in combination with
pemetrexed, cisplatin, or paclitaxel and compared these to the efficacy observed
in mice exposed only to the single agents. Combining TTFields with these
therapeutic agents enhanced treatment efficacy in comparison with the respective
single agents and control groups in all animal models. Together, these findings
suggest that combining TTFields therapy with chemotherapy may provide an
additive efficacy benefit in the management of NSCLC.
Copyright © 2014. Published by Elsevier Inc.
DOI: 10.1053/j.seminoncol.2014.09.006
PMID: 25213867 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23499444 | 1. Cell Rep. 2013 Mar 28;3(3):892-904. doi: 10.1016/j.celrep.2013.02.028. Epub
2013 Mar 14.
Eukaryotic replisome components cooperate to process histones during chromosome
replication.
Foltman M(1), Evrin C, De Piccoli G, Jones RC, Edmondson RD, Katou Y, Nakato R,
Shirahige K, Labib K.
Author information:
(1)Paterson Institute for Cancer Research, University of Manchester, Wilmslow
Road, Manchester M20 4BX, UK.
DNA unwinding at eukaryotic replication forks displaces parental histones, which
must be redeposited onto nascent DNA in order to preserve chromatin structure.
By screening systematically for replisome components that pick up histones
released from chromatin into a yeast cell extract, we found that the Mcm2
helicase subunit binds histones cooperatively with the FACT (facilitiates
chromatin transcription) complex, which helps to re-establish chromatin during
transcription. FACT does not associate with the Mcm2-7 helicase at replication
origins during G1 phase but is subsequently incorporated into the replisome
progression complex independently of histone binding and uniquely among histone
chaperones. The amino terminal tail of Mcm2 binds histones via a conserved motif
that is dispensable for DNA synthesis per se but helps preserve subtelomeric
chromatin, retain the 2 micron minichromosome, and support growth in the absence
of Ctf18-RFC. Our data indicate that the eukaryotic replication and
transcription machineries use analogous assemblies of multiple chaperones to
preserve chromatin integrity.
Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.celrep.2013.02.028
PMID: 23499444 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18330528 | 1. Wien Med Wochenschr. 2008;158(3-4):116-8. doi: 10.1007/s10354-007-0494-7.
The use of Duloxetine in the treatment of male stress urinary incontinence.
Fink KG(1), Huber J, Würnschimmel E, Schmeller NT.
Author information:
(1)Department of Urology and Andrology, Paracelsus Private Medical University
Salzburg, Salzburg, Austria. [email protected]
Stress urinary incontinence (SUI) is a known complication after prostate
surgery. To date no pharmacologic treatment is available. Currently Duloxetine,
a serotonin and norepinephrine reuptake inhibitor, is available for women with
SUI. This study investigates the effect of Duloxetine on men with SUI after
prostate surgery. 56 patients were included in our study. 49 after radical
prostatectomy and 7 after TURP. All patients were initially treated with pelvic
floor exercises. Thereafter 40 mg Duloxetine was administered twice daily. When
taking Duloxetine, the average use of incontinence pads decreased from 3.3 to
1.5 per day. 14 patients needed no and 18 a single pad per day. Most patients
reported mild and temporary side effects, 13 patients assessed them to be
moderate and 9 being severe. The results of this off-label use show that
Duloxetine is effective in men with SUI after prostate surgery even if standard
pelvic floor exercises have failed.
DOI: 10.1007/s10354-007-0494-7
PMID: 18330528 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20492723 | 1. BMC Cancer. 2010 May 23;10:229. doi: 10.1186/1471-2407-10-229.
TTFields alone and in combination with chemotherapeutic agents effectively
reduce the viability of MDR cell sub-lines that over-express ABC transporters.
Schneiderman RS(1), Shmueli E, Kirson ED, Palti Y.
Author information:
(1)NovoCure Ltd, MATAM Advanced Technology Centre, Haifa 31905, Israel.
BACKGROUND: Exposure of cancer cells to chemotherapeutic agents may result in
reduced sensitivity to structurally unrelated agents, a phenomenon known as
multidrug resistance, MDR. The purpose of this study is to investigate cell
growth inhibition of wild type and the corresponding MDR cells by Tumor Treating
Fields--TTFields, a new cancer treatment modality that is free of systemic
toxicity. The TTFields were applied alone and in combination with paclitaxel and
doxorubicin.
METHODS: Three pairs of wild type/MDR cell lines, having resistivity resulting
from over-expression of ABC transporters, were studied: a clonal derivative
(C11) of parental Chinese hamster ovary AA8 cells and their emetine-resistant
sub-line EmtR1; human breast cancer cells MCF-7 and their mitoxantrone-resistant
sub lines MCF-7/Mx and human breast cancer cells MDA-MB-231 and their
doxorubicin resistant MDA-MB-231/Dox cells. TTFields were applied for 72 hours
with and without the chemotherapeutic agents. The numbers of viable cells in the
treated cultures and the untreated control groups were determined using the XTT
assay. Student t-test was applied to asses the significance of the differences
between results obtained for each of the three cell pairs.
RESULTS: TTFields caused a similar reduction in the number of viable cells of
wild type and MDR cells. Treatments by TTFields/drug combinations resulted in a
similar increased reduction in cell survival of wild type and MDR cells.
TTFields had no effect on intracellular doxorubicin accumulation in both wild
type and MDR cells.
CONCLUSIONS: The results indicate that TTFields alone and in combination with
paclitaxel and doxorubicin effectively reduce the viability of both wild type
and MDR cell sub-lines and thus can potentially be used as an effective
treatment of drug resistant tumors.
DOI: 10.1186/1471-2407-10-229
PMCID: PMC2893108
PMID: 20492723 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19426495 | 1. BMC Bioinformatics. 2009 May 8;10:137. doi: 10.1186/1471-2105-10-137.
On finding minimal absent words.
Pinho AJ(1), Ferreira PJ, Garcia SP, Rodrigues JM.
Author information:
(1)Signal Processing Lab, DETI/IEETA, University of Aveiro, 3810-193 Aveiro,
Portugal. [email protected]
BACKGROUND: The problem of finding the shortest absent words in DNA data has
been recently addressed, and algorithms for its solution have been described. It
has been noted that longer absent words might also be of interest, but the
existing algorithms only provide generic absent words by trivially extending the
shortest ones.
RESULTS: We show how absent words relate to the repetitions and structure of the
data, and define a new and larger class of absent words, called minimal absent
words, that still captures the essential properties of the shortest absent words
introduced in recent works. The words of this new class are minimal in the sense
that if their leftmost or rightmost character is removed, then the resulting
word is no longer an absent word. We describe an algorithm for generating
minimal absent words that, in practice, runs in approximately linear time. An
implementation of this algorithm is publicly available at
ftp://www.ieeta.pt/~ap/maws.
CONCLUSION: Because the set of minimal absent words that we propose is much
larger than the set of the shortest absent words, it is potentially more useful
for applications that require a richer variety of absent words. Nevertheless,
the number of minimal absent words is still manageable since it grows at most
linearly with the string size, unlike generic absent words that grow
exponentially. Both the algorithm and the concepts upon which it depends shed
additional light on the structure of absent words and complement the existing
studies on the topic.
DOI: 10.1186/1471-2105-10-137
PMCID: PMC2698904
PMID: 19426495 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7528809 | 1. J Mol Evol. 1994 Nov;39(5):506-18. doi: 10.1007/BF00173420.
Evolution of secondary structure in the family of 7SL-like RNAs.
Labuda D(1), Zietkiewicz E.
Author information:
(1)Hôpital Sainte-Justine, Département de Pédiatrie, Université de Montréal,
Québec, Canada.
Primate and rodent genomes are populated with hundreds of thousands copies of
Alu and B1 elements dispersed by retroposition, i.e., by genomic reintegration
of their reverse transcribed RNAs. These, as well as primate BC200 and rodent
4.5S RNAs, are ancestrally related to the terminal portions of 7SL RNA sequence.
The secondary structure of 7SL RNA (an integral component of the signal
recognition particle) is conserved from prokaryotes to distant eukaryotic
species. Yet only in primates and rodents did this molecule give rise to
retroposing Alu and B1 RNAs and to apparently functional BC200 and 4.5S RNAs. To
understand this transition and the underlying molecular events, we examined, by
comparative analysis, the evolution of RNA structure in this family of molecules
derived from 7SL RNA. RNA sequences of different simian (mostly human) and
prosimian Alu subfamilies as well as rodent B1 repeats were derived from their
genomic consensus sequences taken from the literature and our unpublished
results (prosimian and New World Monkey). RNA secondary structures were
determined by enzymatic studies (new data on 4.5S RNA are presented) and/or
energy minimization analyses followed by phylogenetic comparison. Although, with
the exception of 4.5S RNA, all 7SL-derived RNA species maintain the cruciform
structure of their progenitor, the details of 7SL RNA folding domains are
modified to a different extent in various RNA groups. Novel motifs found in
retropositionally active RNAs are conserved among Alu and B1 subfamilies in
different genomes. In RNAs that do not proliferate by retroposition these motifs
are modified further. This indicates structural adaptation of 7SL-like RNA
molecules to novel functions, presumably mediated by specific interactions with
proteins; these functions were either useful for the host or served the selfish
propagation of RNA templates within the host genome.
DOI: 10.1007/BF00173420
PMID: 7528809 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25213870 | 1. Semin Oncol. 2014 Oct;41 Suppl 6:S14-24. doi:
10.1053/j.seminoncol.2014.09.009. Epub 2014 Sep 16.
Response patterns of recurrent glioblastomas treated with tumor-treating fields.
Vymazal J(1), Wong ET(2).
Author information:
(1)Department of Radiology, Na Homolce Hospital, Prague, Czech Republic;
Department of Neurology, Charles University in Prague, 1st Medical Faculty,
Prague, Czech Republic. Electronic address: [email protected].
(2)Brain Tumor Center and Neuro-Oncology Unit, Beth Israel Deaconess Medical
Center, Boston, MA. Electronic address: [email protected].
Erratum in
Semin Oncol. 2015 Jun;42(3):e44-55.
Glioblastoma multiforme (GBM) is the most common form of primary malignant brain
cancer. Median overall survival (OS) for newly diagnosed patients is only about
12 to 18 months. GBM tumors invariably recur, and there is no widely recognized
and effective standard treatment for recurrent GBM. NovoTTF Therapy is a novel
and US Food and Drug Administration (FDA)-approved antimitotic treatment for
recurrent GBM with potential benefits compared with other options. Recurrent GBM
patients from two prior trials with demonstrated radiologic tumor response to
single-agent NovoTTF Therapy were analyzed to better characterize tumor response
patterns and evaluate the associations between response, compliance, and OS. In
addition, a compartmental tumor growth model was developed and evaluated for its
ability to predict GBM response to tumor-treating fields (TTFields). The overall
response rate across both trials was 15% (4% complete responses): 14% in the
phase III trial (14/120) and 20% (2/10) in a pilot study. Tumor responses to
NovoTTF Therapy developed slowly (median time to response, 5.2 months) but were
durable (median duration, 12.9 months). Response duration was highly correlated
with OS (r(2) = .92, P<.0001), and median OS for responders was 24.8 months.
Seven of 16 responders exhibited initial tumor growth on magnetic resonance
imaging. Compliance appeared to be linked with both improved response and
survival. The tumor growth model predicted tumor arrest and shrinkage only after
several weeks of continuous NovoTTF Therapy, consistent with the observed
clinical findings of initial transient tumor growth in some patients. NovoTTF
Therapy is a novel antimitotic treatment for recurrent GBM associated with
slowly developing but durable tumor responses in approximately 15% of patients.
Some responders exhibit initial tumor growth before shrinkage, indicating
treatment should not be terminated prior to allowing for the full effect of
NovoTTF Therapy to be realized. OS is longer in responders than in
nonresponders. High daily compliance rates may be associated with increased
likelihood of an objective response and are predictive of improved survival.
Copyright © 2014. Published by Elsevier Inc.
DOI: 10.1053/j.seminoncol.2014.09.009
PMID: 25213870 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20980819 | 1. Cell Cycle. 2010 Nov 1;9(21):4399-410. doi: 10.4161/cc.9.21.13679. Epub 2010
Nov 19.
Identification of novel factors involved in or regulating initiation of DNA
replication by a genome-wide phenotypic screen in Saccharomyces cerevisiae.
Ma L(1), Zhai Y, Feng D, Chan TC, Lu Y, Fu X, Wang J, Chen Y, Li J, Xu K, Liang
C.
Author information:
(1)Sun Yat-sen University, Guangzhou, China.
Comment in
Cell Cycle. 2010 Dec 1;9(23):4610-1. doi: 10.4161/cc.9.23.13930.
DNA replication in eukaryotic cells is tightly regulated to ensure faithful
inheritance of the genetic material. While the replicators, replication origins
and many replication-initiation proteins in Saccharomyces cerevisiae have been
identified and extensively studied, the detailed mechanism that controls the
initiation of DNA replication is still not well understood. It is likely that
some factors involved in or regulating the initiation of DNA replication have
not been discovered. To identify novel DNA replication-initiation proteins and
their regulators, we developed a sensitive and comprehensive phenotypic screen
by combining several established genetic strategies including plasmid loss
assays with plasmids containing a single versus multiple replication origins and
colony color sectoring assays. We isolated dozen of mutants in previously known
initiation proteins and identified several novel factors, including Ctf1p Ctf3p,
Ctf4p, Ctf18p, Adk1p and Cdc60p, whose mutants lose plasmid containing a single
replication origin at high rates but lose plasmid carrying multiple replication
origins at lower rates. We also show that overexpression of replication
initiation proteins causes synthetic dosage lethality or growth defects in ctf1
and ctf18 mutants and that Ctf1p and Ctf18p physically interact with ORC, Cdt1p
and MCM proteins. Furthermore, depletion of both Ctf1p and Ctf18p prevents S
phase entry, retards S phase progression, and reduces pre-RC formation during
the M-to-G₁ transition. These data suggest that Ctf1p and Ctf18p together play
important roles in regulating the initiation of DNA replication.
DOI: 10.4161/cc.9.21.13679
PMID: 20980819 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23383974 | 1. J Altern Complement Med. 2013 Aug;19(8):690-6. doi: 10.1089/acm.2012.0347.
Epub 2013 Feb 5.
Acupuncture for the treatment of hot flashes in patients with breast cancer
receiving antiestrogen therapy: a pilot study in Korean women.
Jeong YJ(1), Park YS, Kwon HJ, Shin IH, Bong JG, Park SH.
Author information:
(1)Department of Surgery, School of Medicine, Catholic University of Daegu,
Daegu, Korea.
OBJECTIVES: Antiestrogen therapy can cause vasomotor symptoms similar to those
occurring during menopause, including hot flashes. Recent studies suggest that
acupuncture is effective in reducing vasomotor symptoms in patients with breast
cancer receiving tamoxifen. The purpose of this study was to assess the
feasibility and safety of acupuncture for treatment of hot flashes in Korean
patients with breast cancer receiving antiestrogen therapy.
DESIGN: This was a prospective single-arm observational study using before and
after measurements.
SETTINGS/LOCATION: The study was located at the East-West Medical Center at
Daegu Catholic University Medical Center, Daegu, Korea.
SUBJECTS: The subjects were 10 patients with breast cancer who were undergoing
antiestrogen therapy with tamoxifen or anastrozole and who were suffering from
hot flashes.
INTERVENTIONS: Acupuncture was administered 3 times a week for 4 consecutive
weeks, for 20±5 minutes at each session.
OUTCOME MEASURES: The outcome measure was severity of hot flashes assessed by
visual analogue scale (VAS) and total hot flash score.
RESULTS: During treatment, severity of hot flashes was reduced by 70%-95% in all
patients. Acupuncture significantly alleviated severity of hot flashes assessed
by a visual analogue scale (F=30.261; p<0.001) as well as the total hot flash
score (F=21.698; p=0.006). Four (4) weeks after the final treatment, symptoms
were not aggravated.
CONCLUSIONS: Acupuncture appeared to provide effective relief from hot flashes
among Korean women receiving antiestrogen therapy after surgery for breast
cancer, and the effects lasted for at least 1 month after termination of
treatment. A randomized controlled prospective study with a larger sample size
is required to clarify the role of acupuncture in the management of hot flashes
in Korean patients with breast cancer.
DOI: 10.1089/acm.2012.0347
PMCID: PMC3731680
PMID: 23383974 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21987713 | 1. Brief Funct Genomics. 2011 Sep;10(5):294-311. doi: 10.1093/bfgp/elr029.
From 'JUNK' to just unexplored noncoding knowledge: the case of transcribed
Alus.
Pandey R(1), Mukerji M.
Author information:
(1)Genomics and Molecular medicine, Institute of Genomics and Integrative
Biology (CSIR-IGIB), Council of Scientific and Industrial Research (CSIR). Mall
Road, Delhi, India. [email protected]
Non-coding RNAs (ncRNAs) are increasingly being implicated in diverse functional
roles. Majority of these ncRNAs have their origin in the repetitive elements of
genome. Significantly, increase in genomic complexity has been correlated with
increase in repetitive content of the genome. Primate-specific Alu repeats,
belonging to SINE class of repeats, is the most abundant repeat class inhabiting
the human genome. Of the many possible functional roles of Alu repeats, they
have been shown to modulate human transcriptome by virtue of harboring diverse
array of functional RNA pol II TFBS, cryptic splice-site-mediated Alu
exonization and as probable miRNA targets. Retro-transposition of Alu harboring
TFBS has shaped up gene-specific regulatory networks. Alu exonized transcripts
are raw material for dsRNA-mediated A-I editing leading to nuclear retention of
transcripts and change in miRNA target. miRNA targets within Alu may titrate the
effective miRNA or transcript concentration, thus acting as 'miRNA sponge'.
Differential levels of Alu RNA during different conditions of stress also await
clear functional understanding. These have contributed toward evolution of
complex regulatory repertoire leading to the evolution of primate-specific
functions. Recent reports of co-localization of pol II and pol III binding sites
near the gene and elsewhere in the genome, increase the possibility of dynamic
co-ordination between both pol II and pol III determining the ultimate
transcriptional outcome. Dynamic and functional Alu repeats seem to be centrally
placed to modulate the transcriptional landscape of human genome.
DOI: 10.1093/bfgp/elr029
PMID: 21987713 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21701592 | 1. PLoS One. 2011;6(6):e21172. doi: 10.1371/journal.pone.0021172. Epub 2011 Jun
20.
Dia2 controls transcription by mediating assembly of the RSC complex.
Andress EJ(1), Holic R, Edelmann MJ, Kessler BM, Yu VP.
Author information:
(1)Eukaryotic Chromatin Dynamics Group, MRC Clinical Sciences Centre, Imperial
College Hammersmith Campus, London, United Kingdom.
BACKGROUND: Dia2 is an F-box protein found in the budding yeast, S. cerevisiae.
Together with Skp1 and Cul1, Dia2 forms the substrate-determining part of an E3
ubiquitin ligase complex, otherwise known as the SCF. Dia2 has previously been
implicated in the control of replication and genome stability via its
interaction with the replisome progression complex.
PRINCIPAL FINDINGS: We identified components of the RSC chromatin remodelling
complex as genetic interactors with Dia2, suggesting an additional role for Dia2
in the regulation of transcription. We show that Dia2 is involved in controlling
assembly of the RSC complex. RSC belongs to a group of ATP-dependent
nucleosome-remodelling complexes that controls the repositioning of nucleosomes.
The RSC complex is expressed abundantly and its 17 subunits are recruited to
chromatin in response to both transcription activation and repression. In the
absence of Dia2, RSC-mediated transcription regulation was impaired, with
concomitant abnormalities in nucleosome positioning.
CONCLUSIONS: Our findings imply that Dia2 is required for the correct assembly
and function of the RSC complex. Dia2, by controlling the RSC chromatin
remodeller, fine-tunes transcription by controlling nucleosome positioning
during transcriptional activation and repression.
DOI: 10.1371/journal.pone.0021172
PMCID: PMC3118812
PMID: 21701592 [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/19037962 | 1. Clin Exp Allergy. 2008 Dec;38(12):1858-65. doi:
10.1111/j.1365-2222.2008.03122.x.
Immunomodulatory therapy of eosinophil-associated gastrointestinal diseases.
Stone KD(1), Prussin C.
Author information:
(1)Laboratory of Allergic Diseases, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, MD 20892-1881, USA.
Eosinophil-associated gastrointestinal disorders (EGIDs), including eosinophilic
esophagitis (EE) and eosinophilic gastroenteritis (EG), are a spectrum of
increasingly recognized inflammatory diseases characterized by gastrointestinal
symptoms and eosinophilic infiltration of the gastrointestinal tract.
Significant morbidity is associated with the development of esophageal
strictures in some patients. Immune-mediated reactions to food allergens appear
to drive the inflammation in a subset of patients, especially those with
solitary EE, but dietary interventions remain difficult in EE and are less
effective in EG. Despite the increasing incidence of these disorders and their
increased recognition by physicians, there are currently no medications that
either United States or European Union regulatory agencies have specifically
approved for use in EGIDs. This lack of safe and effective therapies for EGIDs
is a major obstacle in the care of these patients and underscores the need for
new therapeutic approaches. This review briefly discusses the currently
available 'off label' drug treatments for EGIDs, most notably topical and
systemic corticosteroids. Pathogenesis studies of EGIDs suggest possible
therapeutic targets, and conversely, clinical trials of mechanistically-targeted
therapeutics give insight into disease pathogenesis. Thus, EGID pathogenesis is
discussed as an introduction to mechanistically-targeted immunotherapeutics. The
two biologic categories that have been used in EGIDs, anti-IgE (omalizumab) and
anti-IL-5 (SCH55700/reslizumab and mepolizumab), are discussed. Because there
are similarities in the pathogenesis of EGIDs with asthma and atopic dermatitis,
biologic therapeutics currently in early trials for asthma management are also
briefly discussed as potential therapeutic agents for EGIDs. Given the
deficiencies of current therapeutics and the rapidly advancing knowledge of the
pathogenesis of these disorders, EGIDs are an ideal model for translating recent
advances in understanding immunopathogenesis into mechanistically-based
therapeutics. Further understanding of the early events in pathogenesis is also
needed to develop preventive and disease-modifying treatments.
DOI: 10.1111/j.1365-2222.2008.03122.x
PMCID: PMC2768622
PMID: 19037962 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24275927 | 1. Curr Opin Pulm Med. 2014 Jan;20(1):87-94. doi: 10.1097/MCP.0000000000000007.
Monoclonal antibodies for the treatment of refractory asthma.
Hambly N(1), Nair P.
Author information:
(1)Division of Respirology, Department of Medicine, St Joseph's Healthcare and
McMaster University, Hamilton, Ontario, Canada.
PURPOSE OF REVIEW: A small proportion of patients with asthma have severe
disease characterized by persistent airflow obstruction, airway
hyperresponsiveness and eosinophilic airway inflammation. This review focuses on
the clinical efficacy of inhibiting T helper 2-cytokine-mediated inflammatory
responses using monoclonal antibodies directed against immunoglobulin E (IgE),
interleukin (IL)-5, and IL-4/IL-13 in patients with severe refractory asthma.
RECENT FINDINGS: The heterogeneity of airway inflammation in severe asthma has
led to the recognition of multiple pathophysiologically distinct severe asthma
endotypes. Biomarkers are being developed and evaluated to identify these
endotypes and to guide the use of specific biologics in the appropriate patients
who remain uncontrolled on high doses of inhaled corticosteroids and long-acting
bronchodilators or oral corticosteroids. Examples include the efficacy of
omalizumab in patients with severe refractory atopic asthma characterized by
raised serum total IgE, mepolizumab, reslizumab, and benralizumab in patients
with recurrent eosinophilic exacerbations characterized by blood and sputum
eosinophilia despite high doses of corticosteroids, and lebrikizumab,
pitrakinra, dupilumab, and tralokinumab that target the IL-4/IL-13 signalling
pathways in patients with eosinophilic asthma or raised serum periostin.
SUMMARY: In severe refractory asthma, both an understanding of the underlying
pathophysiologic mechanisms driving airway inflammation and the identification
of appropriate biomarkers in individual patients are critical in guiding the use
of biologics and monoclonal antibodies that target the specific pathological
processes.
DOI: 10.1097/MCP.0000000000000007
PMID: 24275927 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23001136 | 1. Pediatr Surg Int. 2012 Nov;28(11):1045-58. doi: 10.1007/s00383-012-3175-6.
Epub 2012 Sep 23.
Chromosomal and related Mendelian syndromes associated with Hirschsprung's
disease.
Moore SW(1).
Author information:
(1)Division of Pediatric Surgery, Department of Surgical Sciences, Faculty of
Health Sciences, University of Stellenbosch, P.O. Box 19063, Tygerberg, South
Africa. [email protected]
Hirschsprung's disease (HSCR) is a fairly frequent cause of intestinal
obstruction in children. It is characterized as a sex-linked heterogonous
disorder with variable severity and incomplete penetrance giving rise to a
variable pattern of inheritance. Although Hirschsprung's disease occurs as an
isolated phenotype in at least 70% of cases, it is not infrequently associated
with a number of congenital abnormalities and associated syndromes,
demonstrating a spectrum of congenital anomalies. Certain of these syndromic
phenotypes have been linked to distinct genetic sites, indicating underlying
genetic associations of the disease and probable gene-gene interaction, in its
pathogenesis. These associations with HSCR include Down's syndrome and other
chromosomal anomalies, Waardenburg syndrome and other Dominant sensorineural
deafness, the Congenital Central Hypoventilation and Mowat-Wilson and other
brain-related syndromes, as well as the MEN2 and other tumour associations. A
number of other autosomal recessive syndromes include the Shah-Waardenburg, the
Bardet-Biedl and Cartilage-hair hypoplasia, Goldberg-Shprintzen syndromes and
other syndromes related to cholesterol and fat metabolism among others. The
genetics of Hirschsprung's disease are highly complex with the majority of known
genetic sites relating to the main susceptibility pathways (RET an EDNRB).
Non-syndromic non-familial, short-segment HSCR appears to represent a
non-Mendelian condition with variable expression and sex-dependent penetrance.
Syndromic and familial forms, on the other hand, have complex patterns of
inheritance and being reported as autosomal dominant, recessive and polygenic
patterns of inheritance. The phenotypic variability and incomplete penetrance
observed in Hirschsprung's disease could also be explained by the involvement of
modifier genes, especially in its syndromic forms. In this review, we look at
the chromosomal and Mendelian associations and their underlying signalling
pathways, to obtain a better understanding of the pathogenetic mechanisms
involved in developing aganglionosis of the distal bowel.
DOI: 10.1007/s00383-012-3175-6
PMID: 23001136 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20565230 | 1. Curr Med Res Opin. 2010 Aug;26(8):1933-46. doi: 10.1185/03007995.2010.493132.
Current strategies in the management of hypereosinophilic syndrome, including
mepolizumab.
Schwartz LB(1), Sheikh J, Singh A.
Author information:
(1)Division of Rheumatology, Allergy & Immunology, Virginia Commonwealth
University, Richmond, VA 23298, USA. [email protected]
BACKGROUND: Patients with hypereosinophilic syndrome (HES) vary considerably in
their clinical presentation with regard to the severity and pattern of end-organ
involvement. Clinical manifestations range from nonspecific symptoms to
life-threatening, multisystem damage caused by eosinophil infiltration and local
release of proinflammatory mediators and toxic granule products from these
invading cells. The primary objective of treatment is to reduce blood and tissue
eosinophilia and prevent eosinophil-mediated tissue damage as safely as
possible. Systemic corticosteroids, such as prednisone, are first-line therapy
for the management of patients with symptomatic HES who lack the Fip1-like
1-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFRA) gene fusion
mutation. The tyrosine kinase inhibitor, imatinib, is first-line treatment for
FIP1L1-PDGFRA-positive patients). Because of the toxicity and serious
side-effects that can occur with oral corticosteroids, alternative therapies may
need to be introduced to reduce the cumulative corticosteroid exposure while
maintaining disease control.
SCOPE: Among corticosteroid-sparing agents are cytotoxic drugs and
interferon-alpha; anti-interleukin-5 (IL-5) monoclonal antibodies are also
currently under investigation for the treatment of HES. This manuscript reviews
the available treatments for HES and the range of side-effects associated with
long-term corticosteroid use, and then focuses on the anti-IL-5 monoclonal
antibodies, mepolizumab and reslizumab. Of these, only mepolizumab has been
studied in a randomized, placebo-controlled trial. Literature search methodology
utilized www.pubmed.gov and www.clinicaltrials.gov with search terms including
hypereosinophilic syndrome and corticosteroid side-effects coupled with search
terms including eosinophils, mepolizumab and reslizumab through March 2010.
FINDINGS: Three case studies are presented that demonstrate the limitations of
corticosteroid therapy in terms of tolerability and quality of life, and the
subsequent use of mepolizumab as a corticosteroid-sparing agent in these
individuals.
CONCLUSION: Targeted eosinophil-directed therapy with an anti-IL-5 neutralizing
monoclonal antibody reduced the need for corticosteroids in these three HES
patients without disease exacerbations.
DOI: 10.1185/03007995.2010.493132
PMID: 20565230 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22821884 | 1. Am J Med Genet A. 2012 Sep;158A(9):2106-18. doi: 10.1002/ajmg.a.35449. Epub
2012 Jul 20.
A novel HRAS substitution (c.266C>G; p.S89C) resulting in decreased downstream
signaling suggests a new dimension of RAS pathway dysregulation in human
development.
Gripp KW(1), Bifeld E, Stabley DL, Hopkins E, Meien S, Vinette K, Sol-Church K,
Rosenberger G.
Author information:
(1)Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington,
Delaware, USA.
Costello syndrome is caused by HRAS germline mutations affecting Gly(12) or
Gly(13) in >90% of cases and these are associated with a relatively homogeneous
phenotype. Rarer mutations in other HRAS codons were reported in patients with
an attenuated or mild phenotype. Disease-associated HRAS missense mutations
result in constitutive HRAS activation and increased RAF-MEK-ERK and PI3K-AKT
signal flow. Here we report on a novel heterozygous HRAS germline alteration,
c.266C>G (p.S89C), in a girl presenting with severe fetal hydrops and pleural
effusion, followed by a more benign postnatal course. A sibling with the same
mutation and fetal polyhydramnios showed a Dandy-Walker malformation; his
postnatal course was complicated by severe feeding difficulties. Their
apparently asymptomatic father is heterozygous for the c.266C>G change. By
functional analyses we identified reduced levels of active HRAS(S89C) and
diminished MEK, ERK and AKT phosphorylation in cells overexpressing HRAS(S89C) ,
which represent novel consequences of disease-associated HRAS mutations. Given
our patients' difficult neonatal course and presence of this change in their
asymptomatic father, we hypothesize that its harmful consequences may be time
limited, with the late fetal stage being most sensitive. Alternatively, the
phenotype may develop only in the presence of an additional as-yet-unknown
genetic modifier. While the pathogenicity of the HRAS c.266C>G change remains
unproven, our data may illustrate wide functional and phenotypic variability of
germline HRAS mutations.
Copyright © 2012 Wiley Periodicals, Inc.
DOI: 10.1002/ajmg.a.35449
PMCID: PMC4166655
PMID: 22821884 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24324801 | 1. PLoS One. 2013 Dec 4;8(12):e82506. doi: 10.1371/journal.pone.0082506.
eCollection 2013.
Chronic increase of urea leads to carbamylated proteins accumulation in tissues
in a mouse model of CKD.
Pietrement C(1), Gorisse L, Jaisson S, Gillery P.
Author information:
(1)Department of Pediatrics (Nephrology unit), University Hospital of Reims,
Reims, France ; Laboratory of Biochemistry and Molecular Biology, FRE CNRS/URCA
N° 3481, Faculty of Medicine, Reims, France.
Carbamylation is a general process involved in protein molecular ageing due to
the nonenzymatic binding of isocyanic acid, mainly generated by urea
dissociation, to free amino groups. In vitro experiments and clinical studies
have suggested the potential involvement of carbamylated proteins (CPs) in
chronic kidney disease (CKD) complications like atherosclerosis, but their
metabolic fate in vivo is still unknown. To address this issue, we evaluated
protein carbamylation in the plasma and tissues of control and 75%
nephrectomised C57BL/6J mice by LC-MS/MS assay of homocitrulline, the major
carbamylation-derived product (CDP). A basal level of carbamylation was
evidenced under all conditions, showing that carbamylation is a physiological
process of protein modification in vivo. CP plasma concentrations increased in
nephrectomized vs. control mice over the 20 weeks of the experiment (e.g. 335 ±
43 vs. 167 ± 19 μmol homocitrulline/mol lysine (p<0.001) 20 weeks after
nephrectomy). Simultaneously, CP content increased roughly by two-fold in all
tissues throughout the experiment. The progressive accumulation of CPs was
specifically noted in long-lived extracellular matrix proteins, especially
collagen (e.g. 1264 ± 123 vs. 726 ± 99 μmol homocitrulline/mol lysine (p<0.01)
in the skin of nephrectomized vs. control mice after 20 weeks of evolution).
These results show that chronic increase of urea, as seen in CKD, increases the
carbamylation rate of plasma and tissue proteins. These results may be
considered in the perspective of the deleterious effects of CPs demonstrated in
vitro and of the correlation evidenced recently between plasma CPs and
cardiovascular risk or mortality in CKD patients.
DOI: 10.1371/journal.pone.0082506
PMCID: PMC3853192
PMID: 24324801 [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/21378354 | 1. Anticancer Res. 2011 Feb;31(2):671-6.
Premenopausal hormone-responsive breast cancer with extensive axillary nodes
involvement: total estrogen blockade and chemotherapy.
Recchia F(1), Candeloro G, Necozione S, Desideri G, Recchia CO, Piazze J, Rea S.
Author information:
(1)Civilian Hospital, Oncology Department, Avezzano, Italy.
[email protected]
BACKGROUND: Poor prognosis is associated with estrogen- and/or progesterone
receptor-positive (ER(+), PGR(+)) premenopausal breast cancer (PM-BC) with high
Ki-67 labeling index and extensive axillary lymph node involvement. The role of
adjuvant chemotherapy (CT) and hormonal therapy have not yet been established in
these patients.
PATIENTS AND METHODS: Twenty-five PM-BC patients received, in sequence,
leuprorelin, taxane-anthracycline induction chemotherapy, radiation therapy, a
platinum-based intensification high-dose CT, followed by leuprorelin and
anastrazole for five years. Vascular endothelial growth factor (VEGF) levels
were measured as the primary end-point; secondary end-points were 10-year
relapse-free survival (RFS) and overall survival (OS) rates.
RESULTS: The median patient age was 44 years, and the mean number of positive
axillary nodes was 14. All patients were ER(+) and/or PGR(+), with a median
Ki-67 index of 33%. Five patients were Cerb-B2 positive. Grade 4 hematologic
toxicity was observed in all patients, no patient showed a decrease of cardiac
ejection fraction and hot flashes and arthralgias were of moderate intensity.
After a median follow-up of 70 months, VEGF levels significantly decreased
(p<0.001); 10-year RFS and OS were 76% and 78%, respectively.
CONCLUSION: Total estrogen blockade and high-dose CT in PM-BC patients is
feasible, has moderate toxicity, significantly reduces VEGF levels, and seems to
improve the expected RFS and OS.
PMID: 21378354 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12455694 | 1. Eukaryot Cell. 2002 Oct;1(5):758-73. doi: 10.1128/EC.1.5.758-773.2002.
mcl1+, the Schizosaccharomyces pombe homologue of CTF4, is important for
chromosome replication, cohesion, and segregation.
Williams DR(1), McIntosh JR.
Author information:
(1)Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, Colorado 80309-0347, USA. [email protected]
The fission yeast minichromosome loss mutant mcl1-1 was identified in a screen
for mutants defective in chromosome segregation. Missegregation of the
chromosomes in mcl1-1 mutant cells results from decreased centromeric cohesion
between sister chromatids. mcl1+ encodes a beta-transducin-like protein with
similarity to a family of eukaryotic proteins that includes Ctf4p from
Saccharomyces cerevisiae, sepB from Aspergillus nidulans, and AND-1 from humans.
The previously identified fungal members of this protein family also have
chromosome segregation defects, but they primarily affect DNA metabolism.
Chromosomes from mcl1-1 cells were heterogeneous in size or structure on
pulsed-field electrophoresis gels and had elongated heterogeneous telomeres.
mcl1-1 was lethal in combination with the DNA checkpoint mutations rad3delta and
rad26delta, demonstrating that loss of Mcl1p function leads to DNA damage.
mcl1-1 showed an acute sensitivity to DNA damage that affects S-phase
progression. It interacts genetically with replication components and causes an
S-phase delay when overexpressed. We propose that Mcl1p, like Ctf4p, has a role
in regulating DNA replication complexes.
DOI: 10.1128/EC.1.5.758-773.2002
PMCID: PMC126746
PMID: 12455694 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18021699 | 1. Med Sci (Paris). 2007 Nov;23(11):910-6. doi: 10.1051/medsci/20072311910.
[Etiopathogenesis of adolescent idiopathic scoliosis and new molecular
concepts].
[Article in French]
Letellier K(1), Azeddine B, Blain S, Turgeon I, Wang da S, Boiro MS, Moldovan F,
Labelle H, Poitras B, Rivard CH, Grimard G, Parent S, Ouellet J, Lacroix G,
Moreau A.
Author information:
(1)Centre de recherche, CHU Sainte-Justine, Laboratoires de Génétique
Moléculaire et de Biologie Cellulaire et Tissulaire des Maladies
Musculo-Squelettiques, 3175, chemin de la Côte-Ste-Catherine, Montréal (Québec),
H3T 1C5 Canada.
Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis that
affects a significant number of young teenagers, mainly females (0.2-6 % of the
population). Historically, several hypothesis were postulated to explain the
aetiology of AIS, including genetic factors, biochemical factors, mechanics,
neurological, muscular factors and hormonal factors. The neuroendocrine
hypothesis involving a melatonin deficiency as the source for AIS has generated
great interest. This hypothesis stems from the fact that experimental
pinealectomy in chicken, and more recently in rats maintained in a bipedal mode,
produces a scoliosis. The biological relevance of melatonin in idiopathic
scoliosis is controversial since no significant decrease in circulating
melatonin level has been observed in a majority of studies. Analysis of
melatonin signal transduction in musculoskeletal tissues of AIS patients
demonstrated for the first time a defect occurring in a cell autonomous manner
in different cell types isolated from AIS patients suffering of the most severe
form of that disease. These results have led to a classification of AIS patients
in three different functional groups depending on their response to melatonin,
suggesting that the cause of AIS involves several genes. Molecular analysis
showed that melatonin signaling dysfunction is triggered by an increased
phosphorylation of Gi proteins inactivating their function. This discovery has
led to development of a first scoliosis screening assay. This test, using blood
sample, is currently in clinical validation process in Canada and could be used
for screening children at high risk of developing AIS.
DOI: 10.1051/medsci/20072311910
PMID: 18021699 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12566280 | 1. Brain. 2003 Mar;126(Pt 3):590-7. doi: 10.1093/brain/awg059.
Mutations in the neurofilament light chain gene (NEFL) cause early onset severe
Charcot-Marie-Tooth disease.
Jordanova A(1), De Jonghe P, Boerkoel CF, Takashima H, De Vriendt E, Ceuterick
C, Martin JJ, Butler IJ, Mancias P, Papasozomenos SCh, Terespolsky D, Potocki L,
Brown CW, Shy M, Rita DA, Tournev I, Kremensky I, Lupski JR, Timmerman V.
Author information:
(1)Molecular Genetics Department, Flanders Interuniversity Institute for
Biotechnology, University of Antwerp, Belgium.
Neurofilament light chain polypeptide (NEFL) is one of the most abundant
cytoskeletal components of the neuron. Mutations in the NEFL gene were recently
reported as a cause for autosomal dominant Charcot-Marie-Tooth type 2E (CMT2E)
linked to chromosome 8p21. In order to investigate the frequency and phenotypic
consequences of NEFL mutations, we screened 323 patients with CMT or related
peripheral neuropathies. We detected six disease associated missense mutations
and one 3-bp in-frame deletion clustered in functionally defined domains of the
NEFL protein. Patients have an early onset and often a severe clinical
phenotype. Electrophysiological examination shows moderately to severely slowed
nerve conduction velocities. We report the first nerve biopsy of a CMT patient
with a de novo missense mutation in NEFL, and found an axonal pathology with
axonal regeneration clusters and onion bulb formations. Our findings provide
further evidence that the clinical variation observed in CMT depends on the gene
mutated and the specific type of mutation, and we also suggest that NEFL
mutations need to be considered in the molecular evaluation of patients with
sporadic or dominantly inherited CMT.
DOI: 10.1093/brain/awg059
PMID: 12566280 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8345811 | 1. Metabolism. 1993 Aug;42(8):1059-64. doi: 10.1016/0026-0495(93)90023-h.
Stimulation of brain natriuretic peptide release from the heart by thyroid
hormone.
Kohno M(1), Horio T, Yasunari K, Yokokawa K, Ikeda M, Kurihara N, Nishizawa Y,
Morii H, Takeda T.
Author information:
(1)First Department of Internal Medicine, Osaka City University Medical School,
Japan.
This study was designed to examine the involvement of thyroid hormone in the
release of brain natriuretic peptide (BNP) from the heart. We measured plasma
immunoreactive BNP (ir-BNP) concentrations in patients with untreated
hyperthyroidism. We also measured BNP values in experimental rats with
hyperthyroidism induced by thyroxine (T4) and in rats with hypothyroidism
induced by propylthiouracil (PTU). The in vitro effects of triiodothyronine (T3)
and T4 on the release of BNP were examined in newborn rat atrial and ventricular
myocytes in primary culture. Plasma BNP levels were increased in hyperthyroid
patients compared with normal control subjects. Plasma BNP levels were increased
in hyperthyroid rats and decreased in hypothyroid rats compared with euthyroid
rats. Plasma BNP level was correlated with serum T4 level in hyperthyroid
patients and hyperthyroid rats. A major component of ir-BNP in plasma from
hyperthyroid patients was human BNP-32 and that in plasma from hyperthyroid rats
was rat BNP-45. T4 and T3 stimulated release of ir-BNP from both cultured atrial
and ventricular myocytes in a dose-dependent manner. Plasma BNP concentration is
frequently increased in hyperthyroidism, and thyroid hormone may regulate BNP
release from both atrial and ventricular myocytes.
DOI: 10.1016/0026-0495(93)90023-h
PMID: 8345811 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22096584 | 1. PLoS One. 2011;6(11):e27498. doi: 10.1371/journal.pone.0027498. Epub 2011 Nov
11.
Mild functional differences of dynamin 2 mutations associated to centronuclear
myopathy and Charcot-Marie Tooth peripheral neuropathy.
Koutsopoulos OS(1), Koch C, Tosch V, Böhm J, North KN, Laporte J.
Author information:
(1)Department of Translational Medecine, Institut de Génétique et de Biologie
Moléculaire et Cellulaire, Illkirch, France.
The large GTPase dynamin 2 is a key player in membrane and cytoskeletal dynamics
mutated in centronuclear myopathy (CNM) and Charcot-Marie Tooth (CMT)
neuropathy, two discrete dominant neuromuscular disorders affecting skeletal
muscle and peripheral nerves respectively. The molecular basis for the
tissue-specific phenotypes observed and the physiopathological mechanisms linked
to dynamin 2 mutations are not well established. In this study, we have analyzed
the impact of CNM and CMT implicated dynamin 2 mutants using ectopic expression
of four CNM and two CMT mutations, and patient fibroblasts harboring two dynamin
2 CNM mutations in established cellular processes of dynamin 2 action. Wild type
and CMT mutants were seen in association with microtubules whereas CNM mutants
lacked microtubules association and did not disrupt interphase microtubules
dynamics. Most dynamin 2 mutants partially decreased clathrin-mediated
endocytosis when ectopically expressed in cultured cells; however, experiments
in patient fibroblasts suggested that endocytosis is overall not defective.
Furthermore, CNM mutants were seen in association with enlarged clathrin stained
structures whereas the CMT mutant constructs were associated with clathrin
structures that appeared clustered, similar to the structures observed in Dnm1
and Dnm2 double knock-out cells. Other roles of dynamin 2 including its
interaction with BIN1 (amphiphysin 2), and its function in Golgi maintenance and
centrosome cohesion were not significantly altered. Taken together, these mild
functional defects are suggestive of differences between CMT and CNM
disease-causing dynamin 2 mutants and suggest that a slight impairment in
clathrin-mediated pathways may accumulate over time to foster the respective
human diseases.
DOI: 10.1371/journal.pone.0027498
PMCID: PMC3214065
PMID: 22096584 [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/17662673 | 1. J Cyst Fibros. 2008 Mar;7(2):102-9. doi: 10.1016/j.jcf.2007.06.001. Epub 2007
Jul 27.
Analysis of the CFTR gene in Iranian cystic fibrosis patients: identification of
eight novel mutations.
Alibakhshi R(1), Kianishirazi R, Cassiman JJ, Zamani M, Cuppens H.
Author information:
(1)Department of Medical Genetics, School of Medicine, Tehran University of
Medical Sciences, Tehran, Iran.
BACKGROUND: Cystic fibrosis (CF) is the most common inherited disorder in
Caucasian populations, with over 1400 mutations identified in the Cystic
Fibrosis Transmembrane conductance Regulator (CFTR) gene. Mutations in the CFTR
gene may be also causative for CBAVD (Congenital Bilateral Absence of the Vas
Deferens). The type and distribution of mutations varies widely between
different countries and/or ethnic groups, and is relatively unknown in Iran. We
therefore performed a comprehensive analysis of the CFTR gene in Iranian CF
patients.
METHODS: 69 Iranian CF patients, and 1 CBAVD patient, were analysed for
mutations in the complete coding region, and its exon/intron junctions, of their
CFTR genes, using different methods, such as ARMS (amplification refractory
mutation system)-PCR, SSCP (single stranded conformation polymorphism) analysis,
restriction enzyme digestion analysis, direct sequencing, and MLPA (Multiplex
Ligation-mediated Probe Amplification).
RESULTS: CFTR mutation analysis revealed the identification of 37 mutations in
69 Iranian CF patients. Overall, 81.9% (113/138) CFTR genes derived from Iranian
CF patients could be characterized for a disease-causing mutation. The CBAVD
patient was found to be homozygous for the p.W1145R mutation. The most common
mutations were p.F508del (DeltaF508) (18.1%), c.2183_2184delAAinsG (2183AA>G)
(6.5%), p.S466X (5.8%), p.N1303K (4.3%), c.2789+5G>A (4.3%), p.G542X (3.6%),
c.3120+1G>A (3.6%), p.R334W (2.9%) and c.3130delA (2.9%). These 9 types of
mutant CFTR genes totaled for 52% of all CFTR genes derived from the 69 Iranian
CF patients. Eight mutations, c.406-8T>C, p.A566D, c.2576delA,
c.2752-1_2756delGGTGGCinsTTG, p.T1036I, p.W1145R, c.3850-24G>A,
c.1342-?_1524+?del, were found for the first time in this study.
CONCLUSIONS: We identified 37 CFTR mutations in 69 well characterized Iranian CF
patients, obtaining a CFTR mutation detection rate of 81.9%, the highest
detection rate obtained in the Iranian population so far. These findings will
assist in genetic counseling, prenatal diagnosis and future screening of CF in
Iran.
DOI: 10.1016/j.jcf.2007.06.001
PMID: 17662673 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25209111 | 1. J Proteome Res. 2014 Oct 3;13(10):4436-45. doi: 10.1021/pr500770x. Epub 2014
Sep 23.
Systemic responses of BALB/c mice to Salmonella typhimurium infection.
Zhu X(1), Lei H, Wu J, Li JV, Tang H, Wang Y.
Author information:
(1)Key Laboratory of Magnetic Resonance in Biological Systems, State Key
Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre
for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese
Academy of Sciences , Wuhan 430071, P. R. China.
Salmonella typhimurium is a bacterial pathogen that poses a great threat to
humans and animals. In order to discover hosts' responses to S. typhimurium
infection, we collected and analyzed biofluids and organ tissues from mice which
had ingested S. typhimurium. We employed (1)H NMR spectroscopy coupled with
multivariate data analysis and immunological techniques. The results indicate
that infection leads to a severe impact on mice spleen and ileum, which are
characterized by splenomegaly and edematous villi, respectively. We found that
increased levels of itaconic acid were correlated with the presence of
splenomegaly during infection and may play an important role in
Salmonella-containing vacuole acidification. In addition, metabonomic analyses
of urine displayed the development of salmonellosis in mice, which is
characterized by dynamic changes in energy metabolism. Furthermore, we found
that the presence of S. typhimurium activated an anti-oxidative response in
infected mice. We also observed changes in the gut microbial co-metabolites
(hippurate, TMAO, TMA, methylamine). This investigation sheds much needed light
on the host-pathogen interactions of S. typhimurium, providing further
information to deepen our understanding of the long co-evolution process between
hosts and infective bacteria.
DOI: 10.1021/pr500770x
PMID: 25209111 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25064235 | 1. Acta Diabetol. 2014 Oct;51(5):887-90. doi: 10.1007/s00592-014-0626-7. Epub
2014 Jul 27.
Early pregnancy metabolite profiling discovers a potential biomarker for the
subsequent development of gestational diabetes mellitus.
de Seymour JV(1), Conlon CA, Sulek K, Villas Bôas SG, McCowan LM, Kenny LC,
Baker PN.
Author information:
(1)Liggins Institute, The University of Auckland, Building 505, 85 Park Road,
Grafton, Auckland, New Zealand, [email protected].
Current early pregnancy screening tools to identify women at risk of developing
gestational diabetes mellitus lack both specificity and sensitivity. As a
result, the foetus and mother are often subjected to insult during disease
progression, prior to diagnosis and treatment in later pregnancy. Metabolomics
is an analytical approach, which allows for appraisal of small molecular mass
compounds in a biofluid. The aim of this pilot study was to investigate the
relationship between the early gestation serum metabolite profile and the
subsequent development of gestational diabetes mellitus in the search for early
pregnancy biomarkers and potential metabolic mechanisms. Our nested case-control
study analysed maternal serum at 20 weeks' gestation, obtained from the New
Zealand cohort of the Screening for Pregnancy Endpoints study. Metabolomic
profiling was performed using gas chromatography coupled to mass spectrometry,
and metabolites were identified using R software and an in-house mass spectral
library. Statistical analysis was performed using SPSS version 21.0. Forty-eight
metabolites were identified in the serum samples. Itaconic acid (P = 0.0003),
with a false discovery rate of 0.012, was found to be significantly more
abundant in women who subsequently developed gestational diabetes mellitus, when
compared to controls with uncomplicated pregnancies. The current pilot study
found that itaconic acid may have potential as a novel biomarker in early
pregnancy to predict the subsequent development of gestational diabetes
mellitus. However, the findings from this pilot study require validation with a
larger, diverse population before translation into the clinical setting.
DOI: 10.1007/s00592-014-0626-7
PMID: 25064235 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16483939 | 1. Mol Cell. 2006 Feb 17;21(4):581-7. doi: 10.1016/j.molcel.2006.01.030.
Localization of MCM2-7, Cdc45, and GINS to the site of DNA unwinding during
eukaryotic DNA replication.
Pacek M(1), Tutter AV, Kubota Y, Takisawa H, Walter JC.
Author information:
(1)Department of Biological Chemistry and Molecular Pharmacology, Harvard
Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
Little is known about the architecture and biochemical composition of the
eukaryotic DNA replication fork. To study this problem, we used
biotin-streptavidin-modified plasmids to induce sequence-specific replication
fork pausing in Xenopus egg extracts. Chromatin immunoprecipitation was employed
to identify factors associated with the paused fork. This approach identifies
DNA pol alpha, DNA pol delta, DNA pol epsilon, MCM2-7, Cdc45, GINS, and Mcm10 as
components of the vertebrate replisome. In the presence of the DNA polymerase
inhibitor aphidicolin, which causes uncoupling of a highly processive DNA
helicase from the stalled replisome, only Cdc45, GINS, and MCM2-7 are enriched
at the pause site. The data suggest the existence of a large molecular machine,
the "unwindosome," which separates DNA strands at the replication fork and
contains Cdc45, GINS, and the MCM2-7 holocomplex.
DOI: 10.1016/j.molcel.2006.01.030
PMID: 16483939 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20888651 | 1. Int J Cardiol. 2012 Jan 26;154(2):153-7. doi: 10.1016/j.ijcard.2010.09.002.
Epub 2010 Oct 2.
Low triiodothyronine and exercise capacity in heart failure.
Fontana M(1), Passino C, Poletti R, Zyw L, Prontera C, Scarlattini M, Clerico A,
Emdin M, Iervasi G.
Author information:
(1)Division of Cardiovascular Medicine, Fondazione G. Monasterio CNR-Regione
Toscana, Pisa, Italy.
BACKGROUND: Cardiopulmonary exercise test (CPT) has a prominent value in
assessing clinical severity in chronic heart failure (HF) patients. Reduced free
triiodothyronine (fT3) plasma level is associated with a more severe disease and
prognosis. The aim of this study was to evaluate the relationship between low
fT3 plasma level and reduced exercise capacity in chronic HF, and to determine
the influence of a low T3 status in subsets of patients with different
functional impairment.
METHODS AND RESULTS: 240 HF patients (79% males; age 62 ± 12 years, mean ±
standard deviation; left ventricular ejection fraction, EF, 30 ± 9%) underwent a
CPT, clinical and neurohormonal characterization (assay for plasma brain
natriuretic peptide, BNP, norepinephrine, aldosterone, renin activity, fT3, free
T4, thyroid-stimulating hormone). At multivariate analysis in the whole
population, age, gender and BNP level were independently associated with peak
VO2, whereas in patients with severe functional impairment (peak VO2 < 14
ml/min/kg) fT3 resulted independently related to peak VO2, together with gender
and BNP. When patients with peak VO2 < 14 ml/min/kg were divided according to
fT3 levels, patients with low T3 syndrome showed reduced exercise capacity and
worse ventilatory efficiency.
CONCLUSIONS: BNP and fT3 are independently associated with exercise capacity in
severely compromised HF patients.
Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.ijcard.2010.09.002
PMID: 20888651 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15510218 | 1. EMBO J. 2004 Nov 10;23(22):4384-93. doi: 10.1038/sj.emboj.7600453. Epub 2004
Oct 28.
Crystal structure of ATF-2/c-Jun and IRF-3 bound to the interferon-beta
enhancer.
Panne D(1), Maniatis T, Harrison SC.
Author information:
(1)Department of Biological Chemistry & Molecular Pharmacology, Howard Hughes
Medical Institute, Harvard Medical School, Boston, MA, USA.
Transcriptional activation of the interferon-beta (IFN-beta) gene requires
assembly of an enhanceosome containing the transcription factors ATF-2/c-Jun,
IRF-3/IRF-7, NF-kappaB and HMGI(Y). These factors cooperatively bind a composite
DNA site and activate expression of the IFN-beta gene. The 3.0 A crystal
structure of the DNA-binding domains of ATF-2/c-Jun and two IRF-3 molecules in a
complex with 31 base pairs (bp) of the PRDIV-PRDIII region of the IFN-beta
enhancer shows that association of the four proteins with DNA creates a
continuous surface for the recognition of 24 bp. The structure, together with in
vitro binding studies and protein mutagenesis, shows that protein-protein
interactions are not critical for cooperative binding. Instead, cooperativity
arises mainly through nucleotide sequence-dependent structural changes in the
DNA that allow formation of complementary DNA conformations. Because the binding
sites overlap on the enhancer, the unit of recognition is the entire nucleotide
sequence, not the individual subsites.
DOI: 10.1038/sj.emboj.7600453
PMCID: PMC526468
PMID: 15510218 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22870736 | 1. Acta Cardiol. 2012 Jun;67(3):291-6. doi: 10.1080/ac.67.3.2160717.
The role of brain natriuretic peptide and serum triiodothyronine in the
diagnosis and prognosis of chronic heart failure.
Du JB(1), Da CH, Zhao Y, Guo Y, Guo G, Ju TF, Xu YP.
Author information:
(1)Affiliated Baiyin Hospital of Lanzhou University, Baiyin, China.
[email protected]
OBJECTIVE: The objective of this paper was to investigate the diagnostic and
prognostic value of plasma B type natriuretic peptide (BNP) and serum
triiodothyronine (T3) in chronic congestive heart failure (CHF).
METHODS: 156 cases of CHF patients and 75 cases of cardiac function I patients
hospitalized over the same period were utilized in this study. On admission, the
patient's BNP and T3 plasma concentrations were measured. The correlation
analysis of plasma BNP and T3 in CHF patients with cardiac function
classification was conducted.
RESULTS: According to the NYHA grading systems, the plasma BNP levels in
patients with II, III, and IV grade CHF were significantly higher than those
with cardiac function I (P < 0.05); BNP levels and NYHA grading of cardiac
function correlated positively. The BNP concentrations increased with CHF
progression (P < 0.01). The T3 level and NYHA grading of cardiac function
correlated negatively.TheT3 level decreased as the degree of heart failure
increased. Using CHF in combination with BNP to predict the occurrence of CHF
had a sensitivity value of 90.8% with 95.5% specificity, 86.3% accuracy, and a
negative predictive value of 87.7%.
CONCLUSIONS: Plasma BNP was more sensitive than T3 in the diagnosis of CHF. The
T3 was more meaningful than the BNP in the prognosis of CHF. The BNP and T3
combination detection was more valuable in determining the severity of CHF and
prognosis.
DOI: 10.1080/ac.67.3.2160717
PMID: 22870736 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25533115 | 1. G Ital Cardiol (Rome). 2014 Dec;15(12):664-9. doi: 10.1714/1718.18766.
[Role of secreted and lipoprotein-associated phospholipase A2 in cardiovascular
risk].
[Article in Italian]
Ferri N, Corsini A.
Phospholipase A(2) (PLA(2)) are enzymes that hydrolyze the ester bond of
glycerophospholipids releasing free fatty acids and lysophospholipids, including
the arachidonic acid, the precursor of the eicosanoids and the inflammatory
cascades. PLA(2) are present in the atherosclerotic plaques and their direct
involvement in the proatherogenic inflammatory response is well documented.
Epidemiological and genetic studies have demonstrated the correlation of the
PLA(2) mass and enzymatic activity with the incidence of cardiovascular
diseases. The potential pro-atherogenic role of PLA(2) led to the development of
two small molecules, varespladib, a reversible sPLA(2) inhibitor, and
darapladib, a selective Lp-PLA(2) inhibitor. Both molecules have demonstrated
antiatherosclerotic properties in animal models, and positive effects on
atherosclerotic plaque composition evaluated in phase 2 clinical trials. On
these grounds, the results of three phase 3 studies have recently been
published: the VISTA-16 study with varespladib in patients with acute coronary
syndrome, and the STABILITY and SOLID-TIMI 52 studies with darapladib in
patients with stable coronary heart disease and acute coronary syndrome,
respectively. Unexpectedly, both studies did not demonstrate an additional
protective action of PLA 2 inhibitors over the standard of care treatment with
statins, antiplatelet drugs, and coronary revascularization. In the present
article, the enzymatic properties and the involvement of sPLA(2) and Lp-PLA(2)
in atherogenesis are reviewed, with a focus on the results of experimental
studies and clinical studies with both varespladib and darapladib inhibitors.
DOI: 10.1714/1718.18766
PMID: 25533115 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24864079 | 1. Eur Heart J. 2014 Jul 14;35(27):1782-91. doi: 10.1093/eurheartj/ehu203. Epub
2014 May 26.
Anti-inflammatory therapies for cardiovascular disease.
Ridker PM(1), Lüscher TF(2).
Author information:
(1)Division of Cardiovascular Medicine, Center for Cardiovascular Disease
Prevention, Brigham and Women's Hospital, Harvard Medical School, 900
Commonwealth Avenue, Boston, MA, 02215 USA Division of Preventive Medicine,
Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital,
Harvard Medical School, 900 Commonwealth Avenue, Boston, MA, 02215 USA
[email protected].
(2)Cardiology, University Heart Center, University Hospital Zurich and Center
for Molecular Cardiology, Campus Schlieren, University Zurich, Zurich,
Switzerland.
Atherothrombosis is no longer considered solely a disorder of lipoprotein
accumulation in the arterial wall. Rather, the initiation and progression of
atherosclerotic lesions is currently understood to have major inflammatory
influences that encompass components of both the innate and acquired immune
systems. Promising clinical data for 'upstream' biomarkers of inflammation such
as interleukin-6 (IL-6) as well as 'downstream' biomarkers such as C-reactive
protein, observations regarding cholesterol crystals as an activator of the
IL-1β generating inflammasome, and recent Mendelian randomization data for the
IL-6 receptor support the hypothesis that inflammatory mediators of
atherosclerosis may converge on the central IL-1, tumour necrosis factor
(TNF-α), IL-6 signalling pathway. On this basis, emerging anti-inflammatory
approaches to vascular protection can be categorized into two broad groups,
those that target the central IL-6 inflammatory signalling pathway and those
that do not. Large-scale Phase III trials are now underway with agents that lead
to marked reductions in IL-6 and C-reactive protein (such as canakinumab and
methotrexate) as well as with agents that impact on diverse non-IL-6-dependent
pathways (such as varespladib and darapladib). Both approaches have the
potential to benefit patients and reduce vascular events. However, care should
be taken when interpreting these trials as outcomes for agents that target IL-6
signalling are unlikely to be informative for therapies that target alternative
pathways, and vice versa. As the inflammatory system is redundant, compensatory,
and crucial for survival, evaluation of risks as well as benefits must drive the
development of agents in this class.
Published on behalf of the European Society of Cardiology. All rights reserved.
© The Author 2014. For permissions please email: [email protected].
DOI: 10.1093/eurheartj/ehu203
PMCID: PMC4155455
PMID: 24864079 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19181292 | 1. J Card Fail. 2009 Feb;15(1):35-40. doi: 10.1016/j.cardfail.2008.08.008. Epub
2008 Oct 4.
Prognostic value of combined measurement of brain natriuretic peptide and
triiodothyronine in heart failure.
Passino C(1), Pingitore A, Landi P, Fontana M, Zyw L, Clerico A, Emdin M,
Iervasi G.
Author information:
(1)Department of Cardiovascular Medicine, G. Monasterio Foundation,
CNR-Institute of Clinical Physiology, Pisa, Italy.
BACKGROUND: Both low free triiodothyronine (fT3) and high brain natriuretic
peptide (BNP) have been separately described as prognostic predictors for
mortality in heart failure (HF). We investigated whether their prognostic value
is independent.
METHODS AND RESULTS: From January of 2001 to December of 2006, we prospectively
evaluated 442 consecutive patients with systolic HF and no thyroid disease or
treatment with drugs affecting thyroid function (age 65+/-12 years, mean +/-
standard deviation, 75% were male, left ventricular ejection fraction 33% +/-
10%, New York Heart Association (NYHA) class I and II: 63%, NYHA class III and
IV: 37%). All patients underwent full clinical and echocardiographic evaluation
and assessment of BNP and thyroid function. Both cardiac and all-cause mortality
(cumulative) were considered as end points. During a median 36-month follow-up
(range 1-86 months), 110 patients (24.8%) died, 64 (14.4%) of cardiac causes.
Univariate Cox model predictors of all-cause mortality and cardiac death were
age, body mass index, creatinine, hemoglobin, ejection fraction, NYHA class,
BNP, fT3, and thyroxine level. Multivariate analysis selected age, NYHA class,
hemoglobin, BNP, and fT3 as independent predictors for all-cause mortality and
NYHA class, BNP, and fT3 as independent predictors for cardiac mortality.
Patients with low fT3 and higher BNP showed the highest risk of all-cause and
cardiac death (odds ratio 11.6, confidence interval, 5.8-22.9; odds ratio 13.8,
confidence interval, 5.4-35.2, respectively, compared with patients with normal
fT3 and low BNP).
CONCLUSION: fT3 and BNP hold an independent and additive prognostic value in HF.
DOI: 10.1016/j.cardfail.2008.08.008
PMID: 19181292 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25671117 | 1. Multidiscip Respir Med. 2015 Jan 16;10(1):1. doi: 10.1186/2049-6958-10-1.
eCollection 2015.
Tailored therapy for severe asthma.
Menzella F(1), Lusuardi M(2), Galeone C(1), Zucchi L(1).
Author information:
(1)Department of Cardiac-Thoracic-Vascular and Intensive Care Medicine,
Pneumology Unit, IRCCS- Arcispedale Santa Maria Nuova, Viale Risorgimento 56,
42123 Reggio Emilia, Italy.
(2)Unit of Respiratory Rehabilitation, AUSL Reggio Emilia, S. Sebastiano
Hospital, Correggio, Italy.
Patients with severe asthma or COPD have often a suboptimal symptom control due
to inadequate treatment. A better understanding of pathogenetic mechanisms,
phenotypes, endotypes and the new technologies available in the fields of
molecular biology and immunogenetics have made it possible to synthesize
specific monoclonal antibodies virtually able to interact with any target
antigen, or to open a way for new therapeutic target options. At the moment, the
only biologic drug available in clinical practice is omalizumab. To overcome the
limits of omalizumab, the research has focused on new monoclonal antibodies
presenting higher avidity for IgE (e.g. ligelizumab and lumiximab) and ability
to interact also with low affinity IgE receptor (FcϵRII). At present, many new
biological drugs with different mechanisms of action and targets are matter of
research. It is very important to identify the asthmatic phenotype in order to
select the most appropriate drug for the individual patient. The most promising
agents are targeted against cytokines of Th2 pattern and related receptors, such
as IL-2 (daclizumab) and IL-13 (lebrikizumab) or IL-5 in patients with
hypereosinophilia (mepolizumab, reslizumab and benralizumab). Other interesting
drugs have as a target TNF-α or its soluble receptor (infliximab, golimumab and
etanercept) or IL-1 (canakinumab), a cytokine with an important systemic
proinflammatory action. Finally, the discovery of increased levels of C5a in the
airways of asthmatic patients has led to the synthesis of a specific monoclonal
antibody (eculizumab). Further help should come from the identification of
biomarkers that can guide in choosing the best treatment for the individual
patient, such as IgE for omalizumab or periostin for lebrikizumab.
DOI: 10.1186/2049-6958-10-1
PMCID: PMC4323120
PMID: 25671117 |
http://www.ncbi.nlm.nih.gov/pubmed/24419257 | 1. Nat Rev Cardiol. 2014 Mar;11(3):130-2. doi: 10.1038/nrcardio.2013.220. Epub
2014 Jan 14.
Acute coronary syndromes: targeting inflammation-what has the VISTA-16 trial
taught us?
O'Donoghue ML(1).
Author information:
(1)TIMI Study Group, Brigham and Women's Hospital, 350 Longwood Avenue, 1st
Floor, Boston, MA 02115, USA.
Comment on
JAMA. 2014 Jan 15;311(3):252-62. doi: 10.1001/jama.2013.282836.
The VISTA-16 trial of varespladib, a secretory phospholipase A2 (sPLA2)
inhibitor, in patients with an acute coronary syndrome was terminated
prematurely owing to futility and a signal towards harm. Despite these
discouraging results, therapies that target inflammation to modify pathways in
atherogenesis remain an area of active investigation.
DOI: 10.1038/nrcardio.2013.220
PMID: 24419257 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12707075 | 1. Arch Neurol. 2003 Apr;60(4):598-604. doi: 10.1001/archneur.60.4.598.
Phenotypical features of a Moroccan family with autosomal recessive
Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1
gene.
Birouk N(1), Azzedine H, Dubourg O, Muriel MP, Benomar A, Hamadouche T,
Maisonobe T, Ouazzani R, Brice A, Yahyaoui M, Chkili T, Le Guern E.
Author information:
(1)Service de Neurologie, Hôpital des Spécialités, Rabat, Morocco.
[email protected]
BACKGROUND: The first locus for demyelinating autosomal recessive
Charcot-Marie-Tooth (ARCMT) disease was identified in 8q13, where mutations in
GDAP1 have been found. Mutations in the same gene have been detected in families
with axonal ARCMT disease.
OBJECTIVE: To determine the clinical, electrophysiologic, and morphologic
characteristics of a consanguineous Moroccan family with ARCMT disease
associated with the S194X mutation in the GDAP1 gene.
METHODS: Four patients from a consanguineous Moroccan family were examined
clinically and electrophysiologically. In one patient, a morphometric and
ultrastructural study of a peroneal nerve biopsy sample was performed. Mutation
in the coding region of the GDAP1 gene was identified by direct sequencing.
RESULTS: Neuropathy was evident early in childhood, walking was delayed in one
patient, and onset of symptoms occurred before 18 months in the others. The
phenotype was severe: foot deformities and disabilities involving the hands and
feet developed toward the end of the first decade, followed by involvement of
proximal muscles in the lower limbs, leading to loss of autonomy.
Electrophysiologic findings were consistent with an axonal form of CMT disease:
motor nerve conduction velocities, recordable in one patient only, were greater
than 40 m/sec. Sensory nerve action potentials were either abolished or
substantially reduced in amplitude. The morphologic data supported the diagnosis
of axonal neuropathy, showing a marked reduction in myelinated fibers and signs
of axonal regeneration, including frequent pseudo-onion bulb formations. The 4
patients in this family were homozygous for the S194X mutation in the GDAP1
gene.
CONCLUSION: Electrophysiologic and pathological findings support the hypothesis
of an axonal disorder in this ARCMT family with the S194X mutation in the GDAP1
gene.
DOI: 10.1001/archneur.60.4.598
PMID: 12707075 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18488247 | 1. Planta. 2008 Aug;228(3):391-9. doi: 10.1007/s00425-008-0743-z. Epub 2008 May
17.
Tissue dependent variations of DNA methylation and endoreduplication levels
during tomato fruit development and ripening.
Teyssier E(1), Bernacchia G, Maury S, How Kit A, Stammitti-Bert L, Rolin D,
Gallusci P.
Author information:
(1)INRA, UMR 619, BP 81, 33883, Villenave d'Ornon, France.
Tomato fruit cells are characterized by a strong increase in nuclear ploidy
during fruit development. Average ploidy levels increased to similar levels
(above 50C) in two distinct fruit tissues, pericarp and locular tissue. However,
ploidy profiles differed significantly between these two tissues suggesting a
tissue-specific control of endoreduplication in tomato fruit. To determine
possible relationships between endoreduplication and epigenetic mechanisms, the
methylation status of genomic DNA from pericarp and locular tissue of tomato
fruit was analysed. Pericarp genomic DNA was characterized by an increase of CG
and/or CNG methylation at the 5S and 18S rDNA loci and at gyspsy-like
retrotransposon sequences during fruit growth. A sharp decrease of the global
DNA methylation level together with a reduction of methylation at the rDNA loci
was also observed in pericarp during fruit ripening. Inversely, no major
variation of DNA methylation either global or locus-specific, was observed in
locular tissue. Thus, tissue-specific variations of DNA methylation are unlikely
to be triggered by the induction of endoreduplication in fruit tissues, but may
reflect tissue-specific ploidy profiles. Expression analysis of eight putative
tomato DNA methyltransferases encoding genes showed that one chromomethylase
(CMT) and two rearranged methyltransferases (DRMs) are preferentially expressed
in the pericarp during fruit growth and could be involved in the locus-specific
increase of methylation observed at this developmental phase in the pericarp.
DOI: 10.1007/s00425-008-0743-z
PMID: 18488247 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17635576 | 1. Eur J Clin Invest. 2007 Aug;37(8):651-7. doi:
10.1111/j.1365-2362.2007.01839.x.
Low triiodothyronine: a strong predictor of outcome in acute stroke patients.
Alevizaki M(1), Synetou M, Xynos K, Pappa T, Vemmos KN.
Author information:
(1)Evgenideion Hospital, Athens University School of Medicine, and Alexandra
Hospital, Athens University School of Medicine, Athens, Greece. [email protected]
BACKGROUND: Low triiodothyronine (T3) has been associated with increased
short-term mortality in intensive care unit patients and long-term mortality in
patients with heart disease. The objective of this study was to investigate
possible associations of thyroid hormone status with clinical outcome in
patients admitted for acute stroke.
MATERIALS AND METHODS: A total of 737 consecutive patients with acute first ever
stroke who presented within 24 h from symptoms' onset were studied. Total T3,
thyroxin (T4) and thyroid-stimulating hormone (TSH) levels were assessed in the
morning following admission. Cases with T3 values < or = 78 ng dL(-1) (1.2 nmol
L(-1)) (median) were characterized as 'low T3'. Cases with T4 values < or = 4.66
microg dL(-1) (60 nmol L(-1)) were characterized as 'low T4'. Basic and clinical
characteristics, stroke risk factors, and brain imaging were evaluated.
Neurological impairment was assessed using the Scandinavian Stroke Scale.
RESULTS: Four hundred and seventeen (56%) patients had T3 values < or = 78 ng
dL(-1) and 320 had normal T3 values. The 1-year mortality was 27.34% for low T3
and 19.37% for normal T3 cases (P = 0.006). A smaller percentage of patients
with low T3 values were independent at 1 year compared to those with normal T3
values [54.2% vs. 68.7%, chi(2) = 12.09, P < 0.001, odds ratio (OR) = 0.53, 95%
confidence interval (CI) 0.37-0.76]. Cox regression analysis revealed that
increased age, haemorrhagic stroke, low Scandinavian Stroke Scale score,
increased glucose and low T3 values (hazards ratio 0.69, CI = 0.48-0.98, P =
0.041) were significant predictors of 1-year mortality.
CONCLUSIONS: A high proportion of patients with acute stroke were found soon
after the event with low T3 values. The low-T3 syndrome is an independent
predictor of early and late survival in patients with acute stroke, and predicts
handicap at 1 year.
DOI: 10.1111/j.1365-2362.2007.01839.x
PMID: 17635576 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21098449 | 1. Circulation. 2010 Dec 7;122(23):2411-8. doi:
10.1161/CIRCULATIONAHA.110.950733. Epub 2010 Nov 22.
The sPLA2 Inhibition to Decrease Enzyme Release after Percutaneous Coronary
Intervention (SPIDER-PCI) trial.
Džavík V(1), Lavi S, Thorpe K, Yip PM, Plante S, Ing D, Overgaard CB, Osten MD,
Lan J, Robbins K, Miner SE, Horlick EM, Cantor WJ.
Author information:
(1)Interventional Cardiology Program, Division of Cardiology, Peter Munk Cardiac
Centre, University Health Network, Toronto, Ontario, Canada.
[email protected]
Comment in
Circulation. 2011 Sep 13;124(11):e298; author reply e299-300. doi:
10.1161/CIRCULATIONAHA.111.021683.
BACKGROUND: Secretory phospholipase A(2) (sPLA(2)) may play a role in
myonecrosis after elective percutaneous coronary intervention (PCI). Inhibition
of this enzyme may have a beneficial effect. The central hypothesis of this
study was that treatment with varespladib, a small-molecule inhibitor of sPLA(2)
would reduce postprocedural release of cardiac biomarkers after elective
percutaneous coronary intervention.
METHODS AND RESULTS: Between October 2007 and June 2009, 144 stable patients
were randomized in a phase II trial to receive varespladib 500 mg PO BID or
placebo 3 to 5 days before and for 5 days after elective percutaneous coronary
intervention. The primary end point was elevation of troponin I or creatine
kinase-MB above the upper limit of normal at 6 to 8 or 18 to 24 hours after
percutaneous coronary intervention. Mean age was 63±10 and 64±10 years, with 38%
and 42% with diabetes mellitus and 29% and 28% with prior myocardial infarction
for the varespladib and placebo groups, respectively. The primary end point
occurred in 75% of varespladib and 63% of placebo patients (P=0.14). Troponin I
3 times the upper limit of normal was observed in 57% and 50% (P=0.39) and
creatine kinase-MB 2 times the upper limit of normal in 14% and 3% (P=0.018).
Median (first and third quartiles) change in high-sensitivity C-reactive protein
in these 2 groups was 0.65 mg/L (-0.18 and 1.48) and 0.70 mg/L (0.00 and 1.50)
at 18 to 24 hours (P=0.81) and 0.20 mg/L (-0.70 and 1.40) and 0.60 mg/L (-0.12
and 1.72) at 3 to 5 days (P=0.23), whereas change in sPLA(2) activity at 3 to 5
days in a subset was -2.85 ng/ml (-3.40 and -1.85) and 0.25 ng/ml (-0.20 and
0.85) (P<0.001).
CONCLUSIONS: Inhibition of sPLA(2) by varespladib administered for 3 to 5 days
before the procedure does not reduce periprocedural myonecrosis associated with
elective percutaneous coronary intervention.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique
identifier: NCT00533039.
DOI: 10.1161/CIRCULATIONAHA.110.950733
PMID: 21098449 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25402275 | 1. PLoS One. 2014 Nov 17;9(11):e112394. doi: 10.1371/journal.pone.0112394.
eCollection 2014.
The sodium-glucose co-transporter 2 inhibitor empagliflozin improves
diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model
by interfering with oxidative stress and glucotoxicity.
Oelze M(1), Kröller-Schön S(1), Welschof P(1), Jansen T(1), Hausding M(1),
Mikhed Y(1), Stamm P(1), Mader M(1), Zinßius E(1), Agdauletova S(1), Gottschlich
A(1), Steven S(1), Schulz E(1), Bottari SP(2), Mayoux E(3), Münzel T(1), Daiber
A(1).
Author information:
(1)2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes
Gutenberg University, Mainz, Germany.
(2)Laboratory of Fundamental and Applied, Bioenergetics, INSERM U1055,
Grenoble-Alpes Université et Pôle de Biologie, CHU, Grenoble, France.
(3)Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
OBJECTIVE: In diabetes, vascular dysfunction is characterized by impaired
endothelial function due to increased oxidative stress. Empagliflozin, as a
selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), offers a novel
approach for the treatment of type 2 diabetes by enhancing urinary glucose
excretion. The aim of the present study was to test whether treatment with
empagliflozin improves endothelial dysfunction in type I diabetic rats via
reduction of glucotoxicity and associated vascular oxidative stress.
METHODS: Type I diabetes in Wistar rats was induced by an intravenous injection
of streptozotocin (60 mg/kg). One week after injection empagliflozin (10 and 30
mg/kg/d) was administered via drinking water for 7 weeks. Vascular function was
assessed by isometric tension recording, oxidative stress parameters by
chemiluminescence and fluorescence techniques, protein expression by Western
blot, mRNA expression by RT-PCR, and islet function by insulin ELISA in serum
and immunohistochemical staining of pancreatic tissue. Advanced glycation end
products (AGE) signaling was assessed by dot blot analysis and mRNA expression
of the AGE-receptor (RAGE).
RESULTS: Treatment with empagliflozin reduced blood glucose levels, normalized
endothelial function (aortic rings) and reduced oxidative stress in aortic
vessels (dihydroethidium staining) and in blood (phorbol ester/zymosan
A-stimulated chemiluminescence) of diabetic rats. Additionally, the
pro-inflammatory phenotype and glucotoxicity (AGE/RAGE signaling) in diabetic
animals was reversed by SGLT2i therapy.
CONCLUSIONS: Empagliflozin improves hyperglycemia and prevents the development
of endothelial dysfunction, reduces oxidative stress and improves the metabolic
situation in type 1 diabetic rats. These preclinical observations illustrate the
therapeutic potential of this new class of antidiabetic drugs.
DOI: 10.1371/journal.pone.0112394
PMCID: PMC4234367
PMID: 25402275 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: T.M. and A.D. received
research grants from Boehringer Ingelheim Pharma GmbH & Co. KG. E.M. is an
employee of Boehringer Ingelheim Pharma GmbH & Co. KG. The remaining authors
declare that they have no competing interests in connection with this
manuscript. This does not alter the authors' adherence to PLOS ONE policies on
sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/22585137 | 1. Curr Neurol Neurosci Rep. 2012 Aug;12(4):376-85. doi:
10.1007/s11910-012-0279-2.
Adenosine A2A antagonists in Parkinson's disease: what's next?
Hickey P(1), Stacy M.
Author information:
(1)Duke University Medical Center, DUMC Box 3333, Durham, NC 27205, USA.
[email protected]
Parkinson's disease (PD) is the second most prevalent neurodegenerative
disorder, affecting up to 10 million people worldwide. Current treatment
primarily involves symptom management with dopaminergic replacement therapy.
Levodopa remains the most effective oral treatment, although long-term use is
associated with complications such as wearing off, dyskinesias, and on-off
fluctuations. Non-dopaminergic medications that improve PD symptoms and motor
fluctuations are in demand. Adenosine A2A receptors are abundantly expressed
within the basal ganglia and offer a unique target to modify abnormal striatal
signaling associated with PD. Preclinical animal models have shown the ability
of adenosine A2A receptor antagonists to improve PD motor symptoms, reduce motor
fluctuations and dyskinesia, as well as protect against toxin-induced neuronal
degeneration. Both istradefylline and preladenant have demonstrated moderate
efficacy in reducing off time in PD patients with motor fluctuations. The safety
and efficacy of this class of compounds continues to be defined and future
studies should focus on non-motor symptoms, dyskinesias, and neuroprotection.
DOI: 10.1007/s11910-012-0279-2
PMID: 22585137 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16360419 | 1. Hum Pathol. 2006 Jan;37(1):78-86. doi: 10.1016/j.humpath.2005.09.022. Epub
2005 Nov 17.
Expression and localization of inhibitor of apoptosis proteins in normal human
tissues.
Vischioni B(1), van der Valk P, Span SW, Kruyt FA, Rodriguez JA, Giaccone G.
Author information:
(1)Department of Medical Oncology, VU University Medical Center, HV1081
Amsterdam, The Netherlands.
The family of inhibitor of apoptosis (IAP) proteins can suppress apoptosis
induced by a variety of triggers. Among the IAPs, cIAP1, cIAP2, and XIAP have
been characterized as inhibitors of specific caspases, and their expression,
together with that of survivin, has been shown in several studies to play a role
as tumor marker and prognostic factor for the survival of patients with cancer.
Although survivin is usually not expressed in normal adult tissues, cIAP1,
cIAP2, and XIAP have been found broadly expressed at messenger RNA level within
normal cells. Here, we report an immunohistochemical study in a comprehensive
panel of normal human tissues, and we confirm at the protein level the wide
expression of IAPs. These results are consistent with a physiological role of
IAPs in normal cells. Moreover, we show that IAPs' expression levels and
localization patterns differ depending on the cell lineage. The variable
subcellular localization of the IAPs within different cell types suggests that
compartmentalization may contribute to regulate their function. The
physiological role of these proteins should be further investigated to help
tailor IAP-targeted therapeutic strategies for patients with cancer and
circumvent possible side effects.
DOI: 10.1016/j.humpath.2005.09.022
PMID: 16360419 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18851962 | 1. Exp Cell Res. 2008 Dec 10;314(20):3692-700. doi: 10.1016/j.yexcr.2008.09.016.
Epub 2008 Oct 1.
A novel function of CEP135 as a platform protein of C-NAP1 for its centriolar
localization.
Kim K(1), Lee S, Chang J, Rhee K.
Author information:
(1)Department of Biological Sciences and Research Center for Functional
Cellulomics, Seoul National University, Seoul 151-747, Republic of Korea.
A proteomic study predicted that about one hundred kinds of proteins constitute
a basic structure of the centrosome. Most of the core centrosomal proteins
contain extensive coiled-coil domains, suggesting that the protein-protein
interaction is a critical force for the core centrosome configuration. In the
present study, we investigated a novel interaction between CEP135 and C-NAP1,
two core centriolar proteins. Depletion of CEP135 caused a premature centrosome
splitting. Reduction of the centrosomal C-NAP1 level was accompanied in a
specific manner. Ectopic expression of the CEP135 mutant proteins also caused
centrosome splitting in association with the reduction of the centrosomal C-NAP1
levels. Based on these results, we propose that CEP135 acts as a platform
protein for C-NAP1 at the centriole.
DOI: 10.1016/j.yexcr.2008.09.016
PMID: 18851962 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16952785 | 1. J Card Fail. 2006 Sep;12(7):520-6. doi: 10.1016/j.cardfail.2006.05.009.
Early activation of an altered thyroid hormone profile in asymptomatic or mildly
symptomatic idiopathic left ventricular dysfunction.
Pingitore A(1), Iervasi G, Barison A, Prontera C, Pratali L, Emdin M, Giannessi
D, Neglia D.
Author information:
(1)Institute of Clinical Physiology, CNR, Pisa, Italy.
BACKGROUND: Although an altered thyroid metabolism has been documented in
patients with overt heart failure, no evaluation has been made of a
heart-thyroid interaction in mildly symptomatic patients with idiopathic left
ventricular dysfunction (ILVD). We wanted to assess the thyroid state in
patients with ILVD.
METHODS AND RESULTS: Eighty-six patients (age 60 +/- 10 years) were enrolled
into the study. Thyroxine (T4), triiodothyronine (T3), thyrotropin, brain and
atrial natriuretic peptides (BNP, ANP), noradrenaline, aldosterone, renin
activity, and interleukin-6 were measured. Patients were divided into three
groups: Group N with LV ejection fraction (EF) > or = 50% (n = 28), Group I with
LVEF > 35%-< 50% (n = 34), Group II with LVEF < or = 35% (n = 24). There was a
significant correlation between T3 and LVEF (r = 0.25, P = .02) and a negative
correlation between T3 and BNP (r = -0.37, P < .0001). At univariate analysis T3
was a predictor of LV dysfunction, whereas BNP was the most important predictor
at multivariate analysis (P = .002). T3 was the only predictor of New York Heart
Association class at multivariate analysis.
CONCLUSION: An altered thyroid profile characterized by a reduction in
peripheral production of biologically active T3 is related to LV dysfunction and
early symptoms of heart failure in patients with ILVD.
DOI: 10.1016/j.cardfail.2006.05.009
PMID: 16952785 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21974927 | 1. J Cardiovasc Magn Reson. 2011 Oct 5;13(1):56. doi: 10.1186/1532-429X-13-56.
Regional contrast agent quantification in a mouse model of myocardial infarction
using 3D cardiac T1 mapping.
Coolen BF(1), Geelen T, Paulis LE, Nicolay K, Strijkers GJ.
Author information:
(1)Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of
Technology, PO BOX 513, 5600MB, Eindhoven, the Netherlands.
BACKGROUND: Quantitative relaxation time measurements by cardiovascular magnetic
resonance (CMR) are of paramount importance in contrast-enhanced studies of
experimental myocardial infarction. First, compared to qualitative measurements
based on signal intensity changes, they are less sensitive to specific parameter
choices, thereby allowing for better comparison between different studies or
during longitudinal studies. Secondly, T1 measurements may allow for
quantification of local contrast agent concentrations. In this study, a recently
developed 3D T1 mapping technique was applied in a mouse model of myocardial
infarction to measure differences in myocardial T1 before and after injection of
a liposomal contrast agent. This was then used to assess the concentration of
accumulated contrast agent.
MATERIALS AND METHODS: Myocardial ischemia/reperfusion injury was induced in 8
mice by transient ligation of the LAD coronary artery. Baseline quantitative T1
maps were made at day 1 after surgery, followed by injection of a Gd-based
liposomal contrast agent. Five mice served as control group, which followed the
same protocol without initial surgery. Twenty-four hours post-injection, a
second T1 measurement was performed. Local ΔR1 values were compared with
regional wall thickening determined by functional cine CMR and correlated to ex
vivo Gd concentrations determined by ICP-MS.
RESULTS: Compared to control values, pre-contrast T1 of infarcted myocardium was
slightly elevated, whereas T1 of remote myocardium did not significantly differ.
Twenty-four hours post-contrast injection, high ΔR1 values were found in regions
with low wall thickening values. However, compared to remote tissue (wall
thickening > 45%), ΔR1 was only significantly higher in severe infarcted tissue
(wall thickening < 15%). A substantial correlation (r = 0.81) was found between
CMR-based ΔR1 values and Gd concentrations from ex vivo ICP-MS measurements.
Furthermore, regression analysis revealed that the effective relaxivity of the
liposomal contrast agent was only about half the value determined in vitro.
CONCLUSIONS: 3D cardiac T1 mapping by CMR can be used to monitor the
accumulation of contrast agents in contrast-enhanced studies of murine
myocardial infarction. The contrast agent relaxivity was decreased under in vivo
conditions compared to in vitro measurements, which needs consideration when
quantifying local contrast agent concentrations.
DOI: 10.1186/1532-429X-13-56
PMCID: PMC3207957
PMID: 21974927 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25260362 | 1. Int J Toxicol. 2014 Nov-Dec;33(6):436-49. doi: 10.1177/1091581814551648. Epub
2014 Sep 26.
Nonclinical safety of the sodium-glucose cotransporter 2 inhibitor
empagliflozin.
Bogdanffy MS(1), Stachlewitz RF(2), van Tongeren S(2), Knight B(2), Sharp DE(2),
Ku W(2), Hart SE(2), Blanchard K(2).
Author information:
(1)Nonclinical Drug Safety, Boehringer Ingelheim Pharmaceuticals, Inc,
Ridgefield, CT, USA [email protected].
(2)Nonclinical Drug Safety, Boehringer Ingelheim Pharmaceuticals, Inc,
Ridgefield, CT, USA.
Empagliflozin, a selective inhibitor of the renal tubular sodium-glucose
cotransporter 2, was developed for treatment of type 2 diabetes mellitus.
Nonclinical safety of empagliflozin was studied in a battery of tests to support
global market authorization. Safety pharmacology studies indicated no effect of
empagliflozin on measures of respiratory or central nervous system function in
rats or cardiovascular safety in telemeterized dogs. In CD-1 mouse, Wistar Han
rat, or beagle dogs up to 13, 26, or 52 weeks of treatment, respectively,
empagliflozin exhibited a toxicity profile consistent with secondary
supratherapeutic pharmacology related to glucose loss and included decreased
body weight and body fat, increased food consumption, diarrhea, dehydration,
decreased serum glucose and increases in other serum parameters reflective of
increased protein catabolism, gluconeogenesis, and electrolyte imbalances, and
urinary changes such as polyuria and glucosuria. Microscopic changes were
consistently observed in kidney and included tubular nephropathy and
interstitial nephritis (dog), renal mineralization (rat) and tubular epithelial
cell karyomegaly, single cell necrosis, cystic hyperplasia, and hypertrophy
(mouse). Empagliflozin was not genotoxic. Empagliflozin was not carcinogenic in
female mice or female rats. Renal adenoma and carcinoma were induced in male
mice only at exposures 45 times the maximum clinical dose. These tumors were
associated with a spectrum of nonneoplastic changes suggestive of a
nongenotoxic, cytotoxic, and cellular proliferation-driven mechanism. In male
rats, testicular interstitial cell tumors and hemangiomas of the mesenteric
lymph node were observed; both tumors are common in rats and are unlikely to be
relevant to humans. These studies demonstrate the nonclinical safety of
empagliflozin.
© The Author(s) 2014.
DOI: 10.1177/1091581814551648
PMID: 25260362 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10747925 | 1. J Biol Chem. 2000 Jun 2;275(22):16910-7. doi: 10.1074/jbc.M000524200.
Signaling pathways to the assembly of an interferon-beta enhanceosome. Chemical
genetic studies with a small molecule.
Kim T(1), Kim TY, Lee WG, Yim J, Kim TK.
Author information:
(1)National Creative Research Initiative Center for Genetic Reprogramming,
Institute for Molecular Biology and Genetics, Seoul National University, Seoul
151-742, Korea. [email protected]
Small molecules that modulate specific protein functions are valuable tools for
dissecting complex signaling pathways. Here, we identified a small molecule that
induces the assembly of the interferon-beta (IFN-beta) enhanceosome by
stimulating all the enhancer-binding activator proteins: ATF2/c-JUN, IRF3, and
p50/p65 of NF-kappaB. This compound stimulates mitogen-activated protein kinase
kinase kinase 1 (MEKK1), which is a member of a family of proteins involved in
stress-mediated signaling pathways. Consistent with this, MEKK1 activates IRF3
in addition to ATF2/c-JUN and NF-kappaB for the assembly of the IFN-beta
enhanceosome. MEKK1 activates IRF3 through the c-JUN amino-terminal kinase (JNK)
pathway but not the p38 and IkappaB kinase (IKK) pathway. Taken together with
previous observations, these results implicate that, for the assembly of an
IFN-beta enhanceosome, MEKK1 can induce IRF3 and ATF2/c-JUN through the JNK
pathway, whereas it can induce NF-kappaB through the IKK pathway. Thus, specific
MEKK family proteins may be able to integrate some of multiple signal
transduction pathways leading to the specific activation of the IFN-beta
enhanceosome.
DOI: 10.1074/jbc.M000524200
PMID: 10747925 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18620103 | 1. Heart Lung. 2008 Jul-Aug;37(4):275-85. doi: 10.1016/j.hrtlng.2007.05.010.
Diagnostic and prognostic impact of brain natriuretic peptide in cardiac and
noncardiac diseases.
Zakynthinos E(1), Kiropoulos T, Gourgoulianis K, Filippatos G.
Author information:
(1)Critical Care Department, School of Medicine, University Hospital of
Thessaly, Thessaly, Greece.
OBJECTIVE: Cardiac secretion of brain natriuretic peptide (BNP) increases with
the progression of congestive heart failure (CHF). The plasma measurement of BNP
emerged recently as a useful, cost-effective biomarker for the diagnosis and
prognosis of CHF.
METHODS: BNP assay is useful for evaluating patients with acute dyspnea, because
a low level can help rule out CHF in primary care settings and reduce the demand
for echocardiography. Equally, BNP level can be particularly useful in
recognizing heart failure in a patient with acute dyspnea and a history of
chronic obstructive pulmonary disease.
RESULTS: However, although the clinical use of BNP as a biomarker in CHF is
increasing, the specificity of BNP in CHF is not strong, suggesting that other
mechanisms beyond simple ventricular stretch stimulate BNP release. Multiple
disorders in the intensive care unit, apart from CHF, cause elevated BNP levels,
including cardiovascular disease states such as ischemia, arrhythmias, cardiac
hypertrophy, and coronary endothelial dysfunction, as well as disorders of no
cardiac origin, such as sepsis, septic shock, and acute respiratory distress
syndrome. Moreover, the impact of increased BNP in patients with sepsis is not
clear. The relationship between BNP and both left ventricular ejection fraction
and left-sided filling pressures is weak, and data on the prognostic impact of
high BNP levels in patients with sepsis are conflicting.
CONCLUSION: Nevertheless, this review highlights the potential benefits of BNP
in the recognition and management of heart failure, and defines the gray zones
of BNP levels; it also identifies conditions influencing BNP levels in relation
to a certain heart failure and describes conditions of no cardiac origin with
increased BNP.
DOI: 10.1016/j.hrtlng.2007.05.010
PMID: 18620103 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22161952 | 1. Magn Reson Med. 2012 Oct;68(4):1127-34. doi: 10.1002/mrm.23323. Epub 2011 Dec
9.
Fast cardiac T1 mapping in mice using a model-based compressed sensing method.
Li W(1), Griswold M, Yu X.
Author information:
(1)Department of Biomedical Engineering, Case Western Reserve University,
Cleveland, Ohio 44106, United States of America.
Direct measurement of the longitudinal relaxation time T1 provides objective and
quantitative diagnostic information. However, current T1 mapping methods are
generally time consuming without the aid of fast imaging. This study used a
model-based compressed sensing method for fast cardiac T1 mapping in small
animals. Based on the physics of magnetization recovery, the aliasing artifact
associated with under-sampling was removed by exploiting the sparsity of the
signals in the T1 recovery direction. Simulation study was performed to evaluate
the reconstruction accuracy under various experimental conditions. Several
approaches that accounted for phase variations were compared for optimized
reconstruction in the phantom study. In vivo validation was performed on a
cardiac manganese-enhanced MRI study using mice. Accurate reconstruction of the
under-sampled images and the resulting T1 maps were achieved in both simulation
and MRI studies on phantom and in vivo mice. These results suggest that the
current compressed sensing method allows fast (<80 s) T1 mapping of the mouse
heart at high spatial resolution (234×469 μm2).
Copyright © 2011 Wiley Periodicals, Inc.
DOI: 10.1002/mrm.23323
PMCID: PMC3324650
PMID: 22161952 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23390498 | 1. PLoS One. 2013;8(2):e54442. doi: 10.1371/journal.pone.0054442. Epub 2013 Feb
4.
Effects of SGLT2 inhibition in human kidney proximal tubular
cells--renoprotection in diabetic nephropathy?
Panchapakesan U(1), Pegg K, Gross S, Komala MG, Mudaliar H, Forbes J, Pollock C,
Mather A.
Author information:
(1)Department of Medicine, The University of Sydney, Renal Research Group,
Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards,
New South Wales, Australia. [email protected]
Sodium/glucose cotransporter 2 (SGLT2) inhibitors are oral hypoglycemic agents
used to treat patients with diabetes mellitus. SGLT2 inhibitors block
reabsorption of filtered glucose by inhibiting SGLT2, the primary glucose
transporter in the proximal tubular cell (PTC), leading to glycosuria and
lowering of serum glucose. We examined the renoprotective effects of the SGLT2
inhibitor empagliflozin to determine whether blocking glucose entry into the
kidney PTCs reduced the inflammatory and fibrotic responses of the cell to high
glucose. We used an in vitro model of human PTCs. HK2 cells (human kidney PTC
line) were exposed to control 5 mM, high glucose (HG) 30 mM or the profibrotic
cytokine transforming growth factor beta (TGFβ1; 0.5 ng/ml) in the presence and
absence of empagliflozin for up to 72 h. SGLT1 and 2 expression and various
inflammatory/fibrotic markers were assessed. A chromatin immunoprecipitation
assay was used to determine the binding of phosphorylated smad3 to the promoter
region of the SGLT2 gene. Our data showed that TGFβ1 but not HG increased SGLT2
expression and this occurred via phosphorylated smad3. HG induced expression of
Toll-like receptor-4, increased nuclear deoxyribonucleic acid binding for
nuclear factor kappa B (NF-κB) and activator protein 1, induced collagen IV
expression as well as interleukin-6 secretion all of which were attenuated with
empagliflozin. Empagliflozin did not reduce high mobility group box protein 1
induced NF-κB suggesting that its effect is specifically related to a reduction
in glycotoxicity. SGLT1 and GLUT2 expression was not significantly altered with
HG or empagliflozin. In conclusion, empagliflozin reduces HG induced
inflammatory and fibrotic markers by blocking glucose transport and did not
induce a compensatory increase in SGLT1/GLUT2 expression. Although HG itself
does not regulate SGLT2 expression in our model, TGFβ increases SGLT2 expression
through phosphorylated smad3.
DOI: 10.1371/journal.pone.0054442
PMCID: PMC3563635
PMID: 23390498 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: Boehringer Ingelheim
provided the Empagliflozin and funding but had no role in the study design, data
analysis and data interpretation of the manuscript. This does not alter the
authors' adherence to all the PLOS ONE policies on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/24931636 | 1. Heart Rhythm. 2014 Sep;11(9):1551-9. doi: 10.1016/j.hrthm.2014.06.012. Epub
2014 Jun 12.
Magnetic resonance post-contrast T1 mapping in the human atrium: validation and
impact on clinical outcome after catheter ablation for atrial fibrillation.
Ling LH(1), McLellan AJ(1), Taylor AJ(2), Iles LM(2), Ellims AH(2), Kumar S(3),
Teh A(1), Lee G(1), Wong MC(1), Azzopardi S(2), Sellenger MA(2), Morton JB(3),
Kalman JM(3), Kistler PM(4).
Author information:
(1)Department of Cardiovascular Medicine, Alfred Hospital and Baker IDI Heart
and Diabetes Institute, Melbourne, Victoria, Australia; Cardiology Department,
Royal Melbourne Hospital, Victoria, Australia; Faculty of Medicine, Dentistry,
and Health Sciences, University of Melbourne, Victoria, Australia.
(2)Department of Cardiovascular Medicine, Alfred Hospital and Baker IDI Heart
and Diabetes Institute, Melbourne, Victoria, Australia.
(3)Cardiology Department, Royal Melbourne Hospital, Victoria, Australia; Faculty
of Medicine, Dentistry, and Health Sciences, University of Melbourne, Victoria,
Australia.
(4)Department of Cardiovascular Medicine, Alfred Hospital and Baker IDI Heart
and Diabetes Institute, Melbourne, Victoria, Australia; Faculty of Medicine,
Dentistry, and Health Sciences, University of Melbourne, Victoria, Australia.
Electronic address: [email protected].
BACKGROUND: The impact of diffuse atrial fibrosis detected by T1 mapping on the
clinical outcome after atrial fibrillation (AF) ablation is unknown.
OBJECTIVE: This study aimed to validate and assess the impact of post-contrast
cardiac magnetic resonance (CMR) imaging atrial T1 mapping on the clinical
outcome after catheter ablation for AF.
METHODS: CMR imaging was performed in 3 groups by using a clinical 1.5-T
scanner: controls, patients with paroxysmal AF, and patients with persistent AF.
A T1 mapping sequence was used to calculate the post-contrast T1 relaxation time
(T1 time) at the interatrial septum as an index of diffuse atrial fibrosis. A
subset underwent left atrial endocardial bipolar voltage mapping for
electrophysiologic correlation. After AF ablation, patients underwent clinical
review and 7-day Holter monitoring at 6-month intervals.
RESULTS: One hundred thirty-two patients (20 controls, 71 (63%) patients with
paroxysmal AF, and 41 (37%) patients with persistent AF) underwent CMR imaging.
Post-contrast atrial T1 time was significantly shorter in AF groups (237 ± 42
ms) than in controls (280 ± 37 ms) (P < .001). Post-contrast atrial T1 time
correlated with mean septal voltage (R2 = .48; P < .001) and global left atrial
voltage (R(2) = .41; P < .001). A diagnosis of AF, AF duration, and left
ventricular end-diastolic volume independently predicted shortened post-contrast
atrial T1 time. The single procedure success rate was 74% at 12 ± 5 months
postablation. Post-contrast atrial T1 time was the only predictor of arrhythmia
recurrence in multivariate analysis (P = .015). A post-contrast atrial T1 time
of >230 ms was associated with freedom from AF in 85% relative to 62% with a
post-contrast atrial T1 time of <230 ms (P = .01).
CONCLUSION: Post-contrast atrial T1 time as measured using CMR imaging provides
an index of atrial fibrosis that correlates with tissue voltage, presence of AF,
and clinical outcomes after catheter ablation.
Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights
reserved.
DOI: 10.1016/j.hrthm.2014.06.012
PMID: 24931636 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25175961 | 1. Int Rev Neurobiol. 2014;119:71-86. doi: 10.1016/B978-0-12-801022-8.00003-9.
An overview of adenosine A2A receptor antagonists in Parkinson's disease.
Jenner P(1).
Author information:
(1)Neurodegenerative Diseases Research Group, Institute of Pharmaceutical
Sciences, School of Biomedical Sciences, King's College, London, United Kingdom.
Electronic address: [email protected].
Adenosine A2A receptor antagonists represent a new way forward in the
symptomatic treatment of Parkinson's disease (PD) through a non-dopaminergic
mechanism. As a class, adenosine A2A antagonists are effective in reversing
motor deficits in haloperidol-treated rodents, 6-OHDA-lesioned rats, and
MPTP-treated primates when combined with low doses of l-dopa or dopamine agonist
drugs. Importantly, they improve motor function without worsening dyskinesia and
they may prevent the onset of involuntary movements. Adenosine A2A receptor
antagonists are active in animal models of reduced cognition, anxiety, and
depression and so this drug class may also be effective in controlling the
neuropsychiatric components of nonmotor symptoms in PD. Preclinical evidence has
shown that A2A antagonists can prevent neuronal loss in experimental models of
PD and their disease modifying activity needs to be explored in man.
Importantly, a number of A2A antagonists have been studied in PD in clinical
trial for their effects on motor function. So far, little evidence has emerged
of an effect of monotherapy with adenosine antagonists in early PD. However, in
later stage, patient populations already treated with dopaminergic drugs but
exhibiting "wearing off," adenosine antagonists have been demonstrated to reduce
"off" time without increasing troublesome dyskinesia in phase IIB trials.
However, in larger phase III evaluations, a consistent significant decrease in
"off" time has proved more difficult to demonstrate-due in part to trial
conduct. So far, only istradefylline has completed phase III development and it
is now marketed for the treatment of PD. Adenosine A2A antagonists are the first
non-dopaminergic approach to the treatment of PD to appear in the recent era.
They represent a novel way of approaching therapy that will provide additional
benefit to that achieved with dopaminergic medication, while avoiding common
side effects and may in addition, improve some nonmotor symptoms of PD that are
currently poorly treated.
© 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/B978-0-12-801022-8.00003-9
PMID: 25175961 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24169285 | 1. Zhonghua Yi Xue Za Zhi. 2013 Jul 9;93(26):2056-8.
[Clinical analysis of tuberous sclerosis complex complicated with renal
angiomyolipoma: a report of 22 cases].
[Article in Chinese]
Ting WY(1), Zhang YS, Li HZ, Zhang XB, Xu WF.
Author information:
(1)Department of Urology, Peking Union Medical College Hospital & Chinese
Academy of Medical Sciences, Beijing 100730, China.
OBJECTIVE: To explore the diagnosis and treatment of tuberous sclerosis complex
complicated with renal angiomyolipoma.
METHODS: The clinical data of 22 patients with tuberous sclerosis complex
complicated with renal angiomyolipoma were analyzed retrospectively.
RESULTS: There were 12 males and 10 females with a mean age of 23 (1-46) years.
All of them had bilateral multiple renal angiomyolipomas. The mean tumor size
was 8.5 (0.7-18.0) cm in diameter. The presence or absence of clinical symptoms
showed a significant correlation with tumor size.Eight patients with
angiomyolipoma under 4 cm in diameter were continuously monitored at an
outpatient clinic. There were 8 patients with lesions of 4-10 cm.Five of them
underwent nephron-sparing surgeries and another 3 monitored at an outpatient
clinic. There were 6 patients with tumor over 10 cm. Three of them underwent
transcatheter arterial embolization and one case took rapamycin after
embolization.One patient with concurrent renal cell carcinoma underwent partial
nephrectomy. Chronic renal failure occurred in one case dying of pulmonary
lymphangiomyomatosis with serious hemoptysis. During a mean follow-up of 25
months, neither severe renal hemorrhage nor symptomatic aggravation was found.In
the case of rapamycin, there was 10% reduction in the size of angiomyolipoma.
CONCLUSIONS: Most cases of tuberous sclerosis complex are complicated with
bilateral multiple renal angiomyolipoma. The small lesions under 4 cm in
diameter may be monitored at an outpatient clinic.For those larger (>4 cm) or
symptomatic ones, medication, embolization or surgery is necessary.
PMID: 24169285 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21279702 | 1. Med Oncol. 2012 Jun;29(2):750-4. doi: 10.1007/s12032-010-9815-6. Epub 2011 Jan
30.
Sequential treatment with sorafenib and sunitinib in metastatic renal cell
carcinoma: clinical outcomes from a retrospective clinical study.
Kontovinis L(1), Laschos K, Karadimou A, Andreadis C, Bamias A, Paraskevopoulos
P, Dimopoulos M, Papazisis K.
Author information:
(1)Medical Oncology Unit, Theagenion Cancer Hospital, Al. Simeonidi street 2,
54007 Thessaloniki, Greece. [email protected]
Sorafenib and sunitinib are inhibitors of receptor protein tyrosine kinases
(TKIs) and are approved for the treatment of metastatic renal cell carcinoma
(mRCC). Although the mTOR inhibitor everolimus is effective for the treatment of
patients who have failed TKI therapy, it is important to consider all available
treatment options before switching therapy mode of action. Herein, we report
outcomes in patients with mRCC switched to sorafenib following disease
progression on sunitinib treatment. The medical records of 35 patients treated
between November 2006 and November 2009 at two large referral centers in Greece
were retrospectively analyzed for time-to-progression (TTP), overall survival
(OS), and tolerability of sorafenib after sunitinib. Median TTP and OS on
sorafenib were 4.9 and 11.5 months, respectively. Among 33 patients evaluable
for tumor response, three had a partial response and 17 achieved disease
stabilization (objective response rate 8.5%; total clinical benefit rate 57%).
Sorafenib was well tolerated, with mostly grade 1/2 adverse events and no
treatment-related deaths. Sorafenib was effective and well tolerated in this
group of patients. The TTP with sorafenib following sunitinib was comparable to
outcomes reported previously, providing further support that TKIs should be used
in sequence before switching to an mTOR inhibitor.
DOI: 10.1007/s12032-010-9815-6
PMID: 21279702 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17553775 | 1. Philos Trans R Soc Lond B Biol Sci. 2007 Dec 29;362(1488):2273-89. doi:
10.1098/rstb.2006.1945.
The biodiversity and ecology of Antarctic lakes: models for evolution.
Laybourn-Parry J(1), Pearce DA.
Author information:
(1)Institute for the Environment, Physical Sciences and Applied Mathematics,
Faculty of Natural Sciences, University of Keele, Keele, Staffordshire, UK.
[email protected]
Antarctic lakes are characterised by simplified, truncated food webs. The lakes
range from freshwater to hypersaline with a continuum of physical and chemical
conditions that offer a natural laboratory in which to study evolution.
Molecular studies on Antarctic lake communities are still in their infancy, but
there is clear evidence from some taxonomic groups, for example the
Cyanobacteria, that there is endemicity. Moreover, many of the bacteria have
considerable potential as sources of novel biochemicals such as low temperature
enzymes and anti-freeze proteins. Among the eukaryotic organisms survival
strategies have evolved, among which dependence on mixotrophy in
phytoflagellates and some ciliates is common. There is also some evidence of
evolution of new species of flagellate in the marine derived saline lakes of the
Vestfold Hills. Recent work on viruses in polar lakes demonstrates high
abundance and high rates of infection, implying that they may play an important
role in genetic exchange in these extreme environments.
DOI: 10.1098/rstb.2006.1945
PMCID: PMC2443172
PMID: 17553775 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11379297 | 1. Hepatogastroenterology. 2001 Mar-Apr;48(38):313-6.
Amifostine (Ethyol) as modulator of hepatic and biliary toxicity from
intraarterial hepatic chemoembolization: results of a phase I study.
Fiorentini G(1), Giovanis P, Leoni M, De Giorgi U, Cariello A, Dazzi C, Caldeo
A.
Author information:
(1)Oncology Department, City Hospital, v.le Randi 5, Ravenna 48100, Italy.
[email protected]
BACKGROUND/AIMS: Hepatic and biliary toxicity are still significant problems
after intraarterial hepatic chemoembolization for liver metastases from large
bowel cancers. In about 30-60% of the patients hepatic and biliary toxicity are
the limiting aspects of intraarterial hepatic chemoembolization and exclude a
lot of patients from a repeated beneficial treatment. Amifostine (Ethyol) is a
prodrug that must be dephosphorylated to the free thiol in which form it can
detoxify free oxygen radicals generated by radiation, hypoxia and by drugs such
anthracyclines, platinum analogues and alkylating agents. Amifostine as inactive
prodrug is primarily metabolized at the tissue site by membrane alkaline
phosphatase, which is highly active in the cell membranes of normal endothelial
cells and biliary tree cells but not in the cell membranes and neovascular
capillaries of tumor. When dephosphorylated to WR-1065, amifostine is rapidly
taken up into normal liver cells by a carrier-mediated facilitated diffusion
transport process. The resulting high thiol content in normal liver tissue
(biliary cells and hepatocytes) compared with the negligible concentration in
liver metastases from large bowel cancers probably provides for selective drug
resistance to intraarterial hepatic chemoembolization protecting normal tissue
and allowing full therapeutic effect on tumor.
METHODOLOGY: From May 1997 we planned a phase I study in patients receiving
intraarterial hepatic chemoembolization for liver metastases from large bowel
cancers. We started at 200 mg/m2 dissolved in 250 cc of normal saline given in
15 min in the intrahepatic artery 20 min before an intraarterial hepatic
chemoembolization consisting of mitomycin 10 mg/m2, epirubicin-50, cisplatin-60
diluted in 10 mL of contrast media, mixed in 15 mL of lipiodol UF followed by a
gelfoam powder solution until stagnation of the flow. The escalating dose, every
3 patients, was: 200 mg/m2, 250 mg/m2, 300 mg/m2, 350 mg/m2.
RESULTS: Toxicity has been observed at 350 mg/m2: 1 patient reported transient
hypotension (Blood pressure 70/50 mm Hg), 1 patient had skin flushing and
dyspnoea. 300 mg/m2 are well tolerated and seem to reduce the level of
transaminases, lactic acid dehydrogenase, and gamma-glutamyl transferase. Also
the duration of necrotic damage, always observed after intraarterial hepatic
chemoembolization, seems shorter compared with historical controls.
CONCLUSIONS: Amifostine can be certainly administered at 300 mg/m2 as
intraarterial infusion and could be a significant step to ameliorate the
therapeutic ratio of intraarterial hepatic chemoembolization.
PMID: 11379297 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11026146 | 1. Acta Med Port. 2000 May-Jun;13(3):93-9.
[Cluster headache].
[Article in Portuguese]
Parreira E(1), Tomé A, Martins IP.
Author information:
(1)Serviço de Neurologia, Hospital de Santa Maria, Lisboa.
We present a review of 60 cases of cluster headache. Most patients were males,
ranging from 19 to 65 years of age at the time of the first visit. Headaches
consisted of short-lasting (from 15 to 210 minutes), intense, unilateral pain
attacks, most frequently in the periorbital area, with ipsilateral autonomic
signs (rhinorrhea, ptosis, tearing and conjunctival injection). Between attacks,
patients were completely free of pain. The attacks occurred in bouts lasting 1
to 6 months, in which patients had daily headaches (one to three times a day).
Headaches responded well to oxygen or ergotamine. Prophylactic therapy in most
cases consisted of verapamil, also with a good response. We present this review
in order to draw attention to this relatively rare form of headache with a
specific therapy.
PMID: 11026146 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20352587 | 1. Semin Neurol. 2010 Apr;30(2):175-85. doi: 10.1055/s-0030-1249226. Epub 2010
Mar 29.
Cluster headache: diagnosis and treatment.
Halker R(1), Vargas B, Dodick DW.
Author information:
(1)Department of Neurology, Mayo Clinic Arizona, Phoenix, Arizona, USA.
Cluster headache is a rare yet exquisitely painful primary headache disorder
occurring in either episodic or chronic patterns. The unique feature of cluster
headache is the distinctive circadian and circannual periodicity in the episodic
forms. The attacks are stereotypic--they are of extreme intensity and short
duration, occur unilaterally, and are associated with robust signs and symptoms
of autonomic dysfunction. Although the pathophysiology of cluster headache
remains to be fully understood, there have been a number of recent seminal
observations. To exclude structural mimics, patients presenting with symptoms
suggestive of cluster headache warrant at least a brain magnetic resonance
imaging (MRI) scan in their work-up. The medical treatment of cluster headache
includes acute, transitional, and maintenance prophylaxis. Agents used for acute
therapy include inhalation of oxygen, triptans, such as sumatriptan, and
dihydroergotamine. Transitional prophylaxis refers to the short-term use of
fast-acting agents. This typically involves either corticosteroids or an
occipital nerve block. The mainstay of prophylactic therapy is verapamil. Yet,
other medications, including lithium, divalproex sodium, topiramate,
methysergide, gabapentin, and even indomethacin, may be useful when the headache
fails to respond to verapamil. For medically refractory patients, surgical
interventions, occipital nerve stimulation, and deep brain stimulation remain an
option. As the sophistication of functional neuroimaging increases, better
insight into the pathophysiological mechanisms that underlie cluster headache is
expected.
Thieme Medical Publishers.
DOI: 10.1055/s-0030-1249226
PMID: 20352587 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24425501 | 1. Circ Cardiovasc Imaging. 2014 Mar;7(2):240-9. doi:
10.1161/CIRCIMAGING.113.000993. Epub 2014 Jan 14.
T₁ mapping detects pharmacological retardation of diffuse cardiac fibrosis in
mouse pressure-overload hypertrophy.
Stuckey DJ(1), McSweeney SJ, Thin MZ, Habib J, Price AN, Fiedler LR, Gsell W,
Prasad SK, Schneider MD.
Author information:
(1)British Heart Foundation Centre of Research Excellence, National Heart and
Lung Institute.
BACKGROUND: Diffuse interstitial fibrosis is present in diverse cardiomyopathies
and associated with poor prognosis. We investigated whether magnetic resonance
imaging-based T1 mapping could quantify the induction and pharmacological
suppression of diffuse cardiac fibrosis in murine pressure-overload hypertrophy.
METHODS AND RESULTS: Mice were subjected to transverse aortic constriction or
sham surgery. The angiotensin receptor blocker losartan was given to half the
animals. Cine-magnetic resonance imaging performed at 7 and 28 days showed
hypertrophy and remodeling and systolic and diastolic dysfunction in transverse
aortic constriction groups as expected. Late gadolinium-enhanced magnetic
resonance imaging revealed focal signal enhancement at the inferior right
ventricular insertion point of transverse aortic constriction mice concordant
with the foci of fibrosis in histology. The extracellular volume fraction,
calculated from pre- and postcontrast T1 measurements, was elevated by
transverse aortic constriction and showed direct linear correlation with
picrosirius red collagen volume fraction, thus confirming the suitability of
extracellular volume fraction as an in vivo measure of diffuse fibrosis.
Treatment with losartan reduced left ventricular dysfunction and prevented
increased extracellular volume fraction, indicating that T1 mapping is sensitive
to pharmacological prevention of fibrosis.
CONCLUSIONS: Magnetic resonance imaging can detect diffuse and focal cardiac
fibrosis in a clinically relevant animal model of pressure overload and is
sensitive to pharmacological reduction of fibrosis by angiotensin receptor
blockade. Thus, T1 mapping can be used to assess antifibrotic therapeutic
strategies.
DOI: 10.1161/CIRCIMAGING.113.000993
PMID: 24425501 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25274537 | 1. Drugs. 2014 Oct;74(15):1769-84. doi: 10.1007/s40265-014-0298-1.
Empagliflozin: a review of its use in patients with type 2 diabetes mellitus.
Scott LJ(1).
Author information:
(1)Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand,
[email protected].
Erratum in
Drugs. 2015 Jan;75(1):141. doi: 10.1007/s40265-014-0336-z. Dosage error in
article text.
Oral empagliflozin (Jardiance(®)), a sodium glucose cotransporter-2 (SGLT2)
inhibitor, is a convenient once-daily treatment for adult patients with type 2
diabetes mellitus. By inhibiting reabsorption of glucose from the proximal
tubules in the kidney via inhibition of SGLT2, empagliflozin provides a novel
insulin-independent mechanism of lowering blood glucose. In several phase III
trials (≤104 weeks' duration; typically 24 weeks' duration) and extension
studies (typically ≥76 weeks' treatment), empagliflozin monotherapy or add-on
therapy to other antihyperglycaemics, including insulin, improved glycaemic
control and reduced bodyweight and systolic blood pressure in adult patients
with type 2 diabetes. In a large phase III trial, as add-on therapy to
metformin, empagliflozin was shown to be noninferior to glimepiride at 52 and
104 weeks and superior to glimepiride at 104 weeks, in terms of reductions in
glycated haemoglobin level (primary endpoint). Empagliflozin was well tolerated
by participants in these clinical trials, with most adverse events being mild or
moderate in intensity. Empagliflozin treatment appeared to have no intrinsic
risk of hypoglycaemia, although hypoglycaemia occurred more frequently when
empagliflozin was coadministered with insulin and/or a sulfonylurea. With its
insulin-independent mechanism of action, empagliflozin monotherapy or
combination therapy with other antidiabetic drugs, including insulin, provides a
useful addition to the therapeutic options for the management of type 2
diabetes. This article reviews the pharmacological properties and clinical use
of empagliflozin in patients with type 2 diabetes.
DOI: 10.1007/s40265-014-0298-1
PMID: 25274537 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22016144 | 1. Dev Dyn. 2011 Nov;240(11):2584-96. doi: 10.1002/dvdy.22752.
The Muenke syndrome mutation (FgfR3P244R) causes cranial base shortening
associated with growth plate dysfunction and premature perichondrial
ossification in murine basicranial synchondroses.
Laurita J(1), Koyama E, Chin B, Taylor JA, Lakin GE, Hankenson KD, Bartlett SP,
Nah HD.
Author information:
(1)Division of Plastic and Reconstructive Surgery, The Children's Hospital of
Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Muenke syndrome caused by the FGFR3(P250R) mutation is an autosomal dominant
disorder mostly identified with coronal suture synostosis, but it also presents
with other craniofacial phenotypes that include mild to moderate midface
hypoplasia. The Muenke syndrome mutation is thought to dysregulate
intramembranous ossification at the cranial suture without disturbing
endochondral bone formation in the skull. We show in this study that knock-in
mice harboring the mutation responsible for the Muenke syndrome (FgfR3(P244R))
display postnatal shortening of the cranial base along with synchondrosis growth
plate dysfunction characterized by loss of resting, proliferating and
hypertrophic chondrocyte zones and decreased Ihh expression. Furthermore,
premature conversion of resting chondrocytes along the perichondrium into
prehypertrophic chondrocytes leads to perichondrial bony bridge formation,
effectively terminating the postnatal growth of the cranial base. Thus, we
conclude that the Muenke syndrome mutation disturbs endochondral and
perichondrial ossification in the cranial base, explaining the midface
hypoplasia in patients.
Copyright © 2011 Wiley Periodicals, Inc.
DOI: 10.1002/dvdy.22752
PMID: 22016144 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22934167 | 1. Autism Res Treat. 2012;2012:104317. doi: 10.1155/2012/104317. Epub 2012 May
31.
Sertraline may improve language developmental trajectory in young children with
fragile x syndrome: a retrospective chart review.
Indah Winarni T(1), Chonchaiya W, Adams E, Au J, Mu Y, Rivera SM, Nguyen DV,
Hagerman RJ.
Author information:
(1)Medical Investigation of Neurodevelopmental Disorders (MIND) Institute and
Department of Pediatrics, University of California-Davis Medical Center,
Sacramento, CA 95817, USA.
Young children with fragile X syndrome (FXS) often experience anxiety,
irritability, and hyperactivity related to sensory hyperarousal. However, there
are no medication recommendations with documented efficacy for children under 5
years old of age with FXS. We examined data through a chart review for 45
children with FXS, 12-50 months old, using the Mullen Scales of Early Learning
(MSEL) for baseline and longitudinal assessments. All children had clinical
level of anxiety, language delays based on MSEL scores, and similar early
learning composite (ELC) scores at their first visit to our clinic. Incidence of
autism spectrum disorder (ASD) was similar in both groups. There were 11
children who were treated with sertraline, and these patients were
retrospectively compared to 34 children who were not treated with sertraline by
chart review. The baseline assessments were done at ages ranging from 18 to 44
months (mean 26.9, SD 7.99) and from 12 to 50 months (mean 29.94, SD 8.64) for
treated and not treated groups, respectively. Mean rate of improvement in both
expressive and receptive language development was significantly higher in the
group who was treated with sertraline (P < 0.0001 and P = 0.0071, resp.). This
data supports the need for a controlled trial of sertraline treatment in young
children with FXS.
DOI: 10.1155/2012/104317
PMCID: PMC3420618
PMID: 22934167 |
http://www.ncbi.nlm.nih.gov/pubmed/23404999 | 1. Cardiovasc Res. 2013 May 1;98(2):277-85. doi: 10.1093/cvr/cvt029. Epub 2013
Feb 11.
Cardiomyocyte ryanodine receptor degradation by chaperone-mediated autophagy.
Pedrozo Z(1), Torrealba N, Fernández C, Gatica D, Toro B, Quiroga C, Rodriguez
AE, Sanchez G, Gillette TG, Hill JA, Donoso P, Lavandero S.
Author information:
(1)Centro de Estudios Moleculares de la Célula, Facultad de Ciencias Químicas y
Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago 8380492,
Chile. [email protected]
AIMS: Chaperone-mediated autophagy (CMA) is a selective mechanism for the
degradation of soluble cytosolic proteins bearing the sequence KFERQ. These
proteins are targeted by chaperones and delivered to lysosomes where they are
translocated into the lysosomal lumen and degraded via the lysosome-associated
membrane protein type 2A (LAMP-2A). Mutations in LAMP2 that inhibit autophagy
result in Danon disease characterized by hypertrophic cardiomyopathy. The
ryanodine receptor type 2 (RyR2) plays a key role in cardiomyocyte
excitation-contraction and its dysfunction can lead to cardiac failure. Whether
RyR2 is degraded by CMA is unknown.
METHODS AND RESULTS: To induce CMA, cultured neonatal rat cardiomyocytes were
treated with geldanamycin (GA) to promote protein degradation through this
pathway. GA increased LAMP-2A levels together with its redistribution and
colocalization with Hsc70 in the perinuclear region, changes indicative of CMA
activation. The inhibition of lysosomes but not proteasomes prevented the loss
of RyR2. The recovery of RyR2 content after incubation with GA by siRNA
targeting LAMP-2A suggests that RyR2 is degraded via CMA. In silico analysis
also revealed that the RyR2 sequence harbours six KFERQ motifs which are
required for the recognition Hsc70 and its degradation via CMA. Our data suggest
that presenilins are involved in RyR2 degradation by CMA.
CONCLUSION: These findings are consistent with a model in which oxidative damage
of the RyR2 targets it for turnover by presenilins and CMA, which could lead to
removal of damaged or leaky RyR2 channels.
DOI: 10.1093/cvr/cvt029
PMCID: PMC3633160
PMID: 23404999 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21710477 | 1. Eur J Immunol. 2011 Oct;41(10):2977-86. doi: 10.1002/eji.201141639. Epub 2011
Aug 17.
Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine
effects through novel mechanisms.
Mkrtichyan M(1), Najjar YG, Raulfs EC, Abdalla MY, Samara R, Rotem-Yehudar R,
Cook L, Khleif SN.
Author information:
(1)Cancer Vaccine Section, National Cancer Institute, National Institutes of
Health, Bethesda, MD 20892, USA.
Programmed death-1 receptor (PD-1) is expressed on T cells following TCR
activation. Binding of this receptor to its cognate ligands, programmed death
ligand (PDL)-1 and PDL-2, down-regulates signals by the TCR, promoting T-cell
anergy and apoptosis, thus leading to immune suppression. Here, we find that
using an anti-PD-1 antibody (CT-011) with Treg-cell depletion by low-dose
cyclophosphamide (CPM), combined with a tumor vaccine, induces synergistic
antigen-specific immune responses and reveals novel activities of each agent in
this combination. This strategy led to complete regression of established tumors
in a significant percentage of treated animals, with survival prolongation. We
show for the first time that combining CT-011 and CPM significantly increases
the number of vaccine-induced tumor-infiltrating CD8(+) T cells, with
simultaneous decrease in infiltrating Treg cells. Interestingly, we find that
CT-011 prolongs Treg-cell inhibition induced by CPM, leading to a sustainable
significant synergistic decrease of splenic and tumor-infiltrated Treg cells.
Surprisingly, we find that the anti-tumor effect elicited by the combination of
CT-011 and CPM is dependent on both CD8(+) and CD4(+) T-cell responses, although
the antigen we used is a class I MHC-restricted peptide. Thus, we describe a
novel and effective therapeutic approach by combining multiple strategies to
target several tumor-mediated immune inhibitory mechanisms.
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/eji.201141639
PMCID: PMC7020689
PMID: 21710477 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest R.R.Y. is an employee of
CureTech Ltd, which provided CT-011. The remaining authors declare no competing
financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/22084632 | 1. Front Pharmacol. 2011 Nov 9;2:71. doi: 10.3389/fphar.2011.00071. eCollection
2011.
Neurotoxins and their binding areas on voltage-gated sodium channels.
Stevens M(1), Peigneur S, Tytgat J.
Author information:
(1)Lab of Toxicology, Katholieke Universiteit Leuven Leuven, Belgium.
Voltage-gated sodium channels (VGSCs) are large transmembrane proteins that
conduct sodium ions across the membrane and by doing so they generate signals of
communication between many kinds of tissues. They are responsible for the
generation and propagation of action potentials in excitable cells, in close
collaboration with other channels like potassium channels. Therefore, genetic
defects in sodium channel genes can cause a wide variety of diseases, generally
called "channelopathies." The first insights into the mechanism of action
potentials and the involvement of sodium channels originated from Hodgkin and
Huxley for which they were awarded the Nobel Prize in 1963. These concepts still
form the basis for understanding the function of VGSCs. When VGSCs sense a
sufficient change in membrane potential, they are activated and consequently
generate a massive influx of sodium ions. Immediately after, channels will start
to inactivate and currents decrease. In the inactivated state, channels stay
refractory for new stimuli and they must return to the closed state before being
susceptible to a new depolarization. On the other hand, studies with neurotoxins
like tetrodotoxin (TTX) and saxitoxin (STX) also contributed largely to our
today's understanding of the structure and function of ion channels and of VGSCs
specifically. Moreover, neurotoxins acting on ion channels turned out to be
valuable lead compounds in the development of new drugs for the enormous range
of diseases in which ion channels are involved. A recent example of a synthetic
neurotoxin that made it to the market is ziconotide (Prialt(®), Elan). The
original peptide, ω-MVIIA, is derived from the cone snail Conus magus and now
FDA/EMA-approved for the management of severe chronic pain by blocking the
N-type voltage-gated calcium channels in pain fibers. This review focuses on the
current status of research on neurotoxins acting on VGSC, their contribution to
further unravel the structure and function of VGSC and their potential as novel
lead compounds in drug development.
DOI: 10.3389/fphar.2011.00071
PMCID: PMC3210964
PMID: 22084632 |
http://www.ncbi.nlm.nih.gov/pubmed/24890556 | 1. QJM. 2014 Dec;107(12):969-75. doi: 10.1093/qjmed/hcu117. Epub 2014 Jun 2.
Helicobacter pylori infection increases subsequent ischemic stroke risk: a
nationwide population-based retrospective cohort study.
Huang WS(1), Tseng CH(1), Lin CL(2), Tsai CH(1), Kao CH(3).
Author information:
(1)From the Department of Neurology, China Medical University Hospital, Graduate
Institute of Clinical Medical Science and School of Medicine, College of
Medicine, Management Office for Health Data, China Medical University Hospital
and Department of Nuclear Medicine and PET Center, China Medical University
Hospital, Taichung, Taiwan From the Department of Neurology, China Medical
University Hospital, Graduate Institute of Clinical Medical Science and School
of Medicine, College of Medicine, Management Office for Health Data, China
Medical University Hospital and Department of Nuclear Medicine and PET Center,
China Medical University Hospital, Taichung, Taiwan.
(2)From the Department of Neurology, China Medical University Hospital, Graduate
Institute of Clinical Medical Science and School of Medicine, College of
Medicine, Management Office for Health Data, China Medical University Hospital
and Department of Nuclear Medicine and PET Center, China Medical University
Hospital, Taichung, Taiwan.
(3)From the Department of Neurology, China Medical University Hospital, Graduate
Institute of Clinical Medical Science and School of Medicine, College of
Medicine, Management Office for Health Data, China Medical University Hospital
and Department of Nuclear Medicine and PET Center, China Medical University
Hospital, Taichung, Taiwan From the Department of Neurology, China Medical
University Hospital, Graduate Institute of Clinical Medical Science and School
of Medicine, College of Medicine, Management Office for Health Data, China
Medical University Hospital and Department of Nuclear Medicine and PET Center,
China Medical University Hospital, Taichung, Taiwan [email protected].
BACKGROUND AND PURPOSE: The association of Helicobacter pylori infection (HP-I)
with ischemic stroke (IS) incidence has been studied, but conflicting results
have been reported. The purpose of this study was to investigate the association
between chronic HP-I and the risk of acute IS by using data from the Taiwan
National Health Insurance Research Database.
METHODS: We identified17 332 patients with HP-I and 69 328 randomly selected
age- and gender-matched controls from 1 January 2000 to 31 December 2010. Both
cohorts were followed up until the occurrence of IS or until censored. The Cox
proportional hazards model was used for assessing the association of HP-I with
IS.
RESULTS: Compared with the control cohort, patients diagnosed with HP-I
exhibited a higher incidence rate of IS (14.8 vs. 8.45 per 1000 person years)
and a hazard ratio (HR) of 1.52 (95% confidence interval [CI] = 1.40-1.65). The
HRs for IS were 1.49 (1.37-1.62) in patients diagnosed with HP-I who had one
admission, increasing to 2.26 (1.71-1.98) for those who had two or more
admissions when adjusted for age, sex and comorbidities (P for trend < 0.0001).
In addition, we observed a significantly positive association between nonembolic
IS and increased admissions (P for trend < 0.0001) but negative association with
embolic IS.
CONCLUSION: Chronic HP-I is significantly associated with an increased risk of
IS, particularly nonembolic IS. Anti-HP therapy may be beneficial to IS
prevention.
© The Author 2014. Published by Oxford University Press on behalf of the
Association of Physicians. All rights reserved. For Permissions, please email:
[email protected].
DOI: 10.1093/qjmed/hcu117
PMID: 24890556 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9585150 | 1. Life Sci. 1998;62(17-18):1641-5. doi: 10.1016/s0024-3205(98)00121-0.
Properties of calcium channels coupled to endogenous glutamate release from the
vascularly perfused rat stomach in vitro.
Okuma Y(1), Yokotani K, Murakami Y, Osumi Y.
Author information:
(1)Department of Pharmacology, Kochi Medical School, Nankoku, Japan.
We have demonstrated that both high-K+ and electrical stimulation of the vagus
nerves release endogenous glutamate from the vascularly-perfused rat stomach in
a calcium-dependent manner. In the present study, we examined properties of
calcium channel subtypes mediating endogenous glutamate release from the
stomach. Application of 50 mM KCl elicited a release of glutamate, and this
release was abolished in calcium-free medium. The release of glutamate was
significantly inhibited by both omega-agatoxin IVA, a P/Q-type calcium channel
antagonist, and isradipine, an L type calcium channel antagonist.
Omega-conotoxin GVIA, an N type calcium channel antagonist and flunarizine, a
nonselective T-type calcium channel antagonist were without effect. In contrast
to this case of glutamate, omega-conotoxin GVIA induced a marked inhibition in
the release of gastric noradrenaline. The combined treatment with omega-agatoxin
IVA plus isradipine produced a marked synergistic inhibition of the glutamate
release. This inhibition was, however, much less than that by cadmium. The
present results suggest that P/Q and L type calcium channels coexist to regulate
the release of gastric glutamate. Furthermore, it is possible that unidentified
calcium channels other than P/Q and L type channels are also involved in the
release of glutamate in the stomach.
DOI: 10.1016/s0024-3205(98)00121-0
PMID: 9585150 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19007595 | 1. J Am Coll Cardiol. 2008 Nov 4;52(19):1574-80. doi: 10.1016/j.jacc.2008.06.049.
Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic
resonance contrast-enhanced T1 mapping.
Iles L(1), Pfluger H, Phrommintikul A, Cherayath J, Aksit P, Gupta SN, Kaye DM,
Taylor AJ.
Author information:
(1)Alfred Hospital and Baker IDI Heart and Diabetes Institute, Melbourne,
Australia.
Comment in
J Am Coll Cardiol. 2008 Nov 4;52(19):1581-3. doi:
10.1016/j.jacc.2008.08.010.
OBJECTIVES: The purpose of this study was to investigate a noninvasive method
for quantifying diffuse myocardial fibrosis with cardiac magnetic resonance
imaging (CMRI).
BACKGROUND: Diffuse myocardial fibrosis is a fundamental process in pathologic
remodeling in cardiomyopathy and is postulated to cause increased cardiac
stiffness and poor clinical outcomes. Although regional fibrosis is easily
imaged with cardiac magnetic resonance, there is currently no noninvasive method
for quantifying diffuse myocardial fibrosis.
METHODS: We performed CMRI on 45 subjects (25 patients with heart failure, 20
control patients), on a clinical 1.5-T CMRI scanner. A prototype T(1) mapping
sequence was used to calculate the post-contrast myocardial T(1) time as an
index of diffuse fibrosis; regional fibrosis was identified by delayed contrast
enhancement. Regional and global systolic function was assessed by cine CMRI in
standard short- and long-axis planes, with echocardiography used to evaluate
diastology. An additional 9 subjects underwent CMRI and endomyocardial biopsy
for histologic correlation.
RESULTS: Post-contrast myocardial T(1) times correlated histologically with
fibrosis (R = -0.7, p = 0.03) and were shorter in heart failure subjects than
controls (383 +/- 17 ms vs. 564 +/- 23 ms, p < 0.0001). The T(1) time of heart
failure myocardium was shorter than that in controls even when excluding areas
of regional fibrosis (429 +/- 22 ms vs. 564 +/- 23 ms, p < 0.0001). The
post-contrast myocardial T(1) time shortened as diastolic function worsened (562
+/- 24 ms in normal diastolic function vs. 423 +/- 33 ms in impaired diastolic
function vs. 368 +/- 20 ms in restrictive function, p < 0.001).
CONCLUSIONS: Contrast-enhanced CMRI T(1) mapping identifies changes in
myocardial T(1) times in heart failure, which appear to reflect diffuse
fibrosis.
DOI: 10.1016/j.jacc.2008.06.049
PMID: 19007595 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8585387 | 1. Zh Nevrol Psikhiatr Im S S Korsakova. 1995;95(5):89-92.
[West syndrome in tuberous sclerosis].
[Article in Russian]
Badalian LO, Medvedev MI, Kharlamov DA, Levin PG, Il'ina ES, Iskander MB,
Turyleva MM, Alikhanov AA.
Observation's analysis of 5 children in age from 9 months to 4 years 11 months
with tuberous sclerosis was performed. The initial manifestations of disease
were following: early children form of epilepsy exactly infantile spasms (West
syndrome) appearance, dermal alterations in the form of depigmented spots as
well as nonprogressive delay in psychoverbal development. Together with clinical
symptoms the main criterion in early form of tuberous sclerosis diagnosis
determination turned out to be brain's specific alterations (tubers) which were
revealed by computer tomography. The correlation was observed between epileptic
seizures polymorphism and frequency as well as brain's morphological
alterations. Derivatives of valproic acid were the basic drugs in treatment of
epileptic seizures in patients.
PMID: 8585387 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23438422 | 1. Expert Opin Pharmacother. 2013 Mar;14(4):435-47. doi:
10.1517/14656566.2013.775250.
Kidney stones: an update on current pharmacological management and future
directions.
Xu H(1), Zisman AL, Coe FL, Worcester EM.
Author information:
(1)University of Chicago Medical Center, University of Chicago Pritzker School
of Medicine, Chicago, IL, USA.
INTRODUCTION: Kidney stones are a common problem worldwide with substantial
morbidities and economic costs. Medical therapy reduces stone recurrence
significantly. Much progress has been made in the last several decades in
improving therapy of stone disease.
AREAS COVERED: This review discusses i) the effect of medical expulsive therapy
on spontaneous stone passage, ii) pharmacotherapy in the prevention of stone
recurrence and iii) future directions in the treatment of kidney stone disease.
EXPERT OPINION: Fluid intake to promote urine volume of at least 2.5 L each day
is essential to prevent stone formation. Dietary recommendations should be
adjusted based on individual metabolic abnormalities. Properly dosed thiazide
treatment is the standard therapy for calcium stone formers with idiopathic
hypercalciuria. Potassium alkali therapy is considered for hypocitraturia, but
caution should be taken to prevent potential risk of calcium phosphate stone
formation. For absorptive hyperoxaluria, low oxalate diet and increased dietary
calcium intake are recommended. Pyridoxine has been shown effective in some
cases of primary hyperoxaluria type I. Allopurinol is used in calcium oxalate
stone formers with hyperuricosuria. Treatment of cystine stones remains
challenging. Tiopronin can be used if urinary alkalinization and adequate fluid
intake are insufficient. For struvite stones, complete surgical removal coupled
with appropriate antibiotic therapy is necessary.
DOI: 10.1517/14656566.2013.775250
PMCID: PMC3772648
PMID: 23438422 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7556180 | 1. Eur J Biochem. 1995 Sep 1;232(2):344-50. doi:
10.1111/j.1432-1033.1995.344zz.x.
Hypothyroidism affects the expression of the beta-F1-ATPase gene and limits
mitochondrial proliferation in rat liver at all stages of development.
Izquierdo JM(1), Jiménez E, Cuezva JM.
Author information:
(1)Departamento de Biología Molecular, Centro de Biología Molecular Severo
Ochoa, Universidad Autónoma de Madrid, Spain.
In order to analyze the role of thyroid hormones in mitochondrial biogenesis, we
have studied the expression pattern of the beta subunit of the mitochondrial
ATP-synthase complex in liver and in isolated mitochondria during postnatal
development of hypothyroid rats. Chemically induced hypothyroidism promoted a
significant reduction in body and liver masses at all stages of development.
Furthermore, plasma 3,5,3'-triiodo-L-thyronine (T3) and
3,5,3',5'-tetraiodo-L-thyronine (T4) concentrations were significantly reduced
in hypothyroid animals when compared to euthyroid animals. Remarkably,
steady-state beta-F1-ATPase mRNA levels in livers of hypothyroid animals showed
an approximately 50% reduction when compared to age-matched euthyroid rats at
all stages of development. The relative amounts of beta-F1-ATPase protein
determined in isolated mitochondria of 1-day-old and adult hypothyroid animals
were similar to those determined in mitochondria of age-matched euthyroids,
indicating that hypothyroidism does not affect organelle differentiation in the
liver of suckling and adult rats. In contrast, the relative amount of
beta-F1-ATPase protein in liver homogenates varied (0-30% reduction) due to the
hypothyroid condition during development. These findings suggest the existence
of compensatory mechanisms operating at the translational and/or
post-translational levels which promote proliferation of mitochondria in the
hypothyroid liver. However, when the liver mass was considered, hypothyroidism
significantly reduced overall mitochondrial proliferation in rat liver.
Interestingly, the effects of thyroid hormones on the biogenesis of the ATP
synthase complex at latter stages of development provide an example in which the
hypothyroid condition limits the expression of the nuclear-encoded gene with no
apparent effect on the expression of the mitochondrial-encoded genes (ATP
synthase subunits 6-8).
DOI: 10.1111/j.1432-1033.1995.344zz.x
PMID: 7556180 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24199193 | 1. Biomed Res Int. 2013;2013:421821. doi: 10.1155/2013/421821. Epub 2013 Oct 2.
Role of STAT3 in cancer metastasis and translational advances.
Kamran MZ(1), Patil P, Gude RP.
Author information:
(1)Gude lab, Advanced Centre for Treatment, Research & Education in Cancer
(ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India.
Signal transducer and activator of transcription 3 (STAT3) is a latent
cytoplasmic transcription factor, originally discovered as a transducer of
signal from cell surface receptors to the nucleus. It is activated by tyrosine
phosphorylation at position 705 leading to its dimerization, nuclear
translocation, DNA binding, and activation of gene transcription. Under normal
physiological conditions, STAT3 activation is tightly regulated. However,
compelling evidence suggests that STAT3 is constitutively activated in many
cancers and plays a pivotal role in tumor growth and metastasis. It regulates
cellular proliferation, invasion, migration, and angiogenesis that are critical
for cancer metastasis. In this paper, we first describe the mechanism of STAT3
regulation followed by how STAT3 is involved in cancer metastasis, then we
summarize the various small molecule inhibitors that inhibit STAT3 signaling.
DOI: 10.1155/2013/421821
PMCID: PMC3807846
PMID: 24199193 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23233565 | 1. Hematology Am Soc Hematol Educ Program. 2012;2012:88-96. doi:
10.1182/asheducation-2012.1.88.
Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia.
Wiestner A(1).
Author information:
(1)Hematology Branch, National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, MD20892-1202, USA. [email protected]
Erratum in
Hematology Am Soc Hematol Educ Program. 2013;2013:692.
Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that depend
on host factors in the tissue microenvironment for survival and proliferation.
In vitro, CLL cells rapidly undergo apoptosis unless microenvironmental factors
are provided that support their survival. Signaling pathways activated in the
microenvironment in vivo include the B-cell receptor (BCR) and NF-κB pathways.
Thus, CLL is a disease "addicted to the host" and is dependent on pathways that
promote normal B-cell development, expansion, and survival; this is particularly
true in the case of the BCR signaling cascade. Small-molecule inhibitors of
kinases that are essential for BCR signal transduction abrogate the stimulating
effects of the microenvironment on CLL cells. The orally administered tyrosine
kinase inhibitors fostamatinib and ibrutinib and the phosphatidylinositol
3-kinase inhibitor GS-1101 have induced impressive responses in relapsed and
refractory CLL patients, mostly with moderate side effects. Reductions in
lymphadenopathy and splenomegaly are seen within weeks and are frequently
accompanied by a transient rise in absolute lymphocyte count that is
asymptomatic and probably the result of changes in CLL cell trafficking. This
review discusses the biologic basis for kinase inhibitors as targeted therapy of
CLL and summarizes the exciting early clinical experience with these agents.
DOI: 10.1182/asheducation-2012.1.88
PMID: 23233565 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23146972 | 1. Prostate Cancer Prostatic Dis. 2013 Mar;16(1):107-10. doi:
10.1038/pcan.2012.46. Epub 2012 Nov 13.
Second to fourth digit ratio and prostate cancer severity.
Waters M(1), Rebholz CM, Wood B, Kuske A, McIntyre M, Sartor O.
Author information:
(1)Tulane University School of Medicine, New Orleans, LA 70112, USA.
BACKGROUND: The ratio of the second to the fourth digit (2D:4D ratio) is a
sexually dimorphic trait established in utero that differs between ethnic
groups. It is associated with prenatal androgen exposure, and studies have
evaluated the ratio as a marker for certain traits and disease states known to
be associated with higher levels of in utero androgens, such as prostate cancer.
There are currently no screening tools that stratify men with prostate cancer
according to the severity of their disease. This study aims to investigate the
2D:4D ratio as a potential marker for prostate cancer severity. Our hypothesis
was that lower digit ratios, representing higher in utero androgen exposure,
would be associated with more severe disease.
METHODS: Measurements were taken of the second and fourth digits of the right
hand of male patients diagnosed with prostate cancer. Gleason score, presence of
metastasis, family history, age at diagnosis and race were recorded. The
distribution of demographic and other patient characteristics were compared with
digit ratios to determine relationships.
RESULTS: African-American men with prostate cancer are 3.70 times more likely to
have a low 2D:4D digit ratio than Caucasian men with prostate cancer (95%
confidence interval: 1.98, 6.92; P < 0.0001). There were no statistically
significant differences in the presence of metastasis, Gleason score, family
history or age at diagnosis by digit ratio.
CONCLUSION: 2D:4D ratio shows strong differences between African-Americans and
Caucasians; however, it does not correlate with disease severity in men already
diagnosed with prostate cancer. Although this is a small population sample with
possible confounding factors, it does not provide evidence to support the
hypothesis that prenatal androgens affect prostate cancer grade or progression.
DOI: 10.1038/pcan.2012.46
PMID: 23146972 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23354591 | 1. Cancer Lett. 2013 Jun 10;333(2):213-21. doi: 10.1016/j.canlet.2013.01.033.
Epub 2013 Jan 24.
Long non-coding RNA H19 increases bladder cancer metastasis by associating with
EZH2 and inhibiting E-cadherin expression.
Luo M(1), Li Z, Wang W, Zeng Y, Liu Z, Qiu J.
Author information:
(1)Department of Urology, The Tenth People's Hospital Affiliated to Tongji
University, Shanghai 200072, China.
Comment in
J Urol. 2013 Dec;190(6):2306. doi: 10.1016/j.juro.2013.08.057.
lncRNA H19 is essential for human tumor growth. However, little is known about
whether H19 regulates bladder cancer metastasis. Here we found that H19 levels
are remarkably increased in bladder cancer tissues, and upregulated H19 promotes
bladder cancer cell migration in vitro and in vivo. H19 is associated with
enhancer of zeste homolog 2 (EZH2), and that this association results in
Wnt/β-catenin activation and subsequent downregulation of E-cadherin. A
significant negative correlation is also observed between H19 levels and E-cad
levels in vivo. These data suggest that upregulated H19 enhances bladder cancer
metastasis by associating with EZH2 and inhibiting E-cad expression.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.canlet.2013.01.033
PMID: 23354591 [Indexed for MEDLINE] |