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http://www.ncbi.nlm.nih.gov/pubmed/16697960 | 1. Cancer Cell. 2006 May;9(5):405-16. doi: 10.1016/j.ccr.2006.04.004.
Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in
Ewing's sarcoma.
Smith R(1), Owen LA, Trem DJ, Wong JS, Whangbo JS, Golub TR, Lessnick SL.
Author information:
(1)The Center for Children, Huntsman Cancer Institute, University of Utah, Salt
Lake City, Utah 84112, USA.
Erratum in
Cancer Cell. 2007 Jan;11(1):97.
Comment in
Cancer Cell. 2006 May;9(5):331-2. doi: 10.1016/j.ccr.2006.05.003.
Our understanding of Ewing's sarcoma development mediated by the EWS/FLI fusion
protein has been limited by a lack of knowledge regarding the tumor cell of
origin. To circumvent this, we analyzed the function of EWS/FLI in Ewing's
sarcoma itself. By combining retroviral-mediated RNA interference with
reexpression studies, we show that ongoing EWS/FLI expression is required for
the tumorigenic phenotype of Ewing's sarcoma. We used this system to define the
full complement of EWS/FLI-regulated genes in Ewing's sarcoma. Functional
analysis revealed that NKX2.2 is an EWS/FLI-regulated gene that is necessary for
oncogenic transformation in this tumor. Thus, we developed a highly validated
transcriptional profile for the EWS/FLI fusion protein and identified a critical
target gene in Ewing's sarcoma development.
DOI: 10.1016/j.ccr.2006.04.004
PMID: 16697960 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16006690 | 1. JOP. 2005 Jul 8;6(4):369-74.
Hemolytic-uremic syndrome associated with gemcitabine: a case report and review
of literature.
Saif MW(1), McGee PJ.
Author information:
(1)Division of Hematology-Oncology, Department of Medicine, University of
Alabama at Birmingham, 35294-3300, USA. [email protected]
CONTEXT: Hemolytic uremic syndrome is a rare condition compromising the clinical
triad of acute renal failure, microangiopathic hemolytic anemia, and
thrombocytopenia. Hemolytic uremic syndrome may be associated with a variety of
etiologies, and chemotherapeutic agents have also been reported to be associated
with hemolytic uremic syndrome, including mitomycin, cisplatin, bleomycin, and
most recently gemcitabine.
CASE REPORT: A 72-year-old Caucasian male treated with four cycles of
gemcitabine at 1,000 mg/m2 developed clinical and laboratory findings compatible
with hemolytic uremic syndrome. He developed microangiopathic hemolysis, rapidly
declining renal function with proteinuria and hematuria, and renal biopsy
revealed thrombotic microangiopathy. Hemodialysis, plasmapheresis, and
corticosteroid therapy were utilized but the process ultimately was
irreversible.
CONCLUSION: With multiple reports of hemolytic uremic syndrome complicating
gemcitabine therapy, it is imperative that clinicians heighten their awareness
of this potentially lethal complication.
PMID: 16006690 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24642372 | 1. FEBS Lett. 2014 Apr 17;588(8):1416-22. doi: 10.1016/j.febslet.2014.03.009.
Epub 2014 Mar 15.
The role of pannexin1 in the induction and resolution of inflammation.
Adamson SE(1), Leitinger N(2).
Author information:
(1)Department of Pharmacology, University of Virginia, United States.
(2)Department of Pharmacology, University of Virginia, United States. Electronic
address: [email protected].
Extracellular ATP is an important signaling molecule throughout the inflammatory
cascade, serving as a danger signal that causes activation of the inflammasome,
enhancement of immune cell infiltration, and fine-tuning of several signaling
cascades including those important for the resolution of inflammation. Recent
studies demonstrated that ATP can be released from cells in a controlled manner
through pannexin (Panx) channels. Panx1-mediated ATP release is involved in
inflammasome activation and neutrophil/macrophage chemotaxis, activation of T
cells, and a role for Panx1 in inducing and propagating inflammation has been
demonstrated in various organs, including lung and the central and peripheral
nervous system. The recognition and clearance of dying cells and debris from
focal points of inflammation is critical in the resolution of inflammation, and
Panx1-mediated ATP release from dying cells has been shown to recruit
phagocytes. Moreover, extracellular ATP can be broken down by ectonucleotidases
into ADP, AMP, and adenosine, which is critical in the resolution of
inflammation. Together, Panx1, ATP, purinergic receptors, and ectonucleotidases
contribute to important feedback loops during the inflammatory response, and
thus represent promising candidates for new therapies.
Copyright © 2013 Federation of European Biochemical Societies. Published by
Elsevier B.V. All rights reserved.
DOI: 10.1016/j.febslet.2014.03.009
PMCID: PMC4060616
PMID: 24642372 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16387683 | 1. Ann N Y Acad Sci. 2005 Nov;1056:144-52. doi: 10.1196/annals.1352.032.
Hemolytic uremic syndrome: an example of insufficient complement regulation on
self-tissue.
Atkinson JP(1), Liszewski MK, Richards A, Kavanagh D, Moulton EA.
Author information:
(1)Washington University School of Medicine, Department of Medicine/Rheumatology
Division, 660 South Euclid Avenue, Campus Box 8045, St. Louis, MO 63110, USA.
[email protected]
Hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia,
thrombocytopenia, and acute renal failure. HUS is classified as either diarrhea
associated, most commonly caused by infection with Escherichia coli O157, or the
less common atypical HUS (aHUS), which may be familial or sporadic.
Approximately 50% of patients with aHUS have mutations in one of the complement
control proteins: factor H, factor I, or membrane cofactor protein (MCP). These
proteins regulate complement activation through cofactor activity, the
inactivation of C3b by limited proteolytic cleavage, a desirable event in the
fluid phase (no target) or on healthy self-tissue (wrong target). Complement
activation follows the endothelial cell injury that characterizes HUS. This
disease represents a model of what takes place when inappropriate complement
activation occurs on self-tissues due to the presence of mutated complement
regulatory proteins. Screening for mutations in factor H, factor I, or MCP is
expensive and time consuming. One approach is to perform antigenic screening for
factor H and factor I deficiency and to look for low levels of MCP (CD46)
expression by flow cytometry. Complement regulatory protein deficiency impacts
treatment decisions as patients with aHUS have a recurrence rate in renal
transplants of approximately 50%, whereas those with factor H mutations have an
even higher risk (approximately 80%). By contrast, MCP deficiency can be
corrected in part by a renal allograft. However, caution in the use of
live-related donations is needed because of the high rates of incomplete
penetrance of the described mutations.
DOI: 10.1196/annals.1352.032
PMID: 16387683 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25056878 | 1. Sci Signal. 2014 Jul 22;7(335):ra69. doi: 10.1126/scisignal.2005431.
The membrane protein Pannexin1 forms two open-channel conformations depending on
the mode of activation.
Wang J(1), Ambrosi C(2), Qiu F(1), Jackson DG(1), Sosinsky G(3), Dahl G(4).
Author information:
(1)Department of Physiology and Biophysics, University of Miami School of
Medicine, Miami, FL 33136, USA.
(2)National Center for Microscopy and Imaging Research, Center for Research in
Biological Systems, University of California, San Diego, La Jolla, CA
92093-06083, USA.
(3)National Center for Microscopy and Imaging Research, Center for Research in
Biological Systems, University of California, San Diego, La Jolla, CA
92093-06083, USA. Department of Neurosciences, University of California, San
Diego, La Jolla, CA 92093-06083, USA.
(4)Department of Physiology and Biophysics, University of Miami School of
Medicine, Miami, FL 33136, USA. [email protected].
Pannexin1 (Panx1) participates in several signaling events that involve
adenosine triphosphate (ATP) release, including the innate immune response,
ciliary beat in airway epithelia, and oxygen supply in the vasculature. The view
that Panx1 forms a large ATP release channel has been challenged by the
association of a low-conductance, small anion-selective channel with the
presence of Panx1. We showed that Panx1 membrane channels can function in two
distinct modes with different conductances and permeabilities when
heterologously expressed in Xenopus oocytes. When stimulated by potassium ions
(K(+)), Panx1 formed a high-conductance channel of ~500 pS that was permeable to
ATP. Various physiological stimuli can induce this ATP-permeable conformation of
the channel in several cell types. In contrast, the channel had a low
conductance (~50 pS) with no detectable ATP permeability when activated by
voltage in the absence of K(+). The two channel states were associated with
different reactivities of the terminal cysteine of Panx1 to thiol reagents,
suggesting different conformations. Single-particle electron microscopic
analysis revealed that K(+) stimulated the formation of channels with a larger
pore diameter than those formed in the absence of K(+). These data suggest that
different stimuli lead to distinct channel structures with distinct biophysical
properties.
Copyright © 2014, American Association for the Advancement of Science.
DOI: 10.1126/scisignal.2005431
PMCID: PMC4243966
PMID: 25056878 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20209841 | 1. Tunis Med. 2009 Nov;87(11):790-2.
Pneumococcal infection and hemolytic uremic syndrome.
Tinsa F(1), Siala N, Ncibi N, Fetni I, Kasdalli K, Ben Jballah N, Mehrezi A.
Author information:
(1)Department of Pediatrics B of the Children s Hospital of Tunis Department of
Pediatrics, Monji Slim Hospital, Tunis.
BACKGROUND: Hemolytic uremic syndrome, one of the common causes of acute renal
failure in children, is characterized by the triad of microangiopathy,
haemolytic anemia, thrombocytopenia and acute renal failure. The
diarrhoea-associated Hemolytic uremic syndrome is usually termed as a typical
Hemolytic uremic syndrome. Streptococcus pneumoniae is an uncommon etiological
pathogen for inducing Hemolytic uremic syndrome, and Streptococcus pneumoniae
associated Hemolytic uremic syndrome is also termed as atypical hemolytic uremic
syndrome.
AIM: to report two pediatric cases of invasive S pneumoniae complicated with
hemolytic uremic syndrome HUS.
CASE REPORT: The first patient presented with pneumococcal pneumonia and empyema
and the second patient presented with pneumococcal pneumonia and meningitis. The
two patients were under one year of age and required peritoneal dialysis with
improvement of renal function in one; the other died.
CONCLUSION: Pneumococcal invasive disease may be a cause of severe HUS, so a
high index of suspicion is mandatory to prompt appropriate diagnosis and
management.
PMID: 20209841 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22241085 | 1. Cancer Res. 2012 Mar 1;72(5):1260-9. doi: 10.1158/0008-5472.CAN-11-2254. Epub
2012 Jan 12.
PRAS40 is a functionally critical target for EWS repression in Ewing sarcoma.
Huang L(1), Nakai Y, Kuwahara I, Matsumoto K.
Author information:
(1)Molecular Entomology Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama, Japan.
Ewing sarcoma family tumors (ESFT) are highly aggressive and highly metastatic
tumors caused by a chromosomal fusion between the Ewing sarcoma protein (EWS)
with the transcription factor FLI-1. However, expression of the EWS/FLI-1
chimeric oncogene by itself is insufficient for carcinogenesis, suggesting that
additional events are required. Here, we report the identification of the Akt
substrate PRAS40 as an EWS target gene. EWS negatively regulates PRAS40
expression by binding the 3' untranslated region in PRAS40 mRNA. ESFT cell
proliferation was suppressed by treatment with an Akt inhibitor, and ESFT cell
proliferation and metastatic growth were suppressed by siRNA-mediated PRAS40
knockdown. Furthermore, PRAS40 knockdown was sufficient to reverse an increased
cell proliferation elicited by EWS knockdown. In support of a pathologic role
for PRAS40 elevation in EFST, we documented inverse protein levels of EWS and
PRAS40 in ESFT cells. Together, our findings suggest that PRAS40 promotes the
development of ESFT and might therefore represent a novel therapeutic target in
this aggressive disease.
DOI: 10.1158/0008-5472.CAN-11-2254
PMID: 22241085 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26265890 | 1. Turk Pediatri Ars. 2015 Jun 1;50(2):73-82. doi: 10.5152/tpa.2015.2297.
eCollection 2015 Jun.
Hemolytic uremic syndrome.
Canpolat N(1).
Author information:
(1)Department of Pediatrics, Division of Pediatric Nephrology, İstanbul
University Cerrahpaşa Faculty of Medicine, İstanbul, Turkey.
Hemolytic uremic syndrome (HUS) is a clinical syndrome characterized by the
triad of thrombotic microangiopathy, thrombocytopenia, and acute kidney injury.
Hemolytic uremic syndrome represents a heterogeneous group of disorders with
variable etiologies that result in differences in presentation, management and
outcome. In recent years, better understanding of the HUS, especially those due
to genetic mutations in the alternative complement pathway have provided an
update on the terminology, classification, and treatment of the disease. This
review will provide the updated classification of the disease and the current
diagnostic and therapeutic approaches on the complement-mediated HUS in addition
to STEC-HUS which is the most common cause of the HUS in childhood.
DOI: 10.5152/tpa.2015.2297
PMCID: PMC4523989
PMID: 26265890 |
http://www.ncbi.nlm.nih.gov/pubmed/25765799 | 1. Rinsho Ketsueki. 2015 Feb;56(2):185-93. doi: 10.11406/rinketsu.56.185.
[Atypical HUS caused by complement-related abnormalities].
[Article in Japanese]
Yoshida Y(1), Matsumoto M.
Author information:
(1)Department of Blood Transfusion Medicine, Nara Medical University.
Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by the
triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal
failure. The term aHUS was historically used to distinguish this disorder from
Shiga-toxin producing Escherichia coli (STEC)-HUS. Many aHUS cases
(approximately 70%) are reportedly caused by uncontrolled complement activation
due to genetic mutations in the alternative pathway, including complement factor
H (CFH), complement factor I (CFI), membrane cofactor protein (MCP),
thrombomodulin (THBD), complement component C3 (C3), and complement factor B
(CFB). Mutations in the coagulation pathway, such as diacylglycerol kinase ε
(DGKE) and plasminogen, are also reported to be causes of aHUS. In this review,
we have focused on aHUS due to complement dysfunction. aHUS is suspected based
on plasma ADAMTS13 activity of 10% or more, and being negative for STEC-HUS, in
addition to the aforementioned triad. Complement genetic studies provide a more
specific diagnosis of aHUS. Plasma therapy is the first-line treatment for
patients with aHUS and should be initiated as soon as the diagnosis is
suspected. Recently, eculizumab, a humanized monoclonal antibody against C5, was
shown to be an effective treatment for aHUS. Therefore, early diagnosis and
identification of the underlying pathogenic mechanism is important for improving
the outcome of aHUS.
DOI: 10.11406/rinketsu.56.185
PMID: 25765799 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24516709 | 1. Gut Liver. 2014 Jan;8(1):109-12. doi: 10.5009/gnl.2014.8.1.109. Epub 2014 Jan
13.
Gemcitabine-induced hemolytic uremic syndrome in pancreatic cancer: a case
report and review of the literature.
Lee HW(1), Chung MJ(1), Kang H(1), Choi H(1), Choi YJ(1), Lee KJ(1), Lee SW(1),
Han SH(2), Kim JS(3), Song SY(1).
Author information:
(1)Division of Gastroenterology, Department of Internal Medicine, Yonsei
University College of Medicine, Seoul, Korea.
(2)Division of Nephrology, Department of Internal Medicine, Yonsei University
College of Medicine, Seoul, Korea.
(3)Division of Hematology, Department of Internal Medicine, Yonsei University
College of Medicine, Seoul, Korea.
Hemolytic uremic syndrome (HUS) is a rare thrombotic complication characterized
by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute
renal failure. HUS may be caused by several different conditions, including
infection, malignancy, and chemotherapeutic agents, such as mitomycin,
cisplatin, and most recently, gemcitabine. The outcome of gemcitabine-induced
HUS is poor, and the disease has a high mortality rate. This study reports a
case of gemcitabine-induced HUS in a patient with pancreatic cancer in Korea.
DOI: 10.5009/gnl.2014.8.1.109
PMCID: PMC3916680
PMID: 24516709 [Indexed for MEDLINE]
Conflict of interest statement: No potential conflict of interest relevant to
this article was reported. |
http://www.ncbi.nlm.nih.gov/pubmed/2831711 | 1. Am J Hematol. 1988 Mar;27(3):221-3. doi: 10.1002/ajh.2830270314.
Hemolytic uremic syndrome in a patient with small cell lung cancer.
Avvento L(1), Gordon S, Silberberg JM, Zarrabi MH, Zucker S.
Author information:
(1)Division of Hematology, State University of New York at Stony Brook.
Hemolytic uremic syndrome is a rare entity in patients with carcinoma and
presents with a triad of renal insufficiency, microangiopathic hemolytic anemia,
and thrombocytopenia. We report this syndrome for the first time in a patient
with small cell lung carcinoma. Spontaneous platelet aggregation of washed
normal platelets was demonstrated using patient plasma. Circulating immune
complex levels were not elevated. The entity completely resolved after treatment
with plasma, vincristine, aspirin, and dipyridamole.
DOI: 10.1002/ajh.2830270314
PMID: 2831711 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24694658 | 1. Sci Rep. 2014 Apr 3;4:4576. doi: 10.1038/srep04576.
ATP and potassium ions: a deadly combination for astrocytes.
Jackson DG(1), Wang J(1), Keane RW(1), Scemes E(2), Dahl G(1).
Author information:
(1)Department of Physiology and Biophysics, University of Miami School of
Medicine, Miami, Florida 33136.
(2)Dominick P. Purpura Department of Neuroscience, Albert Einstein College of
Medicine, Bronx, New York, 10461.
The ATP release channel Pannexin1 (Panx1) is self-regulated, i.e. the permeant
ATP inhibits the channel from the extracellular space. The affinity of the ATP
binding site is lower than that of the purinergic P2X7 receptor allowing a
transient activation of Panx1 by ATP through P2X7R. Here we show that the
inhibition of Panx1 by ATP is abrogated by increased extracellular potassium ion
concentration ([K(+)]o) in a dose-dependent manner. Since increased [K(+)]o is
also a stimulus for Panx1 channels, it can be expected that a combination of ATP
and increased [K(+)]o would be deadly for cells. Indeed, astrocytes did not
survive exposure to these combined stimuli. The death mechanism, although
involving P2X7R, does not appear to strictly follow a pyroptotic pathway.
Instead, caspase-3 was activated, a process inhibited by Panx1 inhibitors. These
data suggest that Panx1 plays an early role in the cell death signaling pathway
involving ATP and K(+) ions. Additionally, Panx1 may play a second role once
cells are committed to apoptosis, since Panx1 is also a substrate of caspase-3.
DOI: 10.1038/srep04576
PMCID: PMC3974143
PMID: 24694658 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19227723 | 1. Bol Asoc Med P R. 2008 Apr-Jun;100(2):14-6.
Hemolytic uremic syndrome in children in Puerto Rico: a rare disease with
atypical features.
Pedrogo-Rodríguez Y(1), Pérez-Rodríguez JO, Bonilla-Felix M.
Author information:
(1)Department of Pediatrics, University of Puerto Rico, Medical Sciences Campus,
San Juan, Puerto Rico.
Hemolytic Uremic Syndrome (HUS) consists ofa triad of acquired hemolytic anemia,
thrombocytopenia, and renal failure that occurs acutely in otherwise healthy
individuals. HUS may be divided into two broad categories, typical, preceded by
a diarrheal prodrome, and atypical. The clinical symptoms of HUS as well as its
course, prognosis, and response to treatment appear to be significantly
influenced by a number of factors, including age at onset, type and severity of
underlying infections, and/or systemic diseases. A retrospective case series
review of five patients diagnosed with Hemolytic Uremic Syndrome at the
Pediatric University Hospital in Puerto Rico between 1997-2007 was performed.
The study showed that the incidence of HUS in children in Puerto Rico is lower
than other countries. However, the majority of cases have an atypical
presentation, which places our patients at higher risk for life-threatening
complications.
PMID: 19227723 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21554896 | 1. Physiol Behav. 2011 Nov 30;105(1):52-61. doi: 10.1016/j.physbeh.2011.04.025.
Epub 2011 Apr 28.
Ghrelin, peptide YY and their hypothalamic targets differentially regulate
spontaneous physical activity.
Pfluger PT(1), Castañeda TR, Heppner KM, Strassburg S, Kruthaupt T, Chaudhary N,
Halem H, Culler MD, Datta R, Burget L, Tschöp MH, Nogueiras R, Perez-Tilve D.
Author information:
(1)Obesity Research Center, Dept. of Internal Medicine, University of
Cincinnati, Cincinnati, OH, USA. [email protected]
Recent studies suggest that spontaneous physical activity (SPA) may be under the
non-conscious control of neuroendocrine circuits that are known to control food
intake. To further elucidate endocrine gut-brain communication as a component of
such circuitry, we here analyzed long-term and acute effects of the
gastrointestinal hormones ghrelin and PYY 3-36 as well as their hypothalamic
neuropeptide targets NPY, AgRP and POMC (alpha-MSH), on locomotor activity and
home cage behaviors in rats. For the analysis of SPA, we used an automated
infrared beam break activity measuring system, combined with a novel automated
video-based behavior analysis system (HomeCageScan (HCS)). Chronic (one-month)
peripheral infusion of ghrelin potently increased body weight and fat mass in
rats. Such positive energy balance was intriguingly not due to an overall
increased caloric ingestion, but was predominantly associated with a decrease in
SPA. Chronic intracerebroventricular infusion (7 days) of ghrelin corroborated
the decrease in SPA and suggested a centrally mediated mechanism. Central
administration of AgRP and NPY increased food intake as expected. AgRP
administration led to a delayed decrease in SPA, while NPY acutely (but
transiently) increased SPA. Behavioral dissection using HCS corroborated the
observed acute and transient increases of food intake and SPA by central NPY
infusion. Acute central administration of alpha-MSH rapidly decreased food
intake but did not change SPA. Central administration of the NPY receptor
agonist PYY 3-36 transiently increased SPA. Our data suggest that the control of
spontaneous physical activity by gut hormones or their neuropeptide targets may
represent an important mechanistic component of energy balance regulation.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.physbeh.2011.04.025
PMID: 21554896 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25345382 | 1. Clin Nephrol. 2015 Jun;83(6):363-9. doi: 10.5414/CN108363.
Refractory atypical hemolytic uremic syndrome with monoclonal gammopathy
responsive to bortezomib-based therapy.
Cheungpasitporn W, Leung N, Sethi S, Gertz MA, Fervenza FC.
Atypical hemolytic uremic syndrome (aHUS) is a relatively rare disorder
described by the triad of hemolytic anemia, thrombocytopenia, and renal failure.
Atypical HUS could be genetic, acquired, or idiopathic (without known genetic
changes or environmental triggers). Monoclonal protein has uncommonly been
reported as a cause of microangiopathic hemolytic anemia (MAHA). We report a
59-year-old white man who presented with acute kidney injury (AKI) with MAHA and
was given a diagnosis of aHUS with monoclonal gammopathy. His kidney function
and proteinuria worsened with persistent hemolysis despite eculizumab and later
cyclophosphamide and prednisone treatment. He responded well to VRD (bortezomib,
lenalidomide, and dexamethasone) regimen. Renal function, proteinuria, and
hemolysis all improved, and he was been in remission for more than 15 months. To
our knowledge, this is the first report of successful treatment with
bortezomib-based regimen for a patient with aHUS and monoclonal protein
refractory to eculizumab therapy.
DOI: 10.5414/CN108363
PMID: 25345382 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15795476 | 1. J Physiol Pharmacol. 2005 Mar;56(1):63-85.
Effect of moderate incremental exercise, performed in fed and fasted state on
cardio-respiratory variables and leptin and ghrelin concentrations in young
healthy men.
Zoladz JA(1), Konturek SJ, Duda K, Majerczak J, Sliwowski Z, Grandys M,
Bielanski W.
Author information:
(1)Department of Muscle Physiology, AWF-Krakow, Al. Jana Pawła II 78, 31-571
Cracow, Poland. [email protected]
BACKGROUND: Although hormonal responses to exercise performed in fed state are
well documented, far less in known about the effect of a single exercise bout,
performed after overnight fasting, on cardio-respiratory responses and hormones
secretion. It has been reported that recently discovered hormones as leptin and
ghrelin may affect cardiovascular responses at rest. However, their effect on
the cardiovascular responses to exercise is unknown.
AIMS: This study was designed to determine the effect of overnight fasting on
cardio- respiratory responses during moderate incremental exercise. We have
hypothesised that fasting / exercise induced changes in plasma leptin / ghrelin
concentrations may influence cardiovascular response.
MATERIAL AND METHODS: Eight healthy non-smoking men (means +/- SE.: age 23.0 +/-
0.5 years; body mass 71.9 +/- 1.5 kg; height 179.1 +/- 0.8 cm; BMI 22.42 +/-
0.49 kg x m(-2) with VO2max of 3.71 +/- 0.10 l x min(-1)) volunteered for this
study. The subjects performed twice an incremental exercise test, with the
increase of power output by 30 W every 3 minutes. Tests were performed in a
random order: once in the feed state--cycling until exhaustion and second, about
one week later, after overnight fasting--cycling until reaching 150 W.
RESULTS: In the present study we have compared the results obtained during
incremental exercise performed only up to 150 W (59 +/- 2 % of VO2max) both in
fed and fasted state. Heart rate measured during exercise at each power output,
performed in fasted state was by about 10 bt x min(-1) (p = 0.02) lower then in
fed subjects. Respiratory quotient and plasma lactate concentration in fasted
state were also significantly (p<0.001) lower than in the fed state.
Pre-exercise plasma leptin and ghrelin concentrations were not significantly
different in fed and fasted state. Exercise induced increase in hGH was not
accompanied by a significant changes in the studied gut hormones such as
ghrelin, leptin, and insulin, except for plasma gastrin concentration, which was
significantly (p = 0.008) lower in fasting subjects at the power output of 150
W. Plasma [IL-6] at rest before exercise performed in fasted state was
significantly (p = 0.03) elevated in relation to the fed state. This was
accompanied by significantly higher (p = 0.047) plasma noradrenaline
concentration. Plasma IL-6 concentration at rest in fed subjects was negatively
correlated with plasma ghrelin concentration (r = -0.73, p < 0.05) and
positively correlated with plasma insulin concentration (r = 0.78, p < 0.05).
Significant negative correlation (r = -0.90; p < 0.05) was found between plasma
insulin and ghrelin concentration at rest in fed subjects.
CONCLUSIONS: We have concluded that plasma leptin and ghrelin concentrations
have no significant effect on the fasting-induced attenuation of heart rate
during exercise. We have postulated that this effect is caused by increased
plasma norepinephrine concentration, leading to the increase in systemic
vascular resistance and baroreceptor mediated vagal stimulation. Moreover we
believe, that the fasting-induced significant increase in plasma IL-6
concentration at rest, accompanied by higher plasma norepinephrine concentration
and lower RQ, belongs to the physiological responses, maintaining energy
homeostasis in the fasting state.
PMID: 15795476 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22619704 | 1. J Obes. 2012;2012:730409. doi: 10.1155/2012/730409. Epub 2012 Apr 29.
Influence of running and walking on hormonal regulators of appetite in women.
Larson-Meyer DE(1), Palm S, Bansal A, Austin KJ, Hart AM, Alexander BM.
Author information:
(1)Department of Family and Consumer Sciences, University of Wyoming, Laramie,
WY 82071, USA.
Nine female runners and ten walkers completed a 60 min moderate-intensity (70%
VO(2)max) run or walk, or 60 min rest in counterbalanced order. Plasma
concentrations of the orexogenic peptide ghrelin, anorexogenic peptides peptide
YY (PYY), glucagon-like peptide-1 (GLP-1), and appetite ratings were measured at
30 min interval for 120 min, followed by a free-choice meal. Both orexogenic and
anorexogenic peptides were elevated after running, but no changes were observed
after walking. Relative energy intake (adjusted for cost of exercise/rest) was
negative in the meal following running (-194 ± 206 kcal) versus walking (41 ±
196 kcal) (P = 0.015), although both were suppressed (P < 0.05) compared to rest
(299 ± 308 and 284 ± 121 kcal, resp.). The average rate of change in PYY and
GLP-1 over time predicted appetite in runners, but only the change in GLP-1
predicted hunger (P = 0.05) in walkers. Results provide evidence that
exercise-induced alterations in appetite are likely driven by complex changes in
appetite-regulating hormones rather than change in a single gut peptide.
DOI: 10.1155/2012/730409
PMCID: PMC3350972
PMID: 22619704 |
http://www.ncbi.nlm.nih.gov/pubmed/7487540 | 1. Arq Neuropsiquiatr. 1995 Jun;53(2):284-7. doi:
10.1590/s0004-282x1995000200019.
[Reversible cerebral changes in hemolytic-uremic syndrome].
[Article in Portuguese]
Santos AC(1), Siqueira Neto JI, Fabio SR.
Author information:
(1)Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto
(FMRP), Universidade de São Paulo (USP), Brasil.
The hemolytic-uremic syndrome is a pathology characterized by a triad consisting
of acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia,
with complications of the central nervous system arising in a considerable
number of cases. Altered cranial computerized tomography examinations usually
reveal cerebral infarctions. We present here two cases in which diffuse
hypodensity was observed in the white matter in addition to the infarcts. This
hypodensity was reversible after resolution of the acute phase of the disease,
as is also the case for the alterations described in uremic encephalopathy and
in hypertensive encephalopathy of other etiologies.
DOI: 10.1590/s0004-282x1995000200019
PMID: 7487540 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17064878 | 1. Genomics. 2007 Jan;89(1):113-23. doi: 10.1016/j.ygeno.2006.09.007. Epub 2006
Oct 24.
Connexin43 and the brain transcriptome of newborn mice.
Iacobas DA(1), Iacobas S, Spray DC.
Author information:
(1)Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY
10461, USA. [email protected]
Our previously reported cDNA array datasets from neonatal wild-type and Cx43-/-
(approved gene symbol Gja1) mouse brains were further analyzed to identify
underlying interlinkages in the brain transcriptome. The analysis revealed that
no gene cohort sharing either primary function or chromosomal location was
significantly altered (up-and down-regulation were roughly balanced) in Cx43-/-
brains, but each cohort exhibited significant perturbation of transcript
abundance proportions and reduced expression variability and coordination. By
comparing pairwise expression correlations of all genes with one another in
wild-type brains, we found genes exhibiting remarkable similarity or opposition
to the coordination profile (set of synergistically, antagonistically, and
independently expressed partners) of Cx43, one of the most similar being
pannexin1, a vertebrate homolog of invertebrate gap junction proteins. This
study indicates striking redundancy of expression controls over functional
pathways and suggests that certain genes may play roles similar to or opposite
that of Cx43 in organizing the brain transcriptome.
DOI: 10.1016/j.ygeno.2006.09.007
PMCID: PMC2651831
PMID: 17064878 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19158129 | 1. J Endocrinol. 2009 Apr;201(1):151-9. doi: 10.1677/JOE-08-0500. Epub 2009 Jan
21.
Changes in gut hormone levels and negative energy balance during aerobic
exercise in obese young males.
Ueda SY(1), Yoshikawa T, Katsura Y, Usui T, Nakao H, Fujimoto S.
Author information:
(1)Department of Sports Medicine, Osaka City University Graduate School of
Medicine, Osaka, Japan.
We examined whether changes in gut hormone levels due to a single bout of
aerobic exercise differ between obese young males and normal controls, and
attempted to determine the involvement of hormonal changes during exercise in
the regulation of energy balance (EB) in these obese subjects. Seven obese and
seven age-matched subjects of normal weight participated in exercise and rest
sessions. Subjects consumed a standardized breakfast that was followed by
constant cycling exercise at 50% VO(2max) or rest for 60 min. At lunch, a test
meal was presented, and energy intake (EI) and relative energy intake (REI) were
calculated. Blood samples were obtained at 30 min intervals during both sessions
for measurement of glucose, insulin, glucagon, ghrelin, peptide YY (PYY), and
glucagon-like peptide-1 (GLP-1). Plasma levels of PYY and GLP-1 were increased
by exercise, whereas plasma ghrelin levels were unaffected by exercise. The
areas under the curve (AUC) of the time courses of PYY and GLP-1 levels did not
significantly differ between the two groups. In contrast, EI and REI were
decreased by exercise in both groups, and energy deficit was significantly
larger in obese subjects than in normal controls. The present findings suggest
that short-term EB during a single exercise session might be regulated not by
increased amounts of these gut hormones per se.
DOI: 10.1677/JOE-08-0500
PMID: 19158129 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21680731 | 1. J Biol Chem. 2011 Aug 5;286(31):27494-505. doi: 10.1074/jbc.M111.224089. Epub
2011 Jun 16.
Dipeptidyl peptidases as survival factors in Ewing sarcoma family of tumors:
implications for tumor biology and therapy.
Lu C(1), Tilan JU, Everhart L, Czarnecka M, Soldin SJ, Mendu DR, Jeha D, Hanafy
J, Lee CK, Sun J, Izycka-Swieszewska E, Toretsky JA, Kitlinska J.
Author information:
(1)Department of Biochemistry and Molecular and Cellular Biology, Georgetown
University, Washington, DC 20057, USA.
Ewing sarcoma family of tumors (ESFT) is a group of aggressive pediatric
malignancies driven by the EWS-FLI1 fusion protein, an aberrant transcription
factor up-regulating specific target genes, such as neuropeptide Y (NPY) and its
Y1 and Y5 receptors (Y5Rs). Previously, we have shown that both exogenous NPY
and endogenous NPY stimulate ESFT cell death via its Y1 and Y5Rs. Here, we
demonstrate that this effect is prevented by dipeptidyl peptidases (DPPs), which
cleave NPY to its shorter form, NPY(3-36), not active at Y1Rs. We have shown
that NPY-induced cell death can be abolished by overexpression of DPPs and
enhanced by their down-regulation. Both NPY treatment and DPP blockade activated
the same cell death pathway mediated by poly(ADP-ribose) polymerase (PARP-1) and
apoptosis-inducing factor (AIF). Moreover, the decrease in cell survival induced
by DPP inhibition was blocked by Y1 and Y5R antagonists, confirming its
dependence on endogenous NPY. Interestingly, similar levels of NPY-driven cell
death were achieved by blocking membrane DPPIV and cytosolic DPP8 and DPP9.
Thus, this is the first evidence of these intracellular DPPs cleaving releasable
peptides, such as NPY, in live cells. In contrast, another membrane DPP,
fibroblast activation protein (FAP), did not affect NPY actions. In conclusion,
DPPs act as survival factors for ESFT cells and protect them from cell death
induced by endogenous NPY. This is the first demonstration that intracellular
DPPs are involved in regulation of ESFT growth and may become potential
therapeutic targets for these tumors.
DOI: 10.1074/jbc.M111.224089
PMCID: PMC3149342
PMID: 21680731 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8589282 | 1. J Am Soc Nephrol. 1995 Oct;6(4):1160-9. doi: 10.1681/ASN.V641160.
Recurrent hemolytic uremic syndrome in an adult renal allograft recipient:
current concepts and management.
Agarwal A(1), Mauer SM, Matas AJ, Nath KA.
Author information:
(1)Department of Medicine, University of Minnesota Medical School, Minneapolis,
USA.
Acute renal insufficiency in the setting of hemolysis and thrombocytopenia, a
triad that constitutes adult or pediatric hemolytic uremic syndrome, can be
associated with or triggered by diverse conditions such as
verocytotoxin-producing Escherichia coli, viral infections, pregnancy, malignant
hypertension, scleroderma, renal radiation, allograft rejection, lupus
erythematosus, and assorted medications such as mitomycin C, cyclosporine, and
oral contraceptives. Recurrent and de novo hemolytic uremic syndrome occur after
renal transplantation. Relapses are also common and probably reflect incomplete
resolution of the initial episode. The major differential diagnoses of hemolytic
uremic syndrome in the renal allograft include acute vascular rejection,
cyclosporine, FK506 or antilymphocyte antibody nephrotoxicity, and malignant
hypertension, all of which may display overlapping clinical and histologic
features with primary hemolytic uremic syndrome; in such instances, the exact
diagnosis may be quite difficult. It is possible that the risk of recurrence may
be reduced by proper timing of transplantation and suitable choice of
immunosuppressive agents. Intensive plasmapheresis in conjunction with fresh
frozen plasma and supportive management of renal failure may lessen mortality
and morbidity even in recurrent hemolytic uremic syndrome after transplantation.
DOI: 10.1681/ASN.V641160
PMID: 8589282 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22637579 | 1. J Biol Chem. 2012 Jul 27;287(31):26453-63. doi: 10.1074/jbc.M112.344887. Epub
2012 May 27.
The TGFβ receptor-interacting protein km23-1/DYNLRB1 plays an adaptor role in
TGFβ1 autoinduction via its association with Ras.
Jin Q(1), Ding W, Mulder KM.
Author information:
(1)Department of Biochemistry and Molecular Biology, Penn State Hershey College
of Medicine, Hershey, Pennsylvania 17033, USA.
We have previously elucidated the signaling events that are required for TGFβ1
autoinduction (Yue, J., and Mulder, K. M. (2000) J. Biol. Chem. 275,
30765-30773). Further, we have reported that the TGFβ receptor (TβR)-interacting
protein km23-1 plays an important role in TGFβ signal transduction (Jin, Q.,
Ding, W., and Mulder, K. M. (2007) J. Biol. Chem. 282, 19122-19132). Here we
examined the role of km23-1 in TGFβ1 autoinduction in TGFβ-sensitive epithelial
cells. siRNA blockade of km23-1 reduced TGFβ1 mRNA expression, as well as DNA
binding and transcriptional activation of the relevant activator protein-1 site
in the human TGFβ1 promoter. Further, knockdown of km23-1 inhibited
TGFβ-mediated activation of ERK and JNK, phosphorylation of c-Jun, and
transactivation of the c-Jun promoter. Sucrose gradient analyses indicate that
km23-1 was present in lipid rafts together with Ras and TβRII after TGFβ
treatment. Immunoprecipitation/blot analyses revealed the formation of a
TGFβ-inducible complex between Ras and km23-1 in vivo within minutes of TGFβ
addition. Moreover, we demonstrate for the first time that km23-1 is required
for Ras activation by TGFβ. Our results indicate that km23-1 is required for
TGFβ1 autoinduction through Smad2-independent Ras/ERK/JNK pathways. More
importantly, our findings demonstrate that km23-1 functions as a critical
adaptor coupling TβR activation to activation of Ras effector pathways
downstream.
DOI: 10.1074/jbc.M112.344887
PMCID: PMC3406728
PMID: 22637579 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23079622 | 1. Biochem Biophys Res Commun. 2012 Nov 23;428(3):333-8. doi:
10.1016/j.bbrc.2012.10.047. Epub 2012 Oct 15.
Role of km23-1 in RhoA/actin-based cell migration.
Jin Q(1), Pulipati NR, Zhou W, Staub CM, Liotta LA, Mulder KM.
Author information:
(1)Department of Biochemistry and Molecular Biology, Penn State Hershey College
of Medicine, PA 17033, USA.
km23-1 was originally identified as a TGFß receptor-interacting protein that
plays an important role in TGFß signaling. Moreover, km23-1 is actually part of
an ancient superfamily of NTPase-regulatory proteins, widely represented in
archaea and bacteria. To further elucidate the function of km23-1, we identified
novel protein interacting partners for km23-1 by using tandem affinity
purification (TAP) and tandem mass spectrometry (MS). Here we show that km23-1
interacted with a class of proteins involved in actin-based cell motility and
modulation of the actin cytoskeleton. We further showed that km23-1 modulates
the formation of a highly organized stress fiber network. More significantly, we
demonstrated that knockdown (KD) of km23-1 decreased RhoA activation in Mv1Lu
epithelial cells. Finally, our results demonstrated for the first time that
depletion of km23-1 inhibited cell migration of human colon carcinoma cells
(HCCCs) in wound-healing assays. Overall, our findings demonstrate that km23-1
regulates RhoA and motility-associated actin modulating proteins, suggesting
that km23-1 may represent a novel target for anti-metastatic therapy.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bbrc.2012.10.047
PMCID: PMC3513371
PMID: 23079622 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11321513 | 1. J Physiol Pharmacol. 2001 Mar;52(1):53-70.
Leptin, gastrointestinal and stress hormones in response to exercise in fasted
or fed subjects and before or after blood donation.
Sliwowski Z(1), Lorens K, Konturek SJ, Bielanski W, Zoładź JA.
Author information:
(1)Department of Physiology, University College of Medicine, Cracow, Poland.
Leptin, an ob gene product of adipocytes, plays a key role in the control of
food intake and energy expenditure but little is known about leptin response to
strenuous exercise in fasted and fed subjects or before and after blood
donation. This study was designed to determine the immediate effects of
strenuous exercise in healthy volunteers under fasting or fed conditions and
before and one day after blood donation (450 ml) on plasma levels of leptin and
gut hormones [gastrin, cholecystokinin (CCK), pancreatic polypeptide (PP) and
insulin], as well as on "stress" hormones (cortisol, catecholamines and growth
hormone. Two groups (A and B) of healthy non-smoking male volunteers were
studied. All subjects performed incremental exercise tests until exhaustion (up
to maximal oxygen uptake--VO2max), followed by 2 h of rest session. Group A
perfomed the tests on a treadmill, while group B on a cycloergometer. In group
A, one exercise was performed under fasting conditions and the second following
ingestion of a standard liquid meal. In group B, one exercise test was performed
as a control test and the second 24 h after blood donation (450 ml). Blood
samples were withdrawn 5 min before the start of the test, at the VO2max, and 2
h after finishing the exercise. No significant change in plasma teptin were
observed both immediately and 2 h after the exercise in fasted subjects, but
after the meal the plasma leptin at VO2max and 2 h after the test was
significantly higher, while after blood donation was significantly reduced. The
postprandial rise in plasma leptin was accompanied by a marked increment in gut
hormones; gastrin, CCK and PP and stress hormones such as norepinephrine,
cortisol and GH. These hormonal changes could contribute to the postprandial
rise in plasma leptin concentrations, while the fall of leptin after blood
donation could be attributed to the inadequate response of stress hormones and
autonomic nervous system to exhausting exercise. We conclude that strenuous
physical exercise; 1) fails to affect plasma leptin level but when performed
after meal but not after blood withdrawal it results in an increase and fall in
plasma leptin, and 2) the release of gut hormones (gastrin, CCK and PP) and
stress hormones (norepinephrine, cortisol, GH) increase immediately after
exercise independently of feeding or blood donation and 3) following blood
donation the strenuous exercise resulted in a marked reduction in the plasma
leptin, cortisol and GH concentrations, possibly due to the impairment in the
autonomic nervous control of these hormones.
PMID: 11321513 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16942616 | 1. Nutr Metab (Lond). 2006 Aug 30;3:34. doi: 10.1186/1743-7075-3-34.
Population variation and differences in serum leptin independent of adiposity: a
comparison of Ache Amerindian men of Paraguay and lean American male distance
runners.
Bribiescas RG(1), Hickey MS.
Author information:
(1)Reproductive Ecology Laboratory, Department of Anthropology, Yale University,
New Haven, CT 06520-8277, USA. [email protected]
BACKGROUND: Serum leptin variation is commonly associated with fat percentage
(%), body mass index (BMI), and activity. In this investigation, we report
population differences in mean leptin levels in healthy men as well as
associations with fat % and BMI that are independent of these factors and
reflect likely variation resulting from chronic environmental conditions.
METHODS: Serum leptin levels, fat %, and BMI were compared between lean American
distance runners and healthy Ache Native Americans of Paraguay. Mean levels were
compared as were the regressions between fat %, BMI, and leptin. Comparisons
were performed between male American distance runners (n = 13, mean age 32.2 +/-
9.2 SD) and highly active male New World indigenous population (Ache of
Paraguay, n = 20, mean age 32.8 +/- 9.2) in order to determine whether
significant population variation in leptin is evident in physically active
populations living under different ecological circumstances independent of
adiposity and BMI.
RESULTS: While the Ache were hypothesized to exhibit higher leptin due to
significantly greater adiposity (fat %, Ache 17.9 +/- 1.8 SD; runners 9.7 +/-
3.2, p < 0.0001), leptin levels were nonetheless significantly higher in
American runners (Ache 1.13 ng/ml +/- 0.38 SD; runners 2.19 +/- 1.15; p <
0.007). Significant differences in the association between leptin and fat % was
also evident between Ache and runner men. Although fat % was significantly
related with leptin in runners (r = 0.90, p < 0.0001) fat % was negatively
related in Ache men (r = -0.50, p < 0.03).
CONCLUSION: These results illustrate that chronic ecological conditions in
addition to activity are likely factors that contribute to population variation
in leptin levels and physiology. Population variation independent of adiposity
should be considered to be an important source of variation, especially in light
of ethnic and population differences in the incidence and etiology of obesity,
diabetes, and other metabolic conditions.
DOI: 10.1186/1743-7075-3-34
PMCID: PMC1564401
PMID: 16942616 |
http://www.ncbi.nlm.nih.gov/pubmed/25432979 | 1. J Neurointerv Surg. 2015 Feb;7(2):84-9. doi: 10.1136/neurintsurg-2014-011543.
Epub 2014 Nov 28.
A meta-analysis of prospective randomized controlled trials evaluating
endovascular therapies for acute ischemic stroke.
Fargen KM(1), Neal D(1), Fiorella DJ(2), Turk AS(3), Froehler M(4), Mocco J(5).
Author information:
(1)Department of Neurosurgery, University of Florida, Gainesville, Florida, USA.
(2)Cerebrovascular Center, Department of Neurosurgery, Stony Brook University
Medical Center, Stony Brook, NY, USA.
(3)Department of Radiology, Medical University of South Carolina, Charleston,
South Carolina, USA.
(4)Cerebrovascular Program, Vanderbilt University, Nashville, Tennessee, USA.
(5)Department of Neurosurgery, New York, New York, USA.
INTRODUCTION: A recent randomized controlled trial (RCT), the Multicenter
Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in
the Netherlands (MR CLEAN), demonstrated better outcomes with endovascular
treatment compared with medical therapy for acute ischemic stroke (AIS).
However, previous trials have provided mixed results regarding the efficacy of
endovascular treatment for AIS. A meta-analysis of all available trial data was
performed to summarize the available evidence.
METHODS: A literature search was performed to identify all prospective RCTs
comparing endovascular therapies with medical management for AIS. Two datasets
were created: (1) all patients randomized after confirmation of large vessel
occlusion (LVO) (consistent with the contemporary standard of practice at the
majority of centers); and (2) all patients with outcome data who underwent
randomization regardless of qualifying vascular imaging. The pre-specified
primary outcome measure was modified Rankin Scale score of 0-2 at 90 days. A
fixed-effect model was used to determine significance.
RESULTS: Five prospective RCTs comparing endovascular therapies with medical
management were included in dataset 1 (1183 patients) and six were included in
dataset 2 (1903 total patients). Endovascular therapies were associated with
significantly improved outcomes compared with medical management (OR 1.67, 95%
CI 1.29 to 1.16, p=0.0001) for patients with LVO (dataset 1). This benefit
persisted when patients from all six RCTs were included, even in the absence of
confirmation of LVO (OR 1.27, 95% CI 1.05 to 1.54, p=0.019; dataset 2).
CONCLUSIONS: A meta-analysis of prospective RCTs comparing endovascular
therapies with medical management demonstrates superior outcomes in patients
randomized to endovascular therapy.
Published by the BMJ Publishing Group Limited. For permission to use (where not
already granted under a licence) please go to
http://group.bmj.com/group/rights-licensing/permissions.
DOI: 10.1136/neurintsurg-2014-011543
PMID: 25432979 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18987287 | 1. Am J Physiol Regul Integr Comp Physiol. 2009 Jan;296(1):R29-35. doi:
10.1152/ajpregu.90706.2008. Epub 2008 Nov 5.
Influence of resistance and aerobic exercise on hunger, circulating levels of
acylated ghrelin, and peptide YY in healthy males.
Broom DR(1), Batterham RL, King JA, Stensel DJ.
Author information:
(1)Department of Medicine, School of Sport and Exercise Sciences, Loughborough
Univ., Leicestershire, LE11 3TU, UK.
Resistance (muscle strengthening) exercise is a key component of exercise
recommendations for weight control, yet very little is known about the effects
of resistance exercise on appetite. We investigated the effects of resistance
and aerobic exercise on hunger and circulating levels of the gut hormones
acylated ghrelin and peptide YY (PYY). Eleven healthy male students: age 21.1
+/- 0.3 yr, body mass index 23.1 +/- 0.4 kg/m(2), maximum oxygen uptake 62.1 +/-
1.8 ml.kg(-1).min(-1) (means +/- SE) undertook three, 8-h trials, 1) resistance
exercise: a 90-min free weight lifting session followed by a 6.5-h rest period,
2) aerobic exercise: a 60-min run followed by a 7-h rest period, 3) control: an
8-h rest, in a randomized crossover design. Meals were provided 2 and 5 h into
each trial. Hunger ratings and plasma concentrations of acylated ghrelin and PYY
were measured throughout. Two-way ANOVA revealed significant (P < 0.05)
interaction effects for hunger, acylated ghrelin, and PYY, indicating suppressed
hunger and acylated ghrelin during aerobic and resistance exercise and increased
PYY during aerobic exercise. A significant trial effect was observed for PYY,
indicating higher concentrations on the aerobic exercise trial than the other
trials (8 h area under the curve: control 1,411 +/- 110, resistance 1,381 +/-
97, aerobic 1,750 +/- 170 pg/ml 8 h). These findings suggest ghrelin and PYY may
regulate appetite during and after exercise, but further research is required to
establish whether exercise-induced changes in ghrelin and PYY influence
subsequent food intake.
DOI: 10.1152/ajpregu.90706.2008
PMID: 18987287 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20690071 | 1. Exp Clin Endocrinol Diabetes. 2011 Mar;119(3):163-6. doi:
10.1055/s-0030-1262790. Epub 2010 Aug 5.
Effects of exercise on the levels of peptide YY and ghrelin.
Li JB(1), Asakawa A, Li Y, Cheng K, Inui A.
Author information:
(1)Department of Psychosomatic Internal Medicine, Kagoshima University Graduate
School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan.
Ghrelin and peptide YY (PYY) are brain-gut peptides that have a variety of
physiological functions and are involved in energy regulation. Thus far,
abnormalities in the expression and secretion of ghrelin and PYY are known to
occur in lifestyle-related diseases, including obesity, and the improvement of
these abnormalities has become an important challenge. Exercise has recently
been reported to influence ghrelin and PYY concentrations. Exercise increases
the PYY secretion. The effects of exercise on ghrelin levels vary with the study
subject, timing of exercise, and duration of exercise. Here, we review the
findings of recent studies on the association of PYY and ghrelin with obesity,
particularly, on the influence of exercise on PYY and ghrelin levels.
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.
DOI: 10.1055/s-0030-1262790
PMID: 20690071 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19571232 | 1. Am J Physiol Gastrointest Liver Physiol. 2009 Sep;297(3):G480-7. doi:
10.1152/ajpgi.00154.2009. Epub 2009 Jul 1.
Identification of dynein light chain road block-1 as a novel interaction partner
with the human reduced folate carrier.
Ashokkumar B(1), Nabokina SM, Ma TY, Said HM.
Author information:
(1)Department of Medical Research, Veterans Affairs Medical Center, Long Beach,
California 90822, USA.
The reduced folate carrier (RFC) is a major folate transport system in mammalian
cells. RFC is highly expressed in the intestine and believed to play a role in
folate absorption. Studies from our laboratory and others have characterized
different aspects of the intestinal folate absorption process, but little is
known about possible existence of accessory protein(s) that interacts with RFC
and influences its physiology and/or cell biology. We investigated this issue by
employing a bacterial two-hybrid system to screen a BacterioMatch II human
intestinal cDNA library using the large intracellular loop between transmembrane
domains 6 and 7 of the human RFC (hRFC) as bait. Our screening has resulted in
the identification of dynein light chain road block-1 (DYNLRB1) as an
interacting partner with hRFC. Existence of a direct protein-protein interaction
between hRFC and DYNLRB1 was confirmed by in vitro pull-down assay and in vivo
mammalian two-hybrid luciferase assay and coimmunoprecipitation analysis.
Furthermore, confocal imaging of live human intestinal epithelial HuTu-80 cells
demonstrated colocalization of DYNLRB1 with hRFC. Coexpression of DYNLRB1 with
hRFC led to a significant (P < 0.05) increase in folate uptake. On the other
hand, inhibiting the endogenous DYNLRB1 with gene-specific small interfering RNA
or pharmacologically with a specific inhibitor (vanadate) led to a significant
(P < 0.05) decrease in folate uptake. This study demonstrates for the first time
the identification of DYNLRB1 as an interacting protein partner with hRFC.
Furthermore, DYNLRB1 appears to influence the function and cell biology of hRFC.
DOI: 10.1152/ajpgi.00154.2009
PMCID: PMC2739825
PMID: 19571232 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19625716 | 1. N Engl J Med. 2009 Jul 23;361(4):345-57. doi: 10.1056/NEJMoa0810739.
Thrombomodulin mutations in atypical hemolytic-uremic syndrome.
Delvaeye M(1), Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero
J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM.
Author information:
(1)VIB-K.U.Leuven Vesalius Research Center, Leuven, Belgium.
Comment in
N Engl J Med. 2009 Oct 8;361(15):1511; author reply 1511. doi:
10.1056/NEJMc091704.
BACKGROUND: The hemolytic-uremic syndrome consists of the triad of
microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The
common form of the syndrome is triggered by infection with Shiga toxin-producing
bacteria and has a favorable outcome. The less common form of the syndrome,
called atypical hemolytic-uremic syndrome, accounts for about 10% of cases, and
patients with this form of the syndrome have a poor prognosis. Approximately
half of the patients with atypical hemolytic-uremic syndrome have mutations in
genes that regulate the complement system. Genetic factors in the remaining
cases are unknown. We studied the role of thrombomodulin, an endothelial
glycoprotein with anticoagulant, antiinflammatory, and cytoprotective
properties, in atypical hemolytic-uremic syndrome.
METHODS: We sequenced the entire thrombomodulin gene (THBD) in 152 patients with
atypical hemolytic-uremic syndrome and in 380 controls. Using purified proteins
and cell-expression systems, we investigated whether thrombomodulin regulates
the complement system, and we characterized the mechanisms. We evaluated the
effects of thrombomodulin missense mutations associated with atypical
hemolytic-uremic syndrome on complement activation by expressing thrombomodulin
variants in cultured cells.
RESULTS: Of 152 patients with atypical hemolytic-uremic syndrome, 7 unrelated
patients had six different heterozygous missense THBD mutations. In vitro,
thrombomodulin binds to C3b and factor H (CFH) and negatively regulates
complement by accelerating factor I-mediated inactivation of C3b in the presence
of cofactors, CFH or C4b binding protein. By promoting activation of the plasma
procarboxypeptidase B, thrombomodulin also accelerates the inactivation of
anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin variants
associated with atypical hemolytic-uremic syndrome had diminished capacity to
inactivate C3b and to activate procarboxypeptidase B and were thus less
protected from activated complement.
CONCLUSIONS: Mutations that impair the function of thrombomodulin occur in about
5% of patients with atypical hemolytic-uremic syndrome.
2009 Massachusetts Medical Society
DOI: 10.1056/NEJMoa0810739
PMCID: PMC3530919
PMID: 19625716 [Indexed for MEDLINE]
Conflict of interest statement: Drs. C.T. Esmon and N.L. Esmon report holding
licenses and patents related to protein C and activated protein C that are
unrelated to this article; and Dr. Conway, holding a patent for the use of the
lectinlike domain of thrombomodulin as an antiinflammatory agent. No other
potential conflict of interest relevant to this article was reported. |
http://www.ncbi.nlm.nih.gov/pubmed/21927572 | 1. J Sports Sci Med. 2009 Dec 1;8(4):574-583.
Effects of endurance running and dietary fat on circulating ghrelin and peptide
YY.
Russel RR(1), Willis KS, Ravussin E, Larson-Meyer ED.
Author information:
(1)Pennington Biomedical Research Center, Louisiana State University, Baton
Rouge, LA.
Ghrelin and peptide YY (PYY) are newly recognized gut peptides involved in
appetite regulation. Plasma ghrelin concentrations are elevated in fasting and
suppressed following a meal, while PYY concentrations are suppressed in fasting
and elevated postprandially. We determine whether ghrelin and PYY are altered by
a low-fat, high-carbohydrate (10% fat, 75% carbohydrate) or moderate-fat,
moderate-carbohydrate (35% fat, 50% carbohydrate) diet and; whether these
peptides are affected by intense endurance running (which is likely to
temporarily suppress appetite). Twenty-one endurance-trained runners followed a
controlled diet (25% fat) and training regimen for 3 days before consuming the
low-fat or isoenergetic moderate-fat diet for another 3 days in random
cross-over fashion. On day 7 runners underwent glycogen restoration and then
completed a 90-minute pre-loaded 10-km time trial on day 8, following a control
breakfast. Blood samples were obtained on days 4 and 7 (fasting), and day 8
(non-fasting) before and after exercise for analysis of ghrelin, PYY, insulin
and growth hormone (GH). Insulin, GH, Ghrelin and PYY changed significantly over
time (p < 0.0001) but were not influenced by diet. Ghrelin was elevated during
fasting (days 4 and 7), while insulin and PYY were suppressed. Following the
pre-exercise meal, ghrelin was suppressed ~17% and insulin and PYY were elevated
~157 and ~40%, respectively, relative to fasting (day 7). Following exercise,
PYY, ghrelin, and GH were significantly (p < 0.0001) increased by ~11, ~16 and
~813%, respectively. The noted disruption in the typical inverse relationship
between ghrelin and PYY following exercise suggests that interaction of these
peptides may be at least partially responsible for post-exercise appetite
suppression. These peptides do not appear to be influenced by dietary fat
intake.
PMCID: PMC3172724
PMID: 21927572 |
http://www.ncbi.nlm.nih.gov/pubmed/24056933 | 1. Nature. 2013 Nov 21;503(7476):360-4. doi: 10.1038/nature12632. Epub 2013 Sep
22.
Nanog, Pou5f1 and SoxB1 activate zygotic gene expression during the
maternal-to-zygotic transition.
Lee MT(1), Bonneau AR, Takacs CM, Bazzini AA, DiVito KR, Fleming ES, Giraldez
AJ.
Author information:
(1)1] Department of Genetics, Yale University School of Medicine, New Haven,
Connecticut 06510, USA [2].
After fertilization, maternal factors direct development and trigger zygotic
genome activation (ZGA) at the maternal-to-zygotic transition (MZT). In
zebrafish, ZGA is required for gastrulation and clearance of maternal messenger
RNAs, which is in part regulated by the conserved microRNA miR-430. However, the
factors that activate the zygotic program in vertebrates are unknown. Here we
show that Nanog, Pou5f1 (also called Oct4) and SoxB1 regulate zygotic gene
activation in zebrafish. We identified several hundred genes directly activated
by maternal factors, constituting the first wave of zygotic transcription.
Ribosome profiling revealed that nanog, sox19b and pou5f1 are the most highly
translated transcription factors pre-MZT. Combined loss of these factors
resulted in developmental arrest before gastrulation and a failure to activate
>75% of zygotic genes, including miR-430. Our results demonstrate that maternal
Nanog, Pou5f1 and SoxB1 are required to initiate the zygotic developmental
program and induce clearance of the maternal program by activating miR-430
expression.
DOI: 10.1038/nature12632
PMCID: PMC3925760
PMID: 24056933 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25179366 | 1. Trials. 2014 Sep 1;15:343. doi: 10.1186/1745-6215-15-343.
MR CLEAN, a multicenter randomized clinical trial of endovascular treatment for
acute ischemic stroke in the Netherlands: study protocol for a randomized
controlled trial.
Fransen PS, Beumer D, Berkhemer OA, van den Berg LA, Lingsma H, van der Lugt A,
van Zwam WH, van Oostenbrugge RJ, Roos YB, Majoie CB, Dippel DW(1); MR CLEAN
Investigators.
Collaborators: Dippel DW, Brouwer PA, Roos YB, Majoie CB, van Oostenbrugge RJ,
van Zwam WH, Boiten J, Lycklama à Nijeholt GJ, Wermer MJ, van Walderveen MA,
Kappelle LJ, Lo RT, van Dijk EJ, de Vries J, Schonewille WJ, Vos JA, Hofmeijer
J, van Oostayen JA, Vroomen PC, Eshghi O, de Kort PL, van Rooij WJ, Keizer K,
Tielbeek X, de Bruijn BF, van Dijk LC, van den Bergh JS, van Hasselt BA, Aerden
LA, Dallinga RJ, Schreuder TH, Heijboer RJ, den Hertog HM, Gerrits DG, Visser
MC, Bot JC, Dippel DW, van der Lugt A, Majoie CB, Roos YB, van Oostenbrugge RJ,
van Zwam WH, Majoie CB, van Zwam WH, Lycklama à Nijeholt GJ, van Walderveen MA,
Bot JC, Marquering HA, Beenen LF, Sprengers M, Jenniskens S, van den Berg R, van
der Lugt A, Yoo AJ, Roos YB, Koudstaal PJ, Boiten J, van Dijk EJ, van
Oostenbrugge RJ, Wermer MJ, Flach HZ, Fransen P, Beumer D, Berkhemer O, van den
Berg L, Steyerberg E, Lingsma HF, Brown M, Liebig T, Stijnen T, van der Heijden
ES, Fleitour NM.
Author information:
(1)Department of Neurology, Erasmus MC University Medical Center, PO Box 2040,
3000 CA, Rotterdam, the Netherlands. [email protected].
BACKGROUND: Endovascular or intra-arterial treatment (IAT) increases the
likelihood of recanalization in patients with acute ischemic stroke caused by a
proximal intracranial arterial occlusion. However, a beneficial effect of IAT on
functional recovery in patients with acute ischemic stroke remains unproven. The
aim of this study is to assess the effect of IAT on functional outcome in
patients with acute ischemic stroke. Additionally, we aim to assess the safety
of IAT, and the effect on recanalization of different mechanical treatment
modalities.
METHODS/DESIGN: A multicenter randomized clinical trial with blinded outcome
assessment. The active comparison is IAT versus no IAT. IAT may consist of
intra-arterial thrombolysis with alteplase or urokinase, mechanical treatment or
both. Mechanical treatment refers to retraction, aspiration, sonolysis, or use
of a retrievable stent (stent-retriever). Patients with a relevant intracranial
proximal arterial occlusion of the anterior circulation, who can be treated
within 6 hours after stroke onset, are eligible. Treatment effect will be
estimated with ordinal logistic regression (shift analysis); 500 patients will
be included in the trial for a power of 80% to detect a shift leading to a
decrease in dependency in 10% of treated patients. The primary outcome is the
score on the modified Rankin scale at 90 days. Secondary outcomes are the
National Institutes of Health stroke scale score at 24 hours, vessel patency at
24 hours, infarct size on day 5, and the occurrence of major bleeding during the
first 5 days.
DISCUSSION: If IAT leads to a 10% absolute reduction in poor outcome after
stroke, careful implementation of the intervention could save approximately 1%
of all new stroke cases from death or disability annually.
TRIAL REGISTRATION: NTR1804 (7 May 2009)/ISRCTN10888758 (24 July 2012).
DOI: 10.1186/1745-6215-15-343
PMCID: PMC4162915
PMID: 25179366 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23507008 | 1. J Pediatr Adolesc Gynecol. 2013 Jun;26(3):171-5. doi:
10.1016/j.jpag.2012.12.006. Epub 2013 Mar 16.
Prevalence of pain syndromes, mood conditions, and asthma in adolescents and
young women with endometriosis.
Smorgick N(1), Marsh CA, As-Sanie S, Smith YR, Quint EH.
Author information:
(1)Department of Obstetrics and Gynecology, University of Michigan Health
System, Ann Arbor, Michigan 48109, USA. [email protected]
STUDY OBJECTIVE: Adult women with endometriosis are often diagnosed with
comorbid pain, mood, and autoimmune conditions. This study aims to describe the
occurrence of pain syndromes, mood conditions, and asthma in adolescents and
young women with endometriosis evaluated at our medical center.
DESIGN: Retrospective review of medical records.
SETTING: Department of Obstetrics and Gynecology at a tertiary referral center.
PARTICIPANTS: 138 adolescents/young women who were less than age 24 years at the
time of their initial visit at our medical center, and whose surgical diagnosis
of endometriosis was made at our institution or by outside institutions by the
age of 21.
INTERVENTIONS: None.
MAIN OUTCOME MEASURES: Prevalence of comorbid pain syndromes (defined as
interstitial cystitis, irritable bowel syndrome, chronic headaches, chronic low
back pain, vulvodynia, fibromyalgia, temporomandibular joint disease, and
chronic fatigue syndrome), mood conditions (defined as depression and anxiety),
and asthma.
RESULTS: Comorbid pain syndromes were found in 77 (56%) women, mood conditions
in 66 (48%) women, and asthma in 31 (26%) women. Comparing endometriosis
patients with and without comorbid pain syndromes, no differences were found in
age at time of diagnosis, endometriosis symptoms, and endometriosis stage.
Patients with comorbid pain syndromes were more likely to report mood conditions
(62% vs 30% respectively, P < .001) and smoking (31% vs 10% respectively, P =
.003), underwent more surgeries for endometriosis (median of 2 [range, 1-7] vs 1
[range, 1-5], P < .005), and were more likely to undergo appendectomy or
cholecystectomy (30% vs 13%, P = .02).
CONCLUSIONS: Comorbid pain syndromes, mood conditions and asthma are common in
adolescents and young women with endometriosis.
Copyright © 2013 North American Society for Pediatric and Adolescent Gynecology.
Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jpag.2012.12.006
PMID: 23507008 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25517348 | 1. N Engl J Med. 2015 Jan 1;372(1):11-20. doi: 10.1056/NEJMoa1411587. Epub 2014
Dec 17.
A randomized trial of intraarterial treatment for acute ischemic stroke.
Berkhemer OA(1), Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ,
Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ, van Walderveen MA, Staals J,
Hofmeijer J, van Oostayen JA, Lycklama à Nijeholt GJ, Boiten J, Brouwer PA,
Emmer BJ, de Bruijn SF, van Dijk LC, Kappelle LJ, Lo RH, van Dijk EJ, de Vries
J, de Kort PL, van Rooij WJ, van den Berg JS, van Hasselt BA, Aerden LA,
Dallinga RJ, Visser MC, Bot JC, Vroomen PC, Eshghi O, Schreuder TH, Heijboer RJ,
Keizer K, Tielbeek AV, den Hertog HM, Gerrits DG, van den Berg-Vos RM, Karas GB,
Steyerberg EW, Flach HZ, Marquering HA, Sprengers ME, Jenniskens SF, Beenen LF,
van den Berg R, Koudstaal PJ, van Zwam WH, Roos YB, van der Lugt A, van
Oostenbrugge RJ, Majoie CB, Dippel DW; MR CLEAN Investigators.
Collaborators: Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF,
Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ, van Walderveen MA,
Staals J, Hofmeijer J, van Oostayen JA, Lycklama à Nijeholt GJ, Boiten J,
Brouwer PA, Emmer BJ, de Bruijn SF, van Dijk LC, Kappelle LJ, Lo RH, van Dijk
EJ, de Vries J, de Kort PL, van Rooij WJ, van den Berg JS, van Hasselt BA,
Aerden LA, Dallinga RJ, Visser MC, Bot JC, Vroomen PC, Eshghi O, Schreuder TH,
Heijboer RJ, Keizer K, Tielbeek AV, den Hertog HM, Gerrits DG, van den Berg-Vos
RM, Karas GB, Steyerberg EW, Flach HZ, Marquering HA, Sprengers ME, Jenniskens
SF, Beenen LF, van den Berg R, Koudstaal PJ, van Zwam WH, Roos YB, van der Lugt
A, van Oostenbrugge RJ, Majoie CB, Dippel DW, Brown MM, Liebig T, Stijnen T,
Andersson T, Mattle H, Wahlgren N, van der Heijden E, Ghannouti N, Fleitour N,
Hooijenga I, Puppels C, Pellikaan W, Geerling A, Lindl-Velema A, van Vemde G,
Klinieken I, de Ridder A, Greebe P, de Bont-Stikkelbroeck J, de Meris J, Janssen
K, Struijk W, Licher S, Boodt N, Ros A, Venema E, Slokkers I, Ganpat RJ, Mulder
M, Saiedie N, Heshmatollah A, Schipperen S, Vinken S, van Boxtel T, Koets J,
Boers M, Santos E, Borst J, Jansen I, Kappelhof M, Lucas M, Geuskens R, Barros
RS, Dobbe R, Csizmadia M.
Author information:
(1)The authors' affiliations are listed in the Appendix.
Erratum in
N Engl J Med. 2015 Jan 22;372(4):394.
Comment in
N Engl J Med. 2015 Jan 1;372(1):76-7. doi: 10.1056/NEJMe1413346.
N Engl J Med. 2015 Mar 19;372(12):1178-9. doi: 10.1056/NEJMc1501204.
N Engl J Med. 2015 Mar 19;372(12):1176. doi: 10.1056/NEJMc1501204.
N Engl J Med. 2015 Mar 19;372(12):1176-7. doi: 10.1056/NEJMc1501204.
N Engl J Med. 2015 Mar 19;372(12):1177. doi: 10.1056/NEJMc1501204.
N Engl J Med. 2015 Mar 19;372(12):1177-8. doi: 10.1056/NEJMc1501204.
N Engl J Med. 2015 Mar 19;372(12):1178. doi: 10.1056/NEJMc1501204.
J R Coll Physicians Edinb. 2015 Mar;45(1):43-4. doi: 10.4997/JRCPE.2015.110.
Ann Intern Med. 2015 May 19;162(10):JC2-4. doi:
10.7326/ACPJC-2015-162-10-002.
Evid Based Med. 2015 Dec;20(6):209. doi: 10.1136/ebmed-2015-110187.
Am J Respir Crit Care Med. 2016 Jan 15;193(2):210-2. doi:
10.1164/rccm.201506-1152RR.
BACKGROUND: In patients with acute ischemic stroke caused by a proximal
intracranial arterial occlusion, intraarterial treatment is highly effective for
emergency revascularization. However, proof of a beneficial effect on functional
outcome is lacking.
METHODS: We randomly assigned eligible patients to either intraarterial
treatment plus usual care or usual care alone. Eligible patients had a proximal
arterial occlusion in the anterior cerebral circulation that was confirmed on
vessel imaging and that could be treated intraarterially within 6 hours after
symptom onset. The primary outcome was the modified Rankin scale score at 90
days; this categorical scale measures functional outcome, with scores ranging
from 0 (no symptoms) to 6 (death). The treatment effect was estimated with
ordinal logistic regression as a common odds ratio, adjusted for prespecified
prognostic factors. The adjusted common odds ratio measured the likelihood that
intraarterial treatment would lead to lower modified Rankin scores, as compared
with usual care alone (shift analysis).
RESULTS: We enrolled 500 patients at 16 medical centers in The Netherlands (233
assigned to intraarterial treatment and 267 to usual care alone). The mean age
was 65 years (range, 23 to 96), and 445 patients (89.0%) were treated with
intravenous alteplase before randomization. Retrievable stents were used in 190
of the 233 patients (81.5%) assigned to intraarterial treatment. The adjusted
common odds ratio was 1.67 (95% confidence interval [CI], 1.21 to 2.30). There
was an absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2) in
the rate of functional independence (modified Rankin score, 0 to 2) in favor of
the intervention (32.6% vs. 19.1%). There were no significant differences in
mortality or the occurrence of symptomatic intracerebral hemorrhage.
CONCLUSIONS: In patients with acute ischemic stroke caused by a proximal
intracranial occlusion of the anterior circulation, intraarterial treatment
administered within 6 hours after stroke onset was effective and safe. (Funded
by the Dutch Heart Foundation and others; MR CLEAN Netherlands Trial Registry
number, NTR1804, and Current Controlled Trials number, ISRCTN10888758.).
DOI: 10.1056/NEJMoa1411587
PMID: 25517348 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24330796 | 1. Ned Tijdschr Geneeskd. 2013;157(38):A6409.
[Intra-arterial treatment of ischemic stroke--still no evidence but reason for
further study].
[Article in Dutch]
Dippel DW(1), Boiten J, Vos JA, Majoie CB.
Author information:
(1)*Mede namens de Sectie Neuroradiologie van de Nederlandse Vereniging voor
Radiologie, de Kerncommissie van het Nederlands Neurovasculair Genootschap, het
Nederlands Genootschap voor Interventie Radiologie en de Nederlandse
Neurovasculaire Werkgroep.
In 3 recent randomized controlled trials of intra-arterial treatment of acute
ischemic stroke - IMS-III, SYNTHESIS and MR RESCUE - intra-arterial treatment
increased the proportion of patients with recanalization and the treatment
appeared safe. However, the trials did not show an effect on functional
recovery, although a substantial effect could not be excluded. The delay between
onset of symptoms and treatment was long, and stent retrievers were used in only
a few patients. In our view, a rational and ethical approach would now be to
treat quickly with IV rtPA and when possible, refer and include in new
randomized clinical trials that compare intra-arterial treatment with standard
care, such as MR CLEAN or BASICS in the Netherlands.
PMID: 24330796 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15341718 | 1. Curr Gastroenterol Rep. 2004 Oct;6(5):405-9. doi: 10.1007/s11894-004-0058-6.
Intestinal endometriosis: the great masquerader.
Skoog SM(1), Foxx-Orenstein AE, Levy MJ, Rajan E, Session DR.
Author information:
(1)Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience
Translational and Epidemiologic Research Program, Enteric Neuroscience Program,
Mayo Clinic and Foundation, Charlton 8, 200 First Street SW, Rochester, MN
55905, USA.
Chronic symptoms of abdominal pain and irregular bowel habits in women evoke a
broad differential diagnosis including irritable bowel syndrome, infection,
malabsorption, and inflammatory bowel disease. Endometriosis, a common disorder
in young women that can involve the intestinal tract, deserves consideration as
well. Intestinal endometriosis is typically asymptomatic; however, when symptoms
occur, they can mimic those of irritable bowel syndrome. Identifying intestinal
endometriosis can be challenging, but historical points and key clinical
features aid in diagnosis.
DOI: 10.1007/s11894-004-0058-6
PMID: 15341718 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20061436 | 1. J Clin Endocrinol Metab. 2010 Mar;95(3):1045-53. doi: 10.1210/jc.2009-1005.
Epub 2010 Jan 8.
Regulation of energy balance during long-term physical inactivity induced by bed
rest with and without exercise training.
Bergouignan A(1), Momken I, Schoeller DA, Normand S, Zahariev A, Lescure B,
Simon C, Blanc S.
Author information:
(1)Institut Pluridisciplinaire Hubert Curien, Département d'Ecologie,
Physiologie, et Ethologie, Université de Strasbourg, Centre National de la
Recherche Scientifique, 23 Rue Becquerel, 67087 Strasbourg, France.
BACKGROUND: Short-term physical inactivity affects energy balance and is
considered conducive to weigh gain. Long-term effects are unknown.
OBJECTIVE: The objective of the study was to use a bed-rest model to determine
the long-term effects of physical inactivity on energy balance regulation and
test the effect of exercise training on energy balance adjustment to physical
inactivity.
DESIGN: Sixteen lean women were divided into two groups (n = 8 each): a control
group subjected to a strict 60-d bed rest and an exercise group subjected to a
combined aerobic/resistive exercise training concomitantly to bed rest. Body
composition, spontaneous energy intake, hunger, total energy expenditure (TEE),
and fasting gut hormones were measured.
RESULTS: Based on bed-rest-induced body composition changes, the control group
were in slight negative energy balance (-0.4 +/- 0.4 MJ/d; P = 0.01 vs. zero),
essentially due to muscle atrophy (P < 0.001 vs. zero). The stable fat mass (P =
0.19 vs. zero), and the matching between spontaneous energy intake and TEE
indicated, however, a stable energy balance. Hunger and gut hormones remained
unchanged during the bed rest. In the exercise group, TEE was 24% higher than in
the control group (P = 0.004). Unexpectedly, desire to consume food (P = 0.025)
decreased and spontaneous energy intake (P = NS) was not stimulated, promoting a
negative energy balance (-1.1 +/- 0.5 MJ/d, P = 0.0003 vs. zero).
CONCLUSIONS: Energy balance is regulated during 2 months of physical inactivity,
contrasting with short-term experiments. Conversely, exercise-induced energy
expenditure in bed-resting subjects who have no spontaneous physical activity
did not induce hunger and promoted a negative energy balance, suggesting a
potential role of nonexercise physical activities in energy balance regulation.
DOI: 10.1210/jc.2009-1005
PMID: 20061436 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19694698 | 1. Aust N Z J Obstet Gynaecol. 2009 Aug;49(4):411-4. doi:
10.1111/j.1479-828X.2009.01030.x.
Relevance of gastrointestinal symptoms in endometriosis.
Maroun P(1), Cooper MJ, Reid GD, Keirse MJ.
Author information:
(1)Department of Endogynaecology, Royal Prince Alfred Hospital, Sydney, New
South Wales, Australia. [email protected]
BACKGROUND: Endometriosis commonly presents with a range of symptoms none of
which are particularly specific for the condition, often resulting in
misdiagnosis or delay in diagnosis.
AIM: To investigate gastrointestinal symptoms in women with endometriosis and
compare their frequency with that of the classical gynaecological symptoms.
METHODS: Systematic exploration of symptoms in a consecutive series of 355 women
undergoing operative laparoscopy for suspected endometriosis.
RESULTS: Endometriosis was confirmed by histology in 290 women (84.5%). Bowel
lesions were present in only 7.6%. Ninety per cent of women had gastrointestinal
symptoms, of which bloating was the most common (82.8%), but 71.3% also had
other bowel symptoms. All gastrointestinal symptoms were similarly predictive of
histologically confirmed endometriosis. Seventy-six women (21.4%) had previously
been diagnosed with irritable bowel syndrome and 79% of them had endometriosis
confirmed.
CONCLUSION: Gastrointestinal symptoms are nearly as common as gynaecological
symptoms in women with endometriosis and do not necessarily reflect bowel
involvement.
DOI: 10.1111/j.1479-828X.2009.01030.x
PMID: 19694698 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18478547 | 1. J Neurosci Res. 2008 Sep;86(12):2746-52. doi: 10.1002/jnr.21714.
Inflammation in the uterus induces phosphorylated extracellular signal-regulated
kinase and substance P immunoreactivity in dorsal root ganglia neurons
innervating both uterus and colon in rats.
Li J(1), Micevych P, McDonald J, Rapkin A, Chaban V.
Author information:
(1)Department of Anesthesiology, Harbor-UCLA Medical Center, Los Angeles,
California, USA.
In women, clinical studies suggest that pain syndromes such as irritable bowel
syndrome and interstitial cystitis, which are associated with visceral
hyperalgesia, are often comorbid with endometriosis and chronic pelvic pain. One
of the possible explanations for this phenomenon is viscerovisceral
cross-sensitization, in which increased nociceptive input from an inflamed
pelvic organ sensitizes neurons that receive convergent input to the same dorsal
root ganglion (DRG) from an unaffected visceral organ. Nociception induces
up-regulation of cellular mechanisms such as phosphorylated extracellular
signal-regulated kinase (pERK) and substance P (SP), neurotransmitters
associated with induced pain sensation. The purpose of this study was to
determine, in a rodent model, whether uterine inflammation increased the number
of pERK- and SP-positive neurons that received input from both the uterus and
the colon. Cell bodies of colonic and uterine DRG were retrogradely labeled with
fluorescent tracer dyes microinjected into the colon/rectum and into the uterus.
Ganglia were harvested for fluorescent microscopy to identify positively stained
neurons. Approximately 6% of neurons were colon specific and 10% uterus
specific. Among these uterus- or colon-specific neurons, up to 3-5% of DRG
neurons in the lumbosacral neurons (L1-S3 levels) received input from both
visceral organs. Uterine inflammation increased the number of pERK- and
SP-immunoreactive DRG neurons innervating specifically colon, or innervating
specifically uterus, and those innervating both organs. These results suggest
that a localized inflammation activates primary visceral afferents, regardless
of whether they innervate the affected organ. This visceral sensory integration
in the DRG may underlie the observed comorbidity of female pelvic pain
syndromes.
(c) 2008 Wiley-Liss, Inc.
DOI: 10.1002/jnr.21714
PMCID: PMC4755493
PMID: 18478547 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18715239 | 1. BJOG. 2008 Oct;115(11):1392-6. doi: 10.1111/j.1471-0528.2008.01879.x. Epub
2008 Aug 19.
Endometriosis and its coexistence with irritable bowel syndrome and pelvic
inflammatory disease: findings from a national case-control study--Part 2.
Seaman HE(1), Ballard KD, Wright JT, de Vries CS.
Author information:
(1)Department of Pharmacoepidemiology, Postgraduate Medical School, Faculty of
Health and Medical Sciences, University of Surrey, Guildford, UK.
Comment in
BJOG. 2009 Jan;116(1):129; author reply 129-30. doi:
10.1111/j.1471-0528.2008.01998.x.
OBJECTIVE: To investigate whether the increased chances of having a diagnosis of
irritable bowel syndrome (IBS) and pelvic inflammatory disease (PID) in women
with endometriosis is due to misdiagnosis or co-morbidity.
DESIGN: A case-control study of women aged 15-55 years with endometriosis and
matched controls.
SETTING: Data from the UK's General Practice Research Database for the years
1992-2001.
SAMPLE: A total of 5540 women aged 15-55 years, diagnosed with endometriosis,
each matched to four controls without endometriosis. The index date was defined
as the date of diagnosis.
METHODS: Data were analysed to determine whether women with endometriosis were
more likely to receive a diagnosis of PIDor IBS than women without
endometriosis. Odds ratios were calculated for endometriosis associated with IBS
and PID before and after the index date.
MAIN OUTCOME MEASURES: Diagnosis of IBS or PID before and after the index date.
RESULTS: Compared with the controls, women with endometriosis were 3.5 times
more likely to have received a diagnosis of IBS (OR 3.5 [95% CI: 3.1-3.9]). Even
after women had been diagnosed with endometriosis, they were still two and a
half times more likely to receive a new diagnosis of IBS when compared with the
controls (OR 2.5 [95% CI: 2.2-2.8]). Similarly, women with endometriosis were
more likely than those without endometriosis to have been treated for PID both
before (OR 5.9 [95% CI: 5.1-6.9]) and after (OR 3.8 [95% CI: 3.1-4.6]) being
diagnosed with endometriosis.
CONCLUSIONS: Women with endometriosis are more likely to be diagnosed with IBS
and PID than controls, even after a definitive diagnosis of endometriosis has
been reached.
DOI: 10.1111/j.1471-0528.2008.01879.x
PMID: 18715239 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23111564 | 1. Eur J Appl Physiol. 2013 May;113(5):1147-56. doi: 10.1007/s00421-012-2535-1.
Epub 2012 Oct 31.
Appetite, gut hormone and energy intake responses to low volume sprint interval
and traditional endurance exercise.
Deighton K(1), Barry R, Connon CE, Stensel DJ.
Author information:
(1)School of Sport, Exercise and Health Sciences, Loughborough University,
Loughborough, Leicestershire LE11 3TU, UK.
Sprint interval exercise improves several health markers but the appetite and
energy balance response is unknown. This study compared the effects of sprint
interval and endurance exercise on appetite, energy intake and gut hormone
responses. Twelve healthy males [mean (SD): age 23 (3) years, body mass index
24.2 (2.9) kg m(-2), maximum oxygen uptake 46.3 (10.2) mL kg(-1) min(-1)]
completed three 8 h trials [control (CON), endurance exercise (END), sprint
interval exercise (SIE)] separated by 1 week. Trials commenced upon completion
of a standardised breakfast. Sixty minutes of cycling at 68.1 (4.3) % of maximum
oxygen uptake was performed from 1.75-2.75 h in END. Six 30-s Wingate tests were
performed from 2.25-2.75 h in SIE. Appetite ratings, acylated ghrelin and
peptide YY (PYY) concentrations were measured throughout each trial. Food intake
was monitored from buffet meals at 3.5 and 7 h and an overnight food bag.
Appetite (P < 0.0005) and acylated ghrelin (P < 0.002) were suppressed during
exercise but more so during SIE. Peptide YY increased during exercise but most
consistently during END (P < 0.05). Acylated ghrelin was lowest in the afternoon
of SIE (P = 0.018) despite elevated appetite (P = 0.052). Exercise energy
expenditure was higher in END than that in SIE (P < 0.0005). Energy intake was
not different between trials (P > 0.05). Therefore, relative energy intake
(energy intake minus the net energy expenditure of exercise) was lower in END
than that in CON (15.7 %; P = 0.006) and SIE (11.5 %; P = 0.082). An acute bout
of endurance exercise resulted in lower appetite perceptions in the hours after
exercise than sprint interval exercise and induced a greater 24 h energy deficit
due to higher energy expenditure during exercise.
DOI: 10.1007/s00421-012-2535-1
PMID: 23111564 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15894210 | 1. Gynecol Obstet Fertil. 2005 Apr;33(4):239-46. doi:
10.1016/j.gyobfe.2005.03.010. Epub 2005 Apr 7.
[Women with endometriosis: are they different from others?].
[Article in French]
Audebert A(1).
Author information:
(1)IGF1, 35, rue de Turenne, 33000 Bordeaux, France. [email protected]
The objective of this short review is to identify the particularities of women
with endometriosis, especially those complaining of pain and with the most
severe lesions. Genetic aberrations play, with a high probability, a major role
in the development of this disease, its severity, its tendency to recur and also
in its capacity to degenerate. The abnormalities of the endometrium, with
exacerbated biological activities, are an example. The woman with endometriosis
seems more sensitive to pain through various mechanisms, such as central
hypersensitivity and decrease threshold to somatoceptive pain and several
associated psychological disorders. Endometriosis is often associated with other
painful conditions such as irritable bowel syndrome, interstitial cystitis and
fibromyalgia. Finally, also appears also to have a higher risk to develop non
Hodgkin's lymphoma or ovarian cancer. These particularities, some of them being
still speculative or controversial, should be known in routine practise, in
order to offer a better multidisciplinary management, not only for short term,
but also long term issues.
DOI: 10.1016/j.gyobfe.2005.03.010
PMID: 15894210 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17470516 | 1. J Endocrinol. 2007 May;193(2):251-8. doi: 10.1677/JOE-06-0030.
Effects of exercise on gut peptides, energy intake and appetite.
Martins C(1), Morgan LM, Bloom SR, Robertson MD.
Author information:
(1)School of Biomedical and Molecular Sciences, University of Surrey, Guildford,
UK.
This study investigated the acute effects of exercise on the postprandial levels
of appetite-related hormones and metabolites, energy intake (EI) and subjective
measures of appetite. Ghrelin, polypeptide YY (PYY), glucagon-like peptide-1
(GLP-1) and pancreatic polypeptide (PP) were measured in the fasting state and
postprandially in 12 healthy, normal-weight volunteers (six males and six
females) using a randomised crossover design. One hour after a standardised
breakfast, subjects either cycled for 60 min at 65% of their maximal heart rate
or rested. Subjective appetite was assessed throughout the study using visual
analogue scales and subsequent EI at a buffet meal was measured at the end (3-h
post-breakfast and 1-h post-exercise). Exercise significantly increased mean
PYY, GLP-1 and PP levels, and this effect was maintained during the
post-exercise period for GLP-1 and PP. No significant effect of exercise was
observed on postprandial levels of ghrelin. During the exercise period, hunger
scores were significantly decreased; however, this effect disappeared in the
post-exercise period. Exercise significantly increased subsequent absolute EI,
but produced a significant decrease in relative EI after accounting for the
energy expended during exercise. Hunger scores and PYY, GLP-1 and PP levels
showed an inverse temporal pattern during the 1-h exercise/control intervention.
In conclusion, acute exercise, of moderate intensity, temporarily decreased
hunger sensations and was able to produce a short-term negative energy balance.
This impact on appetite and subsequent energy homeostasis was not explained by
changes in postprandial levels of ghrelin; however, 'exercise-induced anorexia'
may potentially be linked to increased PYY, GLP-1 and PP levels.
DOI: 10.1677/JOE-06-0030
PMID: 17470516 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21615652 | 1. Pediatr Diabetes. 2011 Jun;12(4 Pt 2):372-80. doi:
10.1111/j.1399-5448.2010.00753.x.
Changes in cardiometabolic risk factors, appetite-controlling hormones and
cytokines after a treatment program in overweight adolescents: preliminary
findings from the EVASYON study.
Romeo J(1), Martinez-Gomez D, Diaz LE, Gómez-Martinez S, Marti A,
Martin-Matillas M, Puertollano MA, Veiga OL, Martinez JA, Wärnberg J, Zapatera
B, Garagorri JM, Morandé G, Campoy C, Moreno LA, Marcos A; EVASYON Study Group.
Collaborators: Marcos A, Campoy C, López-Belmonte G, Delgado M, Martín-Matillas
M, Aparicio V, Carbonell A, Agil A, Silva DR, Molina Font JA, Pérez-Ballesteros
C, Piqueras MJ, Chillón P, Tercedor P, Martín-Lagos JA, Martín-Bautista E,
Pérez-Expósito M, Garófano M, Aguilar MJ, Fernández-Mayorga A, Sánchez P, Marcos
A, Gómez-Martínez S, Zapatera B, Nova E, Romeo J, Díaz LE, Pozo T, Wärnberg J,
Puertollano MA, Morandé G, Villaseñor A, Madruga D, Muñoz R, Veiga OL, Villagra
A, Martínez-Gómez D, Garcia RM, Vaquero MP, Pérez-Granados AM, Navas-Carretero
S, Martí A, Azcona C, Moleres A, Rendo T, Marqués M, Martínez JA,
Redondo-Figuero C, García-Fuentes M, DeRufino P, González-Lamuño D, Amigo T,
Lanza R, Noriega MJ, Garagorri JM, Moreno LA, Romero P, De Miguel P, Rodríguez
G, Bueno G, Mesana M, Vicente G, Fernández J, Rey-López P, Muro C, Tomás C,
Wärnberg J, Calle ME, Barrios L.
Author information:
(1)Immunonutrition Research Group, Department of Metabolism and Nutrition,
Institute of Food Science, Technology and Nutrition (ICTAN), Spanish National
Research Council (CSIC), Madrid, Spain.
OBJECTIVE: We investigated the effects of the EVASYON program on body fatness,
cardiometabolic risk factors, gut appetite-controlling hormones and serum levels
of cytokines in adolescents with overweight or obesity (OW/OB).
METHODS: This study comprised 13 boys (10 obese) and 12 girls (8 obese), aged
13-16 years, from a Madrid Hospital. The EVASYON program was based on a
calorie-restricted diet (10-40%), increased physical activity (at least 60
min/day 5 days a week), psychological therapy and nutritional education for 13
months. Anthropometric and blood pressure measurements were measured before and
after intervention. Serum glucose, total cholesterol, high-density lipoprotein
cholesterol, triglycerides, leptin, total peptide YY and insulin levels were
determined before and after intervention. Serum levels of cytokines IL-1β, IL-2,
IL-4, IL-5, IL-6, IL-8, IL-10, and TNF-α were also assessed before and after
intervention.
RESULTS: A decrease in body mass index (BMI), BMI z-score, skinfolds (triceps,
biceps, subscapular, thigh, and calf), sum of six skinfolds and body
circumferences (arm relaxed and flexed, waist, hip, and proximal thigh) values
were observed after the intervention program (all p < 0.05). In addition,
diastolic blood pressure also decreased (p < 0.05). A decrease in serum leptin
levels (-48.4%, p < 0.001) was observed after intervention without changes in
total peptide YY and insulin levels. Levels of IL-8, IL-10, and TNF-α also
decreased (all p < 0.05) after the intervention program.
CONCLUSIONS: These preliminary results evidence that the EVASYON program may
improve body fat, leptin, and some pro-inflammatory cytokines in adolescents
with OW/OB.
© 2011 John Wiley & Sons A/S.
DOI: 10.1111/j.1399-5448.2010.00753.x
PMID: 21615652 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22134016 | 1. Obstet Gynecol Clin North Am. 2011 Dec;38(4):677-86. doi:
10.1016/j.ogc.2011.09.004.
Surgical treatment of endometriosis.
Howard FM(1).
Author information:
(1)Department of Obstetrics and Gynecology, University of Rochester School of
Medicine and Dentistry, Rochester, NY 14642, USA. [email protected]
In this review, the pitfalls that still exist with the surgical treatment of
endometriosisassociatedpelvic pain have been discussed and the best evidence
regarding various aspects of surgical techniques have been reviewed. When
laparoscopy is performed to evaluate a woman with pelvic pain symptoms, it is
important she be counseled that the primary function of the surgery is to
confirm the presence (and allow surgical treatment) of endometriosis, and that
it is not the penultimate diagnostic modality for her pelvic pain. There are
many etiologies of pelvic pain that present with symptoms resembling those of
endometriosis-associated pelvic pain that are not diagnosable with laparoscopy,
such as interstitial cystitis and irritable bowel syndrome. It is unfortunate
that many women are left with the belief that if a laparoscopy fails to provide
a diagnosis of a pain generator, then it means there are no diagnoses other than
that the “pain is in her head,” often disparagingly termed “supratentorial”
byclinicians. In fact, the pain-related diagnoses that are amenable to and
possibly require a laparoscopy are quite limited, a group of diagnoses that this
author terms the “dirty dozen” because there are just 12, and only the first 4
have good evidence to clearly associate them with chronic pelvic pain:1.
Endometriosis 2. Ovarian remnant syndrome 3. Pelvic inflammatory disease 4.
Tuberculous salpingitis 5. Adhesions 6. Benign cystic mesothelioma 7.
Postoperative peritoneal cysts 8. Adnexal cysts (nonendometriotic)9. Chronic
ectopic pregnancy 10. Endosalpingiosis 11. Residual accessory ovary 12. Hernias:
ventral, inguinal, femoral, spigelian.I would argue that diagnostic laparoscopy
in modern gynecology has a limited, if any role, and that when laparoscopy is
planned for women with chronic pelvic pain, it should be with a very high
suspicion of a diagnosis and with plans to treat the disease operatively. In
this era, a negative diagnostic laparoscopy should be a rare event.
DOI: 10.1016/j.ogc.2011.09.004
PMID: 22134016 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21671697 | 1. Expert Rev Pharmacoecon Outcomes Res. 2011 Jun;11(3):281-6. doi:
10.1586/erp.11.29.
Information disclosure to cancer patients: EORTC QLQ-INFO25 questionnaire.
Arraras JI(1), Greimel E, Chie WC, Sezer O, Bergenmar M, Costantini A, Young T,
Kuljanic K, Velikova G; European Organisation for Research and Treatment of
Cancer Quality of Life Group.
Author information:
(1)Oncology Department, Complejo Hospitalario de Navarra, Irunlarrea 3, 31008
Pamplona, Spain. [email protected]
Information is one of the main interventions given to cancer patients. Important
research into information disclosure has been conducted and major advances have
been made. We present the main theoretical models used to understand the
information field and describe the current situation regarding the principal
factors related to information: patients' needs, coping strategies, illness
representations, cross-cultural differences, the role of the family, and
strategies to enhance information giving, such as professional training and
patient-targeted interventions. We highlight the need to assess patients'
characteristics and desires through questionnaires and interviews and present
the European Organisation for Research and Treatment of Cancer Quality of Life
Group information questionnaire (EORTC QLQ-INFO 25). This instrument evaluates
the level of information patients have received in different areas of their
disease, treatment and care, and evaluates qualitative aspects. Finally, we
describe the key areas of the information field and discuss how these areas
could change in the future.
DOI: 10.1586/erp.11.29
PMID: 21671697 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16778097 | 1. Clin Cancer Res. 2006 Jun 15;12(12):3713-5. doi:
10.1158/1078-0432.CCR-06-0800.
Genetic and epigenetic analysis of the putative tumor suppressor km23 in primary
ovarian, breast, and colorectal cancers.
Campbell IG(1), Phillips WA, Choong DY.
Author information:
(1)Victorian Breast Cancer Research Consortium Cancer Genetics Laboratory,
Research Division, Peter MacCallum Cancer Centre, Melbourne, 8006, Australia.
[email protected]
PURPOSE: A very high frequency of somatic mutations in the transforming growth
factor-beta signaling component km23 has been reported in a small series of
ovarian cancers (8 of 19, 42%). Functional studies showed that some mutations
disrupt km23 function, resulting in aberrant transforming growth factor-beta
signaling and presumably enhanced tumorigenicity. If verified, this would
elevate mutation of km23 as the single most frequent somatic event in ovarian
cancer.
EXPERIMENTAL DESIGN: We sought to verify the frequency of silencing of km23
among 104 primary ovarian cancers (49 serous, 18 mucinous, 29 endometrioid/clear
cell, and 8 undifferentiated) as well as 72 breast and 61 colorectal cancers by
undertaking both somatic mutation and promoter methylation analyses. All four
exons of km23 were individually amplified from genomic DNA with primers
complementary to surrounding intronic sequences and analyzed by single-stranded
conformational polymorphism analysis.
RESULTS: Two germ line polymorphisms were identified, but none of the 237 tumors
analyzed harbored somatic km23 mutations. In addition, promoter methylation
analysis showed that in all cases, the 5' CpG island was unmethylated.
CONCLUSIONS: Our data suggest that silencing of km23, either through somatic
genetic mutation or promoter hypermethylation, is rare in ovarian, breast, and
colorectal cancers.
DOI: 10.1158/1078-0432.CCR-06-0800
PMID: 16778097 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17289431 | 1. J Sci Med Sport. 2007 Oct;10(5):291-6. doi: 10.1016/j.jsams.2006.10.002. Epub
2007 Feb 6.
Serum cardiac troponin T, troponin I, plasma BNP and left ventricular mass index
in professional football players.
Löwbeer C(1), Seeberger A, Gustafsson SA, Bouvier F, Hulting J.
Author information:
(1)Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska
University Hospital, Huddinge, Sweden. [email protected]
Concentrations of cardiac troponins (cTn) in serum or plasma may be elevated in
several disease states other than acute coronary syndromes. In heart failure and
end stage renal disease, cardiac troponin T (cTnT) correlates positively with
left ventricular mass index (LVMI). Exercise-induced elevation of cardiac
troponins in well-trained athletes has been confirmed by several reports but the
aetiology and clinical significance is unclear. In the present study, we
measured baseline concentrations of cardiac markers and investigated whether or
not serum cTnT is associated with left ventricular hypertrophy (LVH) in
professional football players.
METHODS: Twenty-three male professional football players with a mean age of 23
years (range 18-32) were studied. Echocardiography and blood sampling were
carried out approx 24h after a training session. Serum cTnT, other cardiac
markers and plasma brain natriuretic peptide (BNP) were compared with LVMI.
RESULTS: cTnT was only detectable in one subject. The prevalence of elevated
cardiac troponin I (cTnI), creatine kinase MB (CKMB) and creatine kinase was
higher than for cTnT. cTnI concentrations were higher in football players than
in controls. LVMI did not correlate with any of the cardiac markers. Plasma BNP
concentrations were normal in all subjects.
CONCLUSION: Serum cTnT concentrations were not elevated in healthy professional
football players with LVH. This argues against the hypothesis that LVH per se
may cause increased cTnT. The finding of higher cTnI in football players than in
non-athletic controls should be confirmed and the aetiology elucidated.
DOI: 10.1016/j.jsams.2006.10.002
PMID: 17289431 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16879068 | 1. Clin Chem Lab Med. 2006;44(8):999-1003. doi: 10.1515/CCLM.2006.179.
Effects of a long-distance run on cardiac markers in healthy athletes.
Leers MP(1), Schepers R, Baumgarten R.
Author information:
(1)Department of Clinical Chemistry and Hematology, Atrium Medical Center
Parkstad, Heerlen, The Netherlands. [email protected]
BACKGROUND: Running a marathon is a stressful event for athletes. Limited
research exists on the role of cardiac markers during such a strenuous event.
The aim of this study was to investigate detailed changes in cardiac markers
before and after a long-distance run.
METHODS: We studied 25 male and 2 female runners (age 34-64 years) who were
running the Visé-Maastricht-Visé marathon. Blood samples were drawn just before
and immediately after finishing the marathon. An additional blood sample was
collected 24 h later.
RESULTS: Running the marathon led to a significant increase in cortisol. This
returned to baseline values 24 h after the marathon. There was a slight increase
in brain natriuretic peptide (BNP); however, this was not statistically
significant. On the contrary, the N-terminal fragment of BNP (NT-pro-BNP) was
significantly increased immediately after the run and was normalized 24 h later
in 26 out of 27 runners (96%). The magnitude of the transient elevations in BNP
and NT-pro-BNP increased with the age of the athletes. Furthermore, in 9 out of
27 runners there was a significant increase in troponin T. However, in all these
runners this increase was transient and troponin-T levels returned to baseline
values 24 h after the marathon.
CONCLUSIONS: Running a marathon significantly increases NT-pro-BNP levels in
healthy adults. This increase could be partially attributed to cardiac stress.
The transient increases in BNP, NT-pro-BNP and troponin T are more likely to
reflect myocardial stunning than cardiomyocyte damage. It seems that the
magnitude of the increase in BNP could serve as a marker of the biological age
of the myocardium.
DOI: 10.1515/CCLM.2006.179
PMID: 16879068 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11320362 | 1. Am Heart J. 2001 May;141(5):751-8. doi: 10.1067/mhj.2001.114371.
Effects of prolonged strenuous exercise on plasma levels of atrial natriuretic
peptide and brain natriuretic peptide in healthy men.
Ohba H(1), Takada H, Musha H, Nagashima J, Mori N, Awaya T, Omiya K, Murayama M.
Author information:
(1)Department of Cardiology, St Marianna University School of Medicine,
Kanagawa, Japan. [email protected]
BACKGROUND: Now that marathon racing is growing in popularity, many thousands of
enthusiastic athletes are participating in various ultramarathons all over the
world each year. However, it remains controversial whether such a sport
contributes to the promotion of health. The occurrence of transient cardiac
dysfunction and irreversible myocardial injury has been reported in association
with such exercise in healthy individuals. Brain natriuretic peptide (BNP) is a
cardiac hormone, as is atrial natriuretic peptide (ANP), and its measurement has
been widely used for clinical evaluation of cardiac dysfunction. However, little
is known about the response of plasma BNP to prolonged strenuous exercise. We
hypothesized that confirmation of minimal cardiac dysfunction or myocardial
injury may be made by measurements of plasma BNP.
METHODS: Levels of plasma ANP, BNP, catecholamines, blood lactate, and serum
cardiac troponin T (cTnT) were determined before and after a 100-km
ultramarathon in 10 healthy men to examine the effects of the exercise on levels
of ANP and BNP and correlations between the natriuretic peptides and cTnT as a
marker for myocardial damage.
RESULTS: Whereas all variables significantly increased after the race, increased
levels of ANP and BNP were most strongly correlated with increases in cTnT
levels. The cTnT level after the race was greater than the upper reference limit
in 9 of 10 men.
CONCLUSIONS: Such exercise significantly increased ANP and BNP levels in healthy
men, and the increases could be partially attributed to myocardial damage during
the race.
DOI: 10.1067/mhj.2001.114371
PMID: 11320362 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17635599 | 1. Headache. 2007 Jul-Aug;47(7):1069-78. doi: 10.1111/j.1526-4610.2007.00784.x.
Endometriosis is associated with prevalence of comorbid conditions in migraine.
Tietjen GE(1), Bushnell CD, Herial NA, Utley C, White L, Hafeez F.
Author information:
(1)Department of Neurology, University of Toledo Medical Center, Health Science
Campus, 3120 Glendale Avenue, Toledo, OH 43614, USA.
OBJECTIVE: To examine the headache characteristics of women with migraine and
endometriosis (EM), and differences in the prevalence of comorbid conditions
between female migraineurs with EM, without EM and nonheadache controls.
BACKGROUND: Migraine and EM are common conditions in women of reproductive age,
and both are influenced by ovarian hormones. The comorbidity of migraine and EM
is newly recognized, but reasons for the association are uncertain.
METHODS: This is a cross-sectional study of female headache outpatients and
healthy controls conducted at University of Toledo and Duke University in 2005
and 2006. After a headache specialist determined headache frequency and
diagnosis (based on criteria of the second International Classification of
Headache Disorders), patients completed a self-administered electronic survey
with information on demographics, headache-related disability, menstrual
disorders, premenstrual dysphoric disorder (PMDD), vascular event risk, and
comorbid conditions, including irritable bowel syndrome (IBS), fibromyalgia
(FM), chronic fatigue syndrome (CFS), interstitial cystitis (IC), depression,
and anxiety.
RESULTS: Study enrolled 171 women with migraine and 104 controls. EM was
reported more commonly in migraineurs than in controls (22% vs 9.6%, P < .01).
Frequency of chronic headache was higher in migraineurs with EM compared to
without EM (P= .002) and median headache-related disability scores were also
higher in the EM group (P= .025). Symptoms of PMDD were more common in
migraineurs, but frequency did not differ by EM status. Migraineurs with EM
reported more menorrhagia, dysmenorrhea, and infertility compared to the
migraine cohort without EM and to controls. Depression, anxiety, IBS, FM, CFS,
and IC were more common in migraine with EM group than in controls. Anxiety (OR
= 2.2, 95% CI 1.0-4.7), IC (OR = 10.6, 95% CI 1.9-56.5), and CFS (OR = 3.6, 95%
CI 1.1-11.5) were more common in migraine with EM group, than in the cohort with
migraine without EM.
CONCLUSION: Prevalence of EM is higher in women with migraine than in
nonheadache controls. Migraineurs with EM have more frequent and disabling
headaches, and are more likely to have other comorbid conditions affecting mood
and pain, compared to migraineurs without EM.
DOI: 10.1111/j.1526-4610.2007.00784.x
PMID: 17635599 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17493437 | 1. Gastroenterol Hepatol. 2007 May;30(5):274-6. doi: 10.1157/13101977.
[Ileal perforation secondary to intestinal endometriosis].
[Article in Spanish]
Vanrell Garau M(1), Ginard Vicens D, Mariño Méndez Z, Bosque López MJ, Reyes
Moreno J, Escarda Gelabert A, Corteza A, Gayá Cantallops J.
Author information:
(1)Servicio de Aparato Digestivo, Hospital Universitario Son Dureta, Andrea
Doria 55, 07014 Palma de Mallorca, Mallorca, Spain.
Endometriosis is defined as the presence of endometrial tissue outside the
uterus. The bowel is not often affected. There are no specific clinical findings
for intestinal endometriosis. It is typically asymptomatic, but sometimes can
present with abdominal pain, diarrhoea, constipation or intestinal obstruction.
Ileal perforation is a rare complication of intestinal endometriosis and only a
few cases have been reported in the literature. Intestinal endometriosis can
mimic many gastrointestinal diseases, such as irritable bowel syndrome,
inflammatory bowel disease, infections and neoplasms. The diagnosis is made by
laparoscopy or laparotomy. We present a case of a woman with intermittent
abdominal pain and ileal perforation secondary to intestinal endometriosis.
DOI: 10.1157/13101977
PMID: 17493437 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12417808 | 1. Cardiology. 2002;98(3):113-5. doi: 10.1159/000066319.
B-type natriuretic peptide is related to left ventricular mass in hypertensive
patients but not in athletes.
Almeida S(1), Azevedo A, Castro A, Friões F, Freitas J, Ferreira A, Bettencourt
P.
Author information:
(1)Department of Medicine, Hospital S João, Faculdade de Medicina, Universidade
do Porto, Unidade de Investigação e Desenvolvimento Cardiovascular, Porto,
Portugal.
A positive correlation has been previously documented between B-type natriuretic
peptide (BNP) levels and left ventricular mass index (LVMI) in hypertensive
patients. We evaluated 8 cycling athletes, 8 healthy age-matched controls; 17
hypertensive patients and 7 age-matched controls. LVMI was significantly higher
in athletes and hypertensive patients than in their controls. Plasma levels of
BNP in hypertensive patients were significantly higher than in athletes and
their age-matched controls. No significant difference was found between athletes
and their controls. Cycling athletes had significantly larger LVMI than
hypertensive patients and controls, without elevated BNP levels. These results
suggest that BNP levels are elevated in patients with increased LVM due to
hypertension but not in physiologically increased LVM. Whether elevated BNP
levels in athletes is a sign of structural heart disease merits further
investigation.
Copyright 2002 S. Karger AG, Basel
DOI: 10.1159/000066319
PMID: 12417808 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19092706 | 1. Med Sci Sports Exerc. 2009 Jan;41(1):26-34. doi: 10.1249/MSS.0b013e31818313ff.
Cardiovascular consequences of completing a 160-km ultramarathon.
Scott JM(1), Esch BT, Shave R, Warburton DE, Gaze D, George K.
Author information:
(1)Cardiovascular Physiology and Rehabilitation Laboratory, 6108 Thunderbird
Blvd., University of British Columbia,Vancouver, BC, Canada.
[email protected]
PURPOSES: To comprehensively investigate the cardiovascular consequences of a
160-km ultramarathon using traditional echocardiography, speckle tracking
imaging, cardiac biomarkers, and heart rate variability (HRV) and to examine the
relationship between the changes in these variables.
METHODS: We examined athletes before an ultramarathon and reassessed all
finishers immediately after the race. Left ventricular (LV) systolic (ejection
fraction [EF], systolic blood pressure/end-systolic volume [SBP/ESV] ratio) and
diastolic (ratio of early [E] to late [A], filling E:A) measurements were
assessed using traditional echocardiography, whereas myocardial peak strain and
strain rate were analyzed using speckle tracking. Cardiac biomarkers measured
were cardiac troponin T (cTnT) and N-terminal pro-brain natriuretic peptide
(NT-pro-BNP). HRV indices were assessed using standard frequency and time domain
measures.
RESULTS: Twenty-five athletes successfully completed the race (25.5 +/- 3.2 h).
Significant pre- to postrace changes in EF (66.8 +/- 3.8 to 61.2 +/- 4.0 %, P <
0.05) and E:A ratio (1.62 +/- 0.37 to 1.35 +/- 0.33, P < 0.05) were reported.
Peak strain was significantly decreased in all planes, with the largest
reduction occurring circumferentially. NT-pro-BNP concentrations increased
significantly (28 +/- 17.1 vs 795 +/- 823 ng x L, P < 0.05), whereas postrace
cTnT were elevated in just five athletes (20%). No significant alterations in
HRV were noted postrace. Reductions in LV function were not significantly
associated with changes in cardiac biomarkers and/or HRV.
CONCLUSIONS: Although the stress of an ultramarathon resulted in a mild
reduction in LV function and biomarker release, the mechanisms behind such
consequences remain unknown. It is likely that factors other than myocardial
damage or strong vagal reactivation contributed to postexercise decreases in LV
function after an ultramarathon.
DOI: 10.1249/MSS.0b013e31818313ff
PMID: 19092706 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12890912 | 1. Circ J. 2003 Aug;67(8):691-6. doi: 10.1253/circj.67.691.
Differential increase in natriuretic peptides in elite dynamic and static
athletes.
Date H(1), Imamura T, Onitsuka H, Maeno M, Watanabe R, Nishihira K, Matsuo T,
Eto T.
Author information:
(1)First Department of Internal Medicine, Miyazaki Medical College, Japan.
The echocardiographic measures and plasma concentrations of either atrial
natriuretic peptide (ANP) or brain natriuretic peptide (BNP) were compared in
elite judo practitioners (static athletes), elite marathon runners (dynamic
athletes) and healthy controls to investigate the relationship between the
different types of left ventricular (LV) hypertrophy and plasma concentrations
of natriuretic peptides in athletes. The LV mass and LV wall thickness of
marathon runners and judo practitioners were significantly greater than those of
controls. The LV end-diastolic dimension index was significantly larger in the
marathon group, but smaller in the judo group. The left atrial dimension (LAD)
index was significantly larger only in marathon runners. Plasma BNP
concentrations were higher in both the judo and marathon groups than in
controls, and positively correlated with LV mass as well as with deceleration
time. Plasma ANP concentrations were significantly higher in marathon runners
than in the controls and judo groups, and positively correlated with the LAD
index, but negatively correlated with ejection fraction. Multivariate analyses
showed that the type of athlete and LAD index were independent predictors of
plasma BNP and ANP concentrations, respectively. Thus, there is an intimate link
between plasma concentrations of natriuretic peptides and cardiac morphology in
different types of athletes.
DOI: 10.1253/circj.67.691
PMID: 12890912 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17701798 | 1. J Obstet Gynaecol. 2007 Jul;27(5):493-5. doi: 10.1080/01443610701405721.
Predicting the presence of rectovaginal endometriosis from the clinical history:
a retrospective observational study.
Griffiths AN(1), Koutsouridou RN, Penketh RJ.
Author information:
(1)Department of Obstetrics and Gynaecology, University Hospital of Wales,
Cardiff, UK. [email protected]
Rectovaginal endometriosis is a severe variant of endometriosis. Common
presenting symptoms for endometriosis include dysmenorrhoea, pelvic pain and
dyspareunia. It is now recognised that there are other less traditional symptoms
of endometriosis that are also relatively common. The aim of this study is to
assess the relative strength of each of the potential symptoms of rectovaginal
endometriosis and compare these with the laparoscopic and histological findings.
In this retrospective, observational study the overall prevalence of
rectovaginal endometriosis in the group was 31.4%. The presence of dyschesia
gave a likelihood ratio of 1.27 (95% CI: 0.56 - 2.89) with a predictive
prevalence of rectovaginal endometriosis of 37%. Apareunia and nausea or
abdominal bloating were particularly strong markers for rectovaginal disease
with a predictive prevalence of 87% and 89%, respectively. The classical
symptoms often attributed to irritable bowel syndrome are also common in women
with rectovaginal disease.
DOI: 10.1080/01443610701405721
PMID: 17701798 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17395308 | 1. Int J Cardiol. 2008 Mar 14;124(3):411-4. doi: 10.1016/j.ijcard.2006.12.076.
Epub 2007 Mar 28.
Use of natriuretic peptides in pre-participation screening of college athletes.
Daniels LB, Allison MA, Clopton P, Redwine L, Siecke N, Taylor K, Fitzgerald R,
Bracker M, Maisel AS.
Current screening methods have poor specificity and sensitivity for detecting
cardiac abnormalities that predispose young athletes to sudden death.
Natriuretic peptides (NPs) show promise in screening asymptomatic populations
for structural heart disease, but little is known about their use in student
athletes. This study sought to describe the distribution and characteristics of
NP levels in a population of college athletes and determine the relationship
between NPs and the pre-participation exam (PPE) and hand-held echocardiography
(HHE). We evaluated 457 college varsity athletes with B-type NP (BNP) and
N-terminal proBNP (NT-proBNP) levels and a standard PPE; 200 also underwent HHE.
NT-proBNP and BNP levels were highly correlated (r=0.87, p<0.001), with a median
of 21 pg/ml and 8 pg/ml respectively. 95% of athletes had NT-proBNP<84 pg/ml and
95% had BNP<33 pg/ml. Levels were higher in athletes with a history of
exertional dizziness/syncope but did not correlate with other elements of the
PPE or with HHE, although no major cardiac structural abnormalities were
identified in this population. In men, there were weak correlations between NP
levels and number of days per week performing distance running, strenuous
exercise, or sprinting. In conclusion, NPs are only weakly correlated with
intensity of physical training, and most college athletes have low NP levels;
further studies are needed to elucidate the significance of elevated NP levels
in this population, as they may provide incremental information beyond that
provided by the PPE and echocardiography.
DOI: 10.1016/j.ijcard.2006.12.076
PMID: 17395308 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21067422 | 1. Climacteric. 2011 Apr;14(2):215-6. doi: 10.3109/13697137.2010.533615. Epub
2010 Nov 11.
Hormone therapy and brain tumors.
Pines A(1).
Author information:
(1)Department of Medicine 'T', Ichilov Hospital, Tel-Aviv, Israel.
The incidence of meningiomas is two to three times higher in women than in men,
yet it is a rare event (around one case per 10 000 woman-years). Preclinical and
clinical studies point at potential effects of female sex hormones on brain
tumors. Results from several prospective, large-scale studies indicate that
postmenopausal hormone therapy may increase the risk for diagnosing meningioma
by 30-80%, but there is no effect in regard to glioma. However, because of the
very low incidence of meningioma in the general population of women, the
absolute excess risk attributed to hormone therapy has no clinical impact.
DOI: 10.3109/13697137.2010.533615
PMID: 21067422 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15006250 | 1. Climacteric. 2003 Dec;6(4):285-92.
Meningioma and hormonal influences.
Wahab M(1), Al-Azzawi F.
Author information:
(1)Department of Obstetrics and Gynaecology, George Eliot Hospital, Nuneaton,
UK.
Meningiomas are slow-growing benign brain tumors. The etiology of meningioma is
largely unknown, and exposure to high-dose ionizing radiation and coexistence
with certain rare genetic conditions explain only a small fraction of the
incidence of the disease. The evidence that implicates gender-specific hormones
in the pathogenesis of meningioma emanates from data showing increased growth of
meningiomas during pregnancy and change in size during menses. Observational
data have identified the menopause and oophorectomy as conferring protection
against the risk of developing meningiomas, while adiposity is positively
associated with the disease. These tumors are also positively associated with
breast cancer, although they express a different gonadal steroid receptor
repertoire. About 70% of meningiomas express progesterone receptors, while fewer
than 31% express estrogen receptors. These observations suggest that
progesterone influences tumor growth. A progesterone antagonist such as
mifepristone therefore may inhibit tumor growth. The use of hormone replacement
therapy in symptomatic postmenopausal women either with previously treated
disease or with dormant tumors is discussed, but remains controversial.
PMID: 15006250 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20091865 | 1. Int J Cancer. 2010 Oct 1;127(7):1692-8. doi: 10.1002/ijc.25184.
Hormone replacement therapy and incidence of central nervous system tumours in
the Million Women Study.
Benson VS(1), Pirie K, Green J, Bull D, Casabonne D, Reeves GK, Beral V; Million
Women Study Collaborators.
Collaborators: Austoker J, Banks E, Beral V, Church J, English R, Green J,
Patnick J, Peto R, Reeves G, Vessey M, Wallis M, Abbott S, Armstrong M, Baker K,
Balkwill A, Benson V, Beral V, Black J, Brown A, Bull D, Cairns B, Chivenga J,
Crossley B, Ewart D, Ewart S, Fletcher L, Gerrard L, Goodill A, Green I, Green
J, Hilton E, Hooley J, Kan SW, Keene C, Kirichek O, Langston N, Liu B, Luque MJ,
MacGregor M, Pank L, Pirie K, Reeves G, Sherman E, Sherry-Starmer E, Simmonds M,
Spencer E, Strange H, Sweetland S, Timadjer A, Tipper S, Travis R, Wang X,
Watson J, Williams S, Wright L, Yang T, Young H.
Author information:
(1)Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom.
[email protected]
We examined the relation between the use of hormone replacement therapy (HRT)
and the incidence of central nervous system (CNS) tumours in a large prospective
study of 1,147,894 postmenopausal women. Women were aged 56.6 years on average
at entry, and HRT use was recorded at recruitment and updated, where possible,
about 3 years later. During a mean follow-up of 5.3 years per woman, 1,266 CNS
tumours were diagnosed, including 557 gliomas, 311 meningiomas and 117 acoustic
neuromas. Compared with never users of HRT, the relative risks (RRs) for all
incident CNS tumours, gliomas, meningiomas and acoustic neuromas in current
users of HRT were 1.20 (95% CI: 1.05-1.36), 1.09 (95% CI: 0.89-1.32), 1.34 (95%
CI: 1.03-1.75) and 1.58 (95% CI: 1.02-2.45), respectively, and there was no
significant difference in the relative risks by tumour type (heterogeneity p =
0.2). In past users of HRT the relative risk was 1.07 (95% CI: 0.93-1.24) for
all CNS tumours. Among current users of HRT, there was significant heterogeneity
by the type of HRT with the users of oestrogen-only HRT at higher risk of all
CNS tumours than users of oestrogen-progestagen HRT (RR = 1.42, 95% CI:
1.21-1.67 versus RR = 0.97, 95% CI: 0.82-1.16) (heterogeneity p < 0.001). Among
current users of oestrogen-only and oestrogen-progestagen HRT, there was no
significant heterogeneity by duration of use, hormonal constituent or mode of
administration of HRT.
DOI: 10.1002/ijc.25184
PMID: 20091865 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16759391 | 1. BMC Cancer. 2006 Jun 7;6:152. doi: 10.1186/1471-2407-6-152.
Hormonal exposures and the risk of intracranial meningioma in women: a
population-based case-control study.
Custer B(1), Longstreth WT Jr, Phillips LE, Koepsell TD, Van Belle G.
Author information:
(1)Department of Epidemiology, School of Public Health and Community Medicine,
University of Washington, Seattle, WA, USA. [email protected]
BACKGROUND: The role of exogenous hormone exposures in the development of
meningioma is unclear, but these exposures have been proposed as one hypothesis
to explain the over-abundance of such tumors in women.
METHODS: The association between oral contraception (OC) or hormone replacement
therapy (HRT) and intracranial meningioma in women was investigated using a
population-based, matched case-control study. Exposures for 143 cases and 286
controls matched on age within five years were obtained by interview. Diagnoses
were confirmed histopathologically and estrogen and progesterone receptor assays
conducted.
RESULTS: Although risk of meningioma appeared modestly elevated in past OC users
(OR = 1.5, 95% CI 0.8 - 2.7), and in current users (OR = 2.5, 95% CI 0.5 -
12.6), the confidence intervals were wide. No significant association between
meningioma risk and duration of OC use was found. Likewise, risk of meningioma
was only weakly associated with past use of HRT (OR = 0.7, 95% CI 0.4 - 1.3),
and not at all with current use of HRT (OR = 1.0, 95% CI 0.5 - 2.2). Of 142
available specimens, 2 (1%) expressed estrogen receptors, whereas 130 (92%)
expressed progesterone receptors (PR). OC use was associated with increased risk
of a meningioma expressing less rather than more PR (OR = 3.2, 95% CI 1.3 -
8.0). Overall, in post menopausal women, HRT use appeared to confer a
non-significant protective effect, and was not associated with low or high PR
expressing meningiomas.
CONCLUSION: This study found little evidence of associations between meningioma
and exogenous hormone exposures in women but did suggest that some hormonal
exposures may influence tumor biology in those women who develop meningioma.
DOI: 10.1186/1471-2407-6-152
PMCID: PMC1524800
PMID: 16759391 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21680301 | 1. Clin Transl Oncol. 2011 Jun;13(6):401-10. doi: 10.1007/s12094-011-0674-1.
The EORTC information questionnaire, EORTC QLQ-INFO25. Validation study for
Spanish patients.
Arraras JI(1), Manterola A, Hernández B, Arias de la Vega F, Martínez M, Vila M,
Eito C, Vera R, Domínguez MÁ.
Author information:
(1)Radiotherapeutic Oncology Department, Hospital de Navarra, Pamplona, Navarra,
Spain. [email protected]
INTRODUCTION: The EORTC QLQ-INFO25 evaluates the information received by cancer
patients. This study assesses the psychometric properties of the QLQ-INFO25 when
applied to a sample of Spanish patients.
MATERIALS AND METHODS: A total of 169 patients with different cancers and stages
of disease completed the EORTC QLQINFO25, the EORTC QLQ-C30 and the information
scales of the inpatient satisfaction module EORTC IN-PATSAT32 on two occasions
during the patients' treatment and follow- up period. Psychometric evaluation of
the structure, reliability, validity and responsiveness to changes was
conducted. Patient acceptability was assessed with a debriefing questionnaire.
RESULTS: Multi-trait scaling confirmed the 4 multi-item scales (information
about disease, medical tests, treatment and other services) and eight single
items. All items met the standards for convergent validity and all except one
met the standards of item discriminant validity. Internal consistency for all
scales (α>0.70) and the whole questionnaire (α>0.90) was adequate in the three
measurements, except information about the disease (0.67) and other services
(0.68) in the first measurement, as was test-retest reliability (intraclass
correlations >0.70). Correlations with related areas of IN-PATSAT32 (r>0.40)
supported convergent validity. Divergent validity was confirmed through low
correlations with EORTC QLQ-C30 scales (r<0.30). The EORTC QLQ-INFO-25
discriminated among groups based on gender, age, education, levels of anxiety
and depression, treatment line, wish for information and satisfaction. One scale
and an item showed changes over time.
CONCLUSIONS: The EORTC QLQ-INFO 25 is a reliable and valid instrument when
applied to a sample of Spanish cancer patients. These results are in line with
those of the EORTC validation study.
DOI: 10.1007/s12094-011-0674-1
PMID: 21680301 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17580362 | 1. Cancer. 2007 Aug 1;110(3):471-6. doi: 10.1002/cncr.22783.
Exogenous hormone use and meningioma risk: what do we tell our patients?
Claus EB(1), Black PM, Bondy ML, Calvocoressi L, Schildkraut JM, Wiemels JL,
Wrensch M.
Author information:
(1)Department of Epidemiology and Public Health, Yale University School of
Medicine, New Haven, Connecticut, USA. [email protected]
The decision to commence or continue use of hormone replacement therapy or oral
contraceptives in women presumed or known to be diagnosed with intracranial
meningioma is a common clinical question in neurosurgery. A review of the
English-language literature was undertaken to examine the association between
the use of exogenous hormones and meningioma risk. Seven publications were
identified, 6 of which met criteria for inclusion. No randomized clinical trial
data were available, hence, results were collected from 2 population-based
case-control studies, 2 hospital-based case-control studies, 1 nested
case-control study drawn from a large national cohort, and 1 retrospective
cohort study. At present, there is no statistical evidence of an increased risk
of meningioma among users of oral contraceptives. Although not definitive,
available data suggest an association between the use of hormone replacement
therapy and increased meningioma risk. Further evaluation of exogenous hormone
use in women with meningioma is needed with particular attention to
stratification by hormone (ie, estrogen and/or progesterone) composition,
duration of and age at use as well as tumor receptor subtype.
(c) 2007 American Cancer Society.
DOI: 10.1002/cncr.22783
PMID: 17580362 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18630737 | 1. Clin Lab. 2008;54(3-4):81-7.
Cardiac markers (BNP, NT-pro-BNP, Troponin I, Troponin T, in female amateur
runners before and up until three days after a marathon.
Frassl W(1), Kowoll R, Katz N, Speth M, Stangl A, Brechtel L, Joscht B, Boldt
LH, Meier-Buttermilch R, Schlemmer M, Roecker L, Gunga HC.
Author information:
(1)Center for Space Medicine Berlin (ZWMB), Department of Physiology, Charité -
University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
[email protected]
PURPOSE: Transient cardiac ventricular dysfunction or sudden cardiac deaths have
been reported for male athletes participating in marathon racing. Less is known
about the myocardial response in females. We examined natriuretic peptides and
cardiac troponins in female athletes after a marathon.
METHODS: At the 31st real,- Berlin Marathon plasma levels of NT-pro-BNP, BNP,
cTnI and cTnT were measured in 15 women (age 35+/-6 years; finishing times
between 3:22 h and 5:21 h) at four different time points (before, immediately
after, day one and day three).
RESULTS: An increase in [NT-pro-BNP] was observed immediately after the marathon
(median [NT-pro-BNP] before: 39.6 pg ml(-1), after: 138.6 pg ml(-1), p=0.003)
with a further increase on day one. [BNP] did not increase immediately after the
marathon but increased on day one (median [BNP] before: 15 pg ml(-1), day one:
27.35 pg ml(-1), p=0.006). On day three, [NT-pro-BNP] and [BNP] returned to
initial values. [cTnI] was under the detection limit prior to the marathon in
all runners. [cTnT] was under the detection limit before the marathon except in
one runner who presented a concentration of 0.03 ng ml(-1). Cardiac troponins
(median [cTnl] after: 0.098 ng ml(-1), p=0.028; median [cTnT] after: 0.032 ng
ml(-1), p=0.012) increased immediately after the marathon and returned to
initial values on day one [cTnT] and three [cTnI].
DISCUSSION: Parameters representing cardiac stress increased in females after a
marathon. Different kinetics of natriuretic peptides BNP and NT-pro-BNP
post-marathon could be due to their different half-lives and dependence on renal
function. The increase of cTnI and cTnT may result from minor myocardial
lesions.
PMID: 18630737 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24067267 | 1. J Med Internet Res. 2013 Sep 25;15(9):e201. doi: 10.2196/jmir.2296.
Effects of an individually tailored Web-based chronic pain management program on
pain severity, psychological health, and functioning.
Nevedal DC(1), Wang C, Oberleitner L, Schwartz S, Williams AM.
Author information:
(1)VA Connecticut Healthcare System, Department of Clinical Health Psychology,
West Haven, CT, USA. [email protected]
BACKGROUND: It is estimated that 30% of adults in the United States experience
daily chronic pain. This results in a significant burden on the health care
system, in particular primary care, and on the workplace. Chronic pain
management with cognitive-behavioral psychological treatment is effective in
reducing pain intensity and interference, health-related quality of life, mood,
and return to work. However, the population of individuals with chronic pain far
exceeds the population of therapists that can provide this care face-to-face.
The use of tailored, Web-based interventions for the management of chronic pain
could address limitations to access by virtue of its unlimited scalability.
OBJECTIVE: To examine the effects of a tailored Web-based chronic pain
management program on subjective pain, activity and work interference, quality
of life and health, and stress.
METHODS: Eligible participants accessed the online pain management program and
informed consent via participating employer or health care benefit systems;
program participants who completed baseline, 1-, and 6-month assessments were
included in the study. Of the 645 participants, the mean age was 56.16 years (SD
12.83), most were female (447/645, 69.3%), and white (505/641, 78.8%). Frequent
pain complaints were joint (249/645, 38.6%), back (218/645, 33.8%), and
osteoarthritis (174/654, 27.0%). The online pain management program used
evidence-based theories of cognitive behavioral intervention, motivational
enhancement, and health behavior change to address self-management, coping,
medical adherence, social support, comorbidities, and productivity. The program
content was individually tailored on several relevant participant variables.
RESULTS: Both pain intensity (mean 5.30, SD 2.46), and unpleasantness (mean
5.43, SD 2.52) decreased significantly from baseline to 1-month (mean 4.16, SD
2.69 and mean 4.24, 2.81, respectively) and 6-month (mean 3.78, SD 2.79 and mean
3.78, SD 2.79, respectively) assessments (P<.001). The magnitude of the 6-month
effects were large. Trends for decreases in pain interference (36.8% reported
moderate or enormous interference) reached significance at 6 months (28.9%,
P<.001). The percentage of the sample reporting fair or poor quality of life
decreased significantly from 20.6% at baseline to 16.5% at 6 months (P=.006).
CONCLUSIONS: Results suggest that the tailored online chronic pain management
program showed promising effects on pain at 1 and 6 months posttreatment and
quality of life at 6 months posttreatment in this naturalistic study. Further
research is warranted to determine the significance and magnitude of the
intervention's effects in a randomized controlled trial.
DOI: 10.2196/jmir.2296
PMCID: PMC3785999
PMID: 24067267 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of Interest: Chun Wang is employed as
a statistician at Wellness & Prevention, Inc. Dana Nevedal, Lindsay Oberleitner,
Steven Schwartz, and Amy Williams are former Wellness & Prevention, Inc
behavioral scientists. |
http://www.ncbi.nlm.nih.gov/pubmed/9781911 | 1. Am J Med Genet. 1998 Oct 2;79(4):294-304. doi:
10.1002/(sici)1096-8628(19981002)79:4<294::aid-ajmg12>3.0.co;2-m.
The syndromes of Sotos and Weaver: reports and review.
Opitz JM(1), Weaver DW, Reynolds JF Jr.
Author information:
(1)Department of Pediatrics, University of Utah, Salt Lake City, USA.
[email protected]
The syndromes of Sotos and Weaver are paradigmatic of the daily nosologic
difficulties faced by clinical geneticists attempting to diagnose and counsel,
and to give accurate prognoses in cases of extensive phenotypic overlap between
molecularly undefined entities. Vertebrate development is constrained into only
very few final or common developmental paths; therefore, no developmental
anomaly seen in humans is unique to ("pathognomonic" of) one syndrome. Thus, it
is not surprising that prenatal overgrowth occurs in several syndromes,
including the Sotos and Weaver syndromes. Are they sufficiently different in
other respects to allow the postulation of locus (rather than allele)
heterogeneity? Phenotypic data in both conditions are biased because of
ascertainment of propositi, and the apparent differences between them may be
entirely artificial as they were between the G and BBB syndromes. On the other
hand, the Sotos syndrome may be a cancer syndrome, the Weaver syndrome not
(though a neuroblastoma was reported in the latter); in the former there is also
remarkably advanced dental maturation rarely commented on in the latter. In
Weaver syndrome there are more conspicuous contractures and a facial appearance
that experts find convincingly different from that of Sotos individuals.
Nevertheless, the hypothesis of locus heterogeneity is testable; at the moment
we are inclined to favor the hypothesis of allele heterogeneity. An
international effort is required to map, isolate, and sequence the causal gene
or genes.
DOI: 10.1002/(sici)1096-8628(19981002)79:4<294::aid-ajmg12>3.0.co;2-m
PMID: 9781911 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20802020 | 1. Cancer Epidemiol Biomarkers Prev. 2010 Oct;19(10):2562-9. doi:
10.1158/1055-9965.EPI-10-0447. Epub 2010 Aug 27.
Reproductive factors and exogenous hormone use in relation to risk of glioma and
meningioma in a large European cohort study.
Michaud DS(1), Gallo V, Schlehofer B, Tjønneland A, Olsen A, Overvad K, Dahm CC,
Kaaks R, Lukanova A, Boeing H, Schütze M, Trichopoulou A, Bamia C, Kyrozis A,
Sacerdote C, Agnoli C, Palli D, Tumino R, Mattiello A, Bueno-de-Mesquita HB, Ros
MM, Peeters PH, van Gils CH, Lund E, Bakken K, Gram IT, Barricarte A, Navarro C,
Dorronsoro M, Sánchez MJ, Rodríguez L, Duell EJ, Hallmans G, Melin BS, Manjer J,
Borgquist S, Khaw KT, Wareham N, Allen NE, Tsilidis KK, Romieu I, Rinaldi S,
Vineis P, Riboli E.
Author information:
(1)Department of Epidemiology and Public Health, Imperial College, London,
United Kingdom. [email protected]
BACKGROUND: The etiologies of glioma and meningioma tumors are largely unknown.
Although reproductive hormones are thought to influence the risk of these
tumors, epidemiologic data are not supportive of this hypothesis; however, few
cohort studies have published on this topic. We examined the relation between
reproductive factors and the risk of glioma and meningioma among women in the
European Prospective Investigation into Cancer and Nutrition (EPIC).
METHODS: After a mean of 8.4 years of follow-up, 193 glioma and 194 meningioma
cases were identified among 276,212 women. Information on reproductive factors
and hormone use was collected at baseline. Cox proportional hazard regression
was used to determine hazard ratios (HR) and 95% confidence intervals (95% CI).
RESULTS: No associations were observed between glioma or meningioma risk and
reproductive factors, including age at menarche, parity, age at first birth,
menopausal status, and age at menopause. A higher risk of meningioma was
observed among postmenopausal women who were current users of hormone
replacement therapy (HR, 1.79; 95% CI, 1.18-2.71) compared with never users.
Similarly, current users of oral contraceptives were at higher risk of
meningioma than never users (HR, 3.61; 95% CI, 1.75-7.46).
CONCLUSION: Our results do not support a role for estrogens and glioma risk. Use
of exogenous hormones, especially current use, seems to increase meningioma
risk. However, these findings could be due to diagnostic bias and require
confirmation.
IMPACT: Elucidating the role of hormones in brain tumor development has
important implications and needs to be further examined using biological
measurements.
©2010 AACR.
DOI: 10.1158/1055-9965.EPI-10-0447
PMCID: PMC2990203
PMID: 20802020 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20738039 | 1. Prescrire Int. 2010 Jun;19(107):120.
Postmenopausal hormone replacement therapy and meningioma.
[No authors listed]
A retrospective study including more than 350,000 women, about 1400 of whom had
developed meningioma, showed that the risk of meningioma was about twice as high
in users of postmenopausal hormone replacement therapy as in non-users. Hormone
replacement therapy should be discontinued if meningioma is diagnosed.
PMID: 20738039 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19011474 | 1. J Pediatr Hematol Oncol. 2008 Oct;30(10):758-60. doi:
10.1097/MPH.0b013e3181758974.
Weaver syndrome and neuroblastoma.
Coulter D(1), Powell CM, Gold S.
Author information:
(1)Division of Hematology-Oncology, Department of Pediatrics, University of
North Carolina School of Medicine, Chapel Hill, NC 27599-7220, USA.
[email protected]
Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and
Weaver syndrome have an increased risk of neoplasia. Two previous cases of
neuroblastoma have been reported in children with Weaver syndrome. We present a
third description of a patient with Weaver syndrome and neuroblastoma. In a
child with phenotypic characteristics consistent with Weaver syndrome,
evaluation for neuroblastoma should be considered.
DOI: 10.1097/MPH.0b013e3181758974
PMID: 19011474 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12807965 | 1. J Med Genet. 2003 Jun;40(6):436-40. doi: 10.1136/jmg.40.6.436.
Spectrum of NSD1 mutations in Sotos and Weaver syndromes.
Rio M(1), Clech L, Amiel J, Faivre L, Lyonnet S, Le Merrer M, Odent S, Lacombe
D, Edery P, Brauner R, Raoul O, Gosset P, Prieur M, Vekemans M, Munnich A,
Colleaux L, Cormier-Daire V.
Author information:
(1)Unité de Recherche sur les Handicaps Génétiques de l'Enfant, INSERM U-393, et
Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France.
Sotos syndrome is an overgrowth syndrome characterised by pre- and postnatal
overgrowth, macrocephaly, advanced bone age, and typical facial features. Weaver
syndrome is a closely related condition characterised by a distinctive
craniofacial appearance, advanced carpal maturation, widened distal long bones,
and camptodactyly. Haploinsufficiency of the NSD1 gene has recently been
reported as the major cause of Sotos syndrome while point mutations accounted
for a minority of cases. We looked for NSD1 deletions or mutations in 39
patients with childhood overgrowth. The series included typical Sotos patients
(23/39), Sotos-like patients (lacking one major criteria, 10/39), and Weaver
patients (6/39). We identified NSD1 deletions (6/33) and intragenic mutations
(16/33) in Sotos syndrome patients. We also identified NSD1 intragenic mutations
in 3/6 Weaver patients. We conclude therefore that NSD1 mutations account for
most cases of Sotos syndrome and a significant number of Weaver syndrome cases
in our series. Interestingly, mental retardation was consistently more severe in
patients with NSD1 deletions. Macrocephaly and facial gestalt but not overgrowth
and advanced bone age were consistently observed in Sotos syndrome patients. We
suggest therefore considering macrocephaly and facial gestalt as mandatory
criteria for the diagnosis of Sotos syndrome and overgrowth and advanced bone
age as minor criteria.
DOI: 10.1136/jmg.40.6.436
PMCID: PMC1735492
PMID: 12807965 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18076361 | 1. Clin Chem Lab Med. 2008;46(2):247-9. doi: 10.1515/CCLM.2008.024.
N-terminal proB-type natriuretic peptide (NT-proBNP) concentrations in elite
rugby players at rest and after active and passive recovery following strenuous
training sessions.
Banfi G(1), D'Eril GM, Barassi A, Lippi G.
Author information:
(1)IRCCS Galeazzi, Milan, Italy. [email protected]
BACKGROUND: The serum biomarker N-terminal proB-type natriuretic peptide
(NT-proBNP), a cleaved fragment of the brain natriuretic peptide (BNP) precursor
(amino acids 1-76), is accepted as a standard marker for evaluating and
monitoring cardiac injury characterized by myocardial wall stress. Strenuous
exercise may generate transitory ischemia, myocardial stress and diastolic left
ventricular dysfunction, possibly inducing increased concentrations of
NT-proBNP. A purported caveat to prolonged strenuous exercise is based on
evidence for biochemical and structural signs of heart dysfunction in
recreational athletes after continuous exertion.
METHODS: We compared NT-proBNP levels in three groups of physically fit
subjects: top-level rugby players, professional soccer players and healthy
controls. NT-proBNP concentrations were measured at rest and after an intensive
training session followed by two different recovery strategies (passive or
active).
RESULTS: A comparison of the three samples showed that NT-proBNP concentrations
in the rugby players were lower than those in controls at rest and were similar
to those in professional soccer players. Elevated post-training NT-proBNP levels
were unaffected by the type of recovery. The relatively high NT-proBNP levels
after active recovery when psychophysical stress is higher, because of cycling
and cold water immersion, suggest that not only endurance exercise, but also
strenuous, stressful short exercise can induce an increase in NT-proBNP
concentrations.
CONCLUSIONS: In this sample of professional athletes, NT-proBNP was low at rest,
and the increase after physical exercise was physiological.
DOI: 10.1515/CCLM.2008.024
PMID: 18076361 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20730482 | 1. Cancer Causes Control. 2010 Dec;21(12):2149-56. doi:
10.1007/s10552-010-9634-2. Epub 2010 Aug 21.
Exogenous sex hormone use and risk of meningioma: a population-based
case-control study in Finland.
Korhonen K(1), Raitanen J, Isola J, Haapasalo H, Salminen T, Auvinen A.
Author information:
(1)Unit of Neurosurgery, Turku University Hospital, PL 52, 20521 Turku, Finland.
[email protected]
BACKGROUND: Previous studies on association of exogenous female sex hormones and
risk for meningioma have yielded conflicting results. The aim of this study was
to evaluate the potential relation between prior use of menopausal hormone
therapy or oral contraception and risk of meningioma.
METHODS: This population-based case-control study was conducted during years
2000-2002 in Finland. All women aged 20-69 years with meningioma diagnosis were
identified from five university hospitals, and frequency-matched controls were
randomly chosen from population register. A total of 264 cases and 505 controls
were interviewed on their use of menopausal hormone therapy, oral and other
contraception, fertility treatment, treatment for gynecological problems, age at
menarche, and number of children. We also analyzed separately tumors expressing
progesterone or estrogen receptors. Of the successfully stained tumor specimens,
86.3% were positive for progesterone receptor and 50% for estrogen receptor.
RESULTS: Postmenopausal hormonal treatment, use of contraceptives, or fertility
treatment did not influence the risk of meningioma. In further analysis by
hormone receptor status, there was some indication for an increased risk of
progesterone receptor-positive meningiomas associated with oral contraceptive
use (OR 1.39, 95% confidence interval 0.92-2.10) and other hormonal
contraception (OR 1.50, 95% CI 0.95-2.36).
CONCLUSIONS: Overall, we found little indication that reproductive factors or
use of exogenous sex hormones affect meningioma risk.
DOI: 10.1007/s10552-010-9634-2
PMID: 20730482 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23592277 | 1. Am J Med Genet C Semin Med Genet. 2013 May;163C(2):86-91. doi:
10.1002/ajmg.c.31359. Epub 2013 Apr 16.
The NSD1 and EZH2 overgrowth genes, similarities and differences.
Tatton-Brown K(1), Rahman N.
Author information:
(1)Institute of Cancer Research, St George's University of London and the Royal
Marsden Hospital, London, UK. [email protected]
NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key
roles in the regulation of transcription through histone modification and
chromatin modeling: NSD1 preferentially methylates lysine residue 36 of histone
3 (H3K36) and is primarily associated with active transcription, while EZH2
shows specificity for lysine residue 27 (H3K27) and is associated with
transcriptional repression. Somatic dysregulation of NSD1 and EZH2 have been
associated with tumorigenesis. NSD1, as a fusion transcript with NUP98, plays a
key role in leukemogenesis, particularly childhood acute myeloid leukemia. EZH2
is a major proto-oncogene and mono- and biallelic activating and inactivating
somatic mutations occur as early events in the development of tumors,
particularly poor prognosis hematopoietic malignancies. Constitutional NSD1 and
EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth
syndromes with considerable phenotypic overlap. NSD1 mutations that cause Sotos
syndrome are loss-of-function, primarily truncating mutations or missense
mutations at key residues in functional domains. EZH2 mutations that cause
Weaver syndrome are primarily missense variants and the rare truncating
mutations reported to date are in the last exon, suggesting that simple
haploinsufficiency is unlikely to be generating the overgrowth phenotype
although the exact mechanism has not yet been determined. Many additional
questions about the molecular and clinical features of NSD1 and EZH2 remain
unanswered. However, studies are underway to address these and, as more cases
are ascertained and technology improves, it is hoped that these will, in time,
be answered.
Copyright © 2013 Wiley Periodicals, Inc.
DOI: 10.1002/ajmg.c.31359
PMCID: PMC4845886
PMID: 23592277 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12464997 | 1. Am J Hum Genet. 2003 Jan;72(1):132-43. doi: 10.1086/345647. Epub 2002 Dec 2.
NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of
Weaver syndrome but are rare in other overgrowth phenotypes.
Douglas J(1), Hanks S, Temple IK, Davies S, Murray A, Upadhyaya M, Tomkins S,
Hughes HE, Cole TR, Rahman N.
Author information:
(1)Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey,
United Kingdom.
Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive
facial appearance, height and head circumference >97th percentile, advanced bone
age, and developmental delay. Weaver syndrome is characterized by the same
criteria but has its own distinctive facial gestalt. Recently, a 2.2-Mb
chromosome 5q35 microdeletion, encompassing NSD1, was reported as the major
cause of Sotos syndrome, with intragenic NSD1 mutations identified in a minority
of cases. We evaluated 75 patients with childhood overgrowth, for intragenic
mutations and large deletions of NSD1. The series was phenotypically scored into
four groups, prior to the molecular analyses: the phenotype in group 1 (n=37)
was typical of Sotos syndrome; the phenotype in group 2 (n=13) was Sotos-like
but with some atypical features; patients in group 3 (n=7) had Weaver syndrome,
and patients in group 4 (n=18) had an overgrowth condition that was neither
Sotos nor Weaver syndrome. We detected three deletions and 32 mutations (13
frameshift, 8 nonsense, 2 splice-site, and 9 missense) that are likely to impair
NSD1 functions. The truncating mutations were spread throughout NSD1, but there
was evidence of clustering of missense mutations in highly conserved functional
domains between exons 13 and 23. There was a strong correlation between presence
of an NSD1 alteration and clinical phenotype, in that 28 of 37 (76%) patients in
group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4
had abnormalities of NSD1. Three patients with Weaver syndrome had NSD1
mutations, all between amino acids 2142 and 2184. We conclude that intragenic
mutations of NSD1 are the major cause of Sotos syndrome and account for some
Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes.
DOI: 10.1086/345647
PMCID: PMC378618
PMID: 12464997 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23101448 | 1. J Neurosurg. 2013 Mar;118(3):649-56. doi: 10.3171/2012.9.JNS12811. Epub 2012
Oct 26.
Exogenous hormone use, reproductive factors, and risk of intracranial meningioma
in females.
Claus EB(1), Calvocoressi L, Bondy ML, Wrensch M, Wiemels JL, Schildkraut JM.
Author information:
(1)Department of Epidemiology and Public Health, Yale University School of
Medicine, New Haven, Connecticut 06520, USA. [email protected]
OBJECT: The 2-fold higher incidence of meningioma in women compared with men has
long suggested a role for hormonally mediated risk factors, but specific
mechanisms remain elusive.
METHODS: The study included data obtained in 1127 women 29-79 years of age with
intracranial meningioma diagnosed among residents of Connecticut, Massachusetts,
North Carolina, the San Francisco Bay Area, and 8 Texas counties between May 1,
2006, and October 6, 2011, and data obtained in 1092 control individuals who
were frequency matched for age group and geography with meningioma patients.
RESULTS: No association was observed for age at menarche, age at menopause, or
parity and meningioma risk. Women who reported breastfeeding for at least 6
months were at reduced risk of meningioma (OR 0.78, 95% CI 0.63-0.96). A
significant positive association existed between meningioma risk and increased
body mass index (p < 0.01) while a significant negative association existed
between meningioma risk and current smoking (p < 0.01). Among premenopausal
women, current use of oral contraceptives was associated with an increased risk
of meningiomas (OR 1.8, 95% CI 1.1-2.9), while current use of hormone
replacement therapy among postmenopausal women was not associated with a
significant elevation in risk (OR 1.1, 95% CI 0.74-1.67). There was no
association between use of fertility medications and meningioma risk.
CONCLUSIONS: The authors' study confirms associations for body mass index,
breastfeeding, and cigarette smoking but provides little evidence for
associations of reproductive and menstrual factors with meningioma risk. The
relationship between current use of exogenous hormones and meningioma remains
unclear, limited by the small numbers of patients currently on oral hormone
medications and a lack of hormone receptor data for meningioma tumors.
DOI: 10.3171/2012.9.JNS12811
PMCID: PMC3756881
PMID: 23101448 [Indexed for MEDLINE]
Conflict of interest statement: Disclosure The authors report no conflict of
interest concerning the materials or methods used in this study or the findings
specified in this paper. The authors had full access to all of the data in the
study and take responsibility for the integrity of the data and the accuracy of
the data analysis. |
http://www.ncbi.nlm.nih.gov/pubmed/24138870 | 1. Cancer Epidemiol. 2013 Dec;37(6):876-80. doi: 10.1016/j.canep.2013.09.017.
Epub 2013 Oct 16.
Hormone replacement therapy and risk of glioma: a nationwide nested case-control
study.
Andersen L(1), Friis S, Hallas J, Ravn P, Gaist D.
Author information:
(1)Department of Neurology, Odense University Hospital, Institute of Clinical
Research, Faculty of Health Sciences, University of Southern Denmark, Sdr.
Boulevard 29, 5000 Odense C, Denmark.
AIM: Several studies indicate that use of hormone replacement therapy (HRT) is
associated with an increased risk of intracranial meningioma, while associations
between HRT use and risk of other brain tumors have been less explored. We
investigated the influence of HRT use on the risk of glioma in a nationwide
setting.
METHODS: Using population-based registries we conducted a case-control study
nested in the Danish female population. We identified all women aged 55-84 years
with a first diagnosis of histologically verified brain glioma during 2000-2009.
Using risk-set sampling, each case was matched on birth year to eight population
controls. Ever use of HRT was defined as ≥2 HRT prescriptions and categorized
according to type (oestrogens only, combined oestrogen-progestagen and
progestagen only) and duration of use (<1, ≥1 to <5, ≥5 to <10, and ≥10 years).
We used conditional logistic regression to compute odds ratios (ORs), with 95%
confidence intervals (CIs), for glioma associated with HRT use, adjusting for
potential confounders.
RESULTS: We identified 658 cases and 4350 controls. Ever use of HRT was
associated with an OR of 0.9 (95% CI: 0.8-1.1) for glioma. For long-term use
(≥10 years) we found ORs of 1.1 (95% CI: 0.7-1.7) for HRT overall, 1.6 (95% CI:
0.9-2.6) for oestrogen only, 0.8 (0.4-1.6) for combined oestrogen-progestagen,
and 2.2 (0.9-5.5) for progestagen. Tests for trends were statistically
non-significant in all strata.
CONCLUSION: Use of HRT overall was not associated with an increased risk of
glioma. However, our findings indicate that prolonged use of oestrogen only or
progestagen may be associated with an increased risk of glioma.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.canep.2013.09.017
PMID: 24138870 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24852293 | 1. J Med Genet. 2014 Aug;51(8):512-7. doi: 10.1136/jmedgenet-2014-102402. Epub
2014 May 22.
Mutations in SETD2 cause a novel overgrowth condition.
Luscan A(1), Laurendeau I(1), Malan V(2), Francannet C(3), Odent S(4), Giuliano
F(5), Lacombe D(6), Touraine R(7), Vidaud M(1), Pasmant E(1), Cormier-Daire
V(8).
Author information:
(1)EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences
Pharmaceutiques et Biologiques, Paris, France Service de Biochimie et de
Génétique Moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin,
Paris, France.
(2)Service d'Histo-Embryo-Cytogénétique, Université Paris Descartes, Sorbonne
Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
(3)Service de Génétique Médicale, CHU Estaing, Clermont-Ferrand, France.
(4)Université de Rennes 1, CNRS UMR6290, Service de Génétique Clinique, CHU
Hôpital Sud, Rennes, France.
(5)Service de Génétique Médicale, CHU Hôpital l'Archet 2, Nice, France.
(6)Service de Génétique Médicale, CHU de Bordeaux et EA4576, Université de
Bordeaux, Bordeaux, France.
(7)Service de Génétique, CHU de Saint-Etienne, hôpital Nord, Saint-Etienne,
France.
(8)INSERM UMR_1163, Département de génétique, Université Paris Descartes
Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants Malades,
Assistance Publique-Hôpitaux de Paris, Paris, France.
BACKGROUND: Overgrowth conditions are a heterogeneous group of disorders
characterised by increased growth and variable features, including macrocephaly,
distinctive facial appearance and various degrees of learning difficulties and
intellectual disability. Among them, Sotos and Weaver syndromes are clinically
well defined and due to heterozygous mutations in NSD1 and EZH2, respectively.
NSD1 and EZH2 are both histone-modifying enzymes. These two epigenetic writers
catalyse two specific post-translational modifications of histones: methylation
of histone 3 lysine 36 (H3K36) and lysine 27 (H3K27). We postulated that
mutations in writers of these two chromatin marks could cause overgrowth
conditions, resembling Sotos or Weaver syndromes, in patients with no NSD1 or
EZH2 abnormalities.
METHODS: We analysed the coding sequences of 14 H3K27 methylation-related genes
and eight H3K36 methylation-related genes using a targeted next-generation
sequencing approach in three Sotos, 11 'Sotos-like' and two Weaver syndrome
patients.
RESULTS: We identified two heterozygous mutations in the SETD2 gene in two
patients with 'Sotos-like' syndrome: one missense p.Leu1815Trp de novo mutation
in a boy and one nonsense p.Gln274* mutation in an adopted girl. SETD2 is
non-redundantly responsible for H3K36 trimethylation. The two probands shared
similar clinical features, including postnatal overgrowth, macrocephaly,
obesity, speech delay and advanced carpal ossification.
CONCLUSIONS: Our results illustrate the power of targeted next-generation
sequencing to identify rare disease-causing variants. We provide a compelling
argument for Sotos and Sotos-like syndromes as epigenetic diseases caused by
loss-of-function mutations of epigenetic writers of the H3K36 histone mark.
Published by the BMJ Publishing Group Limited. For permission to use (where not
already granted under a licence) please go to
http://group.bmj.com/group/rights-licensing/permissions.
DOI: 10.1136/jmedgenet-2014-102402
PMID: 24852293 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25282520 | 1. Lancet. 2015 Jan 24;385(9965):341-50. doi: 10.1016/S0140-6736(14)61374-X. Epub
2014 Oct 1.
Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia
(TESLA Part B): a randomised, double-blind, placebo-controlled trial.
Raal FJ(1), Honarpour N(2), Blom DJ(3), Hovingh GK(4), Xu F(2), Scott R(2),
Wasserman SM(2), Stein EA(5); TESLA Investigators.
Collaborators: Descamps O, Gaudet D, Blaha V, Soska V, Zemek S, Bruckert E,
Farnier M, Sampietro T, Jambart S, Abi-Fadel M, Hovingh GK, Blom D, Raal F,
Fuentes Jimenez F, Karlezi RA, Vidal Pardo JI, Ginsberg H, Stein E, Turner T,
Hennekens CH, Andreotti F, Baigent C, Brown WV, Davis B, Wiviott SD.
Author information:
(1)Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences,
University of Witwatersrand, Johannesburg, South Africa.
(2)Amgen Inc, One Amgen Center Drive, Thousand Oaks, CA, USA.
(3)Division of Lipidology, Department of Medicine, University of Cape Town, UCT
Faculty Health Sciences, Cape Town, South Africa.
(4)Vascular Medicine, Academic Medical Centre, Amsterdam, Netherlands.
(5)Metabolic and Atherosclerosis Research Center, Cincinnati, OH, USA.
Electronic address: [email protected].
Comment in
Lancet. 2015 Jan 24;385(9965):307-10. doi: 10.1016/S0140-6736(14)61702-5.
Nat Rev Cardiol. 2014 Dec;11(12):687. doi: 10.1038/nrcardio.2014.169.
BACKGROUND: Homozygous familial hypercholesterolaemia is a rare, serious
disorder caused by very low or absent plasma clearance of LDL, substantially
raised LDL cholesterol, and accelerated development of cardiovascular disease.
Conventional lipid-lowering treatments are modestly effective. Evolocumab, a
monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9),
reduced LDL cholesterol by 16% in a pilot study. We now report results with
evolocumab in a randomised, double-blind, placebo-controlled phase 3 trial.
METHODS: This randomised, double-blind, placebo-controlled phase 3 trial was
undertaken at 17 sites in ten countries in North America, Europe, the Middle
East, and South Africa. 50 eligible patients (aged ≥12 years) with homozygous
familial hypercholesterolaemia, on stable lipid-regulating therapy for at least
4 weeks, and not receiving lipoprotein apheresis, were randomly allocated by a
computer-generated randomisation sequence in a 2:1 ratio to receive subcutaneous
evolocumab 420 mg or placebo every 4 weeks for 12 weeks. Randomisation was
stratified by LDL cholesterol at screening (<11 mmol/L or ≥11 mmol/L) and
implemented by a computerised interactive voice-response system. Patients, study
personnel, and the funder were masked to treatment and to the efficacy results
by the central laboratory not returning LDL cholesterol or any lipid results to
the clinical sites after the baseline visit. The primary endpoint was percentage
change in ultracentrifugation LDL cholesterol from baseline at week 12 compared
with placebo, analysed by intention-to-treat. This trial is registered with
ClinicalTrials.gov, number NCT01588496.
FINDINGS: Of the 50 eligible patients randomly assigned to the two treatment
groups, 49 actually received the study drug and completed the study (16 in the
placebo group and 33 in the evolocumab group). Compared with placebo, evolocumab
significantly reduced ultracentrifugation LDL cholesterol at 12 weeks by 30·9%
(95% CI -43·9% to -18·0%; p<0·0001). Treatment-emergent adverse events occurred
in ten (63%) of 16 patients in the placebo group and 12 (36%) of 33 in the
evolocumab group. No serious clinical or laboratory adverse events occurred, and
no anti-evolocumab antibody development was detected during the study.
INTERPRETATION: In patients with homozygous familial hypercholesterolaemia
receiving stable background lipid-lowering treatment and not on apheresis,
evolocumab 420 mg administered every 4 weeks was well tolerated and
significantly reduced LDL cholesterol compared with placebo.
FUNDING: Amgen Inc.
Copyright © 2015 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(14)61374-X
PMID: 25282520 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22287508 | 1. Oncotarget. 2012 Jan;3(1):3-4. doi: 10.18632/oncotarget.436.
Histone modification defects in developmental disorders and cancer.
Cross NC.
Comment on
Oncotarget. 2011 Dec;2(12):1127-33. doi: 10.18632/oncotarget.385.
Clinically, Weaver syndrome is closely related to Sotos syndrome, which is
frequently caused by mutations in NSD1. This gene also encodes a histone
methyltransferase, in this case with activity against histone H3 lysine 36. NSD1
is mutated in carcinoma of the upper aerodigestive tract
(www.sanger.ac.uk/genetics/CGP/cosmic/) and also fuses to NUP98 in acute myeloid
leukemia. Looking more widely, whole exome screens in lymphoma, multiple
myeloma, renal carcinoma and other malignancies have identified genes encoding
diverse histone modifiers as targets of somatic mutation. Strikingly, several of
these (e.g. MLL2, EP300, CREBBP, ASXL1) are also mutated in human developmental
disorders thus pointing towards a remarkable and unexpected convergence between
somatic and germline genetics.
DOI: 10.18632/oncotarget.436
PMCID: PMC3292885
PMID: 22287508 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25335165 | 1. Int J Cancer. 2015 May 15;136(10):2369-77. doi: 10.1002/ijc.29274. Epub 2014
Nov 12.
Menopausal hormone therapy and central nervous system tumor risk: large UK
prospective study and meta-analysis.
Benson VS(1), Kirichek O, Beral V, Green J.
Author information:
(1)Cancer Epidemiology Unit, Nuffield Department of Population Health,
University of Oxford, Richard Doll Building, Roosevelt Drive, Oxford, OX3 7LF,
United Kingdom.
Female sex hormones are thought to affect women's risk of developing central
nervous system (CNS) tumors. Some have reported an increased risk in users of
menopausal hormone therapy (HT) but evidence is limited. In the UK General
Practice Research Database we compared prospectively collected information on HT
prescriptions in women aged 50-79 years with CNS tumors diagnosed in 1987-2011
with that in matched controls (four per case). Relative risks (RRs) in relation
to prescribed HT were calculated overall and by CNS tumor subtype. Statistical
tests are two-sided. For all CNS tumors (n = 3,500), glioma (n = 689),
meningioma (n = 1,197), acoustic neuroma (n = 439), and pituitary tumors (n =
273) adjusted RRs for women prescribed HT versus not were, respectively, 1.21
(95% confidence intervals (CI) = 1.10-1.32, p < 0.0001), 1.14 (0.93-1.40, p =
0.2), 1.30 (1.11-1.51, p = 0.001), 1.37 (1.06-1.75, p = 0.01), and 1.35
(0.99-1.85, p = 0.06). There was no significant difference in risk by tumor
subtype (p(heterogeneity) = 0.6). A meta-analysis was conducted, combining our
results with those from other published studies with prospectively collected
exposure information. The meta-analyses yielded significantly increased risks
for all CNS tumors, glioma and meningioma in users of estrogen-only [1.35
(1.22-1.49), 1.23 (1.06-1.42) and 1.31 (1.20-1.43), respectively] but not
estrogen-progestin HT [1.09 (0.99-1.19), 0.92 (0.78-1.08) and 1.05 (0.95-1.16),
respectively]; these differences were statistically significant (p < 0.005 for
each tumor type). There was no significant difference between glioma and
meningioma risk in users of estrogen-only HT. The totality of the available
evidence suggests an increased risk of all CNS tumors (and of glioma and
meningioma separately) in users of estrogen-only HT. Absolute excess risk (2 per
10,000 users over 5 years) is small.
© 2014 UICC.
DOI: 10.1002/ijc.29274
PMID: 25335165 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24953393 | 1. Curr Pharm Des. 2014;20(40):6350-7. doi: 10.2174/1381612820666140620154545.
Hypolipidaemic drug treatment: yesterday is not gone yet, today is challenging
and tomorrow is coming soon; let us combine them all.
Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP(1).
Author information:
(1)Dept. of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal
Free Hospital campus, University College London Medical School, University
College London (UCL), Pond Street, London NW3 2QG, UK. [email protected].
Statins remain the cornerstone of hypolipidaemic drug treatment. The recent
American College of Cardiology (ACC)/American Heart Association (AHA) lipid
guidelines suggest using percent reductions of low density lipoprotein
cholesterol (LDL-C), according to cardiovascular disease (CVD) risk, rather than
specific LDL-C targets. These guidelines raised concerns and other Societies
(US, International, European) have not endorsed them. The implementation of
previous guidelines in clinical practice is suboptimal due to attitudes of
physicians and restrictions in health care systems. Monoclonal antibodies that
inhibit proprotein convertase subtilisin/ kexin type 9 (PCSK9), which degrades
the LDL receptor, like alirocumab and evolocumab, are in phase 3 trials. These
drugs are suitable for statin intolerant or resistant patients, heterozygous
familial hypercholesterolaemia (HeFH) and some forms of homozygous FH (HoFH).
Mipomersen (antisense oligonucleotide against apolipoprotein B) and lomitapide
(microsomal triglyceride transfer protein blocker) have already been approved
for HoFH. Eventually, silencing micro-RNA oligonucleotides may also become
available. The repair or silencing of genes implicated in hyperlipidaemia and/or
atherosclerosis is also on the horizon. If the new therapeutic options mentioned
above prove to be effective and safe then by combining them with statins and/or
ezetimibe we should be able to effectively control acquired or hereditary
dyslipidaemias and substantially further reduce CVD morbidity and mortality.
DOI: 10.2174/1381612820666140620154545
PMID: 24953393 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24678979 | 1. N Engl J Med. 2014 May 8;370(19):1809-19. doi: 10.1056/NEJMoa1316222. Epub
2014 Mar 29.
A 52-week placebo-controlled trial of evolocumab in hyperlipidemia.
Blom DJ(1), Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, Ceska R, Roth
E, Koren MJ, Ballantyne CM, Monsalvo ML, Tsirtsonis K, Kim JB, Scott R,
Wasserman SM, Stein EA; DESCARTES Investigators.
Collaborators: Arya K, McKeirnan M, Sullivan D, Watts G, Paulweber B, Cornelli
K, De Meulemeester M, Mortelmans J, Vanriet D, Bergeron J, Dzongowski P, Gupta
A, Henein S, Lasko B, Powell C, Adamkova V, Cermak O, Ceska R, Charvat J, Hala
T, Hamouz Z, Macha J, Rosolova H, Smejkalova O, Spinar J, Vojacek J, Krogsaa A,
Storgaard Nedergaard B, Wermuth S, Bajnok L, Farsang C, Forster T, Laszlo Z,
Lupkovics G, Papp A, Szakal I, Zsom M, Blom D, Burgess L, Coetzee K, Ebrahim I,
Lombaard J, Middlemost S, Naidoo V, Pillay S, Arslanian A, Ballantyne C, Bays H,
Beasley R, Bolognese M, Brazg R, Connery L, Elinoff V, Harper W, Hoekstra J,
Huehnergarth K, Huling R, Kivitz A, Koren M, Lillestol M, Lipetz R, Makam S,
Marx P, Nakhle S, Oh J, Pleskow W, Rankin B, Remler R, Rhee M, Ries D, Roth E,
Rubino J, Saway W, Schramm R, Strout C, Toth P, Turner T, Watkins L, Weiss R,
Wenker M, Williams H, Hennekens CH, Andreotti F, Baigent C, Brown WV, Davis B,
Wiviott SD, Turner T, Tarr WE Jr.
Author information:
(1)From the Division of Lipidology, Department of Medicine, University of Cape
Town, Cape Town (D.J.B.), and TREAD Research, Cardiology Unit, Department of
Internal Medicine, Tygerberg Hospital and Stellenbosch University, Parow (L.B.)
- both in South Africa; Center for Clinical and Basic Research, Pardubice
(T.H.), and Center of Preventive Cardiology, Third Department of Internal
Medicine, Charles University, Prague (R.C.) - both in the Czech Republic;
Bethesda Health Research Center, Bethesda, MD (M.B.); Lillestol Research, Fargo,
ND (M.J.L.); Midwest Institute for Clinical Research, Indianapolis (P.D.T.);
Sterling Research Group (E.R.) and Metabolic and Atherosclerosis Research Center
(E.A.S.) - both in Cincinnati; Jacksonville Center for Clinical Research,
Jacksonville, FL (M.J.K.); Baylor College of Medicine and the Houston Methodist
DeBakey Heart and Vascular Center, Houston (C.M.B.); Amgen, Thousand Oaks, CA
(M.L.M., J.B.K., R.S., S.M.W.); and Amgen, Uxbridge, United Kingdom (K.T.).
Comment in
N Engl J Med. 2014 Aug 28;371(9):877-8. doi: 10.1056/NEJMc1408237.
N Engl J Med. 2014 Aug 28;371(9):876. doi: 10.1056/NEJMc1408237.
N Engl J Med. 2014 Aug 28;371(9):876-7. doi: 10.1056/NEJMc1408237.
Nature. 2017 Mar 17;543(7646):463-464. doi: 10.1038/nature.2017.21661.
BACKGROUND: Evolocumab, a monoclonal antibody that inhibits proprotein
convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density
lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3
trial to evaluate the safety and efficacy of 52 weeks of treatment with
evolocumab.
METHODS: We stratified patients with hyperlipidemia according to the risk
categories outlined by the Adult Treatment Panel III of the National Cholesterol
Education Program. On the basis of this classification, patients were started on
background lipid-lowering therapy with diet alone or diet plus atorvastatin at a
dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a
dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period
of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter
(1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to
receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end
point was the percent change from baseline in LDL cholesterol, as measured by
means of ultracentrifugation, at week 52.
RESULTS: Among the 901 patients included in the primary analysis, the overall
least-squares mean (±SE) reduction in LDL cholesterol from baseline in the
evolocumab group, taking into account the change in the placebo group, was
57.0±2.1% (P<0.001). The mean reduction was 55.7±4.2% among patients who
underwent background therapy with diet alone, 61.6±2.6% among those who received
10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin,
and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin
and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also
significantly reduced levels of apolipoprotein B, non-high-density lipoprotein
cholesterol, lipoprotein(a), and triglycerides. The most common adverse events
were nasopharyngitis, upper respiratory tract infection, influenza, and back
pain.
CONCLUSIONS: At 52 weeks, evolocumab added to diet alone, to low-dose
atorvastatin, or to high-dose atorvastatin with or without ezetimibe
significantly reduced LDL cholesterol levels in patients with a range of
cardiovascular risks. (Funded by Amgen; DESCARTES ClinicalTrials.gov number,
NCT01516879.).
DOI: 10.1056/NEJMoa1316222
PMID: 24678979 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24859266 | 1. MAbs. 2014 Jul-Aug;6(4):1103-13. doi: 10.4161/mabs.28719. Epub 2014 Apr 16.
Characterization of a quantitative method to measure free proprotein convertase
subtilisin/kexin type 9 in human serum.
Colbert A, Umble-Romero A(1), Prokop S(1), Xu R(1), Gibbs J(1), Pederson S(1).
Author information:
(1)Department of Pharmacokinetics and Drug Metabolism; Amgen Inc.; Seattle, WA
USA.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that
plays an important role in the regulation of serum low-density lipoprotein (LDL)
cholesterol by downregulation of LDL receptor, and as such is considered a novel
target in cholesterol lowering therapy. In support of the drug development
program for Evolocumab, a fully human IgG₂ antibody that targets PCSK9, a
quantitative ELISA to measure free PCSK9 in human serum was developed. PCSK9
serves as a biomarker of pharmacological response during treatment, and
measuring levels of the free ligand post-dosing was of interest as an aid to
establishing the pharmacokinetic and pharmacodynamic properties of the
therapeutic. Given the complexities associated with the measurement of free
ligand in the presence of high concentrations of circulating drug, it was
important to challenge the method with experiments designed to assess ex vivo
conditions that have the potential to affect the binding equilibrium of drug and
ligand within test samples during routine sampling handling and assay
conditions. Herein, we report results of experiments that were conducted to
characterize the assay in alignment with regulatory guidance and industry
standards, and to establish evidence that the method is measuring the free
ligand in circulation at the time serum was collected. A robust supporting data
package was generated that demonstrates the method specifically and reproducibly
measures the free ligand, and is suitable for its intended use.
DOI: 10.4161/mabs.28719
PMCID: PMC4171013
PMID: 24859266 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25002170 | 1. G Ital Cardiol (Rome). 2014 May;15(5):301-5. doi: 10.1714/1563.17029.
[PCSK9 inhibitors and dyslipidemias: an update on clinical evidence].
[Article in Italian]
Norata GD.
Elevated plasma LDL cholesterol (LDL-C) levels are associated with
cardiovascular diseases and statin therapy was proven to decrease LDL-C and
reduce cardiovascular death. However, in patients at high cardiovascular risk,
achievement of optimal LDL-C levels is challenging, and therefore additional
strategies for further loweing LDL-C levels are under development. Recently,
silencing of apolipoprotein B gene and MTP inhibition have been approved for the
treatment of patients with familial hypercholesterolemia, and there is great
interest in the inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9).
PCSK9 promotes the degradation of the LDL receptor. The inhibition of PCSK9
favors LDL catabolism and reduces plasma LDLC levels. Monoclonal antibodies
against PCSK9 represent so far the most advanced approach in clinical
development, with alirocumab, evolocumab and bococizumab under advanced clinical
development. Recent data from the first phase III studies show LDL-C reduction
in monotherapy and on top of statins. Long-term studies on cardiovascular
endpoints are ongoing and the results will be crucial to translate the benefit
of this promising approach into clinical practice.
DOI: 10.1714/1563.17029
PMID: 25002170 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19660540 | 1. Genomics. 2009 Nov;94(5):308-16. doi: 10.1016/j.ygeno.2009.07.005. Epub 2009
Aug 4.
Short ultraconserved promoter regions delineate a class of preferentially
expressed alternatively spliced transcripts.
Rödelsperger C(1), Köhler S, Schulz MH, Manke T, Bauer S, Robinson PN.
Author information:
(1)Institute for Medical Genetics, Charité-Universitätsmedizin Berlin,
Augustenburger Platz 1, 13353 Berlin, Germany.
Ultraconservation has been variously defined to describe sequences that have
remained identical or nearly so over long periods of evolution to a degree that
is higher than expected for sequences under typical constraints associated with
protein-coding sequences, splice sites, or transcription factor binding sites.
Most intergenic ultraconserved elements (UCE) appear to be tissue-specific
enhancers, whereas another class of intragenic UCEs is involved in regulation of
gene expression by means of alternative splicing. In this study we define a set
of 2827 short ultraconserved promoter regions (SUPR) in 5 kb upstream regions of
1268 human protein-coding genes using a definition of 98% identity for at least
30 bp in 7 mammalian species. Our analysis shows that SUPRs are enriched in
genes playing a role in regulation and development. Many of the genes having a
SUPR-containing promoter have additional alternative promoters that do not
contain SUPRs. Comparison of such promoters by CAGE tag, EST, and Solexa read
analysis revealed that SUPR-associated transcripts show a significantly higher
mean expression than transcripts associated with non-SUPR-containing promoters.
The same was true for the comparison between all SUPR-associated and
non-SUPR-associated transcripts on a genome-wide basis. SUPR-associated genes
show a highly significant tendency to occur in regions that are also enriched
for intergenic short ultraconserved elements (SUE) in the vicinity of
developmental genes. A number of predicted transcription factor binding sites
(TFBS) are overrepresented in SUPRs and SUEs, including those for transcription
factors of the homeodomain family, but in contrast to SUEs, SUPRs are also
enriched in core-promoter motifs. These observations suggest that SUPRs
delineate a distinct class of ultraconserved sequences.
DOI: 10.1016/j.ygeno.2009.07.005
PMID: 19660540 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25410046 | 1. Curr Atheroscler Rep. 2015 Jan;17(1):465. doi: 10.1007/s11883-014-0465-6.
Lipoprotein apheresis in the management of familial hypercholesterolaemia:
historical perspective and recent advances.
Stefanutti C(1), Thompson GR.
Author information:
(1)Extracorporeal Therapeutic Techniques Unit, Lipid Clinic and Atherosclerosis
Prevention Centre, Immunohematology and Transfusion Medicine, 'Umberto I'
Hospital, Rome, Italy, [email protected].
At present, lipoprotein apheresis, combined with high-dose statin and ezetimibe
therapy, is the best available means of treating patients with homozygous and
statin-refractory heterozygous familial hypercholesterolaemia (FH). However, the
extent of cholesterol-lowering achieved is often insufficient to meet the
targets set by current guidelines. The recent advent of three new classes of
lipid-lowering agents provides new hope that the latter objective may now be
achievable. These compounds act either by reducing low-density lipoprotein (LDL)
production by inhibiting apolipoprotein B synthesis with an antisense
oligonucleotide (mipomersen) or by inhibiting microsomal triglyceride transfer
protein (lomitapide), or by enhancing LDL catabolism via monoclonal
antibody-mediated inhibition of the activity of proprotein convertase
subtilisin/kexin 9 (PCSK9) (evolocumab). Depending on the outcome of current
trials, it seems likely that these compounds, used alone or combined with
lipoprotein apheresis, will markedly improve the management of refractory FH.
DOI: 10.1007/s11883-014-0465-6
PMID: 25410046 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23393190 | 1. Nucleic Acids Res. 2013 Apr 1;41(6):3600-18. doi: 10.1093/nar/gkt030. Epub
2013 Feb 7.
Highly conserved elements discovered in vertebrates are present in non-syntenic
loci of tunicates, act as enhancers and can be transcribed during development.
Sanges R(1), Hadzhiev Y, Gueroult-Bellone M, Roure A, Ferg M, Meola N, Amore G,
Basu S, Brown ER, De Simone M, Petrera F, Licastro D, Strähle U, Banfi S,
Lemaire P, Birney E, Müller F, Stupka E.
Author information:
(1)Laboratory of Animal Physiology and Evolution, Stazione Zoologica Anton
Dohrn, Villa Comunale, 80121 Naples, Italy.
Co-option of cis-regulatory modules has been suggested as a mechanism for the
evolution of expression sites during development. However, the extent and
mechanisms involved in mobilization of cis-regulatory modules remains elusive.
To trace the history of non-coding elements, which may represent candidate
ancestral cis-regulatory modules affirmed during chordate evolution, we have
searched for conserved elements in tunicate and vertebrate (Olfactores) genomes.
We identified, for the first time, 183 non-coding sequences that are highly
conserved between the two groups. Our results show that all but one element are
conserved in non-syntenic regions between vertebrate and tunicate genomes, while
being syntenic among vertebrates. Nevertheless, in all the groups, they are
significantly associated with transcription factors showing specific functions
fundamental to animal development, such as multicellular organism development
and sequence-specific DNA binding. The majority of these regions map onto
ultraconserved elements and we demonstrate that they can act as functional
enhancers within the organism of origin, as well as in cross-transgenesis
experiments, and that they are transcribed in extant species of Olfactores. We
refer to the elements as 'Olfactores conserved non-coding elements'.
DOI: 10.1093/nar/gkt030
PMCID: PMC3616699
PMID: 23393190 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7578083 | 1. Biochemistry. 1995 Nov 14;34(45):14752-7. doi: 10.1021/bi00045a016.
A cytosine methyltransferase converts 5-methylcytosine in DNA to thymine.
Yebra MJ(1), Bhagwat AS.
Author information:
(1)Department of Chemistry, Wayne State University, Detroit, Michigan
48202-3489, USA.
Sites of cytosine methylation are known to be hot spots for C.G to T.A mutations
in a number of systems, including human cells. Traditionally, spontaneous
hydrolytic deamination of 5-methylcytosine to thymine has been invoked as the
cause of this phenomenon. We show here that a bacterial cytosine
methyltransferase can convert 5-methylcytosine in DNA to thymine and that this
reaction creates a mutational hot spot at a site of DNA methylation. The
reaction is fairly insensitive to the methyl donor in the reaction,
S-adenosylmethionine. In many cancers, the most frequent class of mutations is C
to T changes within CG dinucleotides of the tumor suppressor gene p53. Because
of the similarities of the reaction mechanisms of mammalian and bacterial
enzymes and the physiology of the cancer cells, this reaction is expected to
contribute to mutations at CG dinucleotides in precancerous cells.
DOI: 10.1021/bi00045a016
PMID: 7578083 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24953396 | 1. Curr Pharm Des. 2014;20(40):6220-9. doi: 10.2174/1381612820666140620125213.
Familial hypercholesterolemia: etiology, diagnosis and new treatment options.
Gouni-Berthold I, Berthold HK(1).
Author information:
(1)Center of Endocrinology, Diabetes and Preventive Medicine (ZEDP), University
of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
[email protected].
Familial hypercholesterolemia (FH) is a common genetic disorder that presents
with robust increases in low-density lipoprotein cholesterol (LDL-C) and can
lead to premature cardiovascular disease. There are heterozygous and homozygous
forms. The diagnosis is usually made based on blood cholesterol levels, clinical
signs and family history. Genetic testing can be used to confirm the diagnosis.
Effective lowering of LDL-C in FH can prevent cardiovascular morbidity and
mortality, however, the disease remains greatly underdiagnosed. The mainstay of
pharmacologic therapy in FH patients is high-dose statins, which are often
combined with other lipid-lowering agents. The homozygous form is mainly treated
with lipid apheresis. Guideline-recommended target levels of LDL-C are often not
reached, making new treatment options desirable. Four classes of newer
lipid-lowering drugs offer promising advances in treating FH, namely the
apolipoprotein-B synthesis inhibitors (mipomersen), the microsomal transfer
protein inhibitors (lomitapide), the cholesterol ester transfer protein
inhibitors (anacetrapib, evacetrapib) and the proprotein convertase
subtilisin/kexin type 9 inhibitors (evolocumab, alirocumab). In this review, the
available evidence regarding the use of these drugs in patients with FH is
discussed, with particular focus on their efficacy and safety.
DOI: 10.2174/1381612820666140620125213
PMID: 24953396 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24214728 | 1. Am J Med Genet A. 2013 Dec;161A(12):2972-80. doi: 10.1002/ajmg.a.36229. Epub
2013 Nov 8.
Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.
Tatton-Brown K(1), Murray A, Hanks S, Douglas J, Armstrong R, Banka S, Bird LM,
Clericuzio CL, Cormier-Daire V, Cushing T, Flinter F, Jacquemont ML, Joss S,
Kinning E, Lynch SA, Magee A, McConnell V, Medeira A, Ozono K, Patton M, Rankin
J, Shears D, Simon M, Splitt M, Strenger V, Stuurman K, Taylor C, Titheradge H,
Van Maldergem L, Temple IK, Cole T, Seal S; Childhood Overgrowth Consortium;
Rahman N.
Collaborators: Addor MC, Akgul M, Amor D, Anderson K, Anderson R, Andries S,
Archer H, Armstrong R, Ashton-Prolla P, Bahceci M, Baralle D, Barnicoat A,
Barrow M, Baujat G, Baynam G, Beales P, Becker K, Beckh-Arnold E, Ben-Yehuda A,
Berg J, Bernhard B, Bhal S, Bhat M, Birch J, Bird L, Bitner M, Blair E, Bliek J,
Blyth M, Bottani A, Bradley L, Brady A, Breatnach F, Brueton L, Buehler B, Burke
A, Burn J, Campbell J, Canham N, Castle B, Chandler K, Chandrasena R, Chang E,
Chu C, Christenden C, Cilliers D, Clarke A, Clayton-Smith J, Clericuzio C,
Clowes V, Cole T, Colley A, Collins A, Connell F, Cook J, Cordeiro HI, Crocker
C, Crow Y, Culic V, Cushing T, Dabir T, Dalton A, Danda S, Davidson R, Davies S,
Day R, De Roy M, de Soberanis V, Dearnaley D, Dennis N, Deshpande C, Desouza B,
Devlin L, Differ AM, Dinwiddie R, Dixit A, Dobbie A, Dominguez J, Donaldson A,
Donnai D, Doz M, Dupont J, Eastwood D, Edwards M, Ellis I, Elmslie F, Evans R,
Faravelli F, Firth H, Fisher R, Fiskerstrand T, Fitzpatrick D, Flanagan A,
Flinter F, Foley P, Foulds N, Foulkes W, Franklin J, Fryer A, Gallagher A,
Garcia S, Gardiner C, Gardner M, Garrett C, Gener B, Gerrard M, Gibbons R,
Gillerot Y, Goel H, Goudie D, Gowrishankar K, Graham C, Green A, Gregersen N,
Hale J, Harper J, Harrison R, Hughes H, Henderson A, Henman P, Hennekam R,
Hobson E, Holder M, Holder S, Homfray T, Horovitz D, Huma Z, Hurst J, Hwu WL,
Irvine A, Irving M, Izatt L, Jacquemont ML, Jagadeesh S, Jenkins L, Jessen C,
Johnson D, Jones E, Jones L, Josifova D, Joss S, Kanabar, Kannu P,
Keppler-Noreuil K, Kerr B, Kingston H, Kingston J, Kini U, Kinning E, Krause A,
Kumar A, Kumar D, Lachlan K, Lam W, Lapunzina P, Lees M, Leonard N, Lewis I,
Liebelt J, Livesey A, Longman C, Lopponen T, Lozano, Lucassen A, Lunt P, Lynch
SA, Lyonnet S, MacDonnell J, Magee A, Maher E, Maitz S, Male A, Mansour S,
McConnell V, McDevitt T, McEntagart M, McGillivray G, McGowan R, McKee S,
McKeown C, Meany C, Medeira A, Mehta S, Meiner V, Metcalfe K, Milstein K,
Mohammed S, Monaghan G, Montgomery T, Morgan A, Morland B, Morrison P, Morton J,
Mudgal R, Munaza A, Murday V, Nampoothiri S, Nathanson K, Neas K, Nemeth A, Neri
G, Newbury-Ecob R, Ockeloen C, Oley C, Owen C, Ozono K, Panarello C, Park SM,
Parker M, Patel C, Patton M, Payne S, Pilz D, Pinkney M, Plecko B, Pocha M,
Pottinger C, Prescott K, Price S, Pritchard-Jones K, Proctor A, Quarrell O,
Raith W, Rankin J, Raymond L, Rea G, Reardon W, Reid E, Rees H, Rittinger O,
Robards M, Roposch A, Rosser E, Rothschild A, Rourke D, Ruddy D, Saggar A, Saleh
N, Saletti V, Sampson J, Sandford R, Santos H, Sarkar A, Scott R, Scurr I,
Selicorni A, Semple R, Sharif S, Shaw A, Shaw-Smith C, Shears D, Shelagh J,
Simon M, Smith G, Smithson S, Splitt M, Stevens M, Stewart A, Stopps K, Stuurman
K, Suri M, Swain A, Tanateles G, Taylor A, Taylor C, Teixeira M, Temple K,
Thomas E, Thompson E, Thonney F, Tischkowitz M, Tolmie J, Tomkins S, Turkmen S,
Turner A, Turnpenny P, Van-Haelst M, Van Maldergem L, Vasudevan P, Verellen C,
Verma IC, Vigneron J, Wakeling E, Wainwright L, Walker L, Wheeler P, White K,
Williams D, Wilson L, Winter R, Woods G, Wright M, Yachelevich N, Yeung A, Zankl
A, Stewart F, Stewart H, Sweeney E.
Author information:
(1)Division of Genetics & Epidemiology, Institute of Cancer Research, Sutton,
UK.
Weaver syndrome, first described in 1974, is characterized by tall stature, a
typical facial appearance, and variable intellectual disability. In 2011,
mutations in the histone methyltransferase, EZH2, were shown to cause Weaver
syndrome. To date, we have identified 48 individuals with EZH2 mutations. The
mutations were primarily missense mutations occurring throughout the gene, with
some clustering in the SET domain (12/48). Truncating mutations were uncommon
(4/48) and only identified in the final exon, after the SET domain. Through
analyses of clinical data and facial photographs of EZH2 mutation-positive
individuals, we have shown that the facial features can be subtle and the
clinical diagnosis of Weaver syndrome is thus challenging, especially in older
individuals. However, tall stature is very common, reported in >90% of affected
individuals. Intellectual disability is also common, present in ~80%, but is
highly variable and frequently mild. Additional clinical features which may help
in stratifying individuals to EZH2 mutation testing include camptodactyly, soft,
doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic
overlap between Sotos and Weaver syndromes is also evident. The identification
of an EZH2 mutation can therefore provide an objective means of confirming a
subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos
syndromes. As mutation testing becomes increasingly accessible and larger
numbers of EZH2 mutation-positive individuals are identified, knowledge of the
clinical spectrum and prognostic implications of EZH2 mutations should improve.
© 2013 Wiley Periodicals, Inc.
DOI: 10.1002/ajmg.a.36229
PMID: 24214728 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22094949 | 1. Nat Rev Genet. 2011 Nov 18;12(12):861-74. doi: 10.1038/nrg3074.
Non-coding RNAs in human disease.
Esteller M(1).
Author information:
(1)Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research
Institute, Barcelona, Catalonia, Spain. [email protected]
The relevance of the non-coding genome to human disease has mainly been studied
in the context of the widespread disruption of microRNA (miRNA) expression and
function that is seen in human cancer. However, we are only beginning to
understand the nature and extent of the involvement of non-coding RNAs (ncRNAs)
in disease. Other ncRNAs, such as PIWI-interacting RNAs (piRNAs), small
nucleolar RNAs (snoRNAs), transcribed ultraconserved regions (T-UCRs) and large
intergenic non-coding RNAs (lincRNAs) are emerging as key elements of cellular
homeostasis. Along with microRNAs, dysregulation of these ncRNAs is being found
to have relevance not only to tumorigenesis, but also to neurological,
cardiovascular, developmental and other diseases. There is great interest in
therapeutic strategies to counteract these perturbations of ncRNAs.
DOI: 10.1038/nrg3074
PMID: 22094949 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24255061 | 1. Circulation. 2014 Jan 14;129(2):234-43. doi:
10.1161/CIRCULATIONAHA.113.007012. Epub 2013 Nov 19.
Efficacy and safety of longer-term administration of evolocumab (AMG 145) in
patients with hypercholesterolemia: 52-week results from the Open-Label Study of
Long-Term Evaluation Against LDL-C (OSLER) randomized trial.
Koren MJ(1), Giugliano RP, Raal FJ, Sullivan D, Bolognese M, Langslet G, Civeira
F, Somaratne R, Nelson P, Liu T, Scott R, Wasserman SM, Sabatine MS; OSLER
Investigators.
Author information:
(1)Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); TIMI
Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital
and Harvard Medical School, Boston, MA (R.P.G., M.S.S.); Carbohydrate and Lipid
Metabolism Research Unit, Division of Endocrinology and Metabolism, Department
of Medicine, Faculty of Health Sciences, University of the Witwatersrand,
Johannesburg, South Africa (F.J.R.); Department of Clinical Biochemistry, Royal
Prince Alfred Hospital, Camperdown, Australia (D.S.); Bethesda Health Research
Center, Bethesda, MD (M.B.); Lipid Clinic, Oslo University Hospital, Oslo,
Norway (G.L.); Hospital Universitario Miguel Servet, Zaragoza, Spain (F.C.); and
Amgen Inc, Thousand Oaks, CA (R.S., P.N., T.L., R.S., S.M.W.).
Comment in
Nat Rev Cardiol. 2014 Feb;11(2):63. doi: 10.1038/nrcardio.2013.201.
Blood Transfus. 2016 Sep;14(5):408-12. doi: 10.2450/2016.0027-16.
BACKGROUND: Evolocumab (AMG 145), a monoclonal antibody against proprotein
convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density
lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks' duration. The
longer-term efficacy and safety of PCSK9 inhibition remain undefined.
METHODS AND RESULTS: Of 1359 randomized and dosed patients in the 4 evolocumab
phase 2 parent studies, 1104 (81%) elected to enroll into the Open-Label Study
of Long-term Evaluation Against LDL-C (OSLER) study. Regardless of their
treatment assignment in the parent study, patients were randomized 2:1 to
receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with
standard of care (SOC) (evolocumab+SOC, n=736) or SOC alone (n=368). Ninety-two
percent of patients in the evolocumab+SOC group and 89% of patients in the SOC
group completed 52 weeks of follow-up. Patients who first received evolocumab in
OSLER experienced a mean 52.3% [SE, 1.8%] reduction in LDL-C at week 52
(P<0.0001). Patients who received 1 of 6 dosing regimens of evolocumab in the
parent studies and received evolocumab+SOC in OSLER had persistent LDL-C
reductions (mean reduction, 50.4% [SE, 0.8%] at the end of the parent study
versus 52.1% [SE, 1.0%] at 52 weeks; P=0.31). In patients who discontinued
evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels.
Adverse events and serious adverse events occurred in 81.4% and 7.1% of the
evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients,
respectively.
CONCLUSION: Evolocumab dosed every 4 weeks demonstrated continued efficacy and
encouraging safety and tolerability over 1 year of treatment in the largest and
longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to
date.
CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov. Unique identifier:
NCT01439880.
DOI: 10.1161/CIRCULATIONAHA.113.007012
PMID: 24255061 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24598985 | 1. Eur Heart J. 2014 Sep 1;35(33):2249-59. doi: 10.1093/eurheartj/ehu085. Epub
2014 Mar 4.
Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody
to PCSK9, in hyperlipidaemic patients on various background lipid therapies:
pooled analysis of 1359 patients in four phase 2 trials.
Stein EA(1), Giugliano RP(2), Koren MJ(3), Raal FJ(4), Roth EM(5), Weiss R(6),
Sullivan D(7), Wasserman SM(8), Somaratne R(8), Kim JB(8), Yang J(8), Liu T(8),
Albizem M(8), Scott R(8), Sabatine MS(2); PROFICIO Investigators.
Author information:
(1)Metabolic and Atherosclerosis Research Centre, Cincinnati, OH, USA
[email protected].
(2)TIMI Study Group, Brigham and Women's Hospital, Boston, MA, USA.
(3)Jacksonville Centre for Clinical Research, Jacksonville, FL, USA.
(4)Carbohydrate & Lipid Metabolism Research Unit, University of Witwatersrand,
Johannesburg, South Africa.
(5)Sterling Research Group, Cincinnati, OH, USA.
(6)Maine Research Associates, Auburn, ME, USA.
(7)Department of Clinical Biochemistry, Royal Prince Alfred Hospital,
Camperdown, Australia.
(8)Amgen Inc., Thousand Oaks, CA, USA.
AIMS: Prior trials with monoclonal antibodies to proprotein convertase
subtilizin/kexin type 9 (PCSK9) reported robust low density lipoprotein
cholesterol (LDL-C) reductions. However, the ability to detect potentially
beneficial changes in other lipoproteins such as lipoprotein (a), triglycerides,
high-density lipoprotein cholesterol (HDL-C), and apolipoprotein (Apo) A1, and
adverse events (AEs) was limited by sample sizes of individual trials. We report
a pooled analysis from four phase 2 studies of evolocumab (AMG 145), a
monoclonal antibody to PCSK9.
METHODS AND RESULTS: The trials randomized 1359 patients to various doses of
subcutaneous evolocumab every 2 weeks (Q2W) or 4 weeks (Q4W), placebo, or
ezetimibe for 12 weeks; 1252 patients contributed to efficacy and 1314, to
safety analyses. Mean percentage (95% CI) reductions in LDL-C vs. placebo ranged
from 40.2% (44.6%, 35.8%) to 59.3% (63.7%, 54.8%) among the evolocumab groups
(all P < 0.001). Statistically significant reductions in apolipoprotein B (Apo
B), non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides and
lipoprotein (a) [Lp(a)], and increases in HDL-C were also observed. Adverse
events (AEs) and serious AEs with evolocumab were reported in 56.8 and 2.0% of
patients, compared with 49.2% and 1.2% with placebo. Adjudicated cardiac and
cerebrovascular events were reported in 0.3 and 0% in the placebo and 0.9 and
0.3% in the evolocumab arms, respectively.
CONCLUSION: In addition to LDL-C reduction, evolocumab, dosed either Q2W or Q4W,
demonstrated significant and favourable changes in other atherogenic and
anti-atherogenic lipoproteins, and was well tolerated over the 12-week treatment
period.
Published on behalf of the European Society of Cardiology. All rights reserved.
© The Author 2014. For permissions please email: [email protected].
DOI: 10.1093/eurheartj/ehu085
PMID: 24598985 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25282519 | 1. Lancet. 2015 Jan 24;385(9965):331-40. doi: 10.1016/S0140-6736(14)61399-4. Epub
2014 Oct 1.
PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial
hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind,
placebo-controlled trial.
Raal FJ(1), Stein EA(2), Dufour R(3), Turner T(2), Civeira F(4), Burgess L(5),
Langslet G(6), Scott R(7), Olsson AG(8), Sullivan D(9), Hovingh GK(10), Cariou
B(11), Gouni-Berthold I(12), Somaratne R(13), Bridges I(14), Scott R(13),
Wasserman SM(13), Gaudet D(15); RUTHERFORD-2 Investigators.
Collaborators: Sullivan D, Watts G, Dufour R, Frohlich J, Hegele R, Gaudet D,
Genest J, Bruckert E, Cariou B, Moulin P, Gouni-Berthold I, Steinhagen-Thiessen
E, Tomlinson B, Basart D, Hermann J, Hovingh GK, Janssen S, Kamphuisen P, Rensma
P, Koster T, Van de Wiel A, Scott R, Langslet G, Blom D, Burgess L, Jacovides A,
Raal F, Civeira F, Karlezi R, Alonso A, Marin LM, Miranda JL, Eriksson M, Olsson
A, Miserez A, Kwok S, Le Roux C, Murthy N, Khan M, Wierzbicki A, Stein E, Turner
T.
Author information:
(1)Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences,
University of Witwatersrand, Johannesburg, South Africa. Electronic address:
[email protected].
(2)Metabolic and Atherosclerosis Research Center, Cincinnati, OH, USA.
(3)Institut de Recherches Cliniques de Montreal, University of Montreal,
Montreal, QC, Canada.
(4)University Hospital Miguel Servet, Zaragoza, Spain.
(5)TREAD Research, Department of Internal Medicine, Tygerberg Hospital, Cape
Town, South Africa.
(6)Lipid Clinic, Oslo University Hospital, Oslo, Norway.
(7)Lipid and Diabetes Research Group, University of Otago, Christchurch, New
Zealand.
(8)Linkoping University and Stockholm Heart Centre, Stockholm, Sweden.
(9)Department of Clinical Biochemistry, Royal Prince Alfred Hospital,
Camperdown, NSW, Australia.
(10)Vascular Medicine, Academic Medical Centre, Amsterdam, Netherlands.
(11)Institut du Thorax, Nantes University Hospital, Nantes, France.
(12)Center for Endocrinology, Diabetes and Preventive Medicine, University of
Cologne, Cologne, Germany.
(13)Amgen Inc, Thousand Oaks, CA, USA.
(14)Amgen Ltd, Cambridge Science Park, Milton, Cambridge, UK.
(15)ECOGENE-21, Dyslipidemia, Diabetes and Atherosclerosis Research Group,
Department of Medicine, University of Montreal, Montreal, QC, Canada.
Comment in
Lancet. 2015 Jan 24;385(9965):307-10. doi: 10.1016/S0140-6736(14)61702-5.
Nat Rev Endocrinol. 2015 Jan;11(1):8-9. doi: 10.1038/nrendo.2014.205.
BACKGROUND: Heterozygous familial hypercholesterolaemia is characterised by low
cellular uptake of LDL cholesterol, increased plasma LDL cholesterol
concentrations, and premature cardiovascular disease. Despite intensive statin
therapy, with or without ezetimibe, many patients are unable to achieve
recommended target levels of LDL cholesterol. We investigated the effect of
PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with
this disorder.
METHODS: This multicentre, randomised, double-blind, placebo-controlled trial
was undertaken at 39 sites (most of which were specialised lipid clinics, mainly
attached to academic institutions) in Australia, Asia, Europe, New Zealand,
North America, and South Africa between Feb 7 and Dec 19, 2013. 331 eligible
patients (18-80 years of age), who met clinical criteria for heterozygous
familial hypercholesterolaemia and were on stable lipid-lowering therapy for at
least 4 weeks, with a fasting LDL cholesterol concentration of 2·6 mmol/L or
higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous
evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous
placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer
generated by the study sponsor, implemented by a computerised voice interactive
system, and stratified by LDL cholesterol concentration at screening (higher or
lower than 4·1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study
personnel, investigators, and Amgen study staff were masked to treatment
assignments within dosing frequency groups. The coprimary endpoints were
percentage change from baseline in LDL cholesterol at week 12 and at the mean of
weeks 10 and 12, analysed by intention-to-treat. This trial is registered with
ClinicalTrials.gov, number NCT01763918.
FINDINGS: Of 415 screened patients, 331 were eligible and were randomly assigned
to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111),
evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo
monthly (n=55). 329 patients received at least one dose of study drug. Compared
with placebo, evolocumab at both dosing schedules led to a significant reduction
in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI
53·4-65·1], monthly dose: 61·3% reduction [53·6-69·0]; both p<0·0001) and at the
mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5-65·8] and 65·6% reduction
[59·8-71·3]; both p<0·0001). Evolocumab was well tolerated, with rates of
adverse events similar to placebo. The most common adverse events occurring more
frequently in the evolocumab-treated patients than in the placebo groups were
nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and
muscle-related adverse events (ten patients [5%] vs 1 [1%]).
INTERPRETATION: In patients with heterozygous familial hypercholesterolaemia,
evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well
tolerated and yielded similar and rapid 60% reductions in LDL cholesterol
compared with placebo.
FUNDING: Amgen Inc.
Copyright © 2015 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(14)61399-4
PMID: 25282519 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24661068 | 1. Expert Opin Biol Ther. 2014 Jun;14(6):863-8. doi:
10.1517/14712598.2014.902929. Epub 2014 Mar 24.
Efficacy and safety profile of evolocumab (AMG145), an injectable inhibitor of
the proprotein convertase subtilisin/kexin type 9: the available clinical
evidence.
Cicero AF(1), Tartagni E, Ertek S.
Author information:
(1)S. Orsola-Malpighi University Hospital, Medical and Surgical Sciences
Department, Internal Medicine Unit , Pad. 2, Via Albertoni 15, 40138 Bologna ,
Italy +39 3498558017 ; +39 0516826125 ; [email protected] ,
[email protected].
INTRODUCTION: Despite the proven efficacy of statins, they are often reported to
be inadequate to achieve low-density lipoprotein cholesterol (LDL-C) goals
(especially in high-risk patients). Moreover, a large number of subjects cannot
tolerate statins or full doses of these drugs. Thus, there is a need for
additional effective LDL-C reducing agents.
AREAS COVERED: Evolocumab (AMG145) is a monoclonal antibody inhibiting the
proprotein convertase subtilisin/kexin type 9 that binds to the liver LDL
receptor and prevents it from normal recycling by targeting it for degradation.
Phase I and II trials revealed that its subcutaneous injection, either alone or
in combination with statins, is able to reduce LDL-C from 40 to 80%,
apolipoprotein B100 from 30 to 59% and lipoprotein(a) from 18 to 36% in a
dose-dependent manner. The incidence of side effects seems to be low and mainly
limited to nasopharyngitis, injection site pain, arthralgia and back pain.
EXPERT OPINION: Evolocumab is an innovative powerful lipid-lowering drug,
additive to statins and with an apparently large therapeutic range associated to
a low rate of mild adverse events. If available data will be confirmed in
long-term trials with strong outcomes, Evolocumab will provide an essential tool
to treat high-risk patients who need to reach ambitious LDL-C target.
DOI: 10.1517/14712598.2014.902929
PMID: 24661068 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21187392 | 1. Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):786-91. doi:
10.1073/pnas.1011098108. Epub 2010 Dec 27.
Expression and functional role of a transcribed noncoding RNA with an
ultraconserved element in hepatocellular carcinoma.
Braconi C(1), Valeri N, Kogure T, Gasparini P, Huang N, Nuovo GJ, Terracciano L,
Croce CM, Patel T.
Author information:
(1)Department of Internal Medicine, College of Medicine, Ohio State University,
Columbus, OH 43210, USA.
Although expression of non-protein-coding RNA (ncRNA) can be altered in human
cancers, their functional relevance is unknown. Ultraconserved regions are
noncoding genomic segments that are 100% conserved across humans, mice, and
rats. Conservation of gene sequences across species may indicate an essential
functional role, and therefore we evaluated the expression of ultraconserved
RNAs (ucRNA) in hepatocellular cancer (HCC). The global expression of ucRNAs was
analyzed with a custom microarray. Expression was verified in cell lines by
real-time PCR or in tissues by in situ hybridization using tissue microarrays.
Cellular ucRNA expression was modulated with siRNAs, and the effects on global
gene expression and growth of human and murine HCC cells were evaluated.
Fifty-six ucRNAs were aberrantly expressed in HepG2 cells compared with
nonmalignant hepatocytes. Among these ucRNAs, the greatest change was noted for
ultraconserved element 338 (uc.338), which was dramatically increased in human
HCC compared with noncancerous adjacent tissues. Although uc.338 is partially
located within the poly(rC) binding protein 2 (PCBP2) gene, the transcribed
ncRNA encoding uc.338 is expressed independently of PCBP2 and was cloned as a
590-bp RNA gene, termed TUC338. Functional gene annotation analysis indicated
predominant effects on genes involved in cell growth. These effects were
experimentally demonstrated in both human and murine cells. siRNA to TUC338
decreased both anchorage-dependent and anchorage-independent growth of HCC
cells. These studies identify a critical role for TUC338 in regulation of
transformed cell growth and of transcribed ultraconserved ncRNA as a unique
class of genes involved in the pathobiology of HCC.
DOI: 10.1073/pnas.1011098108
PMCID: PMC3021052
PMID: 21187392 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/1584813 | 1. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4744-8. doi:
10.1073/pnas.89.10.4744.
Mechanism of human methyl-directed DNA methyltransferase and the fidelity of
cytosine methylation.
Smith SS(1), Kaplan BE, Sowers LC, Newman EM.
Author information:
(1)City of Hope National Medical Center, Duarte, CA.
The properties of the methyl-directed DNA (cytosine-5-)-methyltransferase (EC
2.1.1.37) suggest that it is the enzyme that maintains patterns of methylation
in the human genome. Proposals for the enzyme's mechanism of action suggest that
5-methyldeoxycytidine is produced from deoxycytidine via a dihydrocytosine
intermediate. We have used an oligodeoxynucleotide containing
5-fluorodeoxycytidine as a suicide substrate to capture the enzyme and the
dihydrocytosine intermediate. Gel retardation experiments demonstrate the
formation of the expected covalent complex between duplex DNA containing
5-fluorodeoxycytidine and the human enzyme. Formation of the complex was
dependent upon the presence of the methyl donor S-adenosylmethionine, suggesting
that it comprises an enzyme-linked 5-substituted dihydrocytosine moiety in DNA.
Dihydrocytosine derivatives are extremely labile toward hydrolytic deamination
in aqueous solution. Because C-to-T transition mutations are especially
prevalent at CG sites in human DNA, we have used high-performance liquid
chromatography to search for thymidine that might be generated by hydrolysis
during the methyl transfer reaction. Despite the potential for deamination
inherent in the formation of the intermediate, the methyltransferase did not
produce detectable amounts of thymidine. The data suggest that the ability of
the human methyltransferase to preserve genetic information when copying a
methylation pattern (i.e., its fidelity) is comparable to the ability of a
mammalian DNA polymerase to preserve genetic information when copying a DNA
sequence. Thus the high frequency of C-to-T transitions at CG sites in human DNA
does not appear to be due to the normal enzymatic maintenance of methylation
patterns.
DOI: 10.1073/pnas.89.10.4744
PMCID: PMC49160
PMID: 1584813 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24037088 | 1. Cell Death Differ. 2013 Dec;20(12):1675-87. doi: 10.1038/cdd.2013.119. Epub
2013 Sep 13.
HINCUTs in cancer: hypoxia-induced noncoding ultraconserved transcripts.
Ferdin J(1), Nishida N, Wu X, Nicoloso MS, Shah MY, Devlin C, Ling H, Shimizu M,
Kumar K, Cortez MA, Ferracin M, Bi Y, Yang D, Czerniak B, Zhang W, Schmittgen
TD, Voorhoeve MP, Reginato MJ, Negrini M, Davuluri RV, Kunej T, Ivan M, Calin
GA.
Author information:
(1)1] Department of Experimental Therapeutics, The Center for RNA Interference
and Non-Coding RNAs, MD Anderson Cancer Center, The University of Texas, So
Campus Research Building 3, 1881 East Road, Houston, TX 77030, USA [2] Chair of
Genetics, Animal Biotechnology and Immunology, Department of Animal Science,
Biotechnical Faculty, University of Ljubljana, Groblje 3 1230, Domzale,
Slovenia.
Recent data have linked hypoxia, a classic feature of the tumor
microenvironment, to the function of specific microRNAs (miRNAs); however,
whether hypoxia affects other types of noncoding transcripts is currently
unknown. Starting from a genome-wide expression profiling, we demonstrate for
the first time a functional link between oxygen deprivation and the modulation
of long noncoding transcripts from ultraconserved regions, termed
transcribed-ultraconserved regions (T-UCRs). Interestingly, several
hypoxia-upregulated T-UCRs, henceforth named 'hypoxia-induced noncoding
ultraconserved transcripts' (HINCUTs), are also overexpressed in clinical
samples from colon cancer patients. We show that these T-UCRs are predominantly
nuclear and that the hypoxia-inducible factor (HIF) is at least partly
responsible for the induction of several members of this group. One specific
HINCUT, uc.475 (or HINCUT-1) is part of a retained intron of the host
protein-coding gene, O-linked N-acetylglucosamine transferase, which is
overexpressed in epithelial cancer types. Consistent with the hypothesis that
T-UCRs have important function in tumor formation, HINCUT-1 supports cell
proliferation specifically under hypoxic conditions and may be critical for
optimal O-GlcNAcylation of proteins when oxygen tension is limiting. Our data
gives a first glimpse of a novel functional hypoxic network comprising
protein-coding transcripts and noncoding RNAs (ncRNAs) from the T-UCRs category.
DOI: 10.1038/cdd.2013.119
PMCID: PMC3824588
PMID: 24037088 [Indexed for MEDLINE] |