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http://www.ncbi.nlm.nih.gov/pubmed/22570552
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1. Ther Clin Risk Manag. 2012;8:201-8. doi: 10.2147/TCRM.S24436. Epub 2012 May 1.
Role of gabapentin enacarbil XR in restless legs syndrome.
Sivam S(1), Yee BJ.
Author information:
(1)NHMRC Centre for Sleep Health, Woolcock Institute of Medical Research,
University of Sydney, Sydney.
Gabapentin enacarbil XR is a new extended-release formulation which attempts to
overcome the reduced efficacy of shorter-acting gabapentin, with sustained
delivery over a 24-hour period. It is a gabapentin prodrug which is efficiently
and rapidly converted to gabapentin during active transport throughout the
length of the intestine via high-capacity monocarboxylate type 1 nutrient
transporters unlike its predecessor, which is absorbed via low-capacity
transporters largely confined to the upper intestinal region. Its lack of
saturable absorption allows for dose-proportional absorption and hence increased
bioavailability. Several clinical trials addressing its efficacy in moderate to
severe restless legs syndrome (RLS) demonstrate improvements in the
International RLS Rating Scale after a 2-week to 3-month period. Open-label
studies of 52 weeks' duration showed maintenance of symptom reduction with
once-daily administration of the extended-release formulation. The most commonly
reported treatment-emergent adverse effects were somnolence and dizziness.
Although the incidence of emergent adverse effects is high, it is comparable
with that of gabapentin. No studies thus far have documented augmentation as an
issue, unlike that observed with most dopaminergic agents. In addition, both
dopamine precursors and agonists have not been shown to increase slow wave sleep
or improve overall sleep architecture consistently despite improvement in the
periodic leg movement index, in contrast with gabapentin enacarbil. Presently,
gabapentin enacarbil has not been approved by the Therapeutic Goods
Administration or Medsafe for use in RLS. The cost of this medication may also
be a potential barrier for many patients. Future comparative efficacy studies
with gabapentin, first-line dopaminergic agents, rotigotine, being the other
once daily RLS medication, and pregabalin, the structural analog of gabapentin,
will be necessary.
DOI: 10.2147/TCRM.S24436
PMCID: PMC3346203
PMID: 22570552
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http://www.ncbi.nlm.nih.gov/pubmed/25159591
|
1. Invest Ophthalmol Vis Sci. 2014 Aug 26;55(8):5380-1. doi:
10.1167/iovs.14-15231.
3D Printing: Print the future of ophthalmology.
Huang W(1), Zhang X(1).
Author information:
(1)Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun
Yat-Sen University, Guangzhou, People's Republic of China.
The three-dimensional (3D) printer is a new technology that creates physical
objects from digital files. Recent technological advances in 3D printing have
resulted in increased use of this technology in the medical field, where it is
beginning to revolutionize medical and surgical possibilities. It is already
providing medicine with powerful tools that facilitate education, surgical
planning, and organ transplantation research. A good understanding of this
technology will be beneficial to ophthalmologists. The potential applications of
3D printing in ophthalmology, both current and future, are explored in this
article.
Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
DOI: 10.1167/iovs.14-15231
PMID: 25159591 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/15195944
|
1. Mol Plant Microbe Interact. 2004 Jun;17(6):613-22. doi:
10.1094/MPMI.2004.17.6.613.
The expression of MaEXP1, a Melilotus alba expansin gene, is upregulated during
the sweetclover-Sinorhizobium meliloti interaction.
Giordano W(1), Hirsch AM.
Author information:
(1)Department of Molecular, Cell, and Developmental Biology, University of
California, Los Angeles 90095-1606, USA.
Expansins are a highly conserved group of cell wall-localized proteins that
appear to mediate changes in cell wall plasticity during cell expansion or
differentiation. The accumulation of expansin protein or the mRNA for specific
expansin gene family members has been correlated with the growth of various
plant organs. Because expansin proteins are closely associated with plant cell
wall expansion, and as part of a larger study to determine the role of different
gene products in the legume-Rhizobium spp. symbiosis, we investigated whether a
Melilotus alba (white sweetclover) expansin gene is expressed during nodule
development. A cDNA fragment encoding an expansin gene (EXP) was isolated from
Sinorhizobium meliloti-inoculated sweetclover root RNA by reverse-transcriptase
polymerase chain reaction using degenerate primers, and a full-length
sweetclover expansin sequence (MaEXP1) was obtained using 5' and 3' rapid
amplification of cDNA end cloning. The predicted amino acid of the sweetclover
expansin is highly conserved with the various alpha-expansins in the GenBank
database. MaEXP1 contains a series of eight cysteines and four tryptophans that
are conserved in the alpha-expansin protein family. Northern analysis and
whole-mount in situ hybridization analyses indicate that MaEXP1 mRNA expression
is enhanced in roots within hours after inoculation with S. meliloti and in
nodules. Western and immunolocalization studies using a cucumber expansin
antibody demonstrated that a cross-reacting protein accumulated in the expanding
cells of the nodule.
DOI: 10.1094/MPMI.2004.17.6.613
PMID: 15195944 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23771546
|
1. Eur Rev Med Pharmacol Sci. 2013 Jun;17(11):1552-4.
Treatment-resistant insomnia treated with pregabalin.
Di Iorio G(1), Matarazzo I, Di Tizio L, Martinotti G.
Author information:
(1)Department of Neuroscience and Imaging, University, G. d'Annunzio, Chieti,
Italy.
We report a case with refractory insomnia. We diagnosed her case as depression
with high levels of anxiety, weakness, with diminished ability to think or
concentrate and with a sensory-motor disorder. Although this last symptom was
very distressing, it did not satisfy the criteria for RLS (Restless Legs
Syndrome). After treatment with paroxetine (20 mg) and zolpidem (10 mg), anxiety
and mood deflection were attenuated. Nevertheless, a mild depression, an
intermittent awakening (fragmentation of the sleep-wake rhythm) and subsyndromal
RLS persisted. Her resistant insomnia was treated with benzodiazepine sleeping
drugs (triazolam 0.25 mg, lorazepam 2.5 mg, fluorazepam 30 mg) with only partial
insomnia remission, antidepressants (trazodone 150 mg RP, mirtazapine 15-30 mg,
agomelatine 50 mg) and antipsychotics (levomepromazine 25 mg, zuclopentixol 25
mg) without results. Her intractable insomnia was markedly responsive to
pregabalin without side effects. Our hypothesis is that the therapy with
pregabalin may be indicated for resistant insomnia associated with subsyndromal
RLS, even when the latter does not satisfy fully all the criteria for diagnosis.
PMID: 23771546 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18406638
|
1. Fungal Genet Biol. 2008 Jun;45(6):839-50. doi: 10.1016/j.fgb.2008.03.001. Epub
2008 Mar 10.
EglD, a putative endoglucanase, with an expansin like domain is localized in the
conidial cell wall of Aspergillus nidulans.
Bouzarelou D(1), Billini M, Roumelioti K, Sophianopoulou V.
Author information:
(1)Institute of Biology, National Centre for Scientific Research Demokritos,
Aghia Paraskevi, 153 10 Athens, Greece. dbouzarelou@bio.demokritos.gr
Although the process of conidial germination in filamentous fungi has been
extensively studied, many aspects remain to be elucidated since the asexual
spore or conidium is vital in their life cycle. Breakage and reformation of cell
wall polymer bonds along with the maintenance of cell wall plasticity during
conidia germination depend upon a range of hydrolytic enzymes whose activity is
analogous to that of expansins, a highly conserved group of plant cell wall
proteins with characteristic wall loosening activity. In the current study, we
identified and characterized the eglD gene in Aspergillus nidulans, an
expansin-like gene the product of which shows strong similarities with bacterial
and fungal endo-beta1,4-glucanases. However, we failed to show such activity in
vitro. The eglD gene is constitutively expressed in all developmental stages and
compartments of A. nidulans asexual life cycle. However, the EglD protein is
exclusively present in conidial cell walls. The role of the EglD protein in
morphogenesis, growth and germination rate of conidia was investigated. Our
results show that EglD is a conidial cell wall localized expansin-like protein,
which could be involved in cell wall remodeling during germination.
DOI: 10.1016/j.fgb.2008.03.001
PMID: 18406638 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20427750
|
1. Neurology. 2010 Jun 8;74(23):1897-904. doi: 10.1212/WNL.0b013e3181e1ce73. Epub
2010 Apr 28.
Treatment of restless legs syndrome with pregabalin: a double-blind,
placebo-controlled study.
Garcia-Borreguero D(1), Larrosa O, Williams AM, Albares J, Pascual M, Palacios
JC, Fernandez C.
Author information:
(1)Sleep Research Institute, Madrid, Spain. dgb@iis.es
Comment in
J Neurol. 2010 Aug;257(8):1411-4. doi: 10.1007/s00415-010-5668-3.
Evid Based Med. 2011 Feb;16(1):9-10. doi: 10.1136/ebm1127.
Neurology. 2011 Jan 25;76(4):408; author reply 408-9. doi:
10.1212/WNL.0b013e3181fe7217.
OBJECTIVES: To assess the therapeutic efficacy, required dose, and tolerability
of pregabalin in patients with idiopathic restless legs syndrome (RLS).
METHODS: This was a double-blind, placebo-controlled trial with polysomnographic
control, providing Class II evidence. Ninety-eight patients underwent a 2-week
single-blind period with placebo; 58 were randomized to receive pregabalin or
placebo for 12 weeks under a flexible-dose schedule. Endpoints were mean change
from baseline in the International Restless Legs Scale (IRLS) total score,
Clinical Global Impression (CGI), and RLS-6 scales, as well as changes in
periodic limb movements (PLMs) and sleep architecture.
RESULTS: Patients under treatment with pregabalin had a greater improvement in
IRLS score than under placebo (63% vs 38.2%; p < 0.05). The mean effective dose
of pregabalin at the end of treatment was 322.50 mg/day (+/-98.77), although
therapeutic effects were already seen at a mean dose of 139 mg/day. Similarly,
improvements were observed on the CGI, RLS-6 scale, and the Medical Outcomes
Study sleep scale (all p < 0.01) when compared to placebo. Treatment with
pregabalin also resulted in a reduction of the mean (+/-SD) PLM index (p <
0.001). Furthermore, there was a marked improvement in sleep architecture with
an increase in slow wave sleep (p < 0.01), and decreases in wake after sleep
onset and stages 1 and 2 (p < 0.05). Pregabalin was generally well-tolerated.
Adverse events were mild but common, and included unsteadiness, daytime
sleepiness, and headache.
CONCLUSIONS: This study shows significant therapeutic effects of pregabalin on
both sensorial and motor symptoms in restless legs syndrome. Treatment with
pregabalin was associated with an improvement of sleep architecture and periodic
limb movements. Adverse events included unsteadiness and sleepiness and should
be screened carefully in the working population, particularly when pregabalin is
administered in the afternoon.
CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that
pregabalin is effective for the treatment of restless legs syndrome and improves
sleep architecture and periodic limb movements in placebo-unresponsive patients.
DOI: 10.1212/WNL.0b013e3181e1ce73
PMID: 20427750 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20032798
|
1. Menopause. 2010 May-Jun;17(3):480-6. doi: 10.1097/gme.0b013e3181c1ac01.
Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women:
results from a pivotal phase 3 study.
Bachmann GA(1), Komi JO; Ospemifene Study Group.
Author information:
(1)Robert Wood Johnson Medical School, University of Medicine and Dentistry of
New Jersey, New Brunswick, NJ 08901, USA. bachmaga@umdnj.edu
Comment in
Menopause. 2010 May-Jun;17(3):452-3.
OBJECTIVE: The aim of this study was to study the efficacy and safety of
ospemifene, a new selective estrogen receptor modulator, in the treatment of
vulvovaginal atrophy in postmenopausal women.
METHODS: A randomized, double-blind phase 3 study in which 826 postmenopausal
women were randomized 1:1:1 to receive treatment with ospemifene 30 or 60 mg/day
or placebo orally for 12 weeks was conducted. The primary inclusion criteria
were having 5% or less superficial cells on the vaginal smear (maturation
index), vaginal pH greater than 5.0, and at least one moderate or severe symptom
of vulvovaginal atrophy. The four coprimary endpoints were the change from
baseline to 12 weeks in the percentage of superficial and parabasal cells on the
vaginal smear, change in vaginal pH, and change in severity of most bothersome
symptom (vaginal dryness or dyspareunia) compared with placebo. All participants
were given a nonhormonal vaginal lubricant for use as needed.
RESULTS: Ospemifene was statistically significantly superior to placebo in each
of the coprimary endpoints at the 60-mg dose. Statistically significant results
were achieved for all coprimary endpoints with the 30-mg dose except for
dyspareunia. Ospemifene was well tolerated at both doses and demonstrated a
favorable safety profile.
CONCLUSIONS: Ospemifene was shown to be effective and well tolerated for the
treatment of the symptoms of vaginal dryness and dyspareunia associated with
vulvovaginal atrophy over and above the use of provided lubricants.
DOI: 10.1097/gme.0b013e3181c1ac01
PMID: 20032798 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24808958
|
1. Biotechnol Res Int. 2014;2014:970595. doi: 10.1155/2014/970595. Epub 2014 Apr
6.
Evaluation of novel design strategies for developing zinc finger nucleases tools
for treating human diseases.
Bach C(1), Sherman W(2), Pallis J(3), Patra P(1), Bajwa H(4).
Author information:
(1)University of Bridgeport, Biomedical Engineering, 221 University Avenue,
Bridgeport, CT 06604, USA.
(2)Physics Faculty, BHSEC Queens, 30-20 Thomson Avenue, Long Island City, NY
11101, USA.
(3)University of Bridgeport, Mechanical Engineering, 221 University Avenue,
Bridgeport, CT 06604, USA.
(4)University of Bridgeport, Electrical Engineering, 221 University Avenue,
Bridgeport, CT 06604, USA.
Zinc finger nucleases (ZFNs) are associated with cell death and apoptosis by
binding at countless undesired locations. This cytotoxicity is associated with
the binding ability of engineered zinc finger domains to bind dissimilar DNA
sequences with high affinity. In general, binding preferences of transcription
factors are associated with significant degenerated diversity and complexity
which convolutes the design and engineering of precise DNA binding domains.
Evolutionary success of natural zinc finger proteins, however, evinces that
nature created specific evolutionary traits and strategies, such as modularity
and rank-specific recognition to cope with binding complexity that are critical
for creating clinical viable tools to precisely modify the human genome. Our
findings indicate preservation of general modularity and significant alteration
of the rank-specific binding preferences of the three-finger binding domain of
transcription factor SP1 when exchanging amino acids in the 2nd finger.
DOI: 10.1155/2014/970595
PMCID: PMC3997970
PMID: 24808958
|
http://www.ncbi.nlm.nih.gov/pubmed/8965089
|
1. J Neurol Neurosurg Psychiatry. 1996 Oct;61(4):403-6. doi:
10.1136/jnnp.61.4.403.
Depression after surgery for acoustic neuroma.
Blomstedt GC(1), Katila H, Henriksson M, Ekholm A, Jääskeläinen JE, Pyykko I.
Author information:
(1)Department of Neurosurgerey, Helsinki University Central Hospital, Finland
The purpose of this study was to establish the frequency and pattern of
depressive disorders after surgery for acoustic neuroma, and to look for
associations. Twenty seven patients with acoustic neuroma underwent thorough
psychiatric assessment before surgery and at three and 12 months after surgery.
Three patients had a depressive disorder in the preoperative assessment. Of the
remaining 24 patients, nine (38%) had a depressive disorder at the three month
check up. Deterioration of hearing was the only postoperative detriment
associated with a depressive disorder (P = 0·024). All nine patients with a
depressive disorder were women (P = 0·001), giving them a 69% incidence. None of
the patients without preoperative depression required inpatient treatment for
depressive disorder, but three patients out of nine still had a depressive
disorder 12 months after surgery.
DOI: 10.1136/jnnp.61.4.403
PMCID: PMC486583
PMID: 8965089 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22851801
|
1. Sleep. 2012 Aug 1;35(8):1039-62. doi: 10.5665/sleep.1988.
The treatment of restless legs syndrome and periodic limb movement disorder in
adults--an update for 2012: practice parameters with an evidence-based
systematic review and meta-analyses: an American Academy of Sleep Medicine
Clinical Practice Guideline.
Aurora RN(1), Kristo DA, Bista SR, Rowley JA, Zak RS, Casey KR, Lamm CI, Tracy
SL, Rosenberg RS; American Academy of Sleep Medicine.
Author information:
(1)Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
Comment in
Sleep. 2012 Aug 01;35(8):1037. doi: 10.5665/sleep.1986.
A systematic literature review and meta-analyses (where appropriate) were
performed to update the previous AASM practice parameters on the treatments,
both dopaminergic and other, of RLS and PLMD. A considerable amount of
literature has been published since these previous reviews were performed,
necessitating an update of the corresponding practice parameters. Therapies with
a STANDARD level of recommendation include pramipexole and ropinirole. Therapies
with a GUIDELINE level of recommendation include levodopa with dopa
decarboxylase inhibitor, opioids, gabapentin enacarbil, and cabergoline (which
has additional caveats for use). Therapies with an OPTION level of
recommendation include carbamazepine, gabapentin, pregabalin, clonidine, and for
patients with low ferritin levels, iron supplementation. The committee
recommends a STANDARD AGAINST the use of pergolide because of the risks of heart
valve damage. Therapies for RLS secondary to ESRD, neuropathy, and superficial
venous insufficiency are discussed. Lastly, therapies for PLMD are reviewed.
However, it should be mentioned that because PLMD therapy typically mimics RLS
therapy, the primary focus of this review is therapy for idiopathic RLS.
DOI: 10.5665/sleep.1988
PMCID: PMC3397811
PMID: 22851801 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20478643
|
1. J Plant Physiol. 2010 Sep 15;167(14):1204-10. doi:
10.1016/j.jplph.2010.03.017. Epub 2010 May 15.
Synergism between cucumber alpha-expansin, fungal endoglucanase and pectin
lyase.
Wei W(1), Yang C, Luo J, Lu C, Wu Y, Yuan S.
Author information:
(1)Jiangsu Engineering and Technology Research Center for Industrialization of
Microbial Resources, Jiangsu Key Laboratory for Biodiversity and Biotechnology,
College of Life Science, Nanjing Normal University, Nanjing, PR China.
Several recombinant fungal enzymes (endoglucanase and pectinase) were studied
for their interactions with alpha-expansin in cell wall extension and
polysaccharide degradation. Both Cel12A and Cel5A were able to hydrolyze
cellulose CMC-Na and mixed-linkage beta-glucan. In contrast to Cel5A, Cel12A
could also hydrolyze xyloglucan and induce wall extension of cucumber hypocotyls
in an in vitro assay. Combining alpha-expansin, even at high concentrations,
with Cel12A did not enhance the maximum/final wall extension rate induced by
Cel12A alone. These results strongly suggest that modification/degradation of
the xyloglucan molecule/network is the key for cell wall extension, and
alpha-expansin and Cel12A may share the same acting site in the substrate.
Pectinase (Pel1, a pectin lyase) enhanced alpha-expansin-induced wall extension
in a concentration-dependent manner, suggesting that the pectin network may
normally regulate accessibility of expansin to the xyloglucan-cellulose complex.
alpha-Expansin enhanced Cel12A's hydrolytic activity on cellulose CMC-Na but not
on xyloglucan and beta-glucan. Expansin did not affect Cel5A's hydrolytic
activity. Interestingly, expansin also enhanced Pel1's activity on degrading
high esterified pectin. A potential explanation for why expansin could
synergistically interact with only certain enzymes on specific polysaccharides
is discussed. Additional results also suggested that cell wall swelling may not
be a significant event during the action of expansin and hydrolases.
Copyright 2010 Elsevier GmbH. All rights reserved.
DOI: 10.1016/j.jplph.2010.03.017
PMID: 20478643 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15605243
|
1. Planta. 2005 Apr;220(6):889-99. doi: 10.1007/s00425-004-1431-2. Epub 2004 Dec
17.
Differential location of alpha-expansin proteins during the accommodation of
root cells to an arbuscular mycorrhizal fungus.
Balestrini R(1), Cosgrove DJ, Bonfante P.
Author information:
(1)Istituto per la Protezione delle Piante del CNR, Sezione di Micologia and
Dipartimento di Biologia Vegetale dell'Università, Viale Mattioli 25, 10125,
Turin, Italy.
alpha-Expansins are extracellular proteins that increase plant cell-wall
extensibility. We analysed their pattern of expression in cucumber roots in the
presence and in the absence of the mycorrhizal fungus, Glomus versiforme. The
distribution of alpha-expansins was investigated by use of two polyclonal
antibodies (anti-EXPA1 and anti-EXPA2, prepared against two different cucumber
alpha-expansins) in immunoblotting, immunofluorescence, and immunogold
experiments. Immunoblot results indicate the presence of a 30-kDa band specific
for mycorrhizal roots. The two antibodies identify antigens with a different
distribution in mycorrhizal roots: anti-EXPA1 labels the interface zone, but the
plant cell walls only weakly. By contrast, the anti-EXPA2 labels only the plant
cell walls. In order to understand the potential role of alpha-expansins during
the accommodation of the fungus inside root cells, we prepared semi-thin
sections to measure the size of cortical cells and the thickness of cortical
cell walls in mycorrhizal and non-mycorrhizal root. Mycorrhizal cortical cells
were significantly larger than non-mycorrhizal cells and had thicker cell walls.
In double-labelling experiments with cellobiohydrolase-gold complex, we observed
that cellulose was co-localized with alpha-expansins. Taken together, the
results demonstrate that alpha-expansins are more abundant in the cucumber cell
walls upon mycorrhizal infection; we propose that these wall-loosening proteins
are directly involved in the accommodation of the fungus by infected cortical
cells.
DOI: 10.1007/s00425-004-1431-2
PMID: 15605243 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23451191
|
1. PLoS One. 2013;8(2):e57239. doi: 10.1371/journal.pone.0057239. Epub 2013 Feb
22.
Efficient methods for targeted mutagenesis in zebrafish using zinc-finger
nucleases: data from targeting of nine genes using CompoZr or CoDA ZFNs.
Sood R(1), Carrington B, Bishop K, Jones M, Rissone A, Candotti F,
Chandrasekharappa SC, Liu P.
Author information:
(1)Zebrafish Core Facility, Genetics and Molecular Biology Branch, National
Human Genome Research Institute, Bethesda, Maryland, United States of America.
rsood@mail.nih.gov
Recently, it has been shown that targeted mutagenesis using zinc-finger
nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs)
can be used to generate knockout zebrafish lines for analysis of their function
and/or developing disease models. A number of different methods have been
developed for the design and assembly of gene-specific ZFNs and TALENs, making
them easily available to most zebrafish researchers. Regardless of the choice of
targeting nuclease, the process of generating mutant fish is similar. It is a
time-consuming and multi-step process that can benefit significantly from
development of efficient high throughput methods. In this study, we used ZFNs
assembled through either the CompoZr (Sigma-Aldrich) or the CoDA
(context-dependent assembly) platforms to generate mutant zebrafish for nine
genes. We report our improved high throughput methods for 1) evaluation of ZFNs
activity by somatic lesion analysis using colony PCR, eliminating the need for
plasmid DNA extractions from a large number of clones, and 2) a sensitive
founder screening strategy using fluorescent PCR with PIG-tailed primers that
eliminates the stutter bands and accurately identifies even single nucleotide
insertions and deletions. Using these protocols, we have generated multiple
mutant alleles for seven genes, five of which were targeted with CompoZr ZFNs
and two with CoDA ZFNs. Our data also revealed that at least five-fold higher
mRNA dose was required to achieve mutagenesis with CoDA ZFNs than with CompoZr
ZFNs, and their somatic lesion frequency was lower (<5%) when compared to
CopmoZr ZFNs (9-98%). This work provides high throughput protocols for efficient
generation of zebrafish mutants using ZFNs and TALENs.
DOI: 10.1371/journal.pone.0057239
PMCID: PMC3579846
PMID: 23451191 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
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http://www.ncbi.nlm.nih.gov/pubmed/24521108
|
1. N Engl J Med. 2014 Feb 13;370(7):621-31. doi: 10.1056/NEJMoa1303646.
Comparison of pregabalin with pramipexole for restless legs syndrome.
Allen RP(1), Chen C, Garcia-Borreguero D, Polo O, DuBrava S, Miceli J, Knapp L,
Winkelman JW.
Author information:
(1)From the Department of Neurology, Johns Hopkins University, Baltimore
(R.P.A.); Pfizer Global Research and Development, Groton, CT (C.C., S.D., J.M.,
L.K.); Sleep Research Institute, Madrid (D.G.-B.); the Department of Pulmonary
Medicine, Tampere University Hospital, Tampere, Finland (O.P.); and
Massachusetts General Hospital, Boston (J.W.W.).
Comment in
N Engl J Med. 2014 Feb 13;370(7):667-8. doi: 10.1056/NEJMe1313155.
N Engl J Med. 2014 May 22;370(21):2050-1. doi: 10.1056/NEJMc1402987.
N Engl J Med. 2014 May 22;370(21):2049-50. doi: 10.1056/NEJMc1402987.
N Engl J Med. 2014 May 22;370(21):2050. doi: 10.1056/NEJMc1402987.
MMW Fortschr Med. 2014 Dec 15;156(21-22):50.
BACKGROUND: Dopaminergic medications relieve symptoms of the restless legs
syndrome (RLS) but have the potential to cause iatrogenic worsening
(augmentation) of RLS with long-term treatment. Pregabalin may be an effective
alternative.
METHODS: In this 52-week, randomized, double-blind trial, we assessed efficacy
and augmentation in patients with RLS who were treated with pregabalin as
compared with placebo and pramipexole. Patients were randomly assigned to
receive 52 weeks of treatment with pregabalin at a dose of 300 mg per day or
pramipexole at a dose of 0.25 mg or 0.5 mg per day or 12 weeks of placebo
followed by 40 weeks of randomly assigned active treatment. The primary analyses
involved a comparison of pregabalin and placebo over a period of 12 weeks with
use of the International RLS (IRLS) Study Group Rating Scale (on which the score
ranges from 0 to 40, with a higher score indicating more severe symptoms), the
Clinical Global Impression of Improvement scale (which was used to assess the
proportion of patients with symptoms that were "very much improved" or "much
improved"), and a comparison of rates of augmentation with pregabalin and
pramipexole over a period of 40 or 52 weeks of treatment.
RESULTS: A total of 719 participants received daily treatment, 182 with 300 mg
of pregabalin, 178 with 0.25 mg of pramipexole, 180 with 0.5 mg of pramipexole,
and 179 with placebo. Over a period of 12 weeks, the improvement (reduction) in
mean scores on the IRLS scale was greater, by 4.5 points, among participants
receiving pregabalin than among those receiving placebo (P<0.001), and the
proportion of patients with symptoms that were very much improved or much
improved was also greater with pregabalin than with placebo (71.4% vs. 46.8%,
P<0.001). The rate of augmentation over a period of 40 or 52 weeks was
significantly lower with pregabalin than with pramipexole at a dose of 0.5 mg
(2.1% vs. 7.7%, P=0.001) but not at a dose of 0.25 mg (2.1% vs. 5.3%, P=0.08).
There were six cases of suicidal ideation in the group receiving pregabalin,
three in the group receiving 0.25 mg of pramipexole, and two in the group
receiving 0.5 mg of pramipexole.
CONCLUSIONS: Pregabalin provided significantly improved treatment outcomes as
compared with placebo, and augmentation rates were significantly lower with
pregabalin than with 0.5 mg of pramipexole. (Funded by Pfizer;
ClinicalTrials.gov number, NCT00806026.).
DOI: 10.1056/NEJMoa1303646
PMID: 24521108 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23777900
|
1. Menopause. 2014 Mar;21(3):309-19. doi: 10.1097/GME.0b013e31829755ed.
Clinical effects of selective estrogen receptor modulators on vulvar and vaginal
atrophy.
Pinkerton JV(1), Stanczyk FZ.
Author information:
(1)From the 1Department of Obstetrics and Gynecology, UVA Midlife Health Center,
Charlottesville, VA; and 2Departments of Obstetrics and Gynecology, and
Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA.
Comment in
Menopause. 2014 Mar;21(3):213. doi: 10.1097/GME.0000000000000205.
OBJECTIVE: Vaginal estrogen therapy at the lowest effective dose is generally
recommended for the treatment of vulvar and vaginal atrophy (VVA), but not all
women are candidates. Selective estrogen receptor modulators (SERMs) aim to
elicit specific positive effects on targeted tissues with neutral or minimal
negative effects on other tissues. This review compares the vaginal effects of
currently available and investigational SERMs.
METHODS: Relevant English-language articles published between 1980 and 2012 were
identified through the PubMed database (search string "[Selective Estrogen
Receptor Modulator OR SERM] AND [Vulvar OR Vaginal] AND Atrophy"), article
reference lists, and EMBASE searches for individual SERMs. Both authors reviewed
all articles, which formed the basis of this narrative literature review.
RESULTS: Activity profiles of SERMs in various tissues are distinct. Tamoxifen
and arzoxifene have no specific positive vaginal effects but have reported
variable or adverse gynecologic effects. Raloxifene does not improve VVA but can
be used safely in combination with vaginal estrogen. Bazedoxifene has no
demonstrated efficacy for VVA but, in combination with oral conjugated equine
estrogens, improves the signs and symptoms of VVA. SERMs with positive vaginal
effects (such as improvement in the vaginal maturation index, reduced vaginal
pH, and improvement in the signs and symptoms of VVA) on postmenopausal
symptomatic women include lasofoxifene (clinical development on hold) and
ospemifene, which was recently approved for the treatment of VVA-related
dyspareunia, with a class effect warning of potential venous thrombosis risk.
CONCLUSIONS: SERMs that specifically target the pathophysiology underlying VVA
may provide an alternative to vaginal or systemic estrogen therapy.
DOI: 10.1097/GME.0b013e31829755ed
PMID: 23777900 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18656214
|
1. Rev Neurol (Paris). 2008 Aug-Sep;164(8-9):701-21. doi:
10.1016/j.neurol.2008.06.006. Epub 2008 Jul 24.
[Restless-legs syndrome].
[Article in French]
Karroum E(1), Konofal E, Arnulf I.
Author information:
(1)UF pathologies du sommeil, groupe hospitalier Pitié-Salpêtrière, Assistance
publique-Hôpitaux de Paris, pavillon Marguerite-Bottard, Paris cedex, France.
pr_karroum@hotmail.com
Restless-legs syndrome (RLS) is a sensorimotor disorder, characterized by an
irresistible urge to move the legs usually accompanied or caused by
uncomfortable and unpleasant sensations. It begins or worsens during periods of
rest or inactivity, is partially or totally relieved by movements and is
exacerbated or occurs at night and in the evening. RLS sufferers represent 2 to
3% of the general population in Western countries. Supportive criteria include a
family history, the presence of periodic-leg movements (PLM) when awake or
asleep and a positive response to dopaminergic treatment. The RLS phenotypes
include an early onset form, usually idiopathic with a familial history and a
late onset form, usually secondary to peripheral neuropathy. Recently, an
atypical RLS phenotype without PLM and l-DOPA resistant has been characterized.
RLS can occur in childhood and should be distinguished from attention
deficit/hyperactivity disorder, growing pains and sleep complaints in childhood.
RLS should be included in the diagnosis of all patients consulting for sleep
complaints or discomfort in the lower limbs. It should be differentiated from
akathisia, that is, an urge to move the whole body without uncomfortable
sensations. Polysomnographic studies and the suggested immobilization test can
detect PLM. Furthermore, an l-DOPA challenge has recently been validated to
support the diagnosis of RLS. RLS may cause severe-sleep disturbances, poor
quality of life, depressive and anxious symptoms and may be a risk factor for
cardiovascular disease. In most cases, RLS is idiopathic. It may also be
secondary to iron deficiency, end-stage renal disease, pregnancy, peripheral
neuropathy and drugs, such as antipsychotics and antidepressants. The
small-fiber neuropathy can mimic RLS or even trigger it. RLS is associated with
many neurological and sleep disorders including Parkinson's disease, but does
not predispose to these diseases. The pathophysiology of RLS includes an altered
brain-iron metabolism, a dopaminergic dysfunction, a probable role of pain
control systems and a genetic susceptibility with nine loci and three
polymorphisms in genes serving developmental functions. RLS treatment begins
with the elimination of triggering factors and iron supplementation when
deficient. Mild or intermittent RLS is usually treated with low doses of l-DOPA
or codeine; the first-line treatment for moderate to severe RLS is dopaminergic
agonists (pramipexole, ropinirole, rotigotine). In severe, refractory or
neuropathy-associated RLS, antiepileptic (gabapentin, pregabalin) or opioid
(oxycodone, tramadol) drugs can be used.
DOI: 10.1016/j.neurol.2008.06.006
PMID: 18656214 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17711494
|
1. Cephalalgia. 2007 Oct;27(10):1128-35. doi: 10.1111/j.1468-2982.2007.01410.x.
Epub 2007 Aug 17.
Headaches after acoustic neuroma surgery.
Rimaaja T(1), Haanpää M, Blomstedt G, Färkkilä M.
Author information:
(1)Institute of Dentistry, Faculty of Medicine, University of Helsinki,
Helsinki, Finland. tuomas.rimaaja@gmail.com
Headache and depression were studied in patients who had undergone operation for
acoustic neuroma. A questionnaire with headache and Beck Depression Inventory
scale were sent to 228 patients, of whom 192 (84%) responded. Preoperative
headache was reported by 61 (32%) of the respondents (47 migraine and nine
tension-type headache) and 122 (64%) respondents had postoperative headache (15
new migraine and four new tension-type headache). The new postoperative headache
was chronic (>/=3 months) in 86% and continued at the time of the survey in 55%
and presented typically as severe short-lasting attacks provoked by physical
stress, bending or coughing. Non-steroidal anti-inflammatory drugs were
effective in most cases. Depression (usually mild) occurred in 24% of the
respondents, being significantly more common in prolonged postoperative headache
patients. The operation doubled the prevalence of headache (from 32% to 64%).
Headache after acoustic neuroma operation appears to be a specific subgroup of
postcraniotomy headache.
DOI: 10.1111/j.1468-2982.2007.01410.x
PMID: 17711494 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19479322
|
1. Biotechnol Lett. 2009 Sep;31(9):1399-405. doi: 10.1007/s10529-009-0030-5. Epub
2009 May 29.
Transcriptional profiling of cellulase and expansin-related genes in a
hypercellulolytic Trichoderma reesei.
Verbeke J(1), Coutinho P, Mathis H, Quenot A, Record E, Asther M, Heiss-Blanquet
S.
Author information:
(1)Département de Biotechnologie, IFP, 1 et 4 Avenue de Bois-Préau, 92852
Rueil-Malmaison, France.
Expression kinetics of six cellulase and four expansin-related genes were
studied in the hypercellulolytic Trichoderma reesei CL847 mutant in response to
Solka Floc cellulose and soluble inducers. Real-time PCR showed a parallel
increase of transcript levels for the cellulase genes cbh1/cel7a, egl1/cel7b,
egl4/cel61a, the beta-glucosidase genes bgl1/cel3a, bgl2/cel1a, and the swo1
gene, encoding the cell-wall loosening protein swollenin. To evaluate a putative
implication of three newly identified expansin/family 45 endoglucanase-like
(EEL) proteins in lignocellulose degradation, their expression was also
analysed. Only eel2 was found to be transcribed under the present conditions,
and showed constitutive expression similar to the endoglucanase encoding cel5b
gene.
DOI: 10.1007/s10529-009-0030-5
PMID: 19479322 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16816022
|
1. J Med Genet. 2006 Jul;43(7):e35. doi: 10.1136/jmg.2005.038125.
A novel susceptibility locus for Hirschsprung's disease maps to 4q31.3-q32.3.
Brooks AS, Leegwater PA, Burzynski GM, Willems PJ, de Graaf B, van Langen I,
Heutink P, Oostra BA, Hofstra RM, Bertoli-Avella AM.
We report on a multigenerational family with isolated Hirschsprung's disease
(HSCR). Five patients were affected by either short segment or long segment
HSCR. The family consists of two main branches: one with four patients (three
siblings and one maternal uncle) and one with one patient. Analysis of the RET
gene, the major gene involved in HSCR susceptibility, revealed neither linkage
nor mutations. A genome wide linkage analysis was performed, revealing
suggestive linkage to a region on 4q31-q32 with a maximum parametric multipoint
LOD score of 2.7. Furthermore, non-parametric linkage (NPL) analysis of the
genome wide scan data revealed a NPL score of 2.54 (p = 0.003) for the same
region on chromosome 4q (D4S413-D4S3351). The minimum linkage interval spans a
region of 11.7 cM (12.2 Mb). No genes within this chromosomal interval have
previously been implicated in HSCR. Considering the low penetrance of disease in
this family, the 4q locus may be necessary but not sufficient to cause HSCR in
the absence of modifying loci elsewhere in the genome. Our results suggest the
existence of a new susceptibility locus for HSCR at 4q31.3-q32.3.
DOI: 10.1136/jmg.2005.038125
PMCID: PMC2564564
PMID: 16816022 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: there are no competing
interests
|
http://www.ncbi.nlm.nih.gov/pubmed/20389291
|
1. Mol Ther. 2010 Jun;18(6):1103-10. doi: 10.1038/mt.2010.57. Epub 2010 Apr 13.
Gene correction by homologous recombination with zinc finger nucleases in
primary cells from a mouse model of a generic recessive genetic disease.
Connelly JP(1), Barker JC, Pruett-Miller S, Porteus MH.
Author information:
(1)Department of Pediatrics, University of Texas Southwestern Medical Center,
Dallas, Texas, USA.
Zinc Finger nucleases (ZFNs) have been used to create precise genome
modifications at frequencies that might be therapeutically useful in gene
therapy. We created a mouse model of a generic recessive genetic disease to
establish a preclinical system to develop the use of ZFN-mediated gene
correction for gene therapy. We knocked a mutated GFP gene into the ROSA26 locus
in murine embryonic stem (ES) cells and used these cells to create a transgenic
mouse. We used ZFNs to determine the frequency of gene correction by gene
targeting in different primary cells from this model. We achieved targeting
frequencies from 0.17 to 6% in different cell types, including primary
fibroblasts and astrocytes. We demonstrate that ex vivo gene-corrected
fibroblasts can be transplanted back into a mouse where they retained the
corrected phenotype. In addition, we achieved targeting frequencies of over 1%
in ES cells, and the targeted ES cells retained the ability to differentiate
into cell types from all three germline lineages. In summary, potentially
therapeutically relevant frequencies of ZFN-mediated gene targeting can be
achieved in a variety of primary cells and these cells can then be transplanted
back into a recipient.
DOI: 10.1038/mt.2010.57
PMCID: PMC2889743
PMID: 20389291 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18400936
|
1. Plant Physiol. 2008 Jun;147(2):779-89. doi: 10.1104/pp.108.116293. Epub 2008
Apr 9.
Role of swollenin, an expansin-like protein from Trichoderma, in plant root
colonization.
Brotman Y(1), Briff E, Viterbo A, Chet I.
Author information:
(1)Department of Plant Pathology and Microbiology, Faculty of Agricultural, Food
and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot
76100, Israel.
Swollenin, a protein first characterized in the saprophytic fungus Trichoderma
reesei, contains an N-terminal carbohydrate-binding module family 1 domain (CBD)
with cellulose-binding function and a C-terminal expansin-like domain. This
protein was identified by liquid chromatography-mass spectrometry among many
other cellulolytic proteins secreted in the coculture hydroponics medium of
cucumber (Cucumis sativus) seedlings and Trichoderma asperellum, a well-known
biocontrol agent and inducer of plant defense responses. The swollenin gene was
isolated and its coding region was overexpressed in the same strain under the
control of the constitutive pki1 promoter. Trichoderma transformants showed a
remarkably increased ability to colonize cucumber roots within 6 h after
inoculation. On the other hand, overexpressors of a truncated swollenin sequence
bearing a 36-amino acid deletion of the CBD did not differ from the wild type,
showing in vivo that this domain is necessary for full protein activity. Root
colonization rates were reduced in transformants silenced in swollenin gene
expression. A synthetic 36-mer swollenin CBD peptide was shown to be capable of
stimulating local defense responses in cucumber roots and leaves and to afford
local protection toward Botrytis cinerea and Pseudomonas syringae pv lachrymans
infection. This indicates that the CBD domain might be recognized by the plant
as a microbe-associated molecular pattern in the Trichoderma-plant interaction.
DOI: 10.1104/pp.108.116293
PMCID: PMC2409044
PMID: 18400936 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22051029
|
1. J Clin Neurosci. 2012 Feb;19(2):246-51. doi: 10.1016/j.jocn.2011.06.006. Epub
2011 Nov 2.
Factors associated with anxiety and depression in the management of acoustic
neuroma patients.
Brooker JE(1), Fletcher JM, Dally MJ, Briggs RJ, Cousins VC, Malham GM, Smee RI,
Kennedy RJ, Burney S.
Author information:
(1)Southern Synergy, School of Psychology and Psychiatry, Monash University,
Wellington Road Campus, Melbourne, Victoria 3800, Australia.
Joanne.Brooker@monash.edu
The objectives of this study were to describe anxiety and depression levels
among acoustic neuroma patients; examine differences in anxiety and depression
across the acoustic neuroma management options of microsurgery, radiation and
observation; and to investigate management, medical and demographic factors that
might predict anxiety and depression in this patient group. A cross-sectional
questionnaire was completed by 205 adults diagnosed with, or treated for, a
unilateral acoustic neuroma within five years of questionnaire distribution.
Median age of participants was 57.0 years, and 120 (58.5%) were female. Anxiety
and depression were measured using the Hospital Anxiety and Depression Scale
(HADS). Clinically significant anxiety was reported by 29.8% of participants and
10.2% were depressed. Mean anxiety and depression scores did not differ from
general population norms. No significant differences in anxiety and depression
were found across management options. Time since management, number of symptoms
and comorbid medical conditions predicted anxiety, while depression was
predicted by number of symptoms. This appears to be the first study among
acoustic neuroma patients in which anxiety and depression were compared across
management options. Treating physicians should be aware that as the number of
acoustic neuroma symptoms increases, so may the likelihood of clinically
significant anxiety and depression.
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.jocn.2011.06.006
PMID: 22051029 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15806097
|
1. Nature. 2005 Jun 2;435(7042):646-51. doi: 10.1038/nature03556. Epub 2005 Apr
3.
Highly efficient endogenous human gene correction using designed zinc-finger
nucleases.
Urnov FD(1), Miller JC, Lee YL, Beausejour CM, Rock JM, Augustus S, Jamieson AC,
Porteus MH, Gregory PD, Holmes MC.
Author information:
(1)Sangamo BioSciences, Inc., Pt. Richmond Tech Center 501, Canal Blvd, Suite
A100 Richmond, California 94804, USA.
Comment in
Nature. 2005 Jun 2;435(7042):577-9. doi: 10.1038/435577a.
Permanent modification of the human genome in vivo is impractical owing to the
low frequency of homologous recombination in human cells, a fact that hampers
biomedical research and progress towards safe and effective gene therapy. Here
we report a general solution using two fundamental biological processes: DNA
recognition by C2H2 zinc-finger proteins and homology-directed repair of DNA
double-strand breaks. Zinc-finger proteins engineered to recognize a unique
chromosomal site can be fused to a nuclease domain, and a double-strand break
induced by the resulting zinc-finger nuclease can create specific sequence
alterations by stimulating homologous recombination between the chromosome and
an extrachromosomal DNA donor. We show that zinc-finger nucleases designed
against an X-linked severe combined immune deficiency (SCID) mutation in the
IL2Rgamma gene yielded more than 18% gene-modified human cells without
selection. Remarkably, about 7% of the cells acquired the desired genetic
modification on both X chromosomes, with cell genotype accurately reflected at
the messenger RNA and protein levels. We observe comparably high frequencies in
human T cells, raising the possibility of strategies based on zinc-finger
nucleases for the treatment of disease.
DOI: 10.1038/nature03556
PMID: 15806097 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23524988
|
1. Postgrad Med J. 2013 Jul;89(1053):402-10. doi:
10.1136/postgradmedj-2012-131634. Epub 2013 Mar 22.
Restless legs syndrome: pathophysiology and modern management.
Nagandla K(1), De S.
Author information:
(1)Department of Obstetrics and Gynecology, Melaka Manipal Medical College,
Jalan Batu Hampar, Bukit Baru, Melaka, Malaysia. kavitha.nagandla@gmail.com
Restless legs syndrome (RLS) is a common sensory motor neurological disorder
that is characterised by an irresistible urge to move the legs that
significantly affects the quality of life of the patient. Prevalence in the
general population is 5-25% and it is twice as prevalent in women as in men. RLS
is the most common movement disorder in pregnancy with a fourfold increased risk
of developing this disorder later in life. The pathophysiology of RLS is centred
on dopaminergic dysfunction, reduced central nervous system iron, genetic
linkages, or alteration in neurotransmitters such as hypocretins, endorphins
levels and immune dysfunction and inflammatory mechanisms. With the emergence of
new evidence, there are changes to the previous treatment recommendations for
RLS. There is sufficient evidence to conclude that dopamine agonists such as
rotigotine transdermal patch, pramipexole, ropinirole, gabapentin enacarbil,
pregabalin and gabapentin are effective in the short-term treatment of RLS and
rotigotine, followed by gabapentin enacarbil, ropinirole, pramipexole and
gabapentin for long-term treatment. Based on expert consensus, the
recommendation for daily RLS is dopamine agonists or gabapentin or low-potency
opioids. Levodopa is less preferred for treating daily RLS due to its high risk
of augmentation. For intermittent RLS, it is levodopa or dopamine agonists or
low-potency opioids or benzodiazepines. For refractory RLS, the choice is to
change to gabapentin or a different dopamine agonist, addition of a second agent
like gabapentin or benzodiazepine to the existing drug or changing to a
high-potency opioid or tramadol. Medications with safety record in pregnancy
include opioids and antiepileptics such as carbamazepine and gabapentin. There
are concerns that patients with RLS are at risk for metabolic deregulation,
autonomic dysfunction and cardiovascular morbidity. However, a recent study
concluded that RLS is not associated with increased risk of cardiovascular
complications.
DOI: 10.1136/postgradmedj-2012-131634
PMID: 23524988 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23703310
|
1. Curr Treat Options Neurol. 2013 Aug;15(4):396-409. doi:
10.1007/s11940-013-0241-x.
Treatment of restless legs syndrome.
Rios Romenets S(1), Postuma RB.
Author information:
(1)Department of Neurology, McGill University, Montreal General Hospital,
L7-312, 1650 Cedar Ave., Montreal, Quebec, Canada, H3G 1A4.
Restless legs syndrome (RLS) is a common, sensorimotor, circadian sleep disorder
characterized by the urge to move the legs, particularly at nighttime. It is
important to differentiate primary and secondary RLS from other conditions,
which can mimic the symptoms of RLS, in particular neuropathy and cramps.
Despite considerable advances, the understanding of RLS pathophysiology remains
incomplete. Many hypotheses focus on central nervous system structures, although
there is increasing evidence that peripheral structures may also be important.
There is insufficient evidence at the moment to recommend changes in lifestyle,
nutritional supplements and any specific nonpharmacologic treatments. The
first-line drugs continue to be dopaminergic medications, including pramipexole,
ropinirole, rotigotine transdermal patch and levodopa. However, the phenomenon
of RLS augmentation, a paradoxical worsening of symptoms by dopaminergic
treatment remains as major problem in treatment of RLS, and prevention of
augmentation is one of the main goals in the management of RLS. RLS requires
treatment only if it has a significant impact on the patient's nighttime sleep
or daily activities. Doses of dopamine agonists should be kept to the minimum
required for acceptable symptom reduction. Augmentation may require treatment
withdrawal, with prescription of alternate medication. Alternative or additional
pharmacologic treatment with a lower level of overall quality of evidence
includes opioids (codeine, tramadol, and oxycodone) and anticonvulsants
(gabapentin, gabapentin enacarbil, and pregabalin). The choice of the medication
should be based on the severity of RLS and the effectiveness of medication for
the short-term or long-term treatment of RLS. Iron deficiency must be identified
at diagnosis; treatment may improve RLS symptoms and potentially may lower risk
of augmentation. There is no clear evidence for treatment of secondary RLS, but
agents used in primary RLS should be tried. Comparative long-term trials are
required to assess differences in efficacy and augmentation rates between
medications used for treatment of RLS.
DOI: 10.1007/s11940-013-0241-x
PMID: 23703310
|
http://www.ncbi.nlm.nih.gov/pubmed/24223114
|
1. PLoS One. 2013 Nov 6;8(11):e75493. doi: 10.1371/journal.pone.0075493.
eCollection 2013.
An over expression APP model for anti-Alzheimer disease drug screening created
by zinc finger nuclease technology.
Zhang X(1), Li H, Mao Y, Li Z, Wang R, Guo T, Jin L, Song R, Xu W, Zhou N, Zhang
Y, Hu R, Wang X, Huang H, Lei Z, Niu G, Irwin DM, Tan H.
Author information:
(1)Department of Pharmacology, Peking University, Health Science Center,
Beijing, China.
Zinc Finger Nucleases (ZFNs), famous for their ability to precisely and
efficiently modify specific genomic loci, have been employed in numerous
transgenic model organism and cell constructions. Here we employ the ZFNs
technology, with homologous recombination (HR), to construct sequence-specific
Amyloid Precursor Protein (APP) knock-in cells. With the use of ZFNs, we
established APP knock in cell lines with gene-modification efficiencies of about
7%. We electroporated DNA fragment containing the promoter and the protein
coding regions of the zinc finger nucleases into cells, instead of the plasmids,
to avoid problems associated with off target homologous recombination, and
adopted a pair of mutated FokI cleavage domains to reduce the toxic effects of
the ZFNs on cell growth. Since over-expression of APP, or a subdomain of it,
might lead to an immediately lethal effect, we used the Cre-LoxP System to
regulate APP expression. Our genetically transformed cell lines, w5c1 and s12c8,
showed detectable APP and Amyloid β (Aβ) production. The Swedish double mutation
in the APP coding sequence enhanced APP and Aβ abundance. What is more, the
activity of the three key secretases in Aβ formation could be modulated,
indicating that these transgenic cells have potential for drug screening to
modify amyloid metabolism in cells. Our transformed cells could readily be
propagated in culture and should provide an excellent experimental medium for
elucidating aspects of the molecular pathogenesis of Alzheimer's disease,
especially those concerning the amyloidogenic pathways involving mutations in
the APP coding sequence. The cellular models may also serve as a tool for
deriving potentially useful therapeutic agents.
DOI: 10.1371/journal.pone.0075493
PMCID: PMC3819351
PMID: 24223114 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: I have read the journal's
policy and have the following conflicts. Gang Nui is president and CEO of
Beijing N&N Genetech Co. 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/7702086
|
1. Am J Med Genet. 1995 Jan 2;55(1):127-33. doi: 10.1002/ajmg.1320550132.
A common FGFR3 gene mutation is present in achondroplasia but not in
hypochondroplasia.
Stoilov I(1), Kilpatrick MW, Tsipouras P.
Author information:
(1)Department of Pediatrics, University of Connecticut Health Center, Farmington
06030, USA.
Achondroplasia is the most common type of genetic dwarfism. It is characterized
by disproportionate short stature and other skeletal anomalies resulting from a
defect in the maturation of the chondrocytes in the growth plate of the
cartilage. Recent studies mapped the achondroplasia gene on chromosome region
4p16.3 and identified a common mutation in the gene encoding the fibroblast
growth factor receptor 3 (FGFR3). In an analysis of 19 achondroplasia families
from a variety of ethnic backgrounds we confirmed the presence of the G380R
mutation in 21 of 23 achondroplasia chromosomes studied. In contrast, the G380R
mutation was not found in any of the 8 hypochondroplasia chromosomes studied.
Furthermore, linkage studies in a 3-generation family with hypochondroplasia
show discordant segregation with markers in the 4p16.3 region suggesting that at
least some cases of hypochondroplasia are caused by mutations in a gene other
than FGFR3.
DOI: 10.1002/ajmg.1320550132
PMID: 7702086 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16448984
|
1. Ann Med. 2006;38(1):11-9. doi: 10.1080/07853890500442758.
Molecular mechanisms of RET-induced Hirschsprung pathogenesis.
Lantieri F(1), Griseri P, Ceccherini I.
Author information:
(1)Lab. Genetica Molecolare, Ist. G. Gaslini, Genova, Italy.
The RET proto-oncogene is the major gene involved in the pathogenesis of
Hirschsprung (HSCR), a complex genetic disease characterized by lack of ganglia
along variable lengths of the gut. Here we present a survey of the different
molecular mechanisms through which RET mutations lead to the disease
development. Among these, loss of function, gain of function, apoptosis,
aberrant splicing and decreased gene expression are exemplified and considered
with respect to their pathogenetic impact. In particular, RET transcription
regulation represents a new insight into the outline of HSCR susceptibility, and
having reached important progress in the last few years, deserves to be
reviewed. Notably, gene expression impairment seems to be at the basis of the
association of HSCR disease with several RET polymorphisms, allowing us to
define a predisposing haplotype spanning from the promoter to exon 2. Putative
functional variants, in the promoter and in intron 1, and proposed as low
penetrant predisposing alleles, are presented and discussed. Finally, based on
the RET mutation effects thus summarized, we attempt to derive conclusions which
may be useful for HSCR risk prediction and genetic counselling.
DOI: 10.1080/07853890500442758
PMID: 16448984 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/2775668
|
1. Axone. 1989 Sep;11(1):17-9.
Informational needs of patients who undergo excision of an acoustic neuroma.
Glavassevich M, Thomas S, Galloway SC.
Individuals who undergo removal of an acoustic neuroma are usually apprehensive
in spite of the intrinsically benign nature of the disease. Fears surrounding
the experience are related to the real risks involved in surgery near the brain
and the complications which can ensue. The intensity of the patients' feelings
of anxiety and uncertainty might be decreased if nurses were aware of and
attended to the informational needs of these patients. In order to describe the
informational needs of acoustic neuroma patients, a retrospective survey of 21
subjects who had had removal of such a tumor six to eighteen months previously
was carried out. The survey determined: (1) the type of information patients
received preoperatively and postoperatively (2) the type of information patients
wanted (3) the type of problems experienced postoperatively and (4) the length
and severity of the problems if they occurred. Content analysis indicated that
the majority of subjects experienced tiredness, depression, headache, and
dryness of eyes and mouth in the postoperative and convalescent phases. The
actual illness experience persisted much longer than the subjects had expected.
Subjects expressed explicit informational needs related to self-management after
the surgery. The implications for nursing care will be discussed and the
recommendations for an interdisciplinary patient education programme will be
outlined.
PMID: 2775668 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16441254
|
1. Ann Hum Genet. 2006 Jan;70(Pt 1):12-26. doi: 10.1111/j.1529-8817.2005.00196.x.
Haplotypes of the human RET proto-oncogene associated with Hirschsprung disease
in the Italian population derive from a single ancestral combination of alleles.
Lantieri F(1), Griseri P, Puppo F, Campus R, Martucciello G, Ravazzolo R, Devoto
M, Ceccherini I.
Author information:
(1)Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Genova, Italy,
16148.
The RET proto-oncogene is the major gene involved in the complex genetics of
Hirschsprung disease (HSCR), or aganglionic megacolon, showing causative
loss-of-function mutations in 15-30% of the sporadic cases. Several RET
polymorphisms and haplotypes have been described in association with the
disease, suggesting a role for this gene in HSCR predisposition, also in the
absence of mutations in the coding region. Finally, the presence of a functional
variant in intron 1 has repeatedly been proposed to explain such findings. Here
we report a case-control study conducted on 97 Italian HSCR sporadic patients
and 85 population matched controls, using 13 RET polymorphisms distributed
throughout the gene, from the basal promoter to the 3'UTR. Linkage
disequilibrium and haplotype analyses have shown increased recombination between
the 5' and 3' portions of the gene and an over-representation, in the cases
studied, of two haplotypes sharing a common allelic combination that extends
from the promoter up to intron 5. We propose that these two disease-associated
haplotypes derive from a single founding locus, extending up to intron 19 and
successively rearranged in correspondence with a high recombination rate region
located between the proximal and distal portions of the gene. Our results
suggests the possibility that a common HSCR predisposing variant, in linkage
disequilibrium with such haplotypes, is located further downstream than the
previously suggested interval encompassing intron 1.
DOI: 10.1111/j.1529-8817.2005.00196.x
PMID: 16441254 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16877807
|
1. J Appl Genet. 2006;47(3):261-7. doi: 10.1007/BF03194634.
Single nucleotide polymorphisms in the RET gene and their correlations with
Hirschsprung disease phenotype.
Smigiel R(1), Lebioda A, Patkowski D, Czernik J, Dobosz T, Pesz K, Kaczmarz M,
Sasiadek MM.
Author information:
(1)Genetics Department, Medical University, Wrocław, Poland.
smigiel@gen.am.wroc.pl
Hirschsprung disease (HSCR) is a congenital, heterogeneous disorder,
characterized by the absence of intestinal ganglion cells. Recent advances show
that the RET gene is a major locus involved in the pathogenesis of HSCR. The aim
of this study was to analyse if the HSCR phenotype in the Polish population is
associated with the presence of polymorphisms in exons 2, 3, 7, 11, 13, 14 and
15 of the RET gene. Molecular results were compared with clinical and long-term
follow-up data in 70 Polish patients with HSCR (84.3% with a short segment and
15.7% with a long segment of aganglionic gut). Single-nucleotide polymorphisms
were analysed by using the minisequencing SNaPshot multiplex method. The 135G>A
polymorphism in RET exon 2 was overrepresented in HSCR patients, compared with a
healthy control group. Moreover, the 135G>A variant was shown to be associated
with the severe HSCR phenotype. Two other polymorphisms, 2071G>A in exon 11 and
2712C>G in exon 15, were underrepresented in the patients. The results confirm
that these RET polymorphisms play a role in the aetiology of HSCR.
DOI: 10.1007/BF03194634
PMID: 16877807 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9254841
|
1. Hum Genet. 1997 Aug;100(2):151-4. doi: 10.1007/pl00008704.
Assignment of human genes for beta 2 and beta 4 subunits of voltage-dependent
Ca2+ channels to chromosomes 10p12 and 2q22-q23.
Taviaux S(1), Williams ME, Harpold MM, Nargeot J, Lory P.
Author information:
(1)CRBM-CNRS, BP 5051-1919, Montpellier, France.
We have used human beta 2 and beta 4 cDNA probes to map the genes encoding two
isoforms of the regulatory beta subunit of voltage-activated Ca2+ channels, viz.
CACNB2 (beta 2) and CACNB4 (beta 4), to human chromosomes 10p12 and 2q22-q23,
respectively, by fluorescence in situ hybridization. The gene encoding the beta
2 protein, first described as a Lambert-Eaton myasthenic syndrome (LEMS) antigen
in humans, is found close to a region that undergoes chromosome rearrangements
in small cell lung cancer, which occurs in association with LEMS. CACNB2 (beta
2) and CACNB4 (beta 4) genes are members of the ion-channel gene superfamily and
it should now be possible to examine their loci by linkage analysis of
ion-channel-related disorders. To date, no such disease-related gene has been
assigned to 10p12 and 2q22-q23.
DOI: 10.1007/pl00008704
PMID: 9254841 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23400839
|
1. Hum Genet. 2013 May;132(5):591-600. doi: 10.1007/s00439-013-1272-9. Epub 2013
Feb 12.
RET and NRG1 interplay in Hirschsprung disease.
Gui H(1), Tang WK, So MT, Proitsi P, Sham PC, Tam PK, Ngan ES, Cherny SS,
Garcia-Barceló MM.
Author information:
(1)Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China.
allenkuei@gmail.com
Erratum in
Hum Genet. 2014 May;133(5):677. Sau-Wai Ngan, Elly [corrected to Ngan, Elly
Sau-Wai].
Hirschsprung disease (HSCR, aganglionic megacolon) is a complex genetic disorder
of the enteric nervous system (ENS) characterized by the absence of enteric
neurons along a variable length of the intestine. While rare variants (RVs) in
the coding sequence (CDS) of several genes involved in ENS development lead to
disease, the association of common variants (CVs) with HSCR has only been
reported for RET (the major HSCR gene) and NRG1. Importantly, RVs in the CDS of
these two genes are also associated with the disorder. To assess independent and
joint effects between the different types of RET and NRG1 variants identified in
HSCR patients, we used 254 Chinese sporadic HSCR patients and 143 ethnically
matched controls for whom the RET and/or NRG1 variants genotypes (rare and
common) were available. Four genetic risk factors were defined and interaction
effects were modeled using conditional logistic regression analyses and
pair-wise Kendall correlations. Our analysis revealed a joint effect of RET CVs
with RET RVs, NRG1 CVs or NRG1 RVs. To assess whether the genetic interaction
translated into functional interaction, mouse neural crest cells (NCCs; enteric
neuron precursors) isolated from embryonic guts were treated with NRG1 (ErbB2
ligand) or/and GDNF (Ret ligand) and monitored during the subsequent neural
differentiation process. Nrg1 inhibited the Gdnf-induced neuronal
differentiation and Gdnf negatively regulated Nrg1-signaling by down-regulating
the expression of its receptor, ErbB2. This preliminary data suggest that the
balance neurogenesis/gliogenesis is critical for ENS development.
DOI: 10.1007/s00439-013-1272-9
PMID: 23400839 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/10932008
|
1. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2000 Aug;17(4):252-5.
[Differentiation of achondroplasia and other similar genetic dwarfism by FGFR3
gene analysis].
[Article in Chinese]
Zhang Y(1), Yu W, Shen M, Fang Q, Fan M.
Author information:
(1)China-Japan Friendship Institute of Clinical Medical Sciences, Beijing, P. R.
China. yuweim@public.bta.net.cn
OBJECTIVE: To study the gene mutation of Chinese patients with
achondroplasia(ACH) and to set up a simple and rapid molecular diagnostic method
to differentiate ACH from other similar genetic dwarfism.
METHODS: The specific fragment of fibroblast growth factor receptor 3(FGFR3)
transmembrane domain was amplified from dried blood spots of 21 patients with
ACH and 6 suspicious patients with ACH by polymerase chain reaction, then
mutation was screened and detected by restrictive enzyme analysis, single strand
conformation polymorphism(SSCP) and denaturing gradient gel
electrophoresis(DGGE).
RESULTS: One out of 6 suspicious cases was ACH and 5 were
pseudoachondroplasia(PSACH). Twenty-one out of 22 patients with ACH bore a G to
A transition at nucleotide 1138 and 1 bore a G to C transversion at this same
position.
CONCLUSION: The nucleotide 1138 of FGFR3 gene is also the hotspot of mutation in
Chinese patients with ACH. A simple and rapid molecular diagnostic method has
been set up to differentiate ACH from other similar genetic dwarfism.
PMID: 10932008 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17108762
|
1. Genet Med. 2006 Nov;8(11):704-10. doi: 10.1097/01.gim.0000245632.06064.f1.
A complex additive model of inheritance for Hirschsprung disease is supported by
both RET mutations and predisposing RET haplotypes.
Ruiz-Ferrer M(1), Fernández RM, Antiñolo G, López-Alonso M, Eng C, Borrego S.
Author information:
(1)Unidad Clínica de Genética y Reproducción, Hospitales Universitarios Virgen
del Rocío, Seville, Spain.
PURPOSE: The RET proto-oncogene is considered to be the major susceptibility
gene involved in Hirschsprung disease. Traditional RET germline mutations
account for a small subset of Hirschsprung disease patients, but several studies
have shown that there is a specific haplotype of RET associated with the
sporadic forms of Hirschsprung disease. We have investigated for RET germline
mutations and analyzed the RET haplotypic distribution in carriers versus
noncarriers of RET germline mutations.
METHODS: We have screened the coding region of RET in 106 Spanish Hirschsprung
disease patients using dHPLC technology. Statistical comparisons of the
distribution of RET haplotypes between sporadic patients with and without a RET
germline mutation were performed.
RESULTS: Nine novel germline mutations and one previously described were
identified. A significant over-transmission of the "Hirschsprung disease
haplotype" was detected when comparing transmitted versus nontransmitted alleles
in the group of Hirschsprung disease triads without mutation. However, no
distortion of the transmission of alleles was found in the group of mutated
families.
CONCLUSIONS: These results would be concordant with a complex additive model of
inheritance. The whole findings seem to suggest that low-penetrance mutations
would be necessary but not sufficient and the additional presence of the
"Hirschsprung disease haplotype" could contribute to the manifestation of the
disease.
DOI: 10.1097/01.gim.0000245632.06064.f1
PMID: 17108762 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/2189179
|
1. Semin Neurol. 1990 Mar;10(1):35-41. doi: 10.1055/s-2008-1041251.
Lambert-Eaton syndrome.
Pascuzzi RM(1), Kim YI.
Author information:
(1)Indiana University Medical Center, Indianapolis 46202.
LES is an autoimmune disorder of the neuromuscular junction in which
autoantibodies directed against voltage-dependent Ca2+ channels block
nerve-evoked Ca2+ entry at the motor nerve terminal. The pathogenic IgG is
likely to produce a similar inhibitory effect on the Ca2+ channel function in
other cholinergic synapses of the autonomic nervous system. This pathophysiology
is sufficient to account for the distinctive clinical, immunologic, and
electrophysiologic manifestations in patients with LES. Etiology of this disease
is uncertain but in view of its frequent association with small cell lung
cancer, this specific type of neoplasm may be implicated in the initiation of
autoimmune response. Recent studies indeed support the possibility that the
antigenic stimulus in the neoplastic form of LES may arise from
voltage-dependent Ca2+ channels found in the lung cancer cells.
DOI: 10.1055/s-2008-1041251
PMID: 2189179 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/1318636
|
1. Acta Physiol Scand. 1992 Apr;144(4):463-8. doi:
10.1111/j.1748-1716.1992.tb09321.x.
Voltage-sensitive calcium channels in a human small-cell lung cancer cell line.
Pancrazio JJ(1), Oie HK, Kim YI.
Author information:
(1)Department of Biomedical Engineering, University of Virginia Health Sciences
Center, Charlottesville 22908.
Utilizing the whole-cell patch-clamp method we assessed the Ca2+ current (ICa)
in well-established cell lines from human small-cell carcinoma (SCC) of the
lung, NCI-H209 and NCI-H187. The Ca2+ current was readily observed in H209
tumour cells (90% of the cells tested), whereas H187 tumour cells only
occasionally expressed Ca2+ channels (26% of the cells tested). H209 Ca2+
current was evoked by potentials greater than -30 mV and exhibited partial
inactivation over the duration of a 40 ms command potential. This inward current
was unchanged by alteration of the holding potential from -80 to -40 mV and the
activation phase of the Ca2+ current was best fitted by Hodgkin-Huxley m(t)2
kinetics. H209 Ca2+ current was reduced over 80% by verapamil (100 microM),
whereas w-conotoxin (5 microM) appeared to be without effect. In contrast, H209
Ca2+ current was rapidly abolished by nifedipine (10 microM), strongly
suggesting the presence of L-type Ca2+ channels. Voltage-gated Ca2+ channels may
be important to the secretion of ectopic hormones and the etiology and
pathogenesis of Lambert-Eaton syndrome, an autoimmune disorder of the motor
nerve terminal in which autoantibodies directed against voltage-gated Ca2+
channels are produced.
DOI: 10.1111/j.1748-1716.1992.tb09321.x
PMID: 1318636 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15221641
|
1. J Hum Genet. 2004;49(8):399-403. doi: 10.1007/s10038-004-0165-0. Epub 2004 Jun
18.
Rapid detection of FGFR3 gene mutation in achondroplasia by DHPLC
system-coupling heteroduplex and fluorescence-enhanced primer-extension
analysis.
Su YN(1), Lee CN(2), Chien SC(2), Hung CC(3), Chien YH(1)(4), Chen CA(5).
Author information:
(1)Department of Medical Genetics, National Taiwan University Hospital, National
Taiwan University, Taipei, Taiwan, ROC.
(2)Department of Obstetrics and Gynecology, National Taiwan University Hospital,
College of Medicine, National Taiwan University, No.7, Chung-Shan South Road,
Taipei, Taiwan, ROC.
(3)Institute of Biomedical Engineering, National Taiwan University, Taipei,
Taiwan, ROC.
(4)Department of Pediatrics, National Taiwan University Hospital, College of
Medicine, National Taiwan University, Taipei, Taiwan, ROC.
(5)Department of Obstetrics and Gynecology, National Taiwan University Hospital,
College of Medicine, National Taiwan University, No.7, Chung-Shan South Road,
Taipei, Taiwan, ROC. cachen@ntumc.org.
Achondroplasia is a common form of human dwarfism with characteristically
rhizomelic shortening of extremities and relative macrocephaly. It is
transmitted as an autosomally dominant inheritance, and about 80% of affected
individuals result from sporadic mutations without positive family histories.
Achondroplasia comes from the genetic point mutations in the fibroblastic growth
factor receptor 3 gene (FGFR3), which enables abnormal cartilage growth-plate
differentiation and insufficient bony development. The most common genetic
mutations in this receptor are G to A at position 1138 (G1138A), which result in
the substitution of glycine to arginine at codon 380. Based on genetic
information, molecular genetic testing can provide an exact diagnosis comparing
to radiological and prenatal ultrasound evaluations. Here we introduce
denaturing high-performance liquid chromatography (DHPLC) for the detection of
17 cases of achondroplasia and 120 unaffected cases. After coupling heteroduplex
and fluorescence-enhanced primer-extension analysis, all affected patients with
G1138A were identified successfully. In conclusion, we demonstrated that DHPLC
is an efficient, accurate, and sensitive technique to detect the single gene
mutation of achondroplasia in clinical applications.
DOI: 10.1007/s10038-004-0165-0
PMID: 15221641 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9727738
|
1. Clin Genet. 1998 Jul;54(1):39-44. doi: 10.1111/j.1399-0004.1998.tb03691.x.
Low frequency of RET mutations in Hirschsprung disease in Sweden.
Svensson PJ(1), Molander ML, Eng C, Anvret M, Nordenskjöld A.
Author information:
(1)Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
Par-Johan.Svensson@cmm.ki.se
Hirschsprung disease is a congenital malformation, where absence of intramural
ganglia in the hindgut results in a defect in the coordination of peristaltic
movement. This leads to ileus in the newborn or, more often, constipation in
children and adults. The disease affects one in 5000 live births. Siblings of
affected cases are at an increased risk (4%) of developing the disease. Among
cases. males are affected more often than females. The first major
susceptibility gene for Hirschsprung disease is the RET proto-oncogene on
10q11.2. Germline RET mutations in Hirschsprung disease are mainly inactivating,
and have been reported to account for up to 20 and 50% of sporadic and familial
cases, respectively. We have screened Swedish population-based samples from 62
sporadic cases and seven familial cases of Hirschsprung disease with single
strand conformation polymorphism (SSCP), and found five mutations.
DOI: 10.1111/j.1399-0004.1998.tb03691.x
PMID: 9727738 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19803409
|
1. Brain Nerve. 2009 Sep;61(9):1083-7.
[Paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome
associated with anti P/Q-type voltage-gated calcium channel antibody in a
patient with primary double lung cancer].
[Article in Japanese]
Iwanami M(1), Odaka M, Nakamura T, Hirata K.
Author information:
(1)Department of Neurology, Dokkyo Medical University, 880 kitobayashi
Kitakobayashi, Mibu-cho, Shimotsuga-gun, Tochigi 321-0293, Japan.
We report the case of a 50-year-old man with paraneoplastic cerebellar
degeneration (PCD) and Lambert-Eaton myasthenic syndrome (LEMS) associated with
primary double lung cancer. He developed acute progressive double vision,
slurred speech, and gait disturbance. Neurological examination revealed
diplopia, mild ptosis, bilateral horizontal gaze-evoked nystagmus, and
cerebellar limb and truncal ataxia. The diffusion image of brain magnetic
resonance imaging (MRI) revealed no abnormal findings in the cerebellum. On the
basis of the diagnosis of acute cerebelitis, he was given methylprednisolone
pulse therapy followed by oral prednisolone, which gradually improved his
neurological signs and symptoms. The analysis of the possible etiology suggested
that the PCD was induced by lung cancer, which led to ataxia. A chest computed
tomography scan revealed mass lesions of irregular shape and unclear margins in
the upper lobe of the right lung and a small nodule tumor in the upper lobe of
the left lung. We performed transbronchial needle aspiration and detected the
bronchioloalveolar carcinoma of the right lung. An electromyogram showed waxing
phenomenon in the ulnar nerve at high-frequency (50Hz) stimulation. The serum
levels of anti-P/Q-type voltage-gated calcium channel (VGCC) antibody were
elavated in the patient. These findings confirmed that the pathogenesis of the
condition of this patient to be associated with LEMS. His cerebellar symptoms
were considered to be caused by the PCD, and the diplopia, ptosis, and
hyporeflexia were attributed to LEMS. We performed upper left lobectomy with
mediastinal lymphnode dissection via video-assisted thoracoscopic surgery. A
histological study detected small cell carcinoma. A diagnosis of double primary
lung cancer was made. Physicians need to be aware that patients may develop PCD
and LEMS associated with anti-VGCC antibody caused by small cell lung cancer,
and a mass survey should be conducted and careful examinations performed.
PMID: 19803409 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15767964
|
1. Rev Mal Respir. 2004 Dec;21(6 Pt 1):1167-70. doi:
10.1016/s0761-8425(04)71594-6.
[Difficulties associated with Lambert-Eaton syndrome].
[Article in French]
Tchouhadjian C(1), Barlesi F, Doddoli C, Escarguel B, Thomas P, Witjas T, Astoul
P, Kleisbauer JP.
Author information:
(1)Service d'Oncologie Thoracique, Département des Maladies Respiratoires,
Hôpital Sainte Marguerite, Marseille, France.
INTRODUCTION: The diagnosis and treatment of the neurological paraneoplastic
syndromes associated with lung cancer can pose a challenge both to general
physicians and neurologists as well as pulmonologists.
CASE REPORT: A 53 year-old heavy smoker presented with a Lambert-Eaton
myasthenic syndrome (LEMS). Bronchoscopy was normal but radiological
examinations revealed a lymph node in site 4R. The pathological diagnosis after
mediastinoscopy was negative. Twenty-five months later, an opacity on chest
X-ray led to a biopsy which revealed a squamous cell carcinoma. A lobectomy was
performed for a pT2N0M0 lesion. A significant improvement of neurological
symptoms was seen. The myasthenic syndrome reappeared 21 months later. A local
and general relapse was diagnosed. The patient died 10 months later despite
chemotherapy.
CONCLUSION: LEMS occurs because of an immunological reaction against
voltage-dependent calcium channels. LEMS is generally associated with small cell
lung cancer occurring in three percent of cases. However, the case that we
report shows the unusual association of LEMS with non small-cell lung cancer and
highlights the difficulties associated in the management of this condition.
DOI: 10.1016/s0761-8425(04)71594-6
PMID: 15767964 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18644631
|
1. J Neuroimmunol. 2008 Sep 15;201-202:153-8. doi:
10.1016/j.jneuroim.2008.05.025. Epub 2008 Jul 21.
The Lambert-Eaton myasthenic syndrome 1988-2008: a clinical picture in 97
patients.
Titulaer MJ(1), Wirtz PW, Kuks JB, Schelhaas HJ, van der Kooi AJ, Faber CG, van
der Pol WL, de Visser M, Sillevis Smitt PA, Verschuuren JJ.
Author information:
(1)Department of Neurology, Leiden University Medical Center, Leiden, The
Netherlands. m.j.titulaer@lumc.nl
BACKGROUND: Neuromuscular symptoms in patients with Lambert-Eaton myasthenic
syndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in
LEMS patients without a SCLC. We studied how this clinical information, which is
readily available at the first consultation, can be used to predict the presence
of SCLC.
PATIENTS AND METHODS: In our study we included 52 LEMS patients with SCLC and 45
non-tumor patients (NT-LEMS). We interviewed patients using a structured
checklist and reviewed their clinical records. We compared frequency and onset
of symptoms during the course of LEMS.
RESULTS: In the first six months, over half the SCLC-LEMS patients had developed
seven separate symptoms, while NT-LEMS patients developed only two symptoms.
Proximal leg weakness and dry mouth were early symptoms in both groups. Rapid
involvement of proximal arm muscles (p=0.0001), distal arm muscles (p=0.0037),
distal leg muscles (p=0.0002), dysartria (p=0.0091) and the presence of erectile
dysfunction (p=0.007) were found significantly more often in SCLC-LEMS patients
in both cohorts. Cerebellar symptoms, although present in 9% of LEMS patients,
were almost exclusively related to SCLC-LEMS.
CONCLUSION: A rapidly progressive course of disease from onset in LEMS patients
should raise a high suspicion of SCLC. Special attention should be paid to
involvement of upper extremities, involvement of distal arm and distal leg
muscles, to erectile dysfunction and probably ataxia in order to discriminate
between SCLC-LEMS and NT-LEMS.
DOI: 10.1016/j.jneuroim.2008.05.025
PMID: 18644631 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8387255
|
1. Am Rev Respir Dis. 1993 May;147(5):1229-32. doi: 10.1164/ajrccm/147.5.1229.
Calcium channel autoantibodies in myasthenic syndrome and small cell lung
cancer.
Pelucchi A(1), Ciceri E, Clementi F, Marazzini L, Foresi A, Sher E.
Author information:
(1)Servizio di Broncopneumologia e Fisiopatologia Respiratoria, G. Campari,
Sesto S. Giovanni, Milan, Italy.
Lambert-Eaton myasthenic syndrome (LEMS) is one of the neurologic paraneoplastic
syndromes often found in patients with lung cancer. It is characterized by a
generalized deficit of neurotransmitter release. Patients with small cell lung
cancer (SCLC) in particular may develop LEMS, and SCLC is very often detected in
patients affected by LEMS. LEMS is an autoimmune disease, and autoantibodies
that interfere with neurotransmitter release by binding to presynaptic
voltage-operated calcium channels (VOCCs) have been found in sera of patients
with LEMS. Both human neuronal and SCLC cell lines express
omega-conotoxin-sensitive VOCCs, and autoantibodies from patients affected by
LEMS can precipitate these channels. We have now screened a large population of
patients and control subjects in order to define the specificity and sensitivity
of the anti-VOCC antibody assay. We have tested sera from 52 patients with LEMS
with and without SCLC; 32 sera from patients with SCLC without LEMS, 31 from
patients with non-SCLC, 34 from patients with inflammatory lung diseases, 17
from patients with other neurologic disorders, and 48 from healthy control
subjects. We have found that a positive result with this radioimmunoassay is
highly specific for LEMS, with or without SCLC, when the antibody titer is
higher than 14.21 pM. Anti-VOCC antibodies have also been found in about 40% of
patients with SCLC without LEMS, but they were absent in all the other
populations tested. We can conclude that this serologic assay is a very useful
aid in the diagnosis of LEMS, and it might be useful also for the early
diagnosis of SCLC.
DOI: 10.1164/ajrccm/147.5.1229
PMID: 8387255 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20392978
|
1. J Neurol Neurosurg Psychiatry. 2011 Mar;82(3):344-6. doi:
10.1136/jnnp.2009.172684. Epub 2010 Apr 14.
Sequential fluctuating paraneoplastic ocular flutter-opsoclonus-myoclonus
syndrome and Lambert-Eaton myasthenic syndrome in small-cell lung cancer.
Simister RJ(1), Ng K, Lang B, Beckles M, Chao D, McCabe DJ.
Author information:
(1)Department of Clinical Neurosciences, UCL Institute of Neurology, Royal Free
Campus, London, UK.
Paraneoplastic cerebellar degeneration may occur in association with
Lambert-Eaton myasthenic syndrome (LEMS), but to our knowledge, the
co-occurrence of paraneoplastic opsoclonus-myoclonus syndrome and LEMS has not
been previously reported. A 67-year-old woman presented with a complex partial
seizure and evolving ocular flutter, opsoclonus, myoclonus and 'cerebellar'
signs, all of which improved spontaneously within 6 weeks. Approximately 8 weeks
after symptom onset, the patient became encephalopathic, she had a further
complex partial seizure, and she became areflexic with potentiation of deep
tendon reflexes. Radiological, bronchoscopic and histological investigations
revealed small-cell lung cancer, and neurophysiological investigations confirmed
a diagnosis of LEMS. High-titre anti-P/Q-type voltage-gated calcium-channel
antibodies were identified in the serum, which increased as the signs of
opsoclonus and myoclonus resolved. The encephalopathy and clinical features of
LEMS responded dramatically to chemotherapy and radiotherapy. Spontaneous
improvement of paraneoplastic opsoclonus-myoclonus syndrome may occur, and this
syndrome may occur in association with LEMS. Antivoltage-gated calcium-channel
antibodies are not implicated in the pathogenesis of paraneoplastic
opsoclonus-myoclonus syndrome.
DOI: 10.1136/jnnp.2009.172684
PMID: 20392978 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22584707
|
1. Clinics (Sao Paulo). 2012;67 Suppl 1(Suppl 1):57-61. doi:
10.6061/clinics/2012(sup01)11.
RET haplotype, not linked to the C620R activating mutation, associated with
Hirschsprung disease in a novel MEN2 family.
Quedas EP(1), Longuini VC, Sekiya T, Coutinho FL, Toledo SP, Tannuri U, Toledo
RA.
Author information:
(1)Division of Endocrinology, Endocrine Genetics Unit, Faculdade de Medicina,
Universidade de São Paulo, São Paulo, SP, Brazil.
Hirschsprung disease is a congenital form of aganglionic megacolon that results
from cristopathy. Hirschsprung disease usually occurs as a sporadic disease,
although it may be associated with several inherited conditions, such as
multiple endocrine neoplasia type 2. The rearranged during transfection (RET)
proto-oncogene is the major susceptibility gene for Hirschsprung disease, and
germline mutations in RET have been reported in up to 50% of the inherited forms
of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease.
The prevalence of Hirschsprung disease in multiple endocrine neoplasia type 2
cases was recently determined to be 7.5% and the cooccurrence of Hirschsprung
disease and multiple endocrine neoplasia type 2 has been reported in at least 22
families so far. It was initially thought that Hirschsprung disease could be due
to disturbances in apoptosis or due to a tendency of the mutated RET receptor to
be retained in the Golgi apparatus. Presently, there is strong evidence favoring
the hypothesis that specific inactivating haplotypes play a key role in the
fetal development of congenital megacolon/Hirschsprung disease. In the present
study, we report the genetic findings in a novel family with multiple endocrine
neoplasia type 2: a specific RET haplotype was documented in patients with
Hirschsprung disease associated with medullary thyroid carcinoma, but it was
absent in patients with only medullary thyroid carcinoma. Despite the limited
number of cases, the present data favor the hypothesis that specific haplotypes
not linked to RET germline mutations are the genetic causes of Hirschsprung
disease.
DOI: 10.6061/clinics/2012(sup01)11
PMCID: PMC3328835
PMID: 22584707 [Indexed for MEDLINE]
Conflict of interest statement: No potential conflict of interest was reported.
|
http://www.ncbi.nlm.nih.gov/pubmed/1339000
|
1. Rev Pneumol Clin. 1992;48(6):275-8.
[Lambert-Eaton syndrome. Apropos of 2 cases].
[Article in French]
Gilbert P(1), Lefebvre P, Richard V, Henriet M, Leconte J, Thiriaux J.
Author information:
(1)Service de Pneumologie, Hôpital Civil de Charleroi, Belgique.
Lambert-Eaton syndrome is a myasthenia-like syndrome of paraneoplastic origin
which is often associated with anaplastic small-cell lung cancer. It seems to be
an autoimmune disease responsible for a deficit of acetylcholine ejection in the
motor end plate. On the occasion of two recent cases, we review the clinical,
physiopathological and diagnostic aspects of this paraneoplastic syndrome.
PMID: 1339000 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17397038
|
1. Hum Mutat. 2007 Aug;28(8):790-6. doi: 10.1002/humu.20517.
Epistatic interactions with a common hypomorphic RET allele in syndromic
Hirschsprung disease.
de Pontual L(1), Pelet A, Clement-Ziza M, Trochet D, Antonarakis SE,
Attie-Bitach T, Beales PL, Blouin JL, Dastot-Le Moal F, Dollfus H, Goossens M,
Katsanis N, Touraine R, Feingold J, Munnich A, Lyonnet S, Amiel J.
Author information:
(1)Université Paris-René Descartes, Faculté de Médecine, INSERM U-781, AP-HP,
Hôpital Necker-Enfant Malades, Paris, France.
Hirschsprung disease (HSCR) stands as a model for genetic dissection of complex
diseases. In this model, a major gene, RET, is involved in most if not all cases
of isolated (i.e., nonsyndromic) HSCR, in conjunction with other autosomal
susceptibility loci under a multiplicative model. HSCR susceptibility alleles
can harbor either heterozygous coding sequence mutations or, more frequently, a
polymorphism within intron 1, leading to a hypomorphic RET allele. On the other
hand, about 30% of HSCR are syndromic. Hitherto, the disease causing gene has
been identified for eight Mendelian syndromes with HSCR: congenital central
hypoventilation (CCHS), Mowat-Wilson (MWS), Bardet-Biedl (BBS), Shah-Waardenburg
(WS4), cartilage-hair-hypoplasia (CHH), Smith-Lemli-Opitz (SLO),
Goldberg-Sprintzsen (GSS), and hydrocephalus due to congenital stenosis of the
aqueduct of sylvius (HSAS). According to the HSCR syndrome, the penetrance of
HSCR trait varies from 5 to 70%. Trisomy 21 (T21) also predisposes to HSCR. We
were able to collect a series of 393 patients affected by CCHS (n = 173), WS4 (n
= 24), BBS (n = 51), MWS (n = 71), T21 (n = 46), and mental retardation (MR)
with HSCR (n = 28). For each syndrome, we studied the RET locus in two subgroups
of patients; i.e., with or without HSCR. We genotyped the RET locus in 393
patients among whom 195 had HSCR, and compared the distribution of alleles and
genotypes within the two groups for each syndrome. RET acts as a modifier gene
for the HSCR phenotype in patients with CCHS, BBS, and Down syndrome, but not in
patients with MWS and WS4. The frequent, low penetrant, predisposing allele of
the RET gene can be regarded as a risk factor for the HSCR phenotype in CCHS,
BBS, and Down syndrome, while its role is not significant in MWS and WS4. These
data highlight the pivotal role of the RET gene in both isolated and syndromic
HSCR.
(c) 2007 Wiley-Liss, Inc.
DOI: 10.1002/humu.20517
PMID: 17397038 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/2833535
|
1. J Neuroimmunol. 1988 May;18(2):97-104. doi: 10.1016/0165-5728(88)90058-6.
Lambert-Eaton syndrome antibodies: reaction with membranes from a small cell
lung cancer xenograft.
Chester KA(1), Lang B, Gill J, Vincent A, Newsom-Davis J.
Author information:
(1)Department of Neurological Science, Royal Free Hospital School of Medicine,
London, U.K.
Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic autoimmune disorder
caused by an IgG-mediated reduction in number of presynaptic voltage-gated
calcium channels (VGCC) at the neuromuscular junction. In at least 50% of cases,
the stimulus for antibody production may be VGCC on small cell lung cancer
(SCLC). In this study membranes isolated from a human small cell lung cancer
xenograft (Mar), that bound [3H]PN200-110, a VGCC antagonist, were subjected to
Western blotting using plasma from 12 LEMS patients and eight controls. Although
one band recognised by 3/12 LEMS IgGs might be associated with the VGCC, a
number of other proteins were recognised both by LEMS plasma, and by plasma from
patients with other disorders. The results illustrate the difficulties found
using Western blotting with autoimmune plasma to identify specific polypeptides
in a crude antigen preparation.
DOI: 10.1016/0165-5728(88)90058-6
PMID: 2833535 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8009147
|
1. Rev Neurol (Paris). 1993;149(8-9):485-8.
[Paraneoplastic myasthenic syndrome].
[Article in French]
Léger JM(1), Bachoud-Lévi AC, Eymard B, Théodore C, Bouche P,
Pierrot-Deseilligny C.
Author information:
(1)Service de Neurologie et Service d'Explorations Fonctionnelles Neurologie,
Clinique Paul Castaigne, Hôpital de la Salpêtrière, Paris.
We report a case of neuromuscular disease overlap between myasthenia gravis and
Lambert-Eaton syndrome (LES). Clinical features were those of LES and occurred
insidiously in this 68-year old man: proximal weakness predominant in the lower
limbs, generalized areflexia, dryness of the mouth and partial right eye palsy.
Investigations disclosed a small cell lung cancer. On the other hand, an
electrophysiological study showed low amplitude of all motor evoked potentials,
and significant decrement in the median nerve at repeated 3 Hz stimulation, but
failed to disclose any increment of the motor evoked potential in abductor
digiti minimi pedis muscle after both maximal voluntary contraction and repeated
20 Hz stimulation. In addition, the patient improved under anticholinesterase
drugs, but failed to respond to guanidine. Titres for both
anti-acetylcholine-receptor antibodies and calcium channel antibodies were
negative. The relationship between our case and recently reported cases of
co-existence of the Lambert-Eaton myasthenic syndrome and myasthenia gravis is
discussed.
PMID: 8009147 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9484375
|
1. Neurology. 1998 Feb;50(2):475-9. doi: 10.1212/wnl.50.2.475.
Antibodies against the calcium channel beta-subunit in Lambert-Eaton myasthenic
syndrome.
Verschuuren JJ(1), Dalmau J, Tunkel R, Lang B, Graus F, Schramm L, Posner JB,
Newsom-Davis J, Rosenfeld MR.
Author information:
(1)Department of Neurology, Leiden University Hospital, The Netherlands.
The sera of patients with Lambert-Eaton myasthenic syndrome (LEMS) contain
autoantibodies against several extracellular and intracellular components of the
voltage-gated calcium channel (VGCC)/synaptic vesicle release complex. An
example of the latter are anti-beta-subunit antibodies (anti-MysB antibodies).
We constructed a full-length cDNA clone of a human VGCC beta-subunit to produce
purified beta-subunit fusion protein (MysB protein). Using this protein, we
demonstrated that anti-beta-subunit antibodies are present in the sera of 23% of
LEMS patients and only, in low titer, in 2% of small cell lung cancer patients
without LEMS. The presence of anti-beta-subunit antibodies was closely
associated with high titers of P/Q- and N-type VGCC antibodies. Immunization of
rats with the purified MysB protein induced high antibody titers, but no signs
of neurologic dysfunction were found. We conclude that anti-beta-subunit
antibodies are not likely to interfere with ion channel function, but their
presence could explain the cross-reactivity of LEMS sera with several subtypes
of VGCCs and the lack of correlation between anti-VGCC antibody titer and
clinical severity of disease.
DOI: 10.1212/wnl.50.2.475
PMID: 9484375 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/1470196
|
1. Muscle Nerve. 1992 Dec;15(12):1325-33. doi: 10.1002/mus.880151206.
Lambert-Eaton syndrome: antigen-antibody interaction and calcium current
inhibition in chromaffin cells.
Viglione MP(1), Creutz CE, Kim YI.
Author information:
(1)Department of Biomedical Engineering, University of Virginia School of
Medicine, Carlottesville.
Plasma and IgG obtained from 10 Lambert-Eaton myasthenic syndrome (LES) patients
(5 with carcinoma, 5 without associated cancer), 6 healthy subjects, and 1
patient with small-cell lung cancer (SCLC) were examined in their ability to
recognize chromaffin cell antigens on Western blots. The pattern of antigen
recognition was compared with the magnitude of inhibition of voltage-dependent
calcium and sodium currents recorded with the patch-clamp technique from
chromaffin cells. Eight of the 11 patients with LES and/or SCLC recognized
plasma membrane proteins and 9 of the patients' IgG interacted with cytoplasmic
antigens with no apparent pattern of antigen recognition between patients. Also,
there was no obvious band pattern distinguishing patients with LES from those
with LES and concurrent SCLC. Eighty percent of the LES patients' antibodies
were capable of reducing the calcium current (ICa) in chromaffin cells. One of
the novel findings of this study is that 30% of the patients had produced
antibodies which were able to inhibit both calcium and sodium currents (INa).
The heterogeneous response of the IgG on the Western blots does not appear to
correlate with the efficacy of reducing the inward currents.
DOI: 10.1002/mus.880151206
PMID: 1470196 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/10439962
|
1. Eur J Hum Genet. 1999 Jul;7(5):560-6. doi: 10.1038/sj.ejhg.5200319.
Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome: a novel
developmental disorder in Gypsies maps to 18qter.
Angelicheva D(1), Turnev I, Dye D, Chandler D, Thomas PK, Kalaydjieva L.
Author information:
(1)Centre for Human Genetics, Edith Cowan University, Perth, Australia.
We have identified a novel developmental disorder with complex phenotypic
characteristics involving primarily the nervous system, which appears to be
common in a specific Gypsy group in Bulgaria. We propose to refer to the
syndrome as congenital cataracts facial dysmorphism neuropathy (CCFDN). We have
assigned the disease locus to the telomeric region of chromosome 18q. Linkage
disequilibrium and highly conserved haplotypes suggest genetic homogeneity and
founder effect. CCFDN co-localises with an EST which shows high homology to a
conserved Drosophila gene involved in the regulation of nervous system
development in vertebrates.
DOI: 10.1038/sj.ejhg.5200319
PMID: 10439962 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12632823
|
1. J Formos Med Assoc. 2002 Dec;101(12):871-4.
Small-cell lung cancer presenting with Lambert-Eaton myasthenic syndrome and
respiratory failure.
Jiang JR(1), Shih JY, Wang HC, Wu RM, Yu CJ, Yang PC.
Author information:
(1)Department of Internal Medicine, National Taiwan University Hospital, 7
Chung-Shan South Road, Taipei, Taiwan.
Erratum in
J Formos Med Assoc. 2003 Jun;111(6):1202.
Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular disorder
characterized by defective neurotransmitter release at presynaptic terminals. It
is caused by an IgG autoantibody reacting against voltage-gated calcium
channels. Severe LEMS complicated by ventilatory failure is rare. We report a
case of small-cell lung cancer (SCLC) presenting with LEMS and ventilatory
failure in a 67-year-old man who initially presented with progressive limb
weakness for 6 months and tachypnea with shallow breathing for 1 week. LEMS was
diagnosed through electrophysiologic studies. Chest radiography and computerized
tomography showed a huge mass lesion over the left anterior and middle
mediastinum with an encasement of the left pulmonary artery. Cytologic
examination of ultrasound-guided fine needle aspiration disclosed SCLC.
Successful treatment in combination with plasma exchange and chemotherapy
resulted in dramatic tumor regression and LEMS remission, which were confirmed
by chest radiography and electrophysiologic studies. This case suggests that
plasma exchange and chemotherapy can be effective in treating SCLC with severe
LEMS that produces ventilatory failure.
PMID: 12632823 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12361237
|
1. Farmaco. 2002 Aug;57(8):685-91. doi: 10.1016/s0014-827x(02)01208-9.
Combination of antibiotic mechanisms in lantibiotics.
Hoffmann A(1), Pag U, Wiedemann I, Sahl HG.
Author information:
(1)Institut für Medizinische Mikrobiologie und Immunologie der Universität Bonn,
Germany.
Recent studies on the mode of action have revealed exciting features of multiple
activities of nisin and related lantibiotics making these peptides interesting
model systems for the design of new antibiotics (Molec. Microbiol. 30 (1998)
317; Science 286 (1999) 2361; J. Biol. Chem. 276 (2001) 1772.). In contrast to
other groups of antibiotic peptides, the lantibiotics display a substantial
degree of specificity for particular components of bacterial membranes.
Mersacidin and actagardine were shown to bind with high affinity to the lipid
coupled peptidoglycan precursor, the so-called lipid II, which prevents the
polymerisation of the cell wall monomers into a functional murein sacculus. The
lantibiotics nisin and epidermin also bind tightly to this cell wall precursor;
however, for these lantibiotics the binding of lipid II has two consequences.
Like with mersacidin blocking of lipid II inhibits peptidoglycan biosynthesis;
in addition, lipid II is used as a specific docking molecule for the formation
of pores. This combination of lethal effects explains the potency of these
peptides, which are active in nanomolar concentration. Other type-A lantibiotics
are believed to also use docking molecules for pore formation, although
identification of such membrane components has not yet been achieved.
DOI: 10.1016/s0014-827x(02)01208-9
PMID: 12361237 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25186864
|
1. Neurology. 2014 Oct 7;83(15):1337-44. doi: 10.1212/WNL.0000000000000874. Epub
2014 Sep 3.
Long-term follow-up in patients with CCFDN syndrome.
Walter MC(1), Bernert G(2), Zimmermann U(2), Müllner-Eidenböck A(2), Moser E(2),
Kalaydjieva L(2), Lochmüller H(2), Müller-Felber W(2).
Author information:
(1)From the Friedrich-Baur Institute (M.C.W.), Department of Neurology,
Ludwig-Maximilians University of Munich, Germany; Gottfried von Preyer'sches
Kinderspital (G.B.), Vienna; Ambulatorium Wiental (U.Z.), Center for
Developmental Neurology, Vienna; Department of Ophthalmology (A.M.-E., E.M.),
University of Vienna, Austria; Harry Perkins Institute for Medical Research and
Centre for Medical Research (L.K.), The University of Western Australia, Perth;
Institute of Genetic Medicine (H.L.), Newcastle University, Newcastle-upon-Tyne,
UK; and Department of Neuropaediatrics (W.M.-F.), Dr. von Hauner'sches
Kinderspital, University of Munich, Germany. maggie.walter@lrz.uni-muenchen.de.
(2)From the Friedrich-Baur Institute (M.C.W.), Department of Neurology,
Ludwig-Maximilians University of Munich, Germany; Gottfried von Preyer'sches
Kinderspital (G.B.), Vienna; Ambulatorium Wiental (U.Z.), Center for
Developmental Neurology, Vienna; Department of Ophthalmology (A.M.-E., E.M.),
University of Vienna, Austria; Harry Perkins Institute for Medical Research and
Centre for Medical Research (L.K.), The University of Western Australia, Perth;
Institute of Genetic Medicine (H.L.), Newcastle University, Newcastle-upon-Tyne,
UK; and Department of Neuropaediatrics (W.M.-F.), Dr. von Hauner'sches
Kinderspital, University of Munich, Germany.
OBJECTIVE: We describe the 10-year follow-up in a cohort of 16 patients with
genetically confirmed congenital cataracts, facial dysmorphism, and neuropathy
(CCFDN) syndrome, providing new insights in the clinical course of the disease.
METHODS: We performed a detailed clinical and paraclinical characterization and
10-year follow-up study in 16 patients with molecularly defined CCFDN syndrome,
illustrating that CCFDN is a severe disabling disorder.
RESULTS: All patients initially presented with congenital cataracts along with
strabismus, facial dysmorphism, short stature, and demyelinating neuropathy. In
all patients, paresis of small hand muscles and foot extensors worsened with
disease progression, while ataxia scores remained stable or improved. Nerve
conduction velocity was normal in early infancy up to 18 months, decreased to
approximately 20 m/s around age 10 years, and then remained stable; distal motor
latency was prolonged. Sensory nerve conduction velocities were slowed, and
initially of normal amplitude. With disease progression, both sensory and motor
nerves showed reduction of amplitudes indicating axonal loss. In 6 patients,
acute severe proximal weakness and myalgia after febrile infections, along with
rhabdomyolysis, myoglobinuria, and hyperCKemia, led to a less favorable outcome
and permanent loss of ambulation in 3 patients.
CONCLUSIONS: CCFDN should be classified as a recessive demyelinating
sensory-motor neuropathy, and axonal loss is a major determinant of long-term
outcomes and disability. Patients benefit from early and ongoing physiotherapy,
and should be thoroughly counseled regarding virus-triggered rhabdomyolysis and
the risk of malignant hyperthermia. Whether supplementation with liposoluble
vitamins results in a therapeutic benefit should be evaluated in further
studies.
© 2014 American Academy of Neurology.
DOI: 10.1212/WNL.0000000000000874
PMID: 25186864 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24069959
|
1. BMC Microbiol. 2013 Sep 26;13:212. doi: 10.1186/1471-2180-13-212.
The two peptide lantibiotic lacticin 3147 acts synergistically with polymyxin to
inhibit Gram negative bacteria.
Draper LA(1), Cotter PD, Hill C, Ross RP.
Author information:
(1)Department of Microbiology, University College Cork, Cork, Ireland.
paul.cotter@teagasc.ie.
BACKGROUND: The emergence of bacterial drug resistance encourages the
re-evaluation of the potential of existing antimicrobials. Lantibiotics are
post-translationally modified, ribosomally synthesised antimicrobial peptides
with a broad spectrum antimicrobial activity. Here, we focussed on expanding the
potential of lacticin 3147, one of the most studied lantibiotics and one which
possesses potent activity against a wide range of Gram positive species
including many nosocomial pathogens. More specifically, our aim was to
investigate if lacticin 3147 activity could be enhanced when combined with a
range of different clinical antibiotics.
RESULTS: Initial screening revealed that polymyxin B and polymyxin E (colistin)
exhibited synergistic activity with lacticin 3147. Checkerboard assays were
performed against a number of strains, including both Gram positive and Gram
negative species. The resultant fractional inhibitory concentration (FIC) index
values established that, while partial synergy was detected against Gram
positive targets, synergy was obvious against Gram negative species, including
Cronobacter and E. coli.
CONCLUSIONS: Combining lacticin 3147 with low levels of a polymyxin could
provide a means of broadening target specificity of the lantibiotic, while also
reducing polymyxin use due to the lower concentrations required as a result of
synergy.
DOI: 10.1186/1471-2180-13-212
PMCID: PMC3849175
PMID: 24069959 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19009315
|
1. J Membr Biol. 2008 Nov-Dec;226(1-3):9-16. doi: 10.1007/s00232-008-9134-4. Epub
2008 Nov 14.
Membrane lipids determine the antibiotic activity of the lantibiotic
gallidermin.
Christ K(1), Al-Kaddah S, Wiedemann I, Rattay B, Sahl HG, Bendas G.
Author information:
(1)Department of Pharmacy, Rheinische Friedrich-Wilhelms-University Bonn, Bonn,
Germany. kchrist@uni-bonn.de
Lantibiotics, a group of lanthionine-containing peptides, display their
antibiotic activity by combining different killing mechanisms within one
molecule. The prototype lantibiotic nisin was shown to possess both inhibition
of peptidoglycan synthesis and pore formation in bacterial membranes by
interacting with lipid II. Gallidermin, which shares the lipid II binding motif
with nisin but has a shorter molecular length, differed from nisin in pore
formation in several strains of bacteria. To simulate the mode of action, we
applied cyclic voltammetry and quartz crystal microbalance to correlate pore
formation with lipid II binding kinetics of gallidermin in model membranes. The
inability of gallidermin to form pores in DOPC
(1,2-dioleoyl-sn-glycero-3-phosphocholine) (C18/1) and DPoPC
(1,2-dipalmitoleoyl-sn-glycero-3-phosphocholine) (C16/1) membranes was related
to the membrane thickness. For a better simulation of bacterial membrane
characteristics, two different phospholipids with branched fatty acids were
incorporated into the DPoPC matrix. Phospholipids with methyl branches in the
middle of the fatty acid chains favored a lipid II-independent DPoPC
permeabilization by gallidermin, while long-branched phospholipids in which the
branch is placed near the hydrophilic region induced an identical lipid
II-dependent pore formation of gallidermin and nisin. Obviously, the branched
lipids altered lipid packing and reduced the membrane thickness. Therefore, the
duality of gallidermin activity (pore formation and inhibition of the cell wall
synthesis) seems to be balanced by the bacterial membrane composition.
DOI: 10.1007/s00232-008-9134-4
PMID: 19009315 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18841652
|
1. Ideggyogy Sz. 2008 Sep 30;61(9-10):325-8.
Paraneoplastic chronic demyelinating neuropathy and Lambert-Eaton myasthenic
syndrome associated with multiple anti-neural antibodies and small-cell lung
cancer.
Rozsa C(1), Vincent A, Aranyi Z, Kovacs GG, Komoly S, Illes Z.
Author information:
(1)Jahn Ferenc Teaching Hospital, Budapest.
Lambert-Eaton myasthenic syndrome (LEMS) developed in a patient with presumed
chronic inflammatory demyelinating polyneuropathy (CIDP) and negative chest CT.
Since antibodies against both Hu and voltage-gated calcium channel (VGCC) were
detected, repeated chest CT was performed, which eventually showed a pulmonary
mass lesion. Biopsy revealed small cell lung cancer (SCLC) indicating the
importance of repeated chest CT in LEMS even when an existing autoimmune-like
disease and negative CT may suggest an autoimmune origin. This is the first
report of paraneoplastic CIDP and LEMS associated with anti-Hu, anti-VGCC and
SCLC.
PMID: 18841652 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19070320
|
1. Ideggyogy Sz. 2008 Nov 30;61(11-12):426-30.
[Screening for hereditary neuromuscular disorders with molecular genetic methods
in the Roma population of Hungary].
[Article in Hungarian]
Herczegfalvi A(1), Pikó H, Karcagi V.
Author information:
(1)Magyarországi Református Egyház Bethesda Gyermekkórháza, Neurológia Osztály,
Budapest. herczegfalvi@bethesda.hu
Recent medical genetic research has identified a number of novel, or previously
known, but rare conditions, caused by private founder mutations. The Finnish and
Ashkenazi Jew populations provide the best examples for identifying genes in
unique genetic disorders. In these populations, research efforts and high-level
medical services resulted in intense improvements of medical care and in
organization of population-based screening programs. Hereditary disorders of the
Roma populations are known for a long time. The genetic background of these
diseases has been established by extensive molecular genetic studies. The Romas
represent 6% of the Hungarian population and live under extremely bad health
conditions. Therefore, our aim was to map the incidence of the hereditary
neuromuscular disorders among the Hungarian Roma population. Moreover, we
intended to provide proper information, genetic counseling and possible
prevention strategies for the families at risk, which should represent a primer
task in public health. Because of our experience in neuromuscular disorders, we
choose six, frequent, autosomal recessive disorders for these clinical and
genetic studies: hereditary motor and sensory neuropathy type Lom (HMSNL),
hereditary motor and sensory neuropathy type Russe (HMSNR), congenital cataracts
facial dysmorphism syndrome (CCFDN), limb-girdle muscular dystrophy 2C (LGMD2C),
congenital myasthenic syndrome (CMS) and spinal muscular atrophy (SMA).
Following identification of the founder mutations, the possibility of prenatal
diagnosis and carrier screening for family members will contribute to the
decrease of the recurrence risk for these severe, mostly untreatable disorders.
PMID: 19070320 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/14517542
|
1. Nat Genet. 2003 Oct;35(2):185-9. doi: 10.1038/ng1243. Epub 2003 Sep 21.
Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is
associated with congenital cataracts facial dysmorphism neuropathy syndrome.
Varon R(1), Gooding R, Steglich C, Marns L, Tang H, Angelicheva D, Yong KK,
Ambrugger P, Reinhold A, Morar B, Baas F, Kwa M, Tournev I, Guerguelcheva V,
Kremensky I, Lochmüller H, Müllner-Eidenböck A, Merlini L, Neumann L, Bürger J,
Walter M, Swoboda K, Thomas PK, von Moers A, Risch N, Kalaydjieva L.
Author information:
(1)Institute of Human Genetics, Charité, Humboldt University, Berlin, Germany.
Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome (OMIM
604168) is an autosomal recessive developmental disorder that occurs in an
endogamous group of Vlax Roma (Gypsies; refs. 1-3). We previously localized the
gene associated with CCFDN to 18qter, where a conserved haplotype suggested a
single founder mutation. In this study, we used recombination mapping to refine
the gene position to a 155-kb critical interval. During haplotype analysis, we
found that the non-transmitted chromosomes of some unaffected parents carried
the conserved haplotype associated with the disease. Assuming such parents to be
completely homozygous across the critical interval except with respect to the
disease-causing mutation, we developed a new 'not quite identical by descent'
(NQIBD) approach, which allowed us to identify the mutation causing the disease
by sequencing DNA from a single unaffected homozygous parent. We show that CCFDN
is caused by a single-nucleotide substitution in an antisense Alu element in
intron 6 of CTDP1 (encoding the protein phosphatase FCP1, an essential component
of the eukaryotic transcription machinery), resulting in a rare mechanism of
aberrant splicing and an Alu insertion in the processed mRNA. CCFDN thus joins
the group of 'transcription syndromes' and is the first 'purely' transcriptional
defect identified that affects polymerase II-mediated gene expression.
DOI: 10.1038/ng1243
PMID: 14517542 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19575156
|
1. Herz. 2009 Jun;34(4):259-66. doi: 10.1007/s00059-009-3236-3.
Sudden cardiac death in athletes: can it be prevented by screening?
Corrado D(1), Migliore F, Bevilacqua M, Basso C, Thiene G.
Author information:
(1)Division of Cardiology, Department of Cardiac, Thoracic and Vascular
Sciences, University of Padua, Padova, Italy. domenico.corrado@unipd.it
In 1982, a nationwide program of preparticipation screening of all individuals
embarking in competitive sports activity was launched in Italy. The screening
protocol includes athlete's personal and family history, physical examination,
and twelve-lead electrocardiogram (ECG) as first-line examination; additional
tests such as echocardiography or exercise testing are requested only for
subjects who have positive findings at the initial evaluation. This screening
algorithm, which has been used for preparticipation evaluation of millions of
Italian athletes over a period of > 25 years has provided adequate sensitivity
and specificity for detection of athletes affected by potentially dangerous
cardiomyopathy or arrhythmia at risk of athletic-field death and has led to
substantial reduction of mortality of young competitive athletes (by
approximately 90%), mostly by preventing sudden death from cardiomyopathy.
DOI: 10.1007/s00059-009-3236-3
PMID: 19575156 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11805249
|
1. Neurology. 2002 Jan 22;58(2):231-6. doi: 10.1212/wnl.58.2.231.
Genetic identity of Marinesco-Sjögren/myoglobinuria and CCFDN syndromes.
Merlini L(1), Gooding R, Lochmüller H, Müller-Felber W, Walter MC, Angelicheva
D, Talim B, Hallmayer J, Kalaydjieva L.
Author information:
(1)Neuromuscular Unit, Istituto Ortopedico Rizzoli, Bologna, Italy.
OBJECTIVE AND BACKGROUND: To describe three Gypsy families with
Marinesco-Sjögren syndrome (MSS), demyelinating neuropathy, and recurrent
episodes of myoglobinuria in five of the six affected subjects. Because these
families originated from the same genetically isolated founder population as did
patients with congenital cataracts facial dysmorphism neuropathy (CCFDN)
syndrome, and because the two syndromes have clinical manifestations in common,
we hypothesized that the two related, albeit distinct, syndromes may represent
clinical variants of a single genetic disorder.
METHODS: Clinical studies were conducted and linkage and haplotype analyses were
performed for the three families. A total of 16 individuals, including the 6
with MSS and 10 unaffected relatives, were genotyped for six polymorphic
microsatellite markers from the CCFDN region on 18qter.
RESULTS: Linkage analysis of markers in the 18qter region, where we previously
had located the CCFDN gene, produced a lod score of 3.55, demonstrating
colocalization of the gene responsible for MSS with demyelinating neuropathy and
myoglobinuria with the CCFDN gene. Moreover, the patients with MSS shared the
conserved marker haplotype found in CCFDN chromosomes.
CONCLUSIONS: These data suggest that Marinesco-Sjögren syndrome with peripheral
neuropathy and myoglobinuria, and congenital cataracts facial dysmorphism
neuropathy syndrome are genetically identical and are caused by a single founder
mutation.
DOI: 10.1212/wnl.58.2.231
PMID: 11805249 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/17578274
|
1. Ideggyogy Sz. 2007 May 30;60(5-6):257-62.
[Congenital cataracts facial dysmorphism neuropathy syndrome--first Hungarian
case report].
[Article in Hungarian]
Siska E(1), Neuwirth M, Rebecca G, Molnár MJ.
Author information:
(1)Országos Pszichiátriai es Neurológiai Intézet, Molekuláris Neurológiai
Osztály, 1021 Budapest. evasiska@t-online.hu
The congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome (OMIM
604168) is a recently described autosomal recessive developmental disorder. It
is almost completely restricted to an endogamous group of the European Vlax Roma
population, called the Rudari. The CCFDN syndrome is a complex phenotype
involving multiple systems, characterized by facial dysmorphism, congenital
cataracts, microcorneae, delayed early motor and intellectual development,
hypogonadotrop hypogonadism, hypomyelination of the peripheral nervous system,
and serious complications related to general anaesthesia. This disorder is
caused by a homozygous mutation of the carboxy-terminal domain phosphatase 1
(CTDP1) gene, localized to the 18q23 region. Authors present one genetically
identified case in a large Roma family. The case documents that the CCFDN
mutation is present also in the Hungarian Roma population. Underlie of
antropomorphological data the authors presume that the CCFDN mutation reached
Hungary as a result of emigration of Vlax Gypsies in the 18th century. The paper
calls attention to the fact that molecular genetic diagnostics can replace
invasive methods and makes possible the identification of heterozygotes without
clinical symptoms. The introduction of the genetic screening enables us to
perform genetic counselling and prevention in this high-risk population.
PMID: 17578274 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21905643
|
1. Biochemistry. 2011 Oct 4;50(39):8362-73. doi: 10.1021/bi200526q. Epub 2011 Sep
9.
Leader peptide-directed processing of labyrinthopeptin A2 precursor peptide by
the modifying enzyme LabKC.
Müller WM(1), Ensle P, Krawczyk B, Süssmuth RD.
Author information:
(1)Fakultät II-Institut für Chemie, Technische Universität Berlin, Strasse des
17. Juni 124, 10623 Berlin, Germany.
Lantibiotics are peptide antibiotics, realizing their unique secondary structure
by posttranslational modifications, the most important one being the formation
of the characteristic amino acid lanthionine. Like other ribosomal peptide
antibiotics, they are synthesized with an N-terminal leader peptide important
for posttranslational processing by modifying enzymes; after peptide maturation,
the leader peptide is proteolytically cleaved off. Numerous studies of the
leader peptides of class I and II lantibiotics already showed their crucial role
in recognition, self-immunity, and extracellular transport. The recently
described labyrinthopeptins, members of the family of class III lantibiotics,
exhibit the characteristic novel amino acid labionin, which was revealed by
elucidation of the structure of labyrinthopeptin A2. The assembly of the
labionin motif in the linear peptide chain is mediated by the
lyase-kinase-cyclase-type enzyme LabKC through a serine side chain
phosphorylation with GTP, elimination of the phosphate group, and a subsequent
2-fold Michael-type addition cyclization. In this work, we systematically
investigated for the first time the importance of the leader peptide in the
processing of class III lantibiotics using the example of the labyrinthopeptin
A2 precursor peptide. In vitro studies with synthetic leader peptide analogues
revealed that a conserved N-terminal hydrophobic patch on a putative helical
structure is required for the proper peptide processing by the modifying enzyme
LabKC. On the other hand, studies showed that the C-terminal part of the leader
peptide serves as a spacer between the binding site and active sites for
phosphorylation and elimination, thus restricting the number of hydroxy amino
acid side chains that could undergo dehydration. Finally, a model for the
peptide recognition and processing by the LabKC has been postulated.
DOI: 10.1021/bi200526q
PMID: 21905643 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/2279154
|
1. BMJ. 1990 Dec 22-29;301(6766):1409-11. doi: 10.1136/bmj.301.6766.1409.
Longevity of men capable of prolonged vigorous physical exercise: a 32 year
follow up of 2259 participants in the Dutch eleven cities ice skating tour.
van Saase JL(1), Noteboom WM, Vandenbroucke JP.
Author information:
(1)Department of Clinical Epidemiology, Leiden University Hospital, The
Netherlands.
OBJECTIVE: To compare the long term survival of a group of athletes taking
prolonged vigorous physical exercise to that of the general population.
DESIGN: Follow up of a cohort of participants in the Dutch eleven cities ice
skating tour (a race and recreational tour) over a distance of 200 kilometers.
SETTING: Data on participation from the organising committee and data on
mortality from all municipalities in The Netherlands.
SUBJECTS: 2259 Male athletes.
MAIN OUTCOME MEASURES: Comparison of all cause mortality in male participants in
the tour with that in the general population of The Netherlands.
RESULTS: The standardised mortality ratio for all participants during 32 years
of follow up was 0.76 (95% confidence interval 0.68 to 0.85), and 0.90 (0.48 to
1.44) for participants in the race, and 0.72 (0.60 to 0.86) for participants in
the recreational tour who finished within the time limit.
CONCLUSIONS: The capacity for prolonged and vigorous physical exercise,
particularly if the exercise is recreational, is a strong indicator of
longevity.
DOI: 10.1136/bmj.301.6766.1409
PMCID: PMC1679864
PMID: 2279154 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16939648
|
1. Orphanet J Rare Dis. 2006 Aug 29;1:32. doi: 10.1186/1750-1172-1-32.
Congenital cataracts-facial dysmorphism-neuropathy.
Kalaydjieva L(1).
Author information:
(1)Western Australian Institute for Medical Research and Centre for Medical
Research, The University of Western Australia, Hospital Avenue, WA 6009
Nedlands, Australia. luba@cyllene.uwa.edu.au
Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN) syndrome is a complex
developmental disorder of autosomal recessive inheritance. To date, CCFDN has
been found to occur exclusively in patients of Roma (Gypsy) ethnicity; over 100
patients have been diagnosed. Developmental abnormalities include congenital
cataracts and microcorneae, primary hypomyelination of the peripheral nervous
system, impaired physical growth, delayed early motor and intellectual
development, mild facial dysmorphism and hypogonadism. Para-infectious
rhabdomyolysis is a serious complication reported in an increasing number of
patients. During general anaesthesia, patients with CCFDN require careful
monitoring as they have an elevated risk of complications. CCFDN is a
genetically homogeneous condition in which all patients are homozygous for the
same ancestral mutation in the CTDP1 gene. Diagnosis is clinical and is
supported by electrophysiological and brain imaging studies. The major
differential diagnosis is Marinesco-Sjögren syndrome. The definitive diagnosis
is molecular, based on homozygosity for the CTDP1 mutation. CTDP1 maps to 18qter
and encodes a protein phosphatase whose only known substrate is the
phosphorylated serine residues of the carboxy-terminal domain of the largest
subunit of RNA polymerase II, indicating that CCFDN affects basic cellular
processes of gene expression and developmental regulation. Families benefit from
genetic counselling and predictive testing. Management includes surgical
treatment of the cataracts, and rehabilitation and corrective orthopaedic
surgery for the peripheral neuropathy. Thus, the most disabling manifestations,
though not curable, are manageable, and allow an acceptable quality of life and
everyday living. Current data indicate that patients survive well into
adulthood.
DOI: 10.1186/1750-1172-1-32
PMCID: PMC1563997
PMID: 16939648 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17195938
|
1. Eur J Pediatr. 2007 Jul;166(7):747-9. doi: 10.1007/s00431-006-0307-9. Epub
2006 Dec 30.
Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome: a rare
cause of parainfectious rhabdomyolysis.
Mastroyianni SD(1), Garoufi A, Voudris K, Skardoutsou A, Stefanidis CJ, Katsarou
E, Gooding R, Kalaydjieva L.
Author information:
(1)Department of Neurology, P & A Kyriakou Children's Hospital, Thivon and
Levadeias str, 115 27 Athens, Greece. smastr@otenet.gr
Congenital cataracts-facial dysmorphism-neuropathy syndrome (CCFDN, MIM:
604168), is a recently delineated neurogenetic disease causing recurrent
episodes of rhabdomyolysis; prevention and early diagnosis of rhabdomyolysis
should be part of the clinical management of the disease.
DOI: 10.1007/s00431-006-0307-9
PMID: 17195938 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/1482192
|
1. Appl Environ Microbiol. 1992 Nov;58(11):3730-43. doi:
10.1128/aem.58.11.3730-3743.1992.
Biosynthesis of the lantibiotic nisin: genomic organization and membrane
localization of the NisB protein.
Engelke G(1), Gutowski-Eckel Z, Hammelmann M, Entian KD.
Author information:
(1)Institut für Mikrobiologie, Johann Wolfgang Goethe-Universität,
Frankfurt/Main, Germany.
Nisin produced by Lactococcus lactis 6F3 is used as a food preservative and is
the most important member of a group of peptide-antibiotics containing
lanthionine bridges (lantibiotics) (N. Schnell, K.-D. Entian, U. Schneider, F.
Götz, H. Zähner, R. Kellner, and G. Jung, Nature [London] 333:276-278, 1988).
Nisin is ribosomally synthesized, and its structural gene, nisA, encodes a
prepeptide that is posttranslationally modified, revealing the active
lantibiotic (C. Kaletta and K.-D. Entian, J. Bacteriol. 171:1597-1601, 1989).
Adjacent to nisA, the additional genes nisB, nisT, and nisC were identified.
Over their entire sequences, these genes were homologous to genes recently
identified as important for the biosynthesis of lantibiotics, that is, subtilin
from Bacillus subtilis ATCC 6633 and epidermin from Staphylococcus epidermidis
Tü 3298. Genes nisB, nisT, and nisC corresponded to open reading frames of 993,
600, and 418 amino acid residues, respectively. The nisT open reading frame is
homologous to proteins of the HlyB (hemolysin B protein of Escherichia coli)
subfamily. Proteins of this subfamily are responsible for the secretion of a
variety of compounds, including large polypeptides, polysaccharides, and
anti-drug tumors, indicating that NisT may be involved in nisin transport.
Northern (RNA) blot analysis revealed a 0.3-kb transcript for the nisA
structural gene, and the transcriptional start point of the nisA gene was
determined by primer extension. Additionally, a mRNA of at least 3 kb was
identified by using a hybridization probe specific to nisB. Antibodies were
raised against the NisB protein, and Western blot (immunoblot) analysis revealed
a molecular weight of about 115 kDa, which is in accordance with the theoretical
protein size of 117.5 kDa as calculated from the nisB open reading frame.
Several amphipathic transmembrane alpha-helices indicated that NisB is
associated with the membrane. This was confirmed by preparing L. lactis
vesicles. The NisB protein was tightly associated with the vesicle fraction and
was released by sodium dodecyl sulfate treatment only. These results suggest
that NisB is membrane associated and that nisin biosynthesis occurs at the cell
membrane.
DOI: 10.1128/aem.58.11.3730-3743.1992
PMCID: PMC183167
PMID: 1482192 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12358793
|
1. J Neurochem. 2002 Aug;82(4):874-84. doi: 10.1046/j.1471-4159.2002.01044.x.
The neuronal choline transporter CHT1 is regulated by immunosuppressor-sensitive
pathways.
Guermonprez L(1), O'Regan S, Meunier FM, Morot-Gaudry-Talarmain Y.
Author information:
(1)Laboratoire de Neurobiologie Cellulaire et Moléculaire, Gif-sur-Yvette,
France. lane@nbcm.cnrs-gif.fr
The immunosuppressor cyclosporin A inhibits the
peptidyl-prolyl-cis/trans-isomerase activity of cyclophilins and the resulting
complex inhibits the phosphatase activity of calcineurin. Both enzymes were
detected in peripheral nerve endings isolated from the electric organ of Torpedo
and shown to be affected by 10 micro m cyclosporin A. Among the cholinergic
properties studied, choline uptake was specifically inhibited by cyclosporin A
to a maximum of 40%. Cyclosporin A decreased the rate of choline transport but
not the binding of the non-transportable choline analogue hemicholinium-3,
indicating that the number of membrane transporters was not affected. Through
the use of two other immunosuppressors, FK506, which also inhibits calcineurin,
and rapamycin, which does not, two different mechanisms of choline uptake
inhibition were uncovered. FK506 inhibited the rate of choline transport,
whereas rapamycin diminished the affinity for choline. The Torpedo homologue of
the high affinity choline transporter CHT1 was cloned and its activity was
reconstituted in Xenopus oocytes. Choline uptake by oocytes expressing tCHT1 was
inhibited by all three immunosuppressors and also by microinjection of the
specific calcineurin autoinhibitory domain A457-481, indicating that the
phosphatase calcineurin regulates CHT1 activity and could be the common target
of cyclosporin and FK506. Rapamycin, which changed the affinity of the
transporter, may have acted through an immunophilin on the isomerization of
critical prolines that are found in the tCHT1 sequence.
DOI: 10.1046/j.1471-4159.2002.01044.x
PMID: 12358793 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15234148
|
1. Ophthalmology. 2004 Jul;111(7):1415-23. doi: 10.1016/j.ophtha.2003.11.007.
Ocular features of the congenital cataracts facial dysmorphism neuropathy
syndrome.
Müllner-Eidenböck A(1), Moser E, Klebermass N, Amon M, Walter MC, Lochmüller H,
Gooding R, Kalaydjieva L.
Author information:
(1)Department of Ophthalmology, University Hospital of Vienna, Vienna, Austria.
andrea.muellner-eidenboeck@akh-wien.ac.at
OBJECTIVE: To determine the nature and course of ophthalmologic abnormalities in
congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome in a
genetically verified group of 9 patients.
STUDY DESIGN: Observational case series.
PARTICIPANTS: Nine affected male individuals of 5 pedigrees aged 1.3 to 16.8
years were examined. Four individuals were recruited during an ongoing
prospective study of congenital cataracts; 5 individuals could be assigned to
the CCFDN group on the basis of our retrospective data.
MAIN OUTCOME MEASURES: Linkage and haplotype analysis, neurologic examinations,
bilateral cataracts, axial length, corneal diameter, pupil diameter and
pupillary reactions, intraoperative and postoperative complications, lid
changes, aphakic correction problems, refractive results, and visual function.
RESULTS: All families originated from the eastern part of Serbia, close to the
border with Romania. The 8 tested individuals were homozygous for the conserved
ancestral CCFDN haplotype in the telomeric region of chromosome 18q. All
patients showed a peripheral, demyelinating neuropathy and varying degrees of
ataxia. In the older patients, muscular atrophy in distal muscles and facial
dysmorphism was evident. Early-onset bilateral congenital cataracts associated
with microcornea, microphthalmos, and micropupil could be found in all patients.
All children had floppy eyelid syndrome and pseudoptosis. An increased
inflammatory reaction to contact lenses and intraocular lenses could be
documented in all. All patients had syndrome-associated nystagmus and congenital
esotropia. Distant visual acuity could be classified as severe to moderate
impairment, whereas near visual acuity was much better (mild to moderate
impairment).
CONCLUSIONS: Early-onset congenital cataracts associated with microcornea,
microphthalmos, and micropupil are essential ocular features of the CCFDN
syndrome and are the first recognizable signs during early infancy. Awareness of
this syndrome by pediatric ophthalmologists is important, because these typical
findings, combined with information on ethnic origin, may lead to very early
diagnosis at an age when the nature and severity of nonophthalmologic features
are not apparent. Affected individuals may benefit from careful ophthalmologic
treatment and follow-up, as well as from early management of the neurologic
problems and developmental delay. Affected families will benefit from genetic
counseling and predictive testing.
DOI: 10.1016/j.ophtha.2003.11.007
PMID: 15234148 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/2600179
|
1. J Pediatr Orthop. 1989 Nov-Dec;9(6):697-701. doi:
10.1097/01241398-198911000-00013.
Calcaneal gait in spastic diplegia after heel cord lengthening: a study with
gait analysis.
Segal LS(1), Thomas SE, Mazur JM, Mauterer M.
Author information:
(1)Division of Orthopaedics and Rehabilitation, Southern Illinois University
School of Medicine, Springfield 62794-9230.
Calcaneal gait or deformity can be a significant complication after heel cord
lengthening. After heel cord lengthening, 20 children with spastic diplegia were
evaluated by gait analysis to define calcaneal gait objectively and describe
associated morbidity. Mean age was 5 years 2 months (range 2 years 7 months to 8
years 2 months), and mean length of follow-up was 5 years 8 months (range 1
years 1 month 11 year 3 months). Calcaneal gait was defined as dorsiflexion 1 SD
beyond the mean in the sagittal plane for all phases of stance. Increased ankle
dorsiflexion during mid-stance most accurately predicts calcaneal gait. Through
gait analysis, a 30% (6 of 20) prevalence of calcaneal gait suggests that an
increased incidence of calcaneal gait may be present after heel cord
lengthening.
DOI: 10.1097/01241398-198911000-00013
PMID: 2600179 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18790802
|
1. Nucleic Acids Res. 2008 Oct;36(18):5822-31. doi: 10.1093/nar/gkn560. Epub 2008
Sep 12.
The SET and transposase domain protein Metnase enhances chromosome decatenation:
regulation by automethylation.
Williamson EA(1), Rasila KK, Corwin LK, Wray J, Beck BD, Severns V, Mobarak C,
Lee SH, Nickoloff JA, Hromas R.
Author information:
(1)Division of Hematology-Oncology, Cancer Research and Treatment Center,
Department of Medicine, University of New Mexico Health Science Center,
Albuquerque, NM 87131, USA.
Metnase is a human SET and transposase domain protein that methylates histone H3
and promotes DNA double-strand break repair. We now show that Metnase physically
interacts and co-localizes with Topoisomerase IIalpha (Topo IIalpha), the key
chromosome decatenating enzyme. Metnase promotes progression through
decatenation and increases resistance to the Topo IIalpha inhibitors ICRF-193
and VP-16. Purified Metnase greatly enhanced Topo IIalpha decatenation of
kinetoplast DNA to relaxed circular forms. Nuclear extracts containing Metnase
decatenated kDNA more rapidly than those without Metnase, and neutralizing
anti-sera against Metnase reversed that enhancement of decatenation. Metnase
automethylates at K485, and the presence of a methyl donor blocked the
enhancement of Topo IIalpha decatenation by Metnase, implying an internal
regulatory inhibition. Thus, Metnase enhances Topo IIalpha decatenation, and
this activity is repressed by automethylation. These results suggest that cancer
cells could subvert Metnase to mediate clinically relevant resistance to Topo
IIalpha inhibitors.
DOI: 10.1093/nar/gkn560
PMCID: PMC2566874
PMID: 18790802 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16723886
|
1. Neurosurgery. 2006 Jun;58(6):1074-80; discussion 1074-80. doi:
10.1227/01.NEU.0000215854.66011.4F.
Single nucleotide polymorphisms of tissue inhibitor of metalloproteinase genes
in familial moyamoya disease.
Kang HS(1), Kim SK, Cho BK, Kim YY, Hwang YS, Wang KC.
Author information:
(1)Department of Neurosurgery, Konkuk University Hospital, Seoul, Korea.
Comment in
Neurosurgery. 2007 Mar;60(3):E582; author reply E582. doi:
10.1227/01.NEU.0000255365.25066.CD.
Neurosurgery. 2008 Jun;62(6):E1384; author reply E1384. doi:
10.1227/01.neu.0000333318.19835.1c.
OBJECTIVE: The genes encoding tissue inhibitor of metalloproteinase (TIMP) 4 and
TIMP2 span chromosomes 3p24.2-p26 and 17q25, respectively, which are the
locations of familial moyamoya disease (FMMD) genes. We investigated single
nucleotide polymorphisms of the TIMP2 and TIMP4 genes in FMMD patients to
determine genetic predispositions.
METHODS: Eleven blood samples from FMMD patients were recruited. Controls
included 50 blood samples from patients with nonfamilial moyamoya disease (MMD)
and another 50 blood samples from non-MMD persons. We evaluated the promoter
regions, exon-intron junctions, and the exons of the TIMP2 and TIMP4 genes by
direct sequencing, and compared single nucleotide polymorphisms frequencies
among the study groups.
RESULTS: A significantly higher frequency of a heterozygous genotype was found
in the TIMP2 promoter region at position -418 in FMMD; that is, the G/C
heterozygous genotype at position -418 was observed in nine of 11 patients with
FMMD, in 16 out of 50 nonfamilial MMD control participants, and in 14 out of 50
non-MMD control participants (FMMD versus nonfamilial MMD: odds ratio, 9.56; 95%
confidence interval, 1.85-49.48; P = 0.005; and FMMD versus non-MMD: odds ratio,
10.50; 95% confidence interval, 2.02-54.55; P = 0.001). This base at position
-418 corresponds to the third base of the GAGGCTGGG sequence, an Sp1 binding
site. Thus, changes in this position may influence Sp1 binding and subsequent
transcription of the gene.
CONCLUSION: Our findings suggest that the presence of a G/C heterozygous
genotype at position -418 in TIMP2 promoter could be a genetic predisposing
factor for FMMD.
DOI: 10.1227/01.NEU.0000215854.66011.4F
PMID: 16723886 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/14512967
|
1. Eur J Hum Genet. 2003 Oct;11(10):770-8. doi: 10.1038/sj.ejhg.5201068.
Homozygosity mapping of Marinesco-Sjögren syndrome to 5q31.
Lagier-Tourenne C(1), Tranebaerg L, Chaigne D, Gribaa M, Dollfus H, Silvestri G,
Bétard C, Warter JM, Koenig M.
Author information:
(1)Institut de Génétique et de Biologie Moléculaire et Cellulaire,
CNRS/INSERM/Université Louis-Pasteur, Illkirch, France.
Marinesco-Sjögren syndrome (MSS), first described in 1931, is an autosomal
recessive condition characterised by somatic and mental retardation, congenital
cataracts and cerebellar ataxia. Progressive myopathy was later reported to be
also a cardinal sign of MSS, with myopathic changes on muscle biopsies.
Hypergonadotrophic hypogonadism and skeletal deformities related to pronounced
hypotonia were also reported. The major differential diagnosis of MSS is the
syndrome defined by congenital cataracts, facial dysmorphism and peripheral
neuropathy (CCFDN), which is localised to 18qter. Using homozygosity mapping
strategy in two large consanguineous families of Turkish and Norwegian origin,
respectively, we have identified the MSS locus on chromosome 5q31. LOD score
calculation, including the consanguinity loops, gave a maximum value of 2.9 and
5.6 at theta=0 for the Turkish and the Norwegian families, respectively,
indicating linkage between the disease and the D5S1995-D5S436 haplotype spanning
a 9.3 cM interval. Patients of the two families presented with the strict
clinical features of MSS. On the other hand, the study of two smaller French and
Italian families, initially diagnosed as presenting an atypical MS syndrome,
clearly excluded linkage from both the MSS locus on 5q31 and the CCFDN locus in
18qter. Patients of the two excluded families had all MSS features (but the
myopathic changes) plus peripheral neuropathy and optic atrophy, and various
combinations of microcornea, hearing impairment, seizures, Type I diabetes,
cerebral atrophy and leucoencephalopathy, indicating that only the pure MSS
syndrome is a homogeneous genetic entity.
DOI: 10.1038/sj.ejhg.5201068
PMID: 14512967 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23241269
|
1. BMJ. 2012 Dec 13;345:e7456. doi: 10.1136/bmj.e7456.
Mortality in former Olympic athletes: retrospective cohort analysis.
Zwiers R(1), Zantvoord FW, Engelaer FM, van Bodegom D, van der Ouderaa FJ,
Westendorp RG.
Author information:
(1)Leyden Academy on Vitality and Ageing, Rijnsburgerweg 10, 2333 AA Leiden,
Netherlands.
Comment in
BMJ. 2012 Dec 13;345:e8338. doi: 10.1136/bmj.e8338.
OBJECTIVE: To assess the mortality risk in subsequent years (adjusted for year
of birth, nationality, and sex) of former Olympic athletes from disciplines with
different levels of exercise intensity.
DESIGN: Retrospective cohort study.
SETTING: Former Olympic athletes.
PARTICIPANTS: 9889 athletes (with a known age at death) who participated in the
Olympic Games between 1896 and 1936, representing 43 types of disciplines with
different levels of cardiovascular, static, and dynamic intensity exercise; high
or low risk of bodily collision; and different levels of physical contact.
MAIN OUTCOME MEASURE: All cause mortality.
RESULTS: Hazard ratios for mortality among athletes from disciplines with
moderate cardiovascular intensity (1.01, 95% confidence interval 0.96 to 1.07)
or high cardiovascular intensity (0.98, 0.92 to 1.04) were similar to those in
athletes from disciplines with low cardiovascular intensity. The underlying
static and dynamic components in exercise intensity showed similar
non-significant results. Increased mortality was seen among athletes from
disciplines with a high risk of bodily collision (hazard ratio 1.11, 1.06 to
1.15) and with high levels of physical contact (1.16, 1.11 to 1.22). In a
multivariate analysis, the effect of high cardiovascular intensity remained
similar (hazard ratio 1.05, 0.89 to 1.25); the increased mortality associated
with high physical contact persisted (hazard ratio 1.13, 1.06 to 1.21), but that
for bodily collision became non-significant (1.03, 0.98 to 1.09) as a
consequence of its close relation with physical contact.
CONCLUSIONS: Among former Olympic athletes, engagement in disciplines with high
intensity exercise did not bring a survival benefit compared with disciplines
with low intensity exercise. Those who engaged in disciplines with high levels
of physical contact had higher mortality than other Olympians later in life.
DOI: 10.1136/bmj.e7456
PMCID: PMC3521875
PMID: 23241269 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: All authors have completed
the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available
on request from the corresponding author) and declare: no support from any
organisation for the submitted work; no financial relationships with any
organisations that might have an interest in the submitted work in the previous
three years; no other relationships or activities that could appear to have
influenced the submitted work.
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http://www.ncbi.nlm.nih.gov/pubmed/21618162
|
1. Int J Sports Med. 2011 Aug;32(8):644-7. doi: 10.1055/s-0031-1271711. Epub 2011
May 26.
Increased average longevity among the "Tour de France" cyclists.
Sanchis-Gomar F(1), Olaso-Gonzalez G, Corella D, Gomez-Cabrera MC, Vina J.
Author information:
(1)Department of Physiology, Faculty of Medicine, University of Valencia, Spain.
It is widely held among the general population and even among health
professionals that moderate exercise is a healthy practice but long term high
intensity exercise is not. The specific amount of physical activity necessary
for good health remains unclear. To date, longevity studies of elite athletes
have been relatively sparse and the results are somewhat conflicting. The Tour
de France is among the most gruelling sport events in the world, during which
highly trained professional cyclists undertake high intensity exercise for a
full 3 weeks. Consequently we set out to determine the longevity of the
participants in the Tour de France, compared with that of the general
population. We studied the longevity of 834 cyclists from France (n=465), Italy
(n=196) and Belgium (n=173) who rode the Tour de France between the years 1930
and 1964. Dates of birth and death of the cyclists were obtained on December 31
(st) 2007. We calculated the percentage of survivors for each age and compared
them with the values for the pooled general population of France, Italy and
Belgium for the appropriate age cohorts. We found a very significant increase in
average longevity (17%) of the cyclists when compared with the general
population. The age at which 50% of the general population died was 73.5 vs.
81.5 years in Tour de France participants. Our major finding is that repeated
very intense exercise prolongs life span in well trained practitioners. Our
findings underpin the importance of exercising without the fear that becoming
exhausted might be bad for one's health.
© Georg Thieme Verlag KG Stuttgart · New York.
DOI: 10.1055/s-0031-1271711
PMID: 21618162 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25967372
|
1. Biochem J. 2015 Jul 15;469(2):223-33. doi: 10.1042/BJ20150396. Epub 2015 May
13.
Nuclear cyclophilins affect spliceosome assembly and function in vitro.
Adams BM(1), Coates MN(1), Jackson SR(2), Jurica MS(1), Davis TL(3).
Author information:
(1)Department of Molecular, Cell and Developmental Biology and Center for
Molecular Biology of RNA, University of California, Santa Cruz, CA 95064, U.S.A.
(2)Department of Biochemistry and Molecular Biology, Drexel University College
of Medicine, Philadelphia, PA 19102, U.S.A.
(3)Department of Molecular, Cell and Developmental Biology and Center for
Molecular Biology of RNA, University of California, Santa Cruz, CA 95064, U.S.A.
Department of Biochemistry and Molecular Biology, Drexel University College of
Medicine, Philadelphia, PA 19102, U.S.A. Tara.Davis@DrexelMed.edu.
Cyclophilins are ubiquitously expressed proteins that bind to prolines and can
catalyse cis/trans isomerization of proline residues. There are 17 annotated
members of the cyclophilin family in humans, ubiquitously expressed and
localized variously to the cytoplasm, nucleus or mitochondria. Surprisingly, all
eight of the nuclear localized cyclophilins are found associated with
spliceosomal complexes. However, their particular functions within this context
are unknown. We have therefore adapted three established assays for in vitro
pre-mRNA splicing to probe the functional roles of nuclear cyclophilins in the
context of the human spliceosome. We find that four of the eight
spliceosom-associated cyclophilins exert strong effects on splicing in vitro.
These effects are dose-dependent and, remarkably, uniquely characteristic of
each cyclophilin. Using both qualitative and quantitative means, we show that at
least half of the nuclear cyclophilins can act as regulatory factors of
spliceosome function in vitro. The present work provides the first quantifiable
evidence that nuclear cyclophilins are splicing factors and provides a novel
approach for future work into small molecule-based modulation of pre-mRNA
splicing.
© 2015 Authors; published by Portland Press Limited.
DOI: 10.1042/BJ20150396
PMCID: PMC4537404
PMID: 25967372 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21925040
|
1. Eur J Intern Med. 2011 Oct;22(5):e36-8. doi: 10.1016/j.ejim.2011.02.007. Epub
2011 Mar 21.
Significant variation of traditional markers of liver injury after a
half-marathon run.
Lippi G(1), Schena F, Montagnana M, Salvagno GL, Banfi G, Guidi GC.
Author information:
(1)U.O. di Diagnostica Ematochimica, Dipartimento di Patologia e Medicina di
Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Italy. glippi@ao.pr.it
BACKGROUND: While the promotion of health-related fitness is thereby widespread,
less focus is currently being given on the biological influence that physical
activity might exert on results of laboratory testing. As such, this study was
undertaken to assess the kinetics of liver injury markers following physical
exercise.
DESIGN AND METHODS: Total and direct bilirubin as well as the activity of
biochemical markers of liver injury including aspartate aminotransferase (AST),
alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate
dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT) and creatine kinase
(CK), were measured before and after a half-marathon.
RESULTS: Significant increases occurred for GGT, AST, LDH, CK, total and direct
bilirubin immediately after the run. AST, LDH, CK, total and direct bilirubin
were still increased 24h thereafter, whereas GGT decreased after 6h. None of the
athletes exceed the upper reference limit for ALT, ALP and GGT, whereas
significant variations were instead observed for LDH, AST, CK, total and direct
bilirubin.
CONCLUSIONS: Taken together, the results of our prospective investigation
clearly attest that an acute bulk of aerobic physical exercise, such as a
half-marathon, might produce significant changes in the activity of traditional
biomarkers of liver injury, which should be carefully considered when
investigating physically active individuals undergoing laboratory testing.
Copyright © 2011 European Federation of Internal Medicine. Published by Elsevier
B.V. All rights reserved.
DOI: 10.1016/j.ejim.2011.02.007
PMID: 21925040 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12832429
|
1. J Appl Physiol (1985). 2003 Oct;95(4):1575-83. doi:
10.1152/japplphysiol.00482.2003. Epub 2003 Jun 27.
Dose-response relationship of the cardiovascular adaptation to endurance
training in healthy adults: how much training for what benefit?
Iwasaki K(1), Zhang R, Zuckerman JH, Levine BD.
Author information:
(1)Institute for Exercise and Environmental Medicine, Presbyterian Hospital, and
University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75231,
USA.
Occupational or recreational exercise reduces mortality from cardiovascular
disease. The potential mechanisms for this reduction may include changes in
blood pressure (BP) and autonomic control of the circulation. Therefore, we
conducted the present long-term longitudinal study to quantify the dose-response
relationship between the volume and intensity of exercise training, and
regulation of heart rate (HR) and BP. We measured steady-state hemodynamics and
analyzed dynamic cardiovascular regulation by spectral and transfer function
analysis of cardiovascular variability in 11 initially sedentary subjects during
1 yr of progressive endurance training sufficient to allow them to complete a
marathon. From this, we found that 1) moderate exercise training for 3 mo
decreased BP, HR, and total peripheral resistance, and increased cardiovascular
variability and arterial baroreflex sensitivity; 2) more prolonged and intense
training did not augment these changes further; and 3) most of these changes
returned to control values at 12 mo despite markedly increased training duration
and intensity equivalent to that routinely observed in competitive athletes. In
conclusion, increases in R-wave-R-wave interval and cardiovascular variability
indexes are consistent with an augmentation of vagal modulation of HR after
exercise training. It appears that moderate doses of training for 3 mo are
sufficient to achieve this response as well as a modest hypotensive effect from
decreasing vascular resistance. However, more prolonged and intense training
does not necessarily lead to greater enhancement of circulatory control and,
therefore, may not provide an added protective benefit via autonomic mechanisms
against death by cardiovascular disease.
DOI: 10.1152/japplphysiol.00482.2003
PMID: 12832429 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18773976
|
1. DNA Repair (Amst). 2008 Dec 1;7(12):1927-37. doi:
10.1016/j.dnarep.2008.08.002. Epub 2008 Sep 18.
The human set and transposase domain protein Metnase interacts with DNA Ligase
IV and enhances the efficiency and accuracy of non-homologous end-joining.
Hromas R(1), Wray J, Lee SH, Martinez L, Farrington J, Corwin LK, Ramsey H,
Nickoloff JA, Williamson EA.
Author information:
(1)Division of Hematology-Oncology, Cancer Research and Treatment Center,
Department of Medicine, University of New Mexico Health Science Center, 900
Camino de Salud, Albuquerque, NM 87131, United States.
Transposase domain proteins mediate DNA movement from one location in the genome
to another in lower organisms. However, in human cells such DNA mobility would
be deleterious, and therefore the vast majority of transposase-related sequences
in humans are pseudogenes. We recently isolated and characterized a SET and
transposase domain protein termed Metnase that promotes DNA double-strand break
(DSB) repair by non-homologous end-joining (NHEJ). Both the SET and transposase
domain were required for its NHEJ activity. In this study we found that Metnase
interacts with DNA Ligase IV, an important component of the classical NHEJ
pathway. We investigated whether Metnase had structural requirements of the free
DNA ends for NHEJ repair, and found that Metnase assists in joining all types of
free DNA ends equally well. Metnase also prevents long deletions from processing
of the free DNA ends, and improves the accuracy of NHEJ. Metnase levels
correlate with the speed of disappearance of gamma-H2Ax sites after ionizing
radiation. However, Metnase has little effect on homologous recombination repair
of a single DSB. Altogether, these results fit a model where Metnase plays a
role in the fate of free DNA ends during NHEJ repair of DSBs.
DOI: 10.1016/j.dnarep.2008.08.002
PMCID: PMC2644637
PMID: 18773976 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that there are no conflicts
of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/18174554
|
1. J Child Neurol. 2007 Dec;22(12):1371-6. doi: 10.1177/0883073807307101.
Familial Moyamoya disease in two European children.
Papavasiliou A(1), Bazigou-Fotopoulou H, Ikeda H.
Author information:
(1)Pendeli Children's Hospital, Department of Paediatric Neurology, Athens,
Greece. theon@otenet.gr
We present familial Moyamoya disease in two European children and emphasize the
importance of familial factors in the pathogenesis of this disease and its
appearance not only in Asians but in the Western population as well. The first
patient, a Greek female infant, also has coagulation disorders. Her mother, also
suffering from Moyamoya and other family members, have similar coagulation
disorders (Factor V Leiden, Methylene-tetrahydrofolic reductase and Factor II
20210A mutations). The second patient, a Scottish boy, is unique in that
familial Moyamoya affects five members of three consecutive generations of his
maternal family. Genetic analysis in the Greek family demonstrated no
abnormality on chromosome 3p26, as in other cases. However, the mitochondrial
DNA and Y chromosomal genotype showed that affected members had the same
sequence of the Mitochondrial 3 portion of D-loop with Japanese patients. These
findings suggest that the pathogenesis of Moyamoya may vary across races and
ethnic groups.
DOI: 10.1177/0883073807307101
PMID: 18174554 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15675354
|
1. No To Hattatsu. 2005 Jan;37(1):15-9.
[No association between moyamoya disease and polymorphism of IGF2R].
[Article in Japanese]
Yamamoto T(1), Akasaka Y, Ohtani K, Hayashi T, Kashiwagi S, Ichiyama T,
Nishikawa M, Kato M, Maegaki Y, Oka A, Ohno K.
Author information:
(1)Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama,
Kanagawa. tyamamoto-jes@umin.ac.jp
Moyamoya disease is a cerebrovascular disorder of unknown etiology. Its high
incidence in East Asia and accumulation in family members suggest a genetic
background. A high incidence of maternal inheritance implicates genomic
imprinting in this disorder. Based on this hypothesis, we studied the
association between moyamoya disease and IGF2R gene on chromosome 6, but found
no evidence for such association between them. On the other hand, heterogeneous
expressions of IGF2R were confirmed in the lymphocytes. Some individuals showed
monoallelic expression and others showed biallelic expression.
PMID: 15675354 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18189160
|
1. Breast Cancer Res Treat. 2008 Dec;112(3):557-63. doi:
10.1007/s10549-008-9894-7. Epub 2008 Jan 13.
Feasibility of two dose-dense FEC regimens with growth factor support for
adjuvant therapy in patients with early breast cancer: results from a randomised
study of the Central European Cooperative Oncology Group (CECOG).
Kahán Z(1), Spanik S, Wagnerova M, Skacel T, Planko B, Fitzthum E, Lindner E,
Soldatenkova V, Zielinski CC, Brodowicz T.
Author information:
(1)University of Szeged, Szeged, Hungary.
Addition of epirubicin to adjuvant chemotherapy can provide important benefits
for patients with early breast cancer, but the optimal dose remains unclear.
Further improvements can be achieved with dose-dense regimens, but densification
of fluorouracil/epirubicin/cyclophosphamide (FEC) has proved difficult, with
FEC(60) providing little benefit over standard chemotherapy and FEC(100)
associated with toxicity. We investigated the feasibility of two intermediate
dose-dense FEC regimens. Patients were randomised to six cycles of FEC(75) or
FEC(90), with all three drugs given on day 1 of each 14-day cycle. Patients also
received pegfilgrastim 6 mg as a single subcutaneous injection on day 2 of each
cycle. The primary efficacy endpoint was the proportion of subjects receiving >
or =85% relative dose intensity and was achieved by 96% and 88% of patients in
the FEC(75) and FEC(90) arms, respectively. Of 147 FEC(75) infusions, 4.1% were
delayed, while 9.8% of 143 FEC(90) infusions were delayed. The most common
reasons for delay were adverse events and personal/logistical reasons. One dose
reduction occurred during the study (FEC(90)), related to diarrhoea. Grade 3-4
haematological toxicities were reported in two patients in the FEC(90) arm.
There were no incidences of febrile neutropenia during the study. The most
common adverse events were increases in liver enzymes and gastrointestinal
events; no event resulted in discontinuation. Only one patient (FEC(90))
experienced serious adverse events (vomiting and throat oedema). In conclusion,
dose-dense FEC(75 )and FEC(90) are feasible with pegfilgrastim support. These
regimens are associated with a very low risk of Grade 3-4 toxicity.
DOI: 10.1007/s10549-008-9894-7
PMID: 18189160 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21631222
|
1. Neurosurg Focus. 2011 Jun;30(6):E20. doi: 10.3171/2011.3.FOCUS1151.
Moyamoya disease: a review of histopathology, biochemistry, and genetics.
Weinberg DG(1), Arnaout OM, Rahme RJ, Aoun SG, Batjer HH, Bendok BR.
Author information:
(1)Department of Neurological Surgery, Feinberg School of Medicine, and McGaw
Medical Center, Northwestern University, Chicago, Illinois 60611, USA.
OBJECT: Moyamoya disease (MMD) is a rare cerebrovascular disorder involving
stenosis of the major vessels of the circle of Willis and proximal portions of
its principal branches. Despite concerted investigation, the pathophysiology of
the disorder has not been fully elucidated. Currently, the major proteins
believed to play an active role in the pathogenesis include vascular endothelial
growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth
factor (HGF), transforming growth factor-β₁ (TGFβ₁), and granulocyte
colony-stimulating factor (G-CSF). In terms of the genetics, recent literature
suggests a low penetrance autosomal dominant or polygenic mode of transmission
involving chromosomes 3, 6, 8, 12, and 17 for familial MMD. This review
summarizes the current knowledge on the histopathology, pathophysiology and
genetics of MMD.
METHODS: A PubMed/Medline systematic study of the literature was performed, from
which 45 articles regarding MMD pathophysiology were identified and analyzed.
CONCLUSIONS: Moyamoya disease is characterized by the intimal thickening and
media attenuation of the proximal vessels of the circle of Willis as well as the
development of an aberrant distal vascular network. The primary proteins that
are currently implicated in the pathophysiology of MMD include VEGF, bFGF, HGF,
TGFβ₁, and G-CSF. Furthermore, the current literature on familial MMD has
pointed to a low penetrance autosomal dominant or polygenic mode of
transmittance at loci on chromosomes 3, 6, 8, 12, and 17.
DOI: 10.3171/2011.3.FOCUS1151
PMID: 21631222 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17409421
|
1. Cancer Res. 2007 Apr 1;67(7):3145-52. doi: 10.1158/0008-5472.CAN-06-4397.
Histone deacetylase 2 modulates p53 transcriptional activities through
regulation of p53-DNA binding activity.
Harms KL(1), Chen X.
Author information:
(1)Department of Cell Biology, University of Alabama at Birmingham, Birmingham,
Alabama, USA.
Histone deacetylase (HDAC) inhibitors are emerging as promising cancer
therapeutics. HDAC inhibitors have been found to induce cellular activities that
are strikingly similar to p53-mediated responses to genotoxic stress. For
example, HDAC inhibitors induce cell cycle arrest, apoptosis, and cellular
senescence. Because at least 11 HDACs are affected by the current HDAC
inhibitors, the HDAC critical for tumor cell survival and proliferation remains
unknown. Thus, we sought to characterize the distinct roles of HDACs in the p53
pathway. Through the use of stable MCF7 cell lines which inducibly express short
hairpin RNA targeting HDAC2, we found that HDAC2 plays important roles in the
p53 pathway. Specifically, we found that knockdown of HDAC2 inhibited cellular
proliferation in a dose-dependent manner which was also partly p53-dependent.
Furthermore, knockdown of HDAC2 induced cellular senescence. Importantly, we
found that knockdown of HDAC2 enhanced p53-dependent trans-repression and
trans-activation of a subset of target genes. We found that the enhancement was
due to increased p53-DNA binding activity but not alterations in p53 stability
or posttranslational modification(s). Thus, for the first time, our data suggest
that HDAC inhibitors function through the p53 pathway, at least in part, by
activating p53-DNA binding activity.
DOI: 10.1158/0008-5472.CAN-06-4397
PMID: 17409421 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24291195
|
1. Vaccine. 2014 Jan 16;32(4):464-9. doi: 10.1016/j.vaccine.2013.11.054. Epub
2013 Nov 27.
A monoclonal antibody that recognizes the E domain of staphylococcal protein A.
Kim HK(1), Emolo C(1), Missiakas D(1), Schneewind O(2).
Author information:
(1)Department of Microbiology, University of Chicago, 920 East 58th Street,
Chicago, IL 60637, USA.
(2)Department of Microbiology, University of Chicago, 920 East 58th Street,
Chicago, IL 60637, USA. Electronic address: oschnee@bsd.uchicago.edu.
Staphylococcal protein A (SpA) binds Fcγ and VH3 clan Fab domains of human and
animal immunoglobulin (Ig) with each of its five Ig binding domains (IgBDs),
thereby supporting Staphylococcus aureus escape from opsonophagocytic killing
and suppressing adaptive B cell responses. The variant SpAKKAA cannot bind Ig
yet retains antigenic properties that elicit SpA-neutralizing antibodies and
disease protection in mice, whereas S. aureus infection or SpA-immunization
cannot elicit neutralizing antibodies. As a test for this model, we analyzed
here mAb 358A76, which was isolated from SpA-immunized mice. Unlike
SpAKKAA-derived mAbs, mAb 358A76 binds only the first IgBD (E) but not any of
the other four IgBDs (D-A-B-C) and its binding can neutralize only the E domain
of SpA, which does not provide disease protection in mice. These results are in
agreement with a model whereby wild-type SpA-immunization generates a limited
antibody response without neutralizing and/or disease protective attributes.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.vaccine.2013.11.054
PMCID: PMC6211298
PMID: 24291195 [Indexed for MEDLINE]
Conflict of interest statement: Disclosure of Potential Conflicts of Interest
Hwan Keun Kim, Dominique Missiakas and Olaf Schneewind declare a conflict of
interest as inventors of patent applications that are related to the development
of Staphylococcus aureus vaccines and are currently under commercial license.
|
http://www.ncbi.nlm.nih.gov/pubmed/19918425
|
1. Cases J. 2009 Aug 11;2:8399. doi: 10.4076/1757-1626-2-8399.
An unusual cause of subarachnoid haemorrhage in a patient with newly diagnosed
neurofibromatosis: a case report.
Weerasinghe C(1), Jesudason P, Peckham D.
Author information:
(1)Department of Respiratory Medicine, St James University Hospital Beckett
Street, Leeds, LS9 7TF UK. chisha_wickrema@yahoo.com
INTRODUCTION: In this report we discuss an unusual cause of subarachnoid
haemorrhage in association with neurofibromatosis.
CASE PRESENTATION: A previously fit 55-year-old man developed sudden onset
headache with loss of consciousness. He was comatose on admission with no focal
neurological signs. Numerous neurofibromas and café-au-lait patches were noted,
indicating neurofibromatosis type 1 which had not been previously diagnosed.
Computer Tomography brain revealed a grade IV subarachnoid haemorrhage in
association with numerous vascular lesions on cerebral angiography.
CONCLUSION: A rare cause of subarachnoid haemorrhages was identified and is
discussed in detail.
DOI: 10.4076/1757-1626-2-8399
PMCID: PMC2769435
PMID: 19918425
|
http://www.ncbi.nlm.nih.gov/pubmed/17138018
|
1. Pediatr Neurol. 2006 Dec;35(6):442-5. doi:
10.1016/j.pediatrneurol.2006.06.016.
Moyamoya syndrome in a child with trisomy 12p syndrome.
Kim YO(1), Baek HJ, Woo YJ, Choi YY, Chung TW.
Author information:
(1)Department of Pediatrics, Chonnam National University Hospital, Gwangju,
Korea. ik052@unitel.co.kr
A female, 2 years and 7 months of age, was admitted to the hospital with stupor
and nystagmus following projectile vomiting. She had been prenatally diagnosed
with trisomy 12p with a familial pericentric inversion of chromosome 12
originating from her mother. She manifested developmental delay and some
dysmorphic features of the face and limbs compatible with the clinical features
of trisomy 12p. Four-vessel cerebral angiography revealed severe stenosis and
occlusion of the supraclinoid portion of the right and left internal carotid
arteries with numerous collateral vessels in the vicinity of the occlusion.
These features are consistent with moyamoya syndrome. This report presents the
first case of moyamoya syndrome with trisomy 12p with a familial pericentric
inversion of chromosome 12.
DOI: 10.1016/j.pediatrneurol.2006.06.016
PMID: 17138018 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24831536
|
1. J Med Chem. 2014 Sep 11;57(17):7145-59. doi: 10.1021/jm500223x. Epub 2014 Jun
3.
From chemical tools to clinical medicines: nonimmunosuppressive cyclophilin
inhibitors derived from the cyclosporin and sanglifehrin scaffolds.
Sweeney ZK(1), Fu J, Wiedmann B.
Author information:
(1)Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville,
California 94608, United States.
The cyclophilins are widely expressed enzymes that catalyze the interconversion
of the cis and trans peptide bonds of prolines. The immunosuppressive natural
products cyclosporine A and sanglifehrin A inhibit the enzymatic activity of the
cyclophilins. Chemical modification of both the cyclosporine and sanglifehrin
scaffolds has produced many analogues that inhibit cyclophilins in vitro but
have reduced immunosuppressive properties. Three nonimmunosuppressive
cyclophilin inhibitors (alisporivir, SCY-635, and NIM811) have demonstrated
clinical efficacy for the treatment of hepatitis C infection. Additional
candidates are in various stages of preclinical development for the treatment of
hepatitis C or myocardial reperfusion injury. Recent publications suggest that
cyclophilin inhibitors may have utility for the treatment of diverse viral
infections, inflammatory indications, and cancer. In this review, we document
the structure-activity relationships of the nonimmunosuppressive cyclosporins
and sanglifehrins in clinical and preclinical development. Aspects of the
pharmacokinetic behavior and chemical biology of these drug candidates are also
described.
DOI: 10.1021/jm500223x
PMID: 24831536 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17054108
|
1. Cancer. 2006 Dec 1;107(11):2535-44. doi: 10.1002/cncr.22227.
Inflammatory breast cancer outcome with epirubicin-based induction and
maintenance chemotherapy: ten-year results from the French Adjuvant Study Group
GETIS 02 Trial.
Veyret C(1), Levy C, Chollet P, Merrouche Y, Roche H, Kerbrat P, Fumoleau P,
Fargeot P, Clavere P, Chevallier B.
Author information:
(1)Department of Medical Oncology, Henri Becquerel Center, Rouen, France.
cveyret@rouen.fnclcc.fr
BACKGROUND: The authors evaluated the long-term efficacy and side effects in
patients with nonmetastatic, unilateral, inflammatory breast cancer (IBC) who
received homogeneous treatment with intensive induction chemotherapy followed by
a maintenance regimen.
METHODS: One hundred twenty patients were randomized to receive high-dose
fluorouracil, epirubicin, and cyclophosphamide (FEC-HD) (fluorouracil 750
mg/m(2) on Days 1 to 4, epirubicin 35 mg/m(2) on Days 2 to 4, and
cyclophosphamide 400 mg/m(2) on Days 2 to 4 for 4 cycles every 21 days) with or
without lenograstim. Locoregional treatment consisted of surgery and/or
radiotherapy. Maintenance chemotherapy was FEC 75 (fluorouracil 500 mg/m(2),
epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) on Day 1 every 21 days
for 4 cycles). No hormone treatment was allowed.
RESULTS: The safety of the FEC-HD regimen was described previously. Among 102
patients who underwent surgery, a pathologic complete response (pCR) was
achieved by 23.5% of patients with breast tumors and by 31.4% of patients with
involved axillary lymph nodes. The overall pCR rate was 14.7%. One hundred nine
patients received FEC 75. After a median 10 years of follow-up, the disease-free
survival (DFS) and overall survival (OS) rates were 35.7% and 41.2%,
respectively. The median DFS was 39 months (95% confidence interval [95% CI],
25-53 months), and the median survival was 61 months (95% CI, 43-79 months).
Five patients developed a temporary decrease in left ventricular ejection
fraction without congestive heart failure. In the lenograstim group, 1 patient
developed acute myeloblastic leukemia M2, and 1 patient developed
myelodysplastic syndrome.
CONCLUSIONS: FEC-HD induction chemotherapy followed by FEC 75 maintenance
regimen had moderate and acute long-term toxicities and lead to high DFS and OS
rates in patients with IBC.
(c) 2006 American Cancer Society.
DOI: 10.1002/cncr.22227
PMID: 17054108 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16606615
|
1. J Biol Chem. 2006 Jun 16;281(24):16279-88. doi: 10.1074/jbc.M600682200. Epub
2006 Apr 10.
Analysis of nucleosome repositioning by yeast ISWI and Chd1 chromatin remodeling
complexes.
Stockdale C(1), Flaus A, Ferreira H, Owen-Hughes T.
Author information:
(1)Division of Gene Regulation and Expression, School of Life Sciences,
University of Dundee, Dundee DD1 5EH, United Kingdom.
ISWI proteins form the catalytic core of a subset of ATP-dependent chromatin
remodeling activities in eukaryotes from yeast to man. Many of these complexes
have been found to reposition nucleosomes but with different directionalities.
We find that the yeast Isw1a, Isw2, and Chd1 enzymes preferentially move
nucleosomes toward more central locations on short DNA fragments whereas Isw1b
does not. Importantly, the inherent positioning properties of the DNA play an
important role in determining where nucleosomes are relocated to by all of these
enzymes. However, a key difference is that the Isw1a, Isw2, and Chd1 enzymes are
unable to move nucleosomes to positions closer than 15 bp from a DNA end,
whereas Isw1b can. We also find that there is a correlation between the
inability of enzymes to move nucleosomes close to DNA ends and the preferential
binding to nucleosomes bearing linker DNA. These observations suggest that the
accessibility of linker DNA together with the positioning properties of the
underlying DNA play important roles in determining the outcome of remodeling by
these enzymes.
DOI: 10.1074/jbc.M600682200
PMCID: PMC1764501
PMID: 16606615 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18483370
|
1. Clin Cancer Res. 2008 May 15;14(10):3044-51. doi:
10.1158/1078-0432.CCR-07-4079.
Phase I safety and pharmacokinetic study of CT-011, a humanized antibody
interacting with PD-1, in patients with advanced hematologic malignancies.
Berger R(1), Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M,
Koren-Michowitz M, Shimoni A, Nagler A.
Author information:
(1)Institute of Oncology and Radiotherapy, Bone Marrow Transplantation, Chaim
Sheba Medical Center, Tel Hashomer, Israel.
PURPOSE: CT-011 is a humanized IgG1 monoclonal antibody that modulates the
immune response through interaction with PD-1, a protein belonging to the B7
receptor family present on lymphocytes. The objectives of this phase I study
were to assess the dose-limiting toxicities, to determine the maximum tolerated
dose, and to study the pharmacokinetics of CT-011 administered once to patients
with advanced hematologic malignancies.
EXPERIMENTAL DESIGN: Seventeen patients were treated with escalating doses of
CT-011 ranging from 0.2 to 6 mg/kg. For pharmacokinetic analysis, blood samples
were withdrawn from the patients before and immediately after treatment and at
24 hours, 48 hours, and on days 7, 14, and 21. CT-011 blood levels were assessed
with a specific ELISA and derived concentrations were used to calculate
pharmacokinetic parameters. Activation of the immune system was assessed by
measuring peripheral blood CD4+, CD8+, and CD69+ lymphocytes.
RESULTS: The study showed the antibody to be safe and well tolerated in this
patient population. No single maximum tolerated dose was defined in this study.
Clinical benefit was observed in 33% of the patients with one complete
remission. Pharmacokinetic analyses show that serum Cmax and the AUC of CT-011
increased proportionally with dose. The median t1/2 of CT-011 ranged from 217 to
410 hours. Sustained elevation in the percentage of peripheral blood CD4+
lymphocytes was observed up to 21 days following CT-011 treatment.
CONCLUSIONS: A single administration of 0.2 to 6.0 mg/kg of CT-011 is safe and
well tolerated in patients with advanced hematologic malignancies.
DOI: 10.1158/1078-0432.CCR-07-4079
PMID: 18483370 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/10974562
|
1. Gene. 2000 Sep 5;255(1):35-42. doi: 10.1016/s0378-1119(00)00299-7.
cDNA cloning and characterization of human cardiac junctin.
Lim KY(1), Hong CS, Kim DH.
Author information:
(1)Department of Life Science, Kwangju Institute of Science and Technology
(K-JIST), 1 Oryong-dong, Puk-gu, 500-712, Kwangju, South Korea.
Junctin is a calsequestrin binding protein detected in junctional sarcoplasmic
reticulum of striated muscles. In the present study, the human cardiac junctin
cDNA has been cloned by human heart cDNA library screening and RT-PCR, and the
cDNA sequence has been determined. The deduced amino acid sequence of human
junctin (210 aa) has 84% sequence identity to that of canine junctin identified
previously. A human junctin isoform (isoform 1, 225 aa) was also identified and
characterized. The isoform 1 has a 15 aa insertion at the amino acid residue 55
of the human junctin. Northern blot analysis revealed that the human junctin was
present both in cardiac and skeletal muscles, and the sizes of the transcripts
were approximately 3.0 and 4.2kb. Amino acid residues 6-78 of human junctin and
35-107 of human aspartyl beta-hydroxylase (hAspH) overlapped perfectly. The gene
copy number of human junctin and hASPH was investigated by genomic Southern blot
analysis using various restriction enzymes and a common DNA probe. The result
showing a single hybridized DNA band at each restriction enzyme suggests that
the same genomic region codes both junctin and hASPH.
DOI: 10.1016/s0378-1119(00)00299-7
PMID: 10974562 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11971980
|
1. Mol Cell Biol. 2002 May;22(10):3497-508. doi:
10.1128/MCB.22.10.3497-3508.2002.
Oncogenic ras and p53 cooperate to induce cellular senescence.
Ferbeyre G(1), de Stanchina E, Lin AW, Querido E, McCurrach ME, Hannon GJ, Lowe
SW.
Author information:
(1)Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in
murine fibroblasts initiates a senescence-like cell cycle arrest that depends on
the ARF/p53 tumor suppressor pathway. To investigate whether p53 is sufficient
to induce senescence, we introduced a conditional murine p53 allele
(p53(val135)) into p53-null mouse embryonic fibroblasts and examined cell
proliferation and senescence in cells expressing p53, oncogenic Ras, or both
gene products. Conditional p53 activation efficiently induced a reversible cell
cycle arrest but was unable to induce features of senescence. In contrast,
coexpression of oncogenic ras or activated mek1 with p53 enhanced both p53
levels and activity relative to that observed for p53 alone and produced an
irreversible cell cycle arrest that displayed features of cellular senescence.
p19(ARF) was required for this effect, since p53(-/-) ARF(-/-) double-null cells
were unable to undergo senescence following coexpression of oncogenic Ras and
p53. Although the levels of exogenous p53 achieved in ARF-null cells were
relatively low, the stabilizing effects of p19(ARF) on p53 could not explain the
cooperation between oncogenic Ras and p53 in promoting senescence. Hence,
enforced p53 expression without oncogenic ras in p53(-/-) mdm2(-/-) double-null
cells produced extremely high p53 levels but did not induce senescence. Taken
together, our results indicate that oncogenic activation of the MAP kinase
pathway in murine fibroblasts converts p53 into a senescence inducer through
both quantitative and qualitative mechanisms.
DOI: 10.1128/MCB.22.10.3497-3508.2002
PMCID: PMC133786
PMID: 11971980 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17634581
|
1. Methods Mol Biol. 2007;371:167-78. doi: 10.1007/978-1-59745-361-5_13.
Inducing cellular senescence using defined genetic elements.
Nakagawa H(1), Opitz OG.
Author information:
(1)Gastroenterology Division, Department of Medicine and Abramson Cancer Center,
University of Pennsylvania, Philadelphia, PA, USA.
Cellular senescence is generally defined as an irreversible state of G1 cell
cycle arrest in which cells are refractory to growth factor stimulation.
Cellular senescence can be induced through several different mechanisms. Primary
mammalian cells display a finite life span, suggesting a mechanism that counts
cell divisions. Those cells initially proliferate but eventually enter a state
of permanent growth arrest, called replicative senescence. Erosion of telomeric
DNA has emerged as a key factor in replicative senescence, which is antagonized
during cell immortalization. Nevertheless, besides telomere shortening, there
are other mechanisms inducing a growth arrest similar to the replicative
senescencent phenotype. Oncogenic or mitogenic signals as well as DNA damage can
induce such a phenotype of cellular senescence. All forms of cellular senescence
share common signaling pathways and morphological features. Thereby, p53 seems
to be essential for the senescence response. Many of these senescence inducing
mechanisms can be experimentally recapitulated by the introduction of defined
genetic elements. Replicative senescence due to telomere shortening can, for
example, be induced by a dominant negative version of telomerase, premature
senescence by the overexpression of oncogenic ras, or p16.
DOI: 10.1007/978-1-59745-361-5_13
PMID: 17634581 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7693420
|
1. Drugs. 1993;45 Suppl 2:38-45. doi: 10.2165/00003495-199300452-00007.
Premenopausal patients with node-positive resectable breast cancer. Preliminary
results of a randomised trial comparing 3 adjuvant regimens: FEC 50 x 6 cycles
vs FEC 50 x 3 cycles vs FEC 75 x 3 cycles. The French Adjuvant Study Group.
Fumoleau P(1), Devaux Y, Vo Van ML, Kerbrat P, Fargeot P, Schraub S, Mihura J,
Namer M, Mercier M.
Author information:
(1)Centre Rene Gauducheau, Centre Regional de Lutte Contre le Cancer
Nantes-Atlantique, Nantes, France.
Anthracyclines are among the most active drugs for the treatment of advanced
breast cancer. Epirubicin has been found to be as effective as doxorubicin at
equimolar doses but significantly better tolerated, especially in terms of
alopecia, leucopenia, and cardiac toxicity. The role of anthracycline-containing
regimens in adjuvant treatment of breast cancer has been studied by only a few
clinical trial teams. In 1986, the French Adjuvant Study Group (FASG) began a
randomised trial aimed to investigate the concept of dose intensity as well as
the optimal duration of treatment in patients with early breast cancer. Between
1986 and 1990, 621 patients were included in the trial, of whom 595 were
evaluable. Patients were randomised to 1 of 3 treatment groups: Group A (n =
207) received FEC 50 (fluorouracil 500 mg/m2, epirubicin 50 mg/m2 plus
cyclophosphamide 500 mg/m2) every 21 days for 6 cycles; Group B (n = 193)
received FEC 50 every 21 days for 3 cycles; Group C (n = 195) received FEC 75
(fluorouracil 500 mg/m2, epirubicin 75 mg/m2 plus cyclophosphamide 500 mg/m2)
every 21 days for 3 cycles. Locoregional radiotherapy was administered after the
third cycle of chemotherapy in all treatment arms. Clinical prognostic factors
were similar between treatment groups. Approximately 62% of all patients had 1
to 3 positive lymph nodes; 50% of patients were hormone receptor positive and
73% were Scarff-Bloom Richardson (SBR) grade 2 to 3. Toxicity was evaluated in
595 patients (207, 193 and 195 patients in Groups A, B and C, respectively), who
received a total of 2301 chemotherapy cycles.(ABSTRACT TRUNCATED AT 250 WORDS)
DOI: 10.2165/00003495-199300452-00007
PMID: 7693420 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18344024
|
1. Breast Cancer Res Treat. 2009 Mar;114(1):103-12. doi:
10.1007/s10549-008-9970-z. Epub 2008 Mar 16.
Delivery of adjuvant sequential dose-dense FEC-Doc to patients with breast
cancer is feasible, but dose reductions and toxicity are dependent on treatment
sequence.
Wildiers H(1), Dirix L, Neven P, Prové A, Clement P, Squifflet P, Amant F,
Skacel T, Paridaens R.
Author information:
(1)Multidisciplinary Breast Center, University Hospitals Leuven, Leuven,
Belgium. hans.wildiers@uzleuven.be
INTRODUCTION: This study prospectively investigates the impact of dose
densification and altering sequence of fluorouracil, epirubicin and
cyclophosphamide [FEC(100)] and docetaxel [Doc] on dose delivery and
tolerability of adjuvant chemotherapy in breast cancer patients.
METHODS: 117 patients with high-risk primary operable breast cancer were
randomized (1:1:2:2) to conventional (three cycles of 3-weekly FEC(100) then
three cycles of 3-weekly Doc 100 mg/m(2) or reverse sequence) or dose-dense (dd)
treatment (four 10- to 11-day cycles of FEC(75) then four 2-weekly cycles of Doc
75 mg/m(2), or the reverse). In the dd arms, pegfilgrastim was given on day 2 of
each cycle, but only as secondary prophylaxis in conventional arms.
RESULTS: The primary endpoint was the proportion of patients completing intended
cycles at relative dose intensity >or=85% and this was achieved by 95% of
patients in each group except for the ddDoc-->FEC group (90%). Dose intensity in
the dd arms increased by 48% for FEC and 11% for docetaxel, compared with the
conventional arms (both P < 0.001). Doc dose reductions were more frequent with
dd treatment and when Doc was given after FEC. Grade 3-4 neutropenia was
significantly more frequent with conventional treatment, while fatigue and
hand-foot syndrome were numerically more common with dd treatment, particularly
when Doc was given after FEC. Discussion Delivery of adjuvant sequential ddFEC
and Doc is feasible with growth factor support, and chemotherapy sequence
appeared to affect delivery of target doses and toxicity.
DOI: 10.1007/s10549-008-9970-z
PMID: 18344024 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22791394
|
1. Age (Dordr). 2013 Aug;35(4):1251-62. doi: 10.1007/s11357-012-9452-4. Epub 2012
Jul 13.
A role for c-Abl in cell senescence and spontaneous immortalization.
Zhang M(1), Li L, Wang Z, Liu H, Hou J, Zhang M, Hao A, Liu Y, He G, Shi Y, He
L, Wang X, Wan Y, Li B.
Author information:
(1)Department of Clinical Laboratory, Beijing Shi Ji Tan Hospital, Capital
Medical University, Beijing, People's Republic of China.
c-Abl is a proto-oncogene that is essential for mouse development and tissue
homeostasis. Misregulation of c-Abl, as seen in the constitutively active
BCR-ABL, is the leading cause of human chronic myeloid leukemia. However, how
the Abl proteins execute their functions still remains largely unknown. Here, we
report an important role for c-Abl in replicative senescence and immortalization
by regulating the expression of two tumor suppressors that induce cellular
senescence, p53 and p16(INK4a). Using primary mouse embryonic fibroblasts
(MEFs), we show that c-Abl (-/-) cells were more resistant to immortalization
than wildtype cells using a standard 3T3 or 3T9 protocol. We could only
immortalize three out of nine c-Abl (-/-) MEF cultures even when we increased
the number of starting cells. This resistance was attributed to premature
senescence and reduced survival in senescent c-Abl (-/-) cells due to an
increase in p16(INK4a) and p53 expression. Deleting p53 allows c-Abl (-/-) p53
(-/-) MEFs to bypass senescence to be spontaneously immortalized. Cell
immortalization, but not senescence, was generally accompanied by mutations in
p53 in both wildtype and c-Abl (-/-) MEFs, although the spectrum is different
from that of human tumors. The role for c-Abl in regulating cell senescence and
immortalization might explain some of the developmental defects in c-Abl (-/-)
mice and how BCR-ABL transforms cells.
DOI: 10.1007/s11357-012-9452-4
PMCID: PMC3705115
PMID: 22791394 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7546221
|
1. Mol Carcinog. 1995 Sep;14(1):23-7. doi: 10.1002/mc.2940140106.
Molecular genetic basis of renal carcinogenesis in the Eker rat model of
tuberous sclerosis (Tsc2).
Hino O(1), Kobayashi E, Hirayama Y, Kobayashi T, Kubo Y, Tsuchiya H, Kikuchi Y,
Mitani H.
Author information:
(1)Department of Experimental Pathology, Cancer Institute, Tokyo, Japan.
We have recently identified on rat chromosome 10q a germline mutation in the
tuberous sclerosis gene (Tsc2), the gene predisposing to renal carcinoma (RC) in
the Eker rat. The homozygous mutant condition is lethal at around the 13th day
of fetal life. In heterozygotes, RCs invariably develop in the first year of
life. Histologically, RCs develop through multiple stages from early
preneoplastic lesions (i.e., phenotypically altered tubules) to adenomas. The
wild-type allele mutation has been found even in the earliest preneoplastic
lesions, fitting Knudson's two-hit hypothesis and supporting the hypothesis that
Tsc2 is a tumor suppressor gene. In this study, homozygous deletion of the Ink4
homologue on rat chromosome 5q was observed in 14 of 24 (58%) RC-derived cell
lines. This may represent involvement of a second tumor suppressor gene,
contributing to tumor progression. Considering previous results of studies of
homozygous deletion of the Ifn alpha gene in five of 24 cases (21%) and the Ifn
beta gene in one of 24 cases (4%), the order of the genes may be Ink4-Ifn
alpha-Ifn beta. Microsatellite instability was not observed in 26 Eker rat
tumors.
DOI: 10.1002/mc.2940140106
PMID: 7546221 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/10956665
|
1. J Biol Chem. 2000 Dec 15;275(50):39543-54. doi: 10.1074/jbc.M006753200.
Aspartyl beta -hydroxylase (Asph) and an evolutionarily conserved isoform of
Asph missing the catalytic domain share exons with junctin.
Dinchuk JE(1), Henderson NL, Burn TC, Huber R, Ho SP, Link J, O'Neil KT, Focht
RJ, Scully MS, Hollis JM, Hollis GF, Friedman PA.
Author information:
(1)Department of Applied Biotechnology, DuPont Pharmaceuticals Research
Laboratories, DuPont Pharmaceuticals Company, Experimental Station, Wilmington,
Delaware 19880, USA. joseph.e.dinchuk@dupontpharma.com
The mouse aspartyl beta-hydroxylase gene (Asph, BAH) has been cloned and
characterized. The mouse BAH gene spans 200 kilobase pairs of genomic DNA and
contains 24 exons. Of three major BAH-related transcripts, the two largest
(6,629 and 4,419 base pairs) encode full-length protein and differ only in the
use of alternative polyadenylation signals. The smallest BAH-related transcript
(2,789 base pairs) uses an alternative 3' terminal exon, resulting in a protein
lacking a catalytic domain. Evolutionary conservation of this noncatalytic
isoform of BAH (humbug) is demonstrated in mouse, man, and Drosophila.
Monoclonal antibody reagents were generated, epitope-mapped, and used to
definitively correlate RNA bands on Northern blots with protein species on
Western blots. The gene for mouse junctin, a calsequestrin-binding protein, was
cloned and characterized and shown to be encoded from the same locus. When
expressed in heart tissue, BAH/humbug preferably use the first exon and often
the fourth exon of junctin while preserving the reading frame. Thus, three
individual genes share common exons and open reading frames and use separate
promoters to achieve differential expression, splicing, and function in a
variety of tissues. This unusual form of exon sharing suggests that the
functions of junctin, BAH, and humbug may be linked.
DOI: 10.1074/jbc.M006753200
PMID: 10956665 [Indexed for MEDLINE]
|
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