pubmed_id
stringlengths 41
43
| abstract
stringlengths 3
18.8k
|
|---|---|
http://www.ncbi.nlm.nih.gov/pubmed/17362198 | 1. Annu Rev Biochem. 2007;76:75-100. doi:
10.1146/annurev.biochem.76.052705.162114.
Functions of site-specific histone acetylation and deacetylation.
Shahbazian MD(1), Grunstein M.
Author information:
(1)Department of Biological Chemistry, Geffen School of Medicine and the
Molecular Biology Institute, University of California, Los Angeles, California
90095, USA.
Histone acetylation regulates many cellular processes, and specific acetylation
marks, either singly or in combination, produce distinct outcomes. For example,
the acetylation pattern on newly synthesized histones is important for their
assembly into nucleosomes by histone chaperones. Additionally, the degree of
chromatin compaction and folding may be regulated by acetylation of histone H4
at lysine 16. Histone acetylation also regulates the formation of
heterochromatin; deacetylation of H4 lysine 16 is important for spreading of
heterochromatin components, whereas acetylation of this site serves as a barrier
to this spreading. Finally, histone acetylation is critical for gene
transcription, but recent results suggest that deacetylation of certain sites
also plays an important role. There are many histone acetyltransferases (HATs)
and deacetylases, with differing preferences for the various histone proteins
and for specific sites on individual histones. Determining how these enzymes
create distinct acetylation patterns and regulate the functional outcome is an
important challenge.
DOI: 10.1146/annurev.biochem.76.052705.162114
PMID: 17362198 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18948739 | 1. Cell Cycle. 2008 Nov 1;7(21):3302-6. doi: 10.4161/cc.7.21.6928. Epub 2008 Nov
5.
Chromatin regulation Tip(60)s the balance in embryonic stem cell self-renewal.
Fazzio TG(1), Huff JT, Panning B.
Author information:
(1)The G.W. Hooper Research Foundation, University of California San Francisco,
San Francisco, California 94143-0552, USA. thomas.fazzio@ucsf.edu
Histone modifications affect chromatin dynamics on several levels by serving as
binding sites for regulatory proteins. In many cell types, including embryonic
stem cells (ESCs), a subset of genes is marked with histone modifications
thought to be both activating and repressing: H3 lysine 4 trimethylation
(H3K4me3) and lysine 27 trimethylation (H3K27me3), respectively. As a result,
genes bearing this "bivalent" mark are transcribed at low levels, but are primed
for activation, should the cell receive the appropriate cues during
differentiation. Recently, we found that the Tip60-p400 acetyltransferase and
histone exchange complex is necessary to maintain normal self-renewal in mouse
ESCs. While Tip60-p400 has histone acetyltransferase activity, which is
generally associated with transcriptional activation, it acts predominantly as a
repressor of genes expressed during differentiation. Surprisingly, in ESCs
Tip60-p400 localizes to the promoters of genes marked by H3K4me3, which include
both highly expressed genes and "bivalent" genes expressed at low levels.
Tip60-p400 acetylates histones at these targets, including the promoters for
developmental regulators it helps to silence in ESCs. This suggests that the
effect of chromatin modifications on transcription is not always simply positive
or negative. Rather, we propose that the impact of specific modifications at
each promoter is determined by the chromatin context in which they are found.
DOI: 10.4161/cc.7.21.6928
PMCID: PMC4476248
PMID: 18948739 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16103216 | 1. Genes Dev. 2005 Aug 15;19(16):1885-93. doi: 10.1101/gad.1333905.
Methylation of histone H4 by arginine methyltransferase PRMT1 is essential in
vivo for many subsequent histone modifications.
Huang S(1), Litt M, Felsenfeld G.
Author information:
(1)Laboratory of Molecular Biology, National Institute of Diabetes and Digestive
and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
20892-0540, USA.
PRMT1 is a histone methyltransferase that methylates Arg3 on histone H4. When we
used siRNA to knock down PRMT1 in an erythroid cell line, it resulted in nearly
complete loss of H4 Arg3 methylation across the chicken beta-globin domain,
which we use as a model system for studying the relationship of gene activity to
histone modification. We observed furthermore a domain-wide loss of histone
acetylation on both histones H3 and H4, as well as an increase in H3 Lys9 and
Lys27 methylation, both marks associated with inactive chromatin. To determine
whether the effect on acetylation was directly related to the loss of H4 Arg3
methylation, we performed an in vitro acetylation reaction on chromatin isolated
from PRMT1-depleted cells. We found that nucleosomes purified from these cells,
and depleted in methylation at Arg3, are readily acetylated by nuclear extracts
from the same cells, if and only if the nucleosomes are incubated with PRMT1
beforehand. Thus, methylation of histones by PRMT1 was sufficient to permit
subsequent acetylation. Consistent with earlier reports of experiments in vitro,
H4 Arg3 methylation by PRMT1 appears to be essential in vivo for the
establishment or maintenance of a wide range of "active" chromatin
modifications.
DOI: 10.1101/gad.1333905
PMCID: PMC1186188
PMID: 16103216 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10825229 | 1. J Cell Physiol. 2000 Jul;184(1):1-16. doi:
10.1002/(SICI)1097-4652(200007)184:1<1::AID-JCP1>3.0.CO;2-7.
Histone deacetylases, transcriptional control, and cancer.
Cress WD(1), Seto E.
Author information:
(1)Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research
Institute, University of South Florida, Tampa, Florida.
A key event in the regulation of eukaryotic gene expression is the
posttranslational modification of nucleosomal histones, which converts regions
of chromosomes into transcriptionally active or inactive chromatin. The most
well studied posttranslational modification of histones is the acetylation of
epsilon-amino groups on conserved lysine residues in the histones'
amino-terminal tail domains. Significant advances have been made in the past few
years toward the identification of histone acetyltransferases and histone
deacetylases. Currently, there are over a dozen cloned histone
acetyltransferases and at least eight cloned human histone deacetylases.
Interestingly, many histone deacetylases can function as transcriptional
corepressors and, often, they are present in multi-subunit complexes. More
intriguing, at least some histone deacetylases are associated with
chromatin-remodeling machines. In addition, several studies have pointed to the
possible involvement of histone deacetylases in human cancer. The availability
of the cloned histone deacetylase genes has provided swift progress in the
understanding of the mechanisms of deacetylases, their role in transcription,
and their possible role in health and disease.
Copyright 2000 Wiley-Liss, Inc.
DOI: 10.1002/(SICI)1097-4652(200007)184:1<1::AID-JCP1>3.0.CO;2-7
PMID: 10825229 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19633430 | 1. Epigenetics. 2009 Jul 1;4(5):302-6. doi: 10.4161/epi.4.5.9369. Epub 2009 Jul
25.
Histone H3 lysine 4 di-methylation: a novel mark for transcriptional fidelity?
Pinskaya M(1), Morillon A.
Author information:
(1)Commissariat d'Etudes Atomiques, Fontenay aux Roses, France.
marina.bischerour-pinskaya@cea.fr
Although histone H3 Lysine 4 methylation (H3K4me) is strongly associated with
active transcription, an increasing number of arguments indicate its repressive
role in gene expression. Recent data in the mammalian and budding yeast systems
have provided evidence for H3K4me2 and H3K4me3 tethering histone deacetylase
complexes (HDACs) to modulate gene expression. In S. cerevisiae, this regulation
is mediated by specific subunits within HDACs that recognize the methylation
status of H3K4 allowing chromatin reorganization to attenuate or repress
transcription. Albeit we are still a long way from understanding the mechanism
and biological consequences, it is becoming clear that H3K4me at certain
chromatin loci may prevent aberrant gene expression or modulate transcriptional
response. This review will provide a brief overview of a novel interpretation of
H3K4me and its outcome on transcription regulation and will suggest future
challenges for the field of epigenetics.
DOI: 10.4161/epi.4.5.9369
PMID: 19633430 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11343896 | 1. Curr Opin Cell Biol. 2001 Jun;13(3):263-73. doi:
10.1016/s0955-0674(00)00208-8.
Histone methylation versus histone acetylation: new insights into epigenetic
regulation.
Rice JC(1), Allis CD.
Author information:
(1)Department of Biochemistry and Molecular Genetics, University of Virginia,
Health Sciences Center, Box 800733 Jordan Hall, Room 6222, Charlottesville, VA
22908-0733, USA.
Post-translational addition of methyl groups to the amino-terminal tails of
histone proteins was discovered more than three decades ago. Only now, however,
is the biological significance of lysine and arginine methylation of histone
tails being elucidated. Recent findings indicate that methylation of certain
core histones is catalyzed by a family of conserved proteins known as the
histone methyltransferases (HMTs). New evidence suggests that site-specific
methylation, catalyzed by HMTs, is associated with various biological processes
ranging from transcriptional regulation to epigenetic silencing via
heterochromatin assembly. Taken together, these new findings suggest that
histone methylation may provide a stable genomic imprint that may serve to
regulate gene expression as well as other epigenetic phenomena.
DOI: 10.1016/s0955-0674(00)00208-8
PMID: 11343896 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9780836 | 1. Bioessays. 1998 Aug;20(8):615-26. doi:
10.1002/(SICI)1521-1878(199808)20:8<615::AID-BIES4>3.0.CO;2-H.
Roles of histone acetyltransferases and deacetylases in gene regulation.
Kuo MH(1), Allis CD.
Author information:
(1)Department of Biology, University of Rochester, NY, USA.
Acetylation of internal lysine residues of core histone N-terminal domains has
been found correlatively associated with transcriptional activation in
eukaryotes for more than three decades. Recent discoveries showing that several
transcriptional regulators possess intrinsic histone acetyltransferase (HAT) and
deacetylase (HDAC) activities strongly suggest that histone acetylation and
deacetylation each plays a causative role in regulating transcription.
Intriguingly, several HATs have been shown an ability to acetylate nonhistone
protein substrates (e.g., transcription factors) in vitro as well, suggesting
the possibility that internal lysine acetylation of multiple proteins exists as
a rapid and reversible regulatory mechanism much like protein phosphorylation.
This article reviews recent developments in histone acetylation and
transcriptional regulation. We also discuss several important, yet unanswered,
questions.
DOI: 10.1002/(SICI)1521-1878(199808)20:8<615::AID-BIES4>3.0.CO;2-H
PMID: 9780836 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19220199 | 1. Biosci Rep. 2009 Apr;29(2):131-41. doi: 10.1042/BSR20080176.
Histone arginine methylations: their roles in chromatin dynamics and
transcriptional regulation.
Litt M(1), Qiu Y, Huang S.
Author information:
(1)Medical Education Center, Ball State University, Muncie, IN 47302, USA.
PRMTs (protein arginine N-methyltransferases) specifically modify the arginine
residues of key cellular and nuclear proteins as well as histone substrates.
Like lysine methylation, transcriptional repression or activation is dependent
upon the site and type of arginine methylation on histone tails. Recent
discoveries imply that histone arginine methylation is an important modulator of
dynamic chromatin regulation and transcriptional controls. However, under the
shadow of lysine methylation, the roles of histone arginine methylation have
been under-explored. The present review focuses on the roles of histone arginine
methylation in the regulation of gene expression, and the interplays between
histone arginine methylation, histone acetylation, lysine methylation and
chromatin remodelling factors. In addition, we discuss the dynamic regulation of
arginine methylation by arginine demethylases, and how dysregulation of PRMTs
and their activities are linked to human diseases such as cancer.
DOI: 10.1042/BSR20080176
PMCID: PMC5433800
PMID: 19220199 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11420716 | 1. Oncogene. 2001 May 28;20(24):3014-20. doi: 10.1038/sj.onc.1204325.
Role of protein methylation in chromatin remodeling and transcriptional
regulation.
Stallcup MR(1).
Author information:
(1)Department of Pathology, and Department of Biochemistry and Molecular
Biology, University of Southern California, Los Angeles, CA 90089, USA.
Recent findings suggest that lysine and arginine-specific methylation of
histones may cooperate with other types of post-translational histone
modification to regulate chromatin structure and gene transcription. Proteins
that methylate histones on arginine residues can collaborate with other
coactivators to enhance the activity of specific transcriptional activators such
as nuclear receptors. Lysine methylation of histones is associated with
transcriptionally active nuclei, regulates other types of histone modifications,
and is necessary for proper mitotic cell divisions. The fact that some
transcription factors and proteins involved in RNA processing can also be
methylated suggests that protein methylation may also contribute in other ways
to regulation of transcription and post-transcriptional steps in gene
regulation. In future work, it will be important to develop methods for
evaluating the precise roles of protein methylation in the regulation of native
genes in physiological settings, e.g. by using chromatin immunoprecipitation
assays, differentiating cell culture systems, and genetically altered cells and
animals. It will also be important to isolate additional protein
methyltransferases by molecular cloning and to characterize new
methyltransferase substrates, the regulation of methyltransferase activities,
and the roles of new methyltransferases and substrates.
DOI: 10.1038/sj.onc.1204325
PMID: 11420716 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24583552 | 1. Biochim Biophys Acta. 2014 Aug;1839(8):702-10. doi:
10.1016/j.bbagrm.2014.02.015. Epub 2014 Feb 28.
Readers of histone methylarginine marks.
Gayatri S(1), Bedford MT(2).
Author information:
(1)Department of Molecular Carcinogenesis, The University of Texas MD Anderson
Cancer Center, Smithville, TX 78957, USA.
(2)Department of Molecular Carcinogenesis, The University of Texas MD Anderson
Cancer Center, Smithville, TX 78957, USA. Electronic address:
mtbedford@mdanderson.org.
Arginine methylation is a common posttranslational modification (PTM) that
alters roughly 0.5% of all arginine residues in the cells. There are three types
of arginine methylation: monomethylarginine (MMA), asymmetric dimethylarginine
(ADMA), and symmetric dimethylarginine (SDMA). These three PTMs are enriched on
RNA-binding proteins and on histones, and also impact signal transduction
cascades. To date, over thirty arginine methylation sites have been cataloged on
the different core histones. These modifications alter protein structure, impact
interactions with DNA, and also generate docking sites for effector molecules.
The primary "readers" of methylarginine marks are Tudor domain-containing
proteins. The complete family of thirty-six Tudor domain-containing proteins has
yet to be fully characterized, but at least ten bind methyllysine motifs and
eight bind methylarginine motifs. In this review, we will highlight the
biological roles of the Tudor domains that interact with arginine methylated
motifs, and also address other types of interactions that are regulated by these
particular PTMs. This article is part of a Special Issue entitled: Molecular
mechanisms of histone modification function.
Copyright © 2014 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbagrm.2014.02.015
PMCID: PMC4099268
PMID: 24583552 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28874563 | 1. Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):10101-10106. doi:
10.1073/pnas.1706978114. Epub 2017 Sep 5.
Epigenetic control via allosteric regulation of mammalian protein arginine
methyltransferases.
Jain K(1), Jin CY(1), Clarke SG(2).
Author information:
(1)Department of Chemistry and Biochemistry, The Molecular Biology Institute,
University of California, Los Angeles, CA 90095.
(2)Department of Chemistry and Biochemistry, The Molecular Biology Institute,
University of California, Los Angeles, CA 90095 clarke@chem.ucla.edu.
Arginine methylation on histones is a central player in epigenetics and in gene
activation and repression. Protein arginine methyltransferase (PRMT) activity
has been implicated in stem cell pluripotency, cancer metastasis, and
tumorigenesis. The expression of one of the nine mammalian PRMTs, PRMT5, affects
the levels of symmetric dimethylarginine (SDMA) at Arg-3 on histone H4, leading
to the repression of genes which are related to disease progression in lymphoma
and leukemia. Another PRMT, PRMT7, also affects SDMA levels at the same site
despite its unique monomethylating activity and the lack of any evidence for
PRMT7-catalyzed histone H4 Arg-3 methylation. We present evidence that
PRMT7-mediated monomethylation of histone H4 Arg-17 regulates PRMT5 activity at
Arg-3 in the same protein. We analyzed the kinetics of PRMT5 over a wide range
of substrate concentrations. Significantly, we discovered that PRMT5 displays
positive cooperativity in vitro, suggesting that this enzyme may be
allosterically regulated in vivo as well. Most interestingly, monomethylation at
Arg-17 in histone H4 not only raised the general activity of PRMT5 with this
substrate, but also ameliorated the low activity of PRMT5 at low substrate
concentrations. These kinetic studies suggest a biochemical explanation for the
interplay between PRMT5- and PRMT7-mediated methylation of the same substrate at
different residues and also suggest a general model for regulation of PRMTs.
Elucidating the exact relationship between these two enzymes when they methylate
two distinct sites of the same substrate may aid in developing therapeutics
aimed at reducing PRMT5/7 activity in cancer and other diseases.
DOI: 10.1073/pnas.1706978114
PMCID: PMC5617285
PMID: 28874563 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/21426252 | 1. Expert Rev Clin Immunol. 2011 Mar;7(2):143-53. doi: 10.1586/eci.11.5.
rhC1INH: a new drug for the treatment of attacks in hereditary angioedema caused
by C1-inhibitor deficiency.
Varga L(1), Farkas H.
Author information:
(1)3rd Department of Internal Medicine, Semmelweis University Budapest, H-1125
Kútvölgyi street 4, Budapest, Hungary. lvarga@kut.sote.hu
Recombinant human C1 esterase inhibitor (rhC1INH) (Ruconest(®), Pharming) is a
new drug developed for the relief of symptoms occurring in patients with
angioedema due to C1-inhibitor deficiency. Pertinent results have already been
published elsewhere; this article summarizes the progress made since then.
Similar to the purified C1-inhibitor derived from human plasma, the therapeutic
efficacy of rhC1INH results from its ability to block the actions of enzymes
belonging to the overactivated bradykinin-forming pathway, at multiple
locations. During clinical trials into the management of acute edema, a total of
190 subjects received recombinant C1-inhibitor by intravenous infusion on 714
occasions altogether. Dose-ranging efficacy studies established 50 U/kg as the
recommended dose, and demonstrated the effectiveness of this agent in all
localizations of hereditary angioedema attacks. Studies into the safety of
rhC1INH based on 300 administrations to healthy subjects or hereditary
angioedema patients followed-up for 90 days have not detected the formation of
autoantibodies against rhC1INH or IgE antibodies directed against rabbit
proteins, even after repeated administration on multiple occasions. These
findings met favorable appraisal by the EMA, which granted European marketing
authorization for rhC1INH. Pharming is expected to file a biological licence
with the US FDA by the end of 2010 to obtain marketing approval in the USA. The
launch of rhC1INH onto the pharmaceutical market may represent an important
progress in the management of hereditary angioedema patients.
DOI: 10.1586/eci.11.5
PMID: 21426252 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35312090 | 1. Muscle Nerve. 2022 Aug;66(2):193-197. doi: 10.1002/mus.27532. Epub 2022 Apr
11.
Time to diagnosis of Duchenne muscular dystrophy remains unchanged: Findings
from the Muscular Dystrophy Surveillance, Tracking, and Research Network,
2000-2015.
Thomas S(1), Conway KM(2), Fapo O(1), Street N(3), Mathews KD(4), Mann JR(5),
Romitti PA(2), Soim A(1), Westfield C(1), Fox DJ(1), Ciafaloni E(6); Muscular
Dystrophy Surveillance, Tracking, and Research Network (MD STARnet).
Author information:
(1)New York State Department of Health, Albany, New York, USA.
(2)Department of Epidemiology, University of Iowa, College of Public Health,
Iowa City, Iowa, USA.
(3)Centers for Disease Control and Prevention, National Center on Birth Defects
and Developmental Disabilities, Atlanta, Georgia, USA.
(4)Stead Family Department of Pediatrics, University of Iowa Carver College of
Medicine, Iowa City, Iowa, USA.
(5)University of Mississippi Medical Center, Jackson, Mississippi, USA.
(6)Department of Neurology, University of Rochester, Rochester, New York, USA.
Comment in
Muscle Nerve. 2022 Aug;66(2):116-117. doi: 10.1002/mus.27574.
INTRODUCTION/AIMS: With current and anticipated disease-modifying treatments,
including gene therapy, an early diagnosis for Duchenne muscular dystrophy (DMD)
is crucial to assure maximum benefit. In 2009, a study from the Muscular
Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) showed an
average diagnosis age of 5 years among males with DMD born from January 1, 1982
to December 31, 2000. Initiatives were implemented by the US Centers for Disease
Control and Prevention (CDC) and patient organizations to reduce time to
diagnosis. We conducted a follow-up study in a surveillance cohort born after
January 1, 2000 to determine whether there has been an improvement in time to
diagnosis.
METHODS: We assessed the age of diagnosis among males with DMD born from January
1, 2000 to December 31, 2015 using data collected by six US MD STARnet
surveillance sites (Colorado, Iowa, western New York State, the Piedmont region
of North Carolina, South Carolina, and Utah). The analytic cohort included 221
males with definite or probable DMD diagnosis without a documented family
history. We computed frequency count and percentage for categorical variables,
and mean, median, and standard deviation (SD) for continuous variables.
RESULTS: The mean [median] ages in years of diagnostic milestones were: first
signs, 2.7 [2.0]; first creatine kinase (CK), 4.6 [4.6]; DNA/muscle biopsy
testing, 4.9 [4.8]; and time from first signs to diagnostic confirmation, 2.2
[1.4].
DISCUSSION: The time interval between first signs of DMD and diagnosis remains
unchanged at 2.2 years. This results in lost opportunities for timely genetic
counseling, implementation of standards of care, initiation of glucocorticoids,
and participation in clinical trials.
© 2022 Wiley Periodicals LLC.
DOI: 10.1002/mus.27532
PMCID: PMC9308714
PMID: 35312090 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICT OF INTEREST Dr. Emma Ciafaloni has
received personal compensation for serving on advisory boards and/or as a
consultant for Viela Bio, Avexis, Biogen, Medscape, Amicus, PTC Therapeutics,
Sarepta Therapeutics, Ra Pharma, Wave, and Strongbridge Biopharma plc. Dr.
Ciafaloni has received personal compensation for serving on a speaker’s bureau
for Biogen as well as research and/or grant support from the CDC, CureSMA,
Muscular Dystrophy Association, National Institutes of Health, Orphazyme, the
Patient-Centered Outcomes Research Institute, Parent Project Muscular Dystrophy,
PTC Therapeutics, Santhera, Sarepta Therapeutics, Orphazyme, and the US Food and
Drug Administration. Dr. Ciafaloni has also received royalties from Oxford
University Press and compensation from Medlink for editorial duties. Dr.
Katherine Mathews receives research funding from NIH (NIAMS) P50 NS053672, NIH
(NINDS) U24 NS-107181, and the Friedreich’s Ataxia Research Alliance, and serves
as a site PI for clinical research sponsored by Italfarmaco, PTC, Sarepta,
Pfizer, Retrotope, Reata and AMO. The other authors declare no conflicts of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/7557061 | 1. Gac Med Mex. 1994 Nov-Dec;130(6):459-64.
[Relations between delayed diagnosis and forms of onset in Duchenne muscular
dystrophy].
[Article in Spanish]
Alvarez Leal M(1), Morales Aguilera A, Pérez Zuno JA, Segura Romero S, Quiroz
Góngora MC, Paredes García A.
Author information:
(1)Unidad de Investigación Biomédica del Noreste, IMSS.
Duchenne Muscular Dystrophy (DMD) is usually diagnosed several years after the
onset of symptoms. The relatives of the patients with DMD frequently consult
family physicians when they notice the first symptom. The purpose of this study
was to determine the cause that influence the delayed diagnosis of DMD.
Twenty-two patients with confirmed diagnosis of DMD were interviewed at two
Neurology Centers (Mexican Social Security Institute) in Monterrey, Nuevo León,
México. Two forms of onset of DMD: Retarded development and locomotion problems
were found, confirming other studies. The mean age of onset of symptoms for 22
patients was 2.4 years. The mean age for DMD diagnosis was 4.9 years. Retarded
development occurred in 12 (54.4%) of all cases and the age of diagnosis was
between 1 and 6 years of age. In 10 cases of the group with locomotion problems
(45.4%) the diagnosis was made between 3 and 11 years of age. The serum Creatine
Kinase was increased in all patients and in the early stages these levels were
much higher than late stages. Family physicians have opportunities to make early
diagnosis of DMD if they are aware of the two forms of onset of the disease:
Retarded development and locomotion problems and of the changes in serum CK
levels. The findings of this study confirm the importance of family physicians
in that respect and also in making recommendations for routine determination of
serum Creatine Kinase (CK) as early as possible in a child with symptoms
suggestive of DMD.
PMID: 7557061 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31573675 | 1. Muscle Nerve. 2020 Jan;61(1):36-43. doi: 10.1002/mus.26720. Epub 2019 Nov 6.
Delays in diagnosis of Duchenne muscular dystrophy: An evaluation of genotypic
and sociodemographic factors.
Counterman KJ(1), Furlong P(1), Wang RT(2)(3), Martin AS(1).
Author information:
(1)Department of Research, Parent Project Muscular Dystrophy, Hackensack, New
Jersey.
(2)Department of Human Genetics, David Geffen School of Medicine, University of
California Los Angeles, California.
(3)Center for Duchenne Muscular Dystrophy, University of California Los Angeles,
Los Angeles, Los Angeles, California.
INTRODUCTION: In this study we investigate associations between genotypic and
sociodemographic factors and the age of diagnosis of Duchenne muscular dystrophy
(DMD).
METHODS: Data were collected from the Duchenne Registry from 2007 to 2019, and
then used to assess the impact genotype, race/ethnicity, neighborhood poverty
levels, and other sociodemographics factors have on the age of diagnosis of DMD
patients without a known family history, using univariate and multivariable
linear regression.
RESULTS: The mean age of diagnosis was 4.43 years. Non-Caucasian patients and
patients from high-poverty neighborhoods were older at diagnosis (P < .01).
Increased year of birth was associated with decreasing age of diagnosis
(P < .001). Specific genetic mutation subtypes were associated with later ages
of symptom onset and diagnosis (P = .005).
DISCUSSION: After adjusting for genotype and year of birth, the average age of
diagnosis was significantly later for traditionally at-risk patients.
© 2019 Wiley Periodicals, Inc.
DOI: 10.1002/mus.26720
PMID: 31573675 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25996334 | 1. Arch Argent Pediatr. 2015 Jun;113(3):e149-52. doi: 10.5546/aap.2015.e149.
[Duchenne muscular dystrophy: Case of atypical presentation and early
diagnosis].
[Article in Spanish]
Cabezudo García P(1), Moreno Medinilla E(2), Calvo Medina R(2), Mora Ramírez
MD(2), Martínez Antón J(2).
Author information:
(1)Unidad de Neurociencias, Hospital Clínico Universitario Virgen de la
Victoria.
(2)Hospital Materno Infantil, Málaga, España.
INTRODUCTION: Duchenne muscular dystrophy is the most common form of muscular
dystrophy, with an incidence of 1/3300 male live births and a prevalence rate in
the total population of 3/100000 individuals. It is often hereditary (X-linked
recessive) but sporadic cases are also frequent. The average age at diagnosis is
4.83 years but an early diagnosis is possible.
CLINICAL CASE: An 18-month male infant in ambulatory study for failure to thrive
and malnutrition was admitted in our hospital for respiratory problems.
Hypertransaminasemia without other data of hepatic involvement in addition to
hypotonia detected in the examination oriented diagnosis towards myopathy,
confirmed by elevated creatine kinase and electromyogram. The genetic study for
Duchenne muscular dystrophy was negative. Mutations were not detected. Muscle
biopsy showed complete absence of dystrophin. A more sensitive genetic study
showed a previously undescribed mutation.
DOI: 10.5546/aap.2015.e149
PMID: 25996334 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16322188 | 1. Pediatrics. 2005 Dec;116(6):1569-73. doi: 10.1542/peds.2005-2448.
Cardiovascular health supervision for individuals affected by Duchenne or Becker
muscular dystrophy.
American Academy of Pediatrics Section on Cardiology and Cardiac Surgery.
Comment in
Pediatrics. 2006 May;117(5):1864; author reply 1865. doi:
10.1542/peds.2005-3189.
Duchenne muscular dystrophy is the most common and severe form of the childhood
muscular dystrophies. The disease is typically diagnosed between 3 and 7 years
of age and follows a predictable clinical course marked by progressive skeletal
muscle weakness with loss of ambulation by 12 years of age. Death occurs in
early adulthood secondary to respiratory or cardiac failure. Becker muscular
dystrophy is less common and has a milder clinical course but also results in
respiratory and cardiac failure. The natural history of the cardiomyopathy in
these diseases has not been well established. As a result, patients
traditionally present for cardiac evaluation only after clinical symptoms become
evident. The purpose of this policy statement is to provide recommendations for
optimal cardiovascular evaluation to health care specialists caring for
individuals in whom the diagnosis of Duchenne or Becker muscular dystrophy has
been confirmed.
DOI: 10.1542/peds.2005-2448
PMID: 16322188 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34800417 | 1. Lancet Neurol. 2021 Dec;20(12):991-1000. doi: 10.1016/S1474-4422(21)00322-7.
Safety and efficacy of erythropoietin for the treatment of patients with optic
neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled
study.
Lagrèze WA(1), Küchlin S(2), Ihorst G(3), Grotejohann B(3), Beisse F(4),
Volkmann M(5), Heinrich SP(2), Albrecht P(6), Ungewiss J(7), Wörner M(8), Hug
MJ(9), Wolf S(10), Diem R(11); TONE study group.
Collaborators: Albrecht P, Aktas O, Beck A, Beckmann A, Beisse F, Berthele A,
Bönig L, Diem R, Elflein H, Fitzner D, Fleischer V, Gingele S, Grotejohann B,
Guthoff T, Guthoff R, Hartmann K, Hassenstein A, Heesen C, Hein K, Heinrich SP,
Hufendiek K, Hug MJ, Huhn K, Hümmert MW, Ihorst G, Klopfer M, Kruse FE, Küchlin
S, Kümpfel T, Lagrèze WA, Linker RA, Lorenz K, Molnár FE, Mulazzani E, Müller M,
Nickel FT, Noll M, Pielen A, Pitz S, Rauer S, Reich M, Rosenkranz S,
Schwenkenbecher P, Siller N, Skripuletz T, Stangel M, Stellmann JP, Stürner K,
Sühs KW, Ungewiss J, Uphaus T, van Oterendorp C, Volkmann M, Wabbels B, Wilhelm
H, Wolf S, Wörner M, Ziemann U, Zipp F.
Author information:
(1)Eye Center, Medical Center, Faculty of Medicine, University of Freiburg,
Freiburg, Germany. Electronic address: wolf.lagreze@uniklinik-freiburg.de.
(2)Eye Center, Medical Center, Faculty of Medicine, University of Freiburg,
Freiburg, Germany.
(3)Clinical Trials Unit, Medical Center, Faculty of Medicine, University of
Freiburg, Freiburg, Germany.
(4)Department of Ophthalmology, University Hospital, University of Heidelberg,
Heidelberg, Germany.
(5)Medical Service Center PD Dr Volkmann and Colleagues, Karlsruhe, Germany.
(6)Department of Neurology, Medical Faculty, Heinrich Heine-Universität
Düsseldorf, Düsseldorf, Germany.
(7)Aalen University of Applied Sciences, Competence Center Vision Research,
Aalen, Germany.
(8)Aalen University of Applied Sciences, Competence Center Vision Research,
Aalen, Germany; Blickshift, Stuttgart, Germany.
(9)Pharmacy, Medical Center, Faculty of Medicine, University of Freiburg,
Freiburg, Germany.
(10)Department of Ophthalmology, Inselspital, University Hospital, University of
Bern, Bern, Switzerland.
(11)Department of Neurology, University Hospital, University of Heidelberg,
Heidelberg, Germany; Clinical Cooperation Unit Neurooncology, German Cancer
Consortium (DKTK), German Cancer Research Center (DFKZ), Heidelberg, Germany.
Comment in
Lancet Neurol. 2021 Dec;20(12):970-971. doi: 10.1016/S1474-4422(21)00378-1.
BACKGROUND: The human cytokine erythropoietin conveys neuroprotection in animal
models but has shown ambiguous results in phase 2 clinical trials in patients
with optic neuritis. We assessed the safety and efficacy of erythropoietin in
patients with optic neuritis as a clinically isolated syndrome in a multicentre,
prospective, randomised clinical trial.
METHODS: This randomised, placebo-controlled, double-blind phase 3 trial,
conducted at 12 tertiary referral centres in Germany, included participants aged
18-50 years, within 10 days of onset of unilateral optic neuritis, with visual
acuity of 0·5 or less, and without a previous diagnosis of multiple sclerosis.
Participants were randomly assigned (1:1) to receive either 33 000 IU
erythropoietin or placebo intravenously for 3 days as an adjunct to high-dose
intravenous methylprednisolone (1000 mg per day). Block randomisation was
performed by the trial statistician using an SAS code that generated randomly
varying block sizes, stratified by study site and distributed using sealed
envelopes. All trial participants and all study staff were masked to treatment
assignment, except the trial pharmacist. The first primary outcome was atrophy
of the peripapillary retinal nerve fibre layer (pRNFL), measured by optic
coherence tomography (OCT) as the difference in pRNFL thickness between the
affected eye at week 26 and the unaffected eye at baseline. The second primary
outcome was low contrast letter acuity at week 26, measured as the 2·5% Sloan
chart score of the affected eye. Analysis was performed in the full analysis set
of all randomised participants for whom treatment was started and at least one
follow-up OCT measurement was available. Safety was analysed in all patients who
received at least one dose of the trial medication. This trial is registered at
ClinicalTrials.gov, NCT01962571.
FINDINGS: 108 participants were enrolled between Nov 25, 2014, and Oct 9, 2017,
of whom 55 were assigned to erythropoietin and 53 to placebo. Five patients were
excluded from the primary analysis due to not receiving the allocated
medication, withdrawn consent, revised diagnosis, or loss to follow-up, yielding
a full analysis set of 52 patients in the erythropoietin group and 51 in the
placebo group. Mean pRNFL atrophy was 15·93 μm (SD 14·91) in the erythropoietin
group and 14·65 μm (15·60) in the placebo group (adjusted mean treatment
difference 1·02 μm; 95% CI -5·51 to 7·55; p=0·76). Mean low contrast letter
acuity scores were 49·60 (21·31) in the erythropoietin group and 49·06 (21·93)
in the placebo group (adjusted mean treatment difference -4·03; -13·06 to 5·01).
Adverse events occurred in 43 (81%) participants in the erythropoietin group and
in 42 (81%) in the placebo group. The most common adverse event was headache,
occuring in 15 (28%) patients in the erythropoietin group and 13 (25%) patients
in the placebo group. Serious adverse events occurred in eight (15%)
participants in the erythropoietin and in four (8%) in the placebo group. One
patient (2%) in the erythropoietin group developed a venous sinus thrombosis,
which was treated with anticoagulants and resolved without sequelae.
INTERPRETATION: Erythropoietin as an adjunct to corticosteroids conveyed neither
functional nor structural neuroprotection in the visual pathways after optic
neuritis. Future research could focus on modified erythropoietin administration,
assess its efficacy independent of corticosteroids, and investigate whether it
affects the conversion of optic neuritis to multiple sclerosis.
FUNDING: German Federal Ministry of Education and Research (BMBF).
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1474-4422(21)00322-7
PMID: 34800417 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests WAL reports grants from
the German Federal Ministry for Education and Research (BMBF) and the German
Research Foundation (DFG). He received speakers' honoraria from and worked on
advisory boards for Alcon, Allergan, Santhera, Boehringer Ingelheim, and Merz
Pharma. SK has received a doctoral fellowship with funding from the University
of Freiburg, Faculty of Medicine, and the Else Kröner-Fresenius Foundation. GI
has received funding from Novartis and Janssen Pharmaceutica. MV has worked on
an advisory board for Roche Pharma. SPH has received funding from the DFG, the
German Federal Institute for Sport Science, and the German Ophthalmological
Society. PA reports grants, personal fees, and non-financial support from
Allergan, Biogen, Celgene, Ipsen, Merck, Merz Pharmaceuticals, Novartis, Roche,
and Teva, outside the submitted work. JU has received a doctoral fellowship with
funding from the Ministry of Science, Research and Arts Baden-Wuerttemberg, as
part of the HAW-Prom programme. She received a speaker's honoraria from AMO
Ireland (affiliated to Johnson & Johnson Vision) and is co-inventor of patents
or patent applications with the numbers 10 2017 126 741, WO 2020/089284 A1, and
20 174 551.0. MW is a managing partner of Blickshift and co-inventor of patent
applications WO 2020/089284 A1 and 20 174 551.0. MJH reports grants from
Bristol-Myers Squibb and speaker's honoraria from Amgen, Baxter Deutschland, CSL
Behring, Biotest Pharma, Fresenius Kabi, Leo Pharma, Merck Serono, Novartis
Pharma, Pfizer, Roche Pharma, and Sun Pharmaceuticals Industries. SW has served
as a consultant for Bayer, Novartis, Chengdu Kanghong Biotech, Zeiss, and Roche
and has received grant support from Zeiss and Heidelberg Engineering. RD was
funded by the BMBF, the DFG, and the Hertie Foundation. BG and FB declare no
competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/25809419 | 1. Liver Int. 2015 Nov;35(11):2474-82. doi: 10.1111/liv.12834. Epub 2015 Apr 8.
The value of serum aspartate aminotransferase and gamma-glutamyl transpetidase
as biomarkers in hepatotoxicity.
Robles-Diaz M(1), Garcia-Cortes M(1), Medina-Caliz I(1), Gonzalez-Jimenez A(1),
Gonzalez-Grande R(2), Navarro JM(3), Castiella A(4), Zapata EM(4), Romero-Gomez
M(5), Blanco S(6), Soriano G(7), Hidalgo R(8), Ortega-Torres M(9), Clavijo E(9),
Bermudez-Ruiz PM(9), Lucena MI(1), Andrade RJ(1); Spanish DILI Registry; Faster
Evidence-based Translation (SAFE-T) Consortium.
Collaborators: Andrade RJ, Lucena MI, Stephens C, Robles-Diaz M, Kullak-Ublick
GA, Merz M, Schuppe-Koistinen I, Andrade RJ, Lucena MI, Stephens C,
García-Cortés M, Robles-Díaz M, Medina-Cáliz I, Sanabria J, García-Muñoz B,
Alcántara R, Moreno I, Gonzalez-Jimenez A, Papineau A, Fernandez-Castañer A,
Ortega-Alonso A, González-Amores Y, Pérez MJ, Grande RG, Fernández MC, Peláez G,
Casado M, González-Sánchez M, Romero-Gómez M, Calle-Sanz R, Millan-Dominguez R,
Fombuena B, Gallego R, Rojas L, Rojas A, Ampuero J, del Campo JA, Castiella A,
Zapata EM, Zubiaurre L, Pérez-Álvarez R, Rodrigo-Sáez L, Navarro JM, Sánchez IM,
Chaves A, Guarner C, Soriano G, Román EM, Hallal H, García-Oltra E, Titos-Arcos
JC, Pérez-Martínez A, Cobarro CS, Egea-Caparrós JM, Arenas J, Osua MI,
Gómez-García A, Esandi FJ, Blanco S, Martínez-Odriozola P, Otazua P, Salmerón J,
Gila A, González JM, Lorenzo S, Prieto M, Garcia-Eliz M, Berenguer M, Primo J,
Molés JR, Garayoa A, Carrascosa M, Gómez-Domínguez E, Montané EM, Costa J,
Barriocanal A, Planas R, Bruguera M, Gines P, Lens S, García JC, Aldea A,
Hernández-Guerra M, Moreno M, San Fiel, del Campo CB, Fernández C, Fernández-Gil
M, Montero JL, de la Mata M, Fuentes-Olmo J, Fernández-Bonilla EM, Moreno JM,
Martínez-Rodenas P, Garrido M, Ávila S, Nogueras F, de la Revilla J, Trapero M,
Gómez M, Aguilar VM, De Sola M, Rendón P, Vergara M, Delgado JS, González-López
O, García-Samaniego J, Madejón A, Cabriada JL, Crespo J, Pons F.
Author information:
(1)Unidad de Gestión Clínica de Enfermedades Digestivas y Hepatología, Servicio
de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA,
Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga,
Spain.
(2)Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de
Investigación Biomédica de Málaga-IBIMA, Hospital Regional Universitario Carlos
Haya, Málaga, Spain.
(3)Unidad de Gestión Clínica de Aparato Digestivo, Hospital Costa del Sol,
Marbella, Málaga, Spain.
(4)Unidad de Gestión Clínica de Enfermedades Digestivas, Hospital de Mendaro,
Guipúzcoa, Spain.
(5)Unidad de Gestión Clínica de Enfermedades Digestivas, Hospital Universitario
de Valme, Sevilla, Spain.
(6)Unidad de Gestión Clínica de Enfermedades Digestivas, Hospital de Basurto,
Bilbao, Spain.
(7)Unidad de Gestión Clínica de Enfermedades Digestivas, Hospital de Sant Pau,
Barcelona, Spain.
(8)Servicio Central de Informática de la Universidad de Málaga, Málaga, Spain.
(9)Unidad de Gestión Clínica Intercentros de Microbiología, Hospitales
Universitarios Regional y Virgen de la Victoria, Málaga, Spain.
BACKGROUND & AIMS: The current definition of the pattern of liver injury in
hepatotoxicity (DILI) is given by the R (ratio) value, dividing alanine
aminotransferase (ALT) and alkaline phosphatase (ALP) in upper limits of normal
at DILI onset. We aimed to explore the validity of using aspartate
aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) as biomarkers of
hepatocelullar and cholestatic damage, respectively, when calculating the R
value.
METHODS: Clinical, laboratory and histological data from 588 DILI episodes
included in the Spanish DILI Registry were analyzed. Linear regression analysis
was performed to establish the most appropriate cut-off points for
hepatocellular and cholestatic patterns when calculating R with AST and GGT.
RESULTS: The overall agreement between ALT/ALP and AST/ALP was 76%, with 96%,
61% and 41% agreement in the hepatocellular (R ≥ 5), cholestatic (R ≤ 2) and
mixed groups respectively (P < 0.001). Classified by the causative drug, the
agreement was higher (87-95%) among drug classes that mainly present with
hepatocellular damage and lower (48-58%) for those in which cholestatic-mixed
injury predominate (P < 0.001)). The overall agreement between ALT/ALP and
ALT/GGT was weak (59%), except for in hepatocellular cases that showed a good
agreement (94%) (P = 0.001). Pattern of injury according to liver histology
demonstrated 65%, 68% and 47% agreement for ALT/ALP, AST/ALP and ALT/GGT ratios
respectively.
CONCLUSIONS: AST can reliably replace ALT when calculating pattern of liver
injury in DILI, while GGT can only substitute ALP when the R value scores as
hepatocellular. The biochemical signature of causative drugs does influence the
validity of the ratios with AST or GGT.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
DOI: 10.1111/liv.12834
PMID: 25809419 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23494880 | 1. Am J Med Genet A. 2013 Apr;161A(4):687-95. doi: 10.1002/ajmg.a.35810. Epub
2013 Mar 12.
Parental perspectives on the diagnostic process for Duchenne and Becker muscular
dystrophy.
Daack-Hirsch S(1), Holtzer C, Cunniff C.
Author information:
(1)College of Nursing, The University of Iowa, Iowa City, IA 52242, USA.
sandra-daack-hirsch@uiowa.edu
Duchenne and Becker muscular dystrophy (DBMD) are allelic, X-linked recessive,
neuromuscular disorders characterized by progressive loss of muscle function.
Despite technological advances in diagnostic genetic testing, the mean age at
diagnosis (4.7 years) has remained unchanged for decades. The purpose of the
study was to characterize parental perceptions of the diagnostic process and
identify factors that influence the timeline. Data collection for this
qualitative study consisted of six individual and five group interviews.
Participants (N = 30) included Hispanic, non-Hispanic black, and non-Hispanic
white parents whose son was diagnosed with DBMD. The "help-seeking behavior
model" provided an analytical framework to analyze the data. Parents did not
move through help-seeking stages unidirectionally as described in other studies.
Delays existed at each stage. We identified personal, familial, social,
cultural, and provider factors that impeded earlier diagnosis. These barriers
prolonged movement through a stage or led families to repeat previous stages.
Results should initiate debate among system administrators, patient advocates,
and healthcare providers regarding which barriers may be most modifiable and
which interventions may reduce the time to diagnosis and limit parental
emotional distress.
Copyright © 2013 Wiley Periodicals, Inc.
DOI: 10.1002/ajmg.a.35810
PMID: 23494880 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24704526 | 1. Gastroenterology. 2014 Jul;147(1):109-118.e5. doi:
10.1053/j.gastro.2014.03.050. Epub 2014 Apr 1.
Use of Hy's law and a new composite algorithm to predict acute liver failure in
patients with drug-induced liver injury.
Robles-Diaz M(1), Lucena MI(2), Kaplowitz N(3), Stephens C(1), Medina-Cáliz
I(1), González-Jimenez A(4), Ulzurrun E(1), Gonzalez AF(4), Fernandez MC(5),
Romero-Gómez M(6), Jimenez-Perez M(7), Bruguera M(8), Prieto M(9), Bessone
F(10), Hernandez N(11), Arrese M(12), Andrade RJ(1); Spanish DILI Registry;
SLatinDILI Network; Safer and Faster Evidence-based Translation Consortium.
Collaborators: Hidalgo D, Andrade R, Lucena M, Robels-Díaz M, Stephens C,
Kullak-Ublick G, Poynard T, Ormarsdottir S, Merz M, Schuppe-Koistinen I, Andrade
R, Lucena M, Stephens C, García-Cortés M, Robles-Diaz M, Medina-Caliz I,
Fernandez-Castañer A, Ulzurrun E, González A, Moreno I, Ruiz J, Papineau A,
Fernández M, Peláez G, Casado M, González-Sánchez M, Romero-Gómez M, Calle-Sanz
R, Millan-Dominguez R, Grande L, Jover M, Prado B, Castiella A, Zapata E,
Pérez-Álvarez R, Navarro J, Sánchez I, Guarner C, Román E, Hallal H, Titos-Arcos
J, Pérez A, Osua M, Blanco S, Martínez-Odriozola P, Otazua P, Jiménez M, Alanís
J, Villar M, González J, Ruiz-Rebollo M, Haya C, Jiménez M, González-Grande R,
Manteca R, Prieto M, Garcia-Elix M, Berenguer M, Primo J, Molés J, Carrascosa M,
Solís-Herruzo J, Costa J, Barriocanal A, Planas R, Bruguera M, Gines P, Aldea A,
Hernandez-Guerra M, Fernandez C, Fernandez-Gil M, Montero J, Servet M, Bessone
F, Montero J, Hernandez N, Sanchez A, Dipace M, Cohen H, Davalos M, Arrese M,
Arancibia J, Girala M, Gadischesky M, Ughelli L, Kershenobich D, Loaeza A, de
Maracaibo, Lizarzabal M, Mengual E, Santos E, Paraná R, Schinoni M,
Méndez-Sánchez N, Berdeja V, Rejas A.
Author information:
(1)Unidad de Gestión Clínica de Enfermedades Digestivas, Servicio de
Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA),
Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga,
Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y
Digestivas, Barcelona, Spain.
(2)Unidad de Gestión Clínica de Enfermedades Digestivas, Servicio de
Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA),
Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga,
Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y
Digestivas, Barcelona, Spain. Electronic address: lucena@uma.es.
(3)University of Southern California Research Center for Liver Diseases, Keck
School of Medicine, Los Angeles, California.
(4)Unidad de Gestión Clínica de Enfermedades Digestivas, Servicio de
Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA),
Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga,
Spain.
(5)Servicio de Farmacia, Hospital de Torrecardenas, Almeria, Spain.
(6)Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y
Digestivas, Barcelona, Spain; Unidad de Gestión Clínica de Enfermedades
Digestivas, Hospital Universitario de Valme, Sevilla, Spain.
(7)Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de
Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario
Carlos Haya, Málaga, Spain.
(8)Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y
Digestivas, Barcelona, Spain; Instituto de Enfermedades Digestivas y
Metabolismo, Hospital Clinic, Barcelona, Spain.
(9)Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y
Digestivas, Barcelona, Spain; Unidad de Gestión Clínica de Enfermedades
Digestivas, Hospital La Fe, Valencia, Spain.
(10)Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología,
Hospital Provincial del Centenario, Universidad Nacional de Rosario, Rosario,
Argentina.
(11)Hospital de Clínicas, Clínica de Gastroenterología, Facultad de Medicina,
Universidad de la Republica, Montevideo, Uruguay.
(12)Departamento de Gastroenterología, Facultad de Medicina Pontificia,
Universidad Católica de Chile, Santiago, Chile.
Comment in
Gastroenterology. 2014 Jul;147(1):20-4. doi: 10.1053/j.gastro.2014.05.027.
Turk J Gastroenterol. 2014 Jun;25(3):347-8. doi: 10.5152/tjg.2014.0014.
Gastroenterology. 2014 Dec;147(6):1442. doi: 10.1053/j.gastro.2014.10.035.
Gastroenterology. 2014 Dec;147(6):1441. doi: 10.1053/j.gastro.2014.07.059.
Gastroenterology. 2015 Feb;148(2):452-3. doi: 10.1053/j.gastro.2014.12.025.
Gastroenterology. 2015 Feb;148(2):452. doi: 10.1053/j.gastro.2014.11.046.
BACKGROUND & AIMS: Hy's Law, which states that hepatocellular drug-induced liver
injury (DILI) with jaundice indicates a serious reaction, is used widely to
determine risk for acute liver failure (ALF). We aimed to optimize the
definition of Hy's Law and to develop a model for predicting ALF in patients
with DILI.
METHODS: We collected data from 771 patients with DILI (805 episodes) from the
Spanish DILI registry, from April 1994 through August 2012. We analyzed data
collected at DILI recognition and at the time of peak levels of alanine
aminotransferase (ALT) and total bilirubin (TBL).
RESULTS: Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury,
female sex, high levels of TBL, and a high ratio of aspartate aminotransferase
(AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's
Law to predict which patients would develop ALF; all included TBL greater than
2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 ×
ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater,
or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/
alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the
R- and nR-based models identified patients who developed ALF with 67% and 63%
specificity, respectively, whereas use of only ALT level identified them with
44% specificity. However, the level of ALT and the nR model each identified
patients who developed ALF with 90% sensitivity, whereas the R criteria
identified them with 83% sensitivity. An equal number of patients who did and
did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An
algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 ×
ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82%
specificity and 80% sensitivity.
CONCLUSIONS: When applied at DILI recognition, the nR criteria for Hy's Law
provides the best balance of sensitivity and specificity whereas our new
composite algorithm provides additional specificity in predicting the ultimate
development of ALF.
Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
DOI: 10.1053/j.gastro.2014.03.050
PMID: 24704526 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32205565 | 1. Curr Opin Gastroenterol. 2020 May;36(3):199-205. doi:
10.1097/MOG.0000000000000636.
Signatures in drug-induced liver injury.
Tillmann HL(1)(2), Rockey DC(3).
Author information:
(1)Division of Gastroenterology, Hepatology and Nutrition, Department of
Medicine, East Carolina University.
(2)Greenville VA Healthcare Center, Greenville, North Carolina.
(3)Department of Medicine, Medical University South Carolina, Charleston, South
Carolina, USA.
PURPOSE OF REVIEW: Drug-induced liver injury (DILI) can be induced by a myriad
of drugs. Assessing whether the patient has DILI and assessing which drug is the
most likely culprit are challenging. There has been too little attention paid to
the concept that certain drugs appear to have unique clinical features or
'phenotypes'.
RECENT FINDINGS: Several case series of DILI because of various drugs have been
published, and analysis of these case series points to the fact that individual
drugs have characteristic DILI signatures. These clinical phenotypes can be
characterized by latency, biochemical features (R-value), as well as clinical
symptoms and signs. Several drugs, including isoniazid, amoxicillin-clavulanic
acid, anabolic steroids, β-interferon and others, have highly unique clinical
features. Such unique properties may be able to be used to improve adjudication
processes.
SUMMARY: Individual drugs have unique clinical DILI phenotypes or signatures.
Furthermore, these may be able to be used to improve adjudication.
DOI: 10.1097/MOG.0000000000000636
PMCID: PMC10896173
PMID: 32205565 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest HLT’s wife is employee of
AbbVie, and holds stocks in AbbVie, Gilead and Abbott, HLT received consulting
fees from Trevena Inc. DCR received consulting fees from Trevena Inc. |
http://www.ncbi.nlm.nih.gov/pubmed/35811082 | 1. Int J Infect Dis. 2022 Sep;122:636-643. doi: 10.1016/j.ijid.2022.07.005. Epub
2022 Jul 8.
Clinical characteristics of the Omicron variant - results from a Nationwide
Symptoms Survey in the Faroe Islands.
Petersen MS(1), Í Kongsstovu S(2), Eliasen EH(3), Larsen S(4), Hansen JL(4),
Vest N(5), Dahl MM(5), Christiansen DH(5), Møller LF(4), Kristiansen MF(6).
Author information:
(1)The Faroese Hospital System, the Department of Occupational Medicine and
Public Health, Tórshavn, Faroe Islands; University of the Faroe Islands, Center
of Health Science, Tórshavn, Faroe Islands. Electronic address: maria@health.fo.
(2)The Faroese Hospital System, the Department of Occupational Medicine and
Public Health, Tórshavn, Faroe Islands.
(3)The Faroese Hospital System, the Department of Occupational Medicine and
Public Health, Tórshavn, Faroe Islands; University of the Faroe Islands, Center
of Health Science, Tórshavn, Faroe Islands.
(4)Chief Medical Office, Tórshavn, Faroe Islands.
(5)Faroese Food and Veterinary Authority, Tórshavn, Faroe Islands.
(6)The Faroese Hospital System, the Department of Occupational Medicine and
Public Health, Tórshavn, Faroe Islands; The National Hospital of the Faroe
Islands, Medical Department, Tórshavn, Faroe Islands.
OBJECTIVES: Omicron appears to lead to a milder illness for patients compared
with previous COVID-19 variants. However, not all infected with Omicron would
describe their illness as mild. In this study, we investigate the experienced
severity and symptoms of the Omicron variant.
METHODS: We conducted a nationwide cross-sectional study, including 5036
individuals of all ages, consisting of reverse transcription-polymerase chain
reaction confirmed SARS-CoV-2 cases from 1 January to 31 January 2022 (n = 4506)
and a control group without SARS-COV-2 infection in December 2021 or January
2022 (n = 530). Omicron was dominant during this period. Cases were asked about
their acute symptoms and answered a web-based questionnaire 10-30 days after
their positive test while controls were asked about symptoms during the past
week.
RESULTS: Among cases, 97% reported at least one symptom during the acute phase
compared with 79% of controls. Just over half the cases assessed their illness
as asymptomatic or mild, whereas 46% assessed their illness as moderate or
severe. Children reported fewer symptoms and less severe illnesses than adults
(P <0.001). The largest risk differences (RDs) between adult cases and controls
due to symptoms were observed for fever (RD = 60.6%, confidence interval [CI]
57.4-63.6), fatigue (RD = 49.6%, CI 44.1-54.7), and chills (RD = 48.8%, CI
43.8-53.2).
CONCLUSION: Most of those infected with Omicron experience symptoms, and the
Omicron variant appears to lead to less severe disease. However, this does not
mean that all the infected experience an Omicron infection as mild. The
unprecedented rate of Omicron infections worldwide leads to urgent questions
about the rate of long COVID after Omicron infections.
Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.ijid.2022.07.005
PMCID: PMC9303132
PMID: 35811082 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35751531 | 1. Eur J Haematol. 2022 Oct;109(4):364-372. doi: 10.1111/ejh.13818. Epub 2022 Jul
16.
Early report on the severity of COVID-19 in hematologic patients infected with
the SARS-CoV2 omicron variant.
Ullrich F(1), Hanoun C(1), Turki AT(1), Liebregts T(1), Breuckmann K(2),
Alashkar F(1), Reinhardt HC(1), von Tresckow B(1), von Tresckow J(1).
Author information:
(1)Department of Hematology and Stem Cell Transplantation, West German Cancer
Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
(2)Department of Radiology and Neuroradiology, University Hospital Essen,
University of Duisburg-Essen, Essen, Germany.
INTRODUCTION: Patients with hematologic disease are at high risk of morbidity
and mortality from COVID-19 due to disease-inherent and therapy-related
immunodeficiency. Whether infection with the SARS-CoV2 omicron variant leads to
attenuated disease severity in these patients is currently unknown.
METHODS: We assessed clinical and laboratory parameters in 61 patients with
underlying hematologic conditions with a SARS-CoV2 omicron variant infection
confirmed by nucleic acid amplification testing.
RESULTS: Fifty patients reported symptoms of COVID-19, most commonly fatigue (37
patients, 60.66%) and cough (32 patients, 52.46%). 39.34% of patients reported
fever. Dyspnea was reported by 10 patients and 7 patients (11.48%) required
oxygen therapy. Anosmia and ageusia were relatively rare, occurring in less than
10% of patients. Severity of SARS-CoV2 infection could be assessed in 60
patients. Five cases of critical illness leading to ICU admission occurred
during the observation period. Overall mortality was 9.84% in this patient
cohort, with heterogeneous causes of death. The majority of omicron-infected
hematologic patients experienced mild symptoms or remained asymptomatic.
DISCUSSION: In this study, symptoms of COVID-19 tended to be milder than
described for previous SARS-CoV2 variants. However, the extent to which
attenuated severity of omicron-variant SARS-CoV2 infection is caused by altered
viral pathogenicity or pre-existing host immunity cannot be inferred from our
data and should be investigated in larger prospective studies.
© 2022 The Authors. European Journal of Haematology published by John Wiley &
Sons Ltd.
DOI: 10.1111/ejh.13818
PMCID: PMC9350268
PMID: 35751531 [Indexed for MEDLINE]
Conflict of interest statement: Fabian Ullrich: reports travel support from
AbbVie and Kite/Gilead. Christine Hanoun: has nothing to disclose. Amin T.
Turki: reports consultancy for CSL Behring and Maat Pharma. Tobias Liebregts:
has nothing to disclose. Katharina Breuckmann: has nothing to disclose. Ferras
Alashkar: has nothing to disclose. Hans‐Christian Reinhardt: has nothing to
disclose. Bastian von Tresckow: is an advisor or consultant for Allogene,
BMS/Celgene, Cerus, Incyte, Miltenyi, Novartis, Pentixafarm, Roche, Amgen,
Pfizer, Takeda, Merck Sharp & Dohme, and Gilead Kite; has received honoraria
from AstraZeneca, Novartis, Roche Pharma AG, Takeda, and Merck Sharp & Dohme;
reports research funding from Novartis (Inst), Merck Sharp & Dohme (Inst), and
Takeda (Inst); and reports travel support from AbbVie, AstraZeneca, Kite‐Gilead,
Merck Sharp & Dohme, Takeda, and Novartis. Julia von Tresckow: is an advisor or
consultant for AbbVie, AstraZeneca, Janssen‐Cilag and Roche, has received
honoraria from AbbVie, AstraZeneca, Janssen‐Cilag and Roche, reports research
funding from Janssen‐Cilag and Roche, and reports travel support from AbbVie,
AstraZeneca, Janssen‐Cilag and Roche. |
http://www.ncbi.nlm.nih.gov/pubmed/36417338 | 1. MEDICC Rev. 2022 Oct 31;24(3-4):68-71. doi: 10.37757/mr2022.v24.n3-4.10.
A Shift in SARS-CoV-2 Omicron Variant's Entry Pathway Might Explain Different
Clinical Outcomes.
Machado-Curbelo C(1), Gutiérrez-Gil J(1), González-Quevedo A(1).
Author information:
(1)Institute of Neurology and Neurosurgery (INN), Havana, Cuba.
Globally, SARS CoV-2 omicron variant has led to a notable increase of COVID-19
diagnoses, although with less severe clinical manifestations and decreased
hospitalizations. The omicron wave swelled faster than previous waves,
completely displacing the delta variant within weeks, and creating worldwide
concern about final, successful pandemic control. Some authors contend that
symptoms associated to omicron differ from 'traditional' symptoms and more
closely resemble those of the common cold. One major COVID-19 symptom frequent
with other variants-loss of taste and smell-is rarely present with omicron. This
may be of interest, since it has also been suggested that direct SARS-CoV-2
invasion into the brainstem through the olfactory nerves by transsynaptic
pathways could provide one explanation for the acute respiratory distress
syndrome refractory to treatment. Brainstem infection by SARS-CoV-2 can severely
damage the respiratory center, triggering functional deviations that affect
involuntary respiration, leading to acute respiratory distress syndrome
refractory to treatment, the main cause of death in COVID-19 patients. A shift
in the omicron SARS-CoV-2 entry pathway from cell-surface fusion, triggered by
TMPRSS2, to cathepsin-dependent fusion within the endosome, may affect
transmission, cellular tropism and pathogenesis. Therefore, we can hypothesize
that this entrance modification may impact transmission from the olfactory nerve
to the brainstem through transsynaptic pathways. A decrement of the virus's
direct invasion into the brainstem could diminish respiratory center
dysfunction, reducing acute respiratory distress syndrome and the need for
mechanical ventilation.
DOI: 10.37757/mr2022.v24.n3-4.10
PMID: 36417338 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35468332 | 1. Lancet Infect Dis. 2022 Jul;22(7):959-966. doi: 10.1016/S1473-3099(22)00141-4.
Epub 2022 Apr 22.
Severity of omicron variant of concern and effectiveness of vaccine boosters
against symptomatic disease in Scotland (EAVE II): a national cohort study with
nested test-negative design.
Sheikh A(1), Kerr S(2), Woolhouse M(2), McMenamin J(3), Robertson C(4); EAVE II
Collaborators.
Collaborators: Simpson CR, Millington T, Shi T, Agrawal U, Shahul Hameed S, Hall
E, Rudan I, Shah SA, Ritchie L, Stock S, McCowan C.
Author information:
(1)Usher Institute, University of Edinburgh, Edinburgh, UK. Electronic address:
aziz.sheikh@ed.ac.uk.
(2)Usher Institute, University of Edinburgh, Edinburgh, UK.
(3)Public Health Scotland, Glasgow, UK.
(4)Public Health Scotland, Glasgow, UK; Department of Mathematics and
Statistics, University of Strathclyde, Glasgow, UK.
Comment in
Lancet Infect Dis. 2022 Jul;22(7):914-915. doi:
10.1016/S1473-3099(22)00174-8.
BACKGROUND: Since its emergence in November, 2021, in southern Africa, the
SARS-CoV-2 omicron variant of concern (VOC) has rapidly spread across the world.
We aimed to investigate the severity of omicron and the extent to which booster
vaccines are effective in preventing symptomatic infection.
METHODS: In this study, using the Scotland-wide Early Pandemic Evaluation and
Enhanced Surveillance of COVID-19 (EAVE II) platform, we did a cohort analysis
with a nested test-negative design incident case-control study covering the
period Nov 1-Dec 19, 2021, to provide initial estimates of omicron severity and
the effectiveness of vaccine boosters against symptomatic disease relative to 25
weeks or more after the second vaccine dose. Primary care data derived from 940
general practices across Scotland were linked to laboratory data and hospital
admission data. We compared outcomes between infection with the delta VOC
(defined as S-gene positive) and the omicron VOC (defined as S-gene negative).
We assessed effectiveness against symptomatic SARS-CoV-2 infection, with
infection confirmed through a positive RT-PCR.
FINDINGS: By Dec 19, 2021, there were 23 840 S-gene-negative cases in Scotland,
which were predominantly among those aged 20-39 years (11 732 [49·2%]). The
proportion of S-gene-negative cases that were possible reinfections was more
than ten times that of S-gene-positive cases (7·6% vs 0·7%; p<0·0001). There
were 15 hospital admissions in S-gene-negative individuals, giving an adjusted
observed-to-expected admissions ratio of 0·32 (95% CI 0·19-0·52). The booster
vaccine dose was associated with a 57% (54-60) reduction in the risk of
symptomatic S-gene-negative infection relative to individuals who tested
positive 25 weeks or more after the second vaccine dose.
INTERPRETATION: These early national data suggest that omicron is associated
with a two-thirds reduction in the risk of COVID-19 hospitalisation compared
with delta. Although offering the greatest protection against delta, the booster
dose of vaccination offers substantial additional protection against the risk of
symptomatic COVID-19 for omicron compared with 25 weeks or more after the second
vaccine dose.
FUNDING: Health Data Research UK, National Core Studies, Public Health Scotland,
Scottish Government, UK Research and Innovation, and University of Edinburgh.
Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All
rights reserved.
DOI: 10.1016/S1473-3099(22)00141-4
PMCID: PMC9033213
PMID: 35468332 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests AS, MW, CR, and JM are
members of the Scottish Government Chief Medical Officer's COVID-19 Advisory
Group and AS is a member of its Standing Committee on Pandemics. AS and JM are
also members of the New and Emerging Respiratory Virus Threats Advisory Group
(NERVTAG). JM is the Chair of the multidisciplinary Scottish COVID-19 National
Incident Management Team. AS is a member of AstraZeneca's Thrombotic
Thrombocytopenic Taskforce. All AS’ roles are unremunerated. CR and MW are
members of the Scientific Pandemic Influenza Group on Modelling. SK declares no
competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35408618 | 1. Molecules. 2022 Mar 29;27(7):2221. doi: 10.3390/molecules27072221.
Can the SARS-CoV-2 Omicron Variant Confer Natural Immunity against COVID-19?
Abas AH(1), Marfuah S(1), Idroes R(2), Kusumawaty D(3), Fatimawali(4), Park
MN(5), Siyadatpanah A(6), Alhumaydhi FA(7), Mahmud S(8), Tallei TE(1), Emran
TB(9), Kim B(5).
Author information:
(1)Department of Biology, Faculty of Mathematics and Natural Sciences, Sam
Ratulangi University, Manado 95115, North Sulawesi, Indonesia.
(2)Department of Pharmacy, Faculty of Mathematics and Natural Sciences,
Universitas Syiah Kuala, Kopelma Darussalam, Banda Aceh 23111, Aceh, Indonesia.
(3)Department of Biology, Faculty of Mathematics and Natural Sciences Education,
Universitas Pendidikan Indonesia, Bandung 40154, West Java, Indonesia.
(4)Pharmacy Study Program, Faculty of Mathematics and Natural Sciences, Sam
Ratulangi University, Manado 95115, North Sulawesi, Indonesia.
(5)College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu,
Seoul 05253, Korea.
(6)Ferdows School of Paramedical and Health, Birjand University of Medical
Sciences, Birjand 97178-53577, Iran.
(7)Department of Medical Laboratories, College of Applied Medical Sciences,
Qassim University, Buraydah 52571, Saudi Arabia.
(8)Department of Genome Science, John Curtin School of Medical Research,
Australian National University, Canberra, ACT 0200, Australia.
(9)Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381,
Bangladesh.
The coronavirus disease 2019 (COVID-19) pandemic is still ongoing, with no signs
of abatement in sight. The severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2), which is the causative agent of this pandemic and has claimed over
5 million lives, is still mutating, resulting in numerous variants. One of the
newest variants is Omicron, which shows an increase in its transmissibility, but
also reportedly reduces hospitalization rates and shows milder symptoms, such as
in those who have been vaccinated. As a result, many believe that Omicron
provides a natural vaccination, which is the first step toward ending the
COVID-19 pandemic. Based on published research and scientific evidence, we
review and discuss how the end of this pandemic is predicted to occur as a
result of Omicron variants being surpassed in the community. In light of the
findings of our research, we believe that it is most likely true that the
Omicron variant is a natural way of vaccinating the masses and slowing the
spread of this deadly pandemic. While the mutation that causes the Omicron
variant is encouraging, subsequent mutations do not guarantee that the disease
it causes will be less severe. As the virus continues to evolve, humans must
constantly adapt by increasing their immunity through vaccination.
DOI: 10.3390/molecules27072221
PMCID: PMC9000495
PMID: 35408618 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35018384 | 1. medRxiv [Preprint]. 2022 Jan 2:2021.12.30.21268495. doi:
10.1101/2021.12.30.21268495.
Comparison of outcomes from COVID infection in pediatric and adult patients
before and after the emergence of Omicron.
Wang L(1)(2), Berger NA(2)(3), Kaelber DC(4), Davis PB(5), Volkow ND(6), Xu
R(1)(3).
Author information:
(1)Center for Artificial Intelligence in Drug Discovery, Case Western Reserve
University School of Medicine, Cleveland, OH, USA.
(2)Center for Science, Health, and Society, Case Western Reserve University
School of Medicine, Cleveland, OH, USA.
(3)Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve
University, Cleveland, OH, USA.
(4)The Center for Clinical Informatics Research and Education, The MetroHealth
System, Cleveland, OH, USA.
(5)Center for Community Health Integration, School of Medicine, Case Western
Reserve University, Cleveland, OH, USA.
(6)National Institute on Drug Abuse, National Institutes of Health, Bethesda,
MD, USA.
BACKGROUND: The Omicron SARS-CoV-2 variant is rapidly spreading in the US since
December 2021 and is more contagious than earlier variants. Currently, data on
the severity of the disease caused by the Omicron variant compared with the
Delta variant is limited. Here we compared 3-day risks of emergency department
(ED) visit, hospitalization, intensive care unit (ICU) admission, and mechanical
ventilation in patients who were first infected during a time period when the
Omicron variant was emerging to those in patients who were first infected when
the Delta variant was predominant.
METHOD: This is a retrospective cohort study of electronic health record (EHR)
data of 577,938 first-time SARS-CoV-2 infected patients from a multicenter,
nationwide database in the US during 9/1/2021-12/24/2021, including 14,054 who
had their first infection during the 12/15/2021-12/24/2021 period when the
Omicron variant emerged ("Emergent Omicron cohort") and 563,884 who had their
first infection during the 9/1/2021-12/15/2021 period when the Delta variant was
predominant ("Delta cohort"). After propensity-score matching the cohorts, the
3-day risks of four outcomes (ED visit, hospitalization, ICU admission, and
mechanical ventilation) were compared. Risk ratios, and 95% confidence intervals
(CI) were calculated.
RESULTS: Of 14,054 patients in the Emergent Omicron cohort (average age, 36.4 ±
24.3 years), 27.7% were pediatric patients (<18 years old), 55.4% female, 1.8%
Asian, 17.1% Black, 4.8% Hispanic, and 57.3% White. The Emergent Omicron cohort
differed significantly from the Delta cohort in demographics, comorbidities, and
socio-economic determinants of health. After propensity-score matching for
demographics, socio-economic determinants of health, comorbidities, medications
and vaccination status, the 3-day risks in the Emergent Omicron cohort outcomes
were consistently less than half those in the Delta cohort: ED visit: 4.55% vs.
15.22% (risk ratio or RR: 0.30, 95% CI: 0.28-0.33); hospitalization: 1.75% vs.
3.95% (RR: 0.44, 95% CI: 0.38-0.52]); ICU admission: 0.26% vs. 0.78% (RR: 0.33,
95% CI:0.23-0.48); mechanical ventilation: 0.07% vs. 0.43% (RR: 0.16, 95% CI:
0.08-0.32). In children under 5 years old, the overall risks of ED visits and
hospitalization in the Emergent Omicron cohort were 3.89% and 0.96%
respectively, significantly lower than 21.01% and 2.65% in the matched Delta
cohort (RR for ED visit: 0.19, 95% CI: 0.14-0.25; RR for hospitalization: 0.36,
95% CI: 0.19-0.68). Similar trends were observed for other pediatric age groups
(5-11, 12-17 years), adults (18-64 years) and older adults (≥ 65 years).
CONCLUSIONS: First time SARS-CoV-2 infections occurring at a time when the
Omicron variant was rapidly spreading were associated with significantly less
severe outcomes than first-time infections when the Delta variant predominated.
DOI: 10.1101/2021.12.30.21268495
PMCID: PMC8750707
PMID: 35018384
Conflict of interest statement: Declaration of interests LW, NAB, PBD, DCK, NDV,
RX have no financial interests to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/35071500 | 1. World J Clin Cases. 2022 Jan 7;10(1):1-11. doi: 10.12998/wjcc.v10.i1.1.
Omicron variant (B.1.1.529) of SARS-CoV-2: Mutation, infectivity, transmission,
and vaccine resistance.
Ren SY(1), Wang WB(2), Gao RD(3), Zhou AM(4).
Author information:
(1)Laser Vascular Surgery, Aviation General Hospital, China Medical University,
Beijing 10012, China. rens66@126.com.
(2)Department of Stomatology, Aviation General Hospital, China Medical
University, Beijing 100012, China.
(3)Laser Vascular Surgery, Aviation General Hospital, China Medical University,
Beijing 10012, China.
(4)Department of General Surgery, Aviation General Hospital, China Medical
University, Beijing 10012, China.
The appearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
variant Omicron (B.1.1.529) has caused panic responses around the world because
of its high transmission rate and number of mutations. This review summarizes
the highly mutated regions, the essential infectivity, transmission, vaccine
breakthrough and antibody resistance of the Omicron variant of SARS-CoV-2. The
Omicron is highly transmissible and is spreading faster than any previous
variant, but may cause less severe symptoms than previous variants. The Omicron
is able to escape the immune system's defenses and coronavirus disease 2019
vaccines are less effective against the Omicron variant. Early careful
preventive steps including vaccination will always be key for the suppression of
the Omicron variant.
©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights
reserved.
DOI: 10.12998/wjcc.v10.i1.1
PMCID: PMC8727245
PMID: 35071500
Conflict of interest statement: Conflict-of-interest statement: The authors
declare that they have no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35305296 | 1. Lancet. 2022 Apr 2;399(10332):1303-1312. doi: 10.1016/S0140-6736(22)00462-7.
Epub 2022 Mar 16.
Comparative analysis of the risks of hospitalisation and death associated with
SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a
cohort study.
Nyberg T(1), Ferguson NM(2), Nash SG(3), Webster HH(3), Flaxman S(4), Andrews
N(5), Hinsley W(6), Bernal JL(7), Kall M(3), Bhatt S(6), Blomquist P(8), Zaidi
A(3), Volz E(6), Aziz NA(3), Harman K(3), Funk S(9), Abbott S(9); COVID-19
Genomics UK (COG-UK) consortium; Hope R(3), Charlett A(10), Chand M(11), Ghani
AC(6), Seaman SR(12), Dabrera G(3), De Angelis D(13), Presanis AM(12), Thelwall
S(3).
Collaborators: Nyberg T, Ferguson NM, Nash SG, Webster HH, Flaxman S, Andrews N,
Hinsley W, Lopez Bernal J, Kall M, Bhatt S, Blomquist P, Zaidi A, Volz E, Abdul
Aziz N, Harman K, Funk S, Abbott S, Hope R, Charlett A, Chand M, Ghani AC,
Seaman SR, Dabrera G, De Angelis D, Presanis AM, Thelwall S.
Author information:
(1)MRC Biostatistics Unit, University of Cambridge, Cambridge, UK. Electronic
address: tommy.nyberg@mrc-bsu.cam.ac.uk.
(2)NIHR Health Protection Research Unit for Modelling and Health Economics, MRC
Centre for Global Infectious Disease Analysis, Jameel Institute, Imperial
College London, London, UK. Electronic address: neil.ferguson@imperial.ac.uk.
(3)COVID-19 National Epidemiology Cell, UK Health Security Agency, London, UK.
(4)Department of Computer Science, University of Oxford, Oxford, UK.
(5)COVID-19 Surveillance Cell, UK Health Security Agency, London, UK.
(6)NIHR Health Protection Research Unit for Modelling and Health Economics, MRC
Centre for Global Infectious Disease Analysis, Jameel Institute, Imperial
College London, London, UK.
(7)NIHR Health Protection Research Unit for Respiratory Infections, Imperial
College London, London, UK; COVID-19 Surveillance Cell, UK Health Security
Agency, London, UK.
(8)Outbreak Surveillance Team, UK Health Security Agency, London, UK.
(9)Centre for the Mathematical Modelling of Infectious Diseases, London School
of Hygiene & Tropical Medicine, London, UK.
(10)NIHR Health Protection Research Unit for Modelling and Health Economics, MRC
Centre for Global Infectious Disease Analysis, Jameel Institute, Imperial
College London, London, UK; Statistics, Modelling and Economics Department, UK
Health Security Agency, London, UK; Joint Modelling Team, UK Health Security
Agency, London, UK; NIHR Health Protection Research Unit for Behavioural Science
and Evaluation at the University of Bristol, University of the West of England,
and University of Cambridge, Bristol, UK.
(11)COVID-19 Genomics Cell, UK Health Security Agency, London, UK.
(12)MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
(13)MRC Biostatistics Unit, University of Cambridge, Cambridge, UK; Statistics,
Modelling and Economics Department, UK Health Security Agency, London, UK; Joint
Modelling Team, UK Health Security Agency, London, UK; NIHR Health Protection
Research Unit for Behavioural Science and Evaluation at the University of
Bristol, University of the West of England, and University of Cambridge,
Bristol, UK.
Comment in
Lancet. 2022 Apr 2;399(10332):1280-1281. doi: 10.1016/S0140-6736(22)00514-1.
Lancet. 2022 Sep 10;400(10355):809. doi: 10.1016/S0140-6736(22)01469-6.
BACKGROUND: The omicron variant (B.1.1.529) of SARS-CoV-2 has demonstrated
partial vaccine escape and high transmissibility, with early studies indicating
lower severity of infection than that of the delta variant (B.1.617.2). We aimed
to better characterise omicron severity relative to delta by assessing the
relative risk of hospital attendance, hospital admission, or death in a large
national cohort.
METHODS: Individual-level data on laboratory-confirmed COVID-19 cases resident
in England between Nov 29, 2021, and Jan 9, 2022, were linked to routine
datasets on vaccination status, hospital attendance and admission, and
mortality. The relative risk of hospital attendance or admission within 14 days,
or death within 28 days after confirmed infection, was estimated using
proportional hazards regression. Analyses were stratified by test date, 10-year
age band, ethnicity, residential region, and vaccination status, and were
further adjusted for sex, index of multiple deprivation decile, evidence of a
previous infection, and year of age within each age band. A secondary analysis
estimated variant-specific and vaccine-specific vaccine effectiveness and the
intrinsic relative severity of omicron infection compared with delta (ie, the
relative risk in unvaccinated cases).
FINDINGS: The adjusted hazard ratio (HR) of hospital attendance (not necessarily
resulting in admission) with omicron compared with delta was 0·56 (95% CI
0·54-0·58); for hospital admission and death, HR estimates were 0·41 (0·39-0·43)
and 0·31 (0·26-0·37), respectively. Omicron versus delta HR estimates varied
with age for all endpoints examined. The adjusted HR for hospital admission was
1·10 (0·85-1·42) in those younger than 10 years, decreasing to 0·25 (0·21-0·30)
in 60-69-year-olds, and then increasing to 0·47 (0·40-0·56) in those aged at
least 80 years. For both variants, past infection gave some protection against
death both in vaccinated (HR 0·47 [0·32-0·68]) and unvaccinated (0·18
[0·06-0·57]) cases. In vaccinated cases, past infection offered no additional
protection against hospital admission beyond that provided by vaccination (HR
0·96 [0·88-1·04]); however, for unvaccinated cases, past infection gave moderate
protection (HR 0·55 [0·48-0·63]). Omicron versus delta HR estimates were lower
for hospital admission (0·30 [0·28-0·32]) in unvaccinated cases than the
corresponding HR estimated for all cases in the primary analysis. Booster
vaccination with an mRNA vaccine was highly protective against hospitalisation
and death in omicron cases (HR for hospital admission 8-11 weeks post-booster vs
unvaccinated: 0·22 [0·20-0·24]), with the protection afforded after a booster
not being affected by the vaccine used for doses 1 and 2.
INTERPRETATION: The risk of severe outcomes following SARS-CoV-2 infection is
substantially lower for omicron than for delta, with higher reductions for more
severe endpoints and significant variation with age. Underlying the observed
risks is a larger reduction in intrinsic severity (in unvaccinated individuals)
counterbalanced by a reduction in vaccine effectiveness. Documented previous
SARS-CoV-2 infection offered some protection against hospitalisation and high
protection against death in unvaccinated individuals, but only offered
additional protection in vaccinated individuals for the death endpoint. Booster
vaccination with mRNA vaccines maintains over 70% protection against
hospitalisation and death in breakthrough confirmed omicron infections.
FUNDING: Medical Research Council, UK Research and Innovation, Department of
Health and Social Care, National Institute for Health Research, Community
Jameel, and Engineering and Physical Sciences Research Council.
Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All
rights reserved.
DOI: 10.1016/S0140-6736(22)00462-7
PMCID: PMC8926413
PMID: 35305296 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests GD declares that his
employer UK Health Security Agency (previously operating as Public Health
England) received funding from GlaxoSmithKline for a research project related to
influenza antiviral treatment. This preceded and had no relation to COVID-19,
and GD had no role in and received no funding from the project. All other
authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/36419108 | 1. BMC Med. 2022 Nov 23;20(1):451. doi: 10.1186/s12916-022-02655-z.
Identifying susceptibility of children and adolescents to the Omicron variant
(B.1.1.529).
Chun JY(#)(1), Jeong H(#)(2), Kim Y(3).
Author information:
(1)Department of Internal Medicine, National Cancer Center, Goyang, South Korea.
june.y.chun@ncc.re.kr.
(2)Department of Statistics, Seoul National University, 56-1 Mountain,
Sillim-dong, Gwanak-gu, Seoul, 08826, South Korea.
(3)Department of Statistics, Seoul National University, 56-1 Mountain,
Sillim-dong, Gwanak-gu, Seoul, 08826, South Korea. ydkim0903@gmail.com.
(#)Contributed equally
BACKGROUND: The Omicron variant (B.1.1.529) is estimated to be more
transmissible than previous strains of SARS-CoV-2 especially among children,
potentially resulting in croup which is a characteristic disease in children.
Current coronavirus disease 2019 (COVID-19) cases among children might be higher
because (i) school-aged children have higher contact rates and (ii) the COVID-19
vaccination strategy prioritizes the elderly in most countries. However, there
have been no reports confirming the age-varying susceptibility to the Omicron
variant to date.
METHODS: We developed an age-structured compartmental model, combining
age-specific contact matrix in South Korea and observed distribution of periods
between each stage of infection in the national epidemiological investigation. A
Bayesian inference method was used to estimate the age-specific force of
infection and, accordingly, age-specific susceptibility, given epidemic data
during the third (pre-Delta), fourth (Delta driven), and fifth (Omicron driven)
waves in South Korea. As vaccine uptake increased, individuals who were
vaccinated were excluded from the susceptible population in accordance with
vaccine effectiveness against the Delta and Omicron variants, respectively.
RESULTS: A significant difference between the age-specific susceptibility to the
Omicron and that to the pre-Omicron variants was found in the younger age group.
The rise in susceptibility to the Omicron/pre-Delta variant was highest in the
10-15 years age group (5.28 times [95% CI, 4.94-5.60]), and the rise in
susceptibility to the Omicron/Delta variant was highest in the 15-19 years age
group (3.21 times [95% CI, 3.12-3.31]), whereas in those aged 50 years or more,
the susceptibility to the Omicron/pre-Omicron remained stable at approximately
twofold.
CONCLUSIONS: Even after adjusting for contact pattern, vaccination status, and
waning of vaccine effectiveness, the Omicron variant of SARS-CoV-2 tends to
propagate more easily among children than the pre-Omicron strains.
© 2022. The Author(s).
DOI: 10.1186/s12916-022-02655-z
PMCID: PMC9684890
PMID: 36419108 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/36285226 | 1. Eur Heart J Case Rep. 2022 Oct 5;6(10):ytac407. doi: 10.1093/ehjcr/ytac407.
eCollection 2022 Oct.
First report of myocarditis in two patients with COVID-19 Omicron variant: case
report.
Fishman B(1), Goitein O(1), Berkovitch A(1), Rahav G(1), Matetzky S(1).
Author information:
(1)Sheba Medical Center, Tel Hashomer, affiliated to Sackler Medical School, Tel
Aviv University, Israel.
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 infection is
responsible for the coronavirus disease 2019 (COVID-19) pandemics. Omicron
(B.1.1.529) variant is the cause for the surge of the COVID-19 pandemics of the
end of 2021 and the beginning of 2022, although its subvariants are responsible
for the following daily increase of COVID-19 cases in July 2022. Early reports
of Omicron variant confirmed patients indicated less severe disease course
compared with the disease caused by previously encountered variants with absence
of data regarding cardiac involvement by Omicron.
CASE SUMMARY: A 42-year-old male who tested positive for Omicron was admitted on
January 2022 with chest pain and ST-segment elevation in the inferior leads.
Coronary angiography revealed non-significant coronary artery disease. Cardiac
magnetic resonance imaging demonstrated features consistent with myocarditis
with involvement of 22% of the left ventricular mass by late gadolinium
enhancement involving both the lateral and the septal walls. The second patient
is a 60-year-old male presented following syncope and palpitations after he was
confirmed with Omicron infection. Upon emergency department arrival he had
ventricular tachycardia of 250 beats/minute and underwent urgent cardioversion.
During his hospitalization, there was no recurrence of malignant arrhythmia,
coronary angiography revealed non-obstructive disease. Cardiac magnetic
resonance imaging demonstrated imaging features suggesting acute myocarditis
with involvement of 19% of the left ventricular mass.
DISCUSSION: This is the first report of myocarditis cases as a possible
complication associated with Omicron variant. Despite preliminary reports of
less severe disease clinicians should be vigilant for potential deleterious
cardiac complications of Omicron.
© The Author(s) 2022. Published by Oxford University Press on behalf of the
European Society of Cardiology.
DOI: 10.1093/ehjcr/ytac407
PMCID: PMC9581207
PMID: 36285226 |
http://www.ncbi.nlm.nih.gov/pubmed/35415869 | 1. Influenza Other Respir Viruses. 2022 Sep;16(5):832-836. doi:
10.1111/irv.12982. Epub 2022 Apr 13.
COVID-19 severity from Omicron and Delta SARS-CoV-2 variants.
Wrenn JO(1), Pakala SB(2), Vestal G(2), Shilts MH(2), Brown HM(2), Bowen SM(3),
Strickland BA(3), Williams T(3), Mallal SA(2), Jones ID(1), Schmitz JE(3), Self
WH(1), Das SR(2)(3)(4).
Author information:
(1)Department of Emergency Medicine, Vanderbilt University Medical Center,
Nashville, Tennessee, USA.
(2)Division of Infectious Disease, Department of Medicine, Vanderbilt University
Medical Center, Nashville, Tennessee, USA.
(3)Department of Pathology Microbiology and Immunology, Vanderbilt University
Medical Center, Nashville, Tennessee, USA.
(4)Department of Otolaryngology, Vanderbilt University Medical Center,
Nashville, Tennessee, USA.
The Omicron variant of SARS-CoV-2 achieved worldwide dominance in late 2021.
Early work suggests that infections caused by the Omicron variant may be less
severe than those caused by the Delta variant. We sought to compare clinical
outcomes of infections caused by these two strains, confirmed by whole genome
sequencing, over a short period of time, from respiratory samples collected from
SARS-CoV-2 positive patients at a large medical center. We found that infections
caused by the Omicron variant caused significantly less morbidity, including
admission to the hospital and requirement for oxygen supplementation, and
significantly less mortality than those caused by the Delta variant.
© 2022 The Authors. Influenza and Other Respiratory Viruses published by John
Wiley & Sons Ltd.
DOI: 10.1111/irv.12982
PMCID: PMC9111734
PMID: 35415869 [Indexed for MEDLINE]
Conflict of interest statement: All authors declare no conflict of interest to
share. |
http://www.ncbi.nlm.nih.gov/pubmed/35583528 | 1. Medicine (Baltimore). 2022 May 13;101(19):e29165. doi:
10.1097/MD.0000000000029165.
Omicron SARS-CoV-2 variant of concern: A review on its transmissibility, immune
evasion, reinfection, and severity.
Mohsin M(1), Mahmud S(2).
Author information:
(1)Applied Statistics, Institute of Statistical Research and Training,
University of Dhaka, Dhaka, Bangladesh.
(2)International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR'B),
68 Shaheed Tajuddin Ahmed Ave, Dhaka, Bangladesh.
Omicron, the new Covid-19 variant, has already become dominant in many countries
and is spreading at an unprecedented speed. The objective of this study was to
review the existing literature on Omicron's transmissibility, immune evasion,
reinfection, and severity.A literature search was performed using "PubMed," "Web
of Science," "Scopus," "ScienceDirect," "Google Scholar," "medRxiv," and
"bioRxiv." Data were extracted from articles that reported at least one of the
following: transmissibility, immune evasion, reinfection, and severity related
to Omicron.We found that Omicron spread faster than any other variant. This
higher transmissibility can be ascribed to its extraordinary ability to evade
the immunity developed by both vaccination and previous infections. However, we
found that infections by Omicron were significantly less severe than those
caused by Delta and other previous variants. We observed a significantly lower
incidence of hospitalization, intensive care unit admission, and mechanical
ventilator use in Omicron infections than in Delta or other variants. A
substantially shorter median hospital stay and lower fatality rate were also
observed in the Omicron infections. Despite Omicron's higher potential to evade
immunity, vaccines and booster shots were found to be still significantly
effective in protecting against severe Covid-19 infections.Omicrons may be less
severe than other variants of concern. However, its immune evasiveness and rapid
spread pose an enormous threat to the global healthcare system.
Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.
DOI: 10.1097/MD.0000000000029165
PMCID: PMC9276130
PMID: 35583528 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no funding and conflicts of
interests to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/35788085 | 1. J Glob Health. 2022 Jul 6;12:05032. doi: 10.7189/jogh.12.05032.
COVID-19 disease severity in persons infected with the Omicron variant compared
with the Delta variant in Qatar.
Butt AA(1)(2)(3), Dargham SR(3), Tang P(4), Chemaitelly H(3), Hasan MR(2)(3),
Coyle PV(1), Kaleeckal AH(1), Latif AN(1), Loka S(1), Shaik RM(1), Zaqout A(1),
Almaslamani MA(1), Al Khal A(1), Bertollini R(5), Abou-Samra AB(1), Abu-Raddad
LJ(3).
Author information:
(1)Hamad Medical Corporation, Doha, Qatar.
(2)Department of Medicine, Weill Cornell Medicine, New York, New York; and Doha,
Qatar.
(3)Department of Population Health Sciences, Weill Cornell Medicine, New York,
New York; and Doha, Qatar.
(4)Sidra Medicine, Doha, Qatar.
(5)Ministry of Public Health Qatar, Doha, Qatar.
BACKGROUND: Understanding the disease severity associated with the Omicron
variant of the SARS-CoV-2 virus is important in determining appropriate
management strategies at the individual and population levels. We determined the
severity of SARS-CoV-2 infection in persons infected with the Omicron vs the
Delta variant.
METHODS: We identified individuals with SARS-CoV-2 infection with Delta and
propensity-score matched controls with Omicron variant infection from the
National COVID-19 Database in Qatar. We excluded temporary visitors to Qatar,
those with a prior documented infection, those ≤18 years old, and those with <14
days of follow up after the index test positive date. We determined the rates of
admission to the hospital, admission to intensive care unit, mechanical
ventilation, or death among those infected with the Delta or Omicron variants.
RESULTS: Among 9763 cases infected with the Delta variant and 11 310 cases
infected with the Omicron variant, we identified 3926 propensity-score matched
pairs. Among 3926 Delta infected, 3259 (83.0%) had mild, 633 (16.1%) had
moderate and 34 (0.9%) had severe/critical disease. Among 3926 Omicron infected,
3866 (98.5%) had mild, 59 (1.5%) had moderate, and only 1 had severe/critical
disease (overall P < 0.001). Factors associated with less moderate or
severe/critical disease included infection with Omicron variant (aOR = 0.06;
confidence interval (CI) = 0.05-0.09) and vaccination including a booster
(aOR = 0.30; 95% CI = 0.09-0.99).
CONCLUSIONS: Omicron variant infection is associated with significantly lower
severity of disease compared with the Delta variant. Vaccination continues to
offer strong protection against severe/critical disease.
Copyright © 2022 by the Journal of Global Health. All rights reserved.
DOI: 10.7189/jogh.12.05032
PMCID: PMC9253930
PMID: 35788085 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: Dr Butt has received
investigator-initiated grant funding from Gilead Sciences (to the institution,
Veterans Health Foundation of Pittsburgh) which is unrelated to the work
presented here. The other authors completed the ICMJE Declaration of Interest
Form (available upon request from the corresponding author), and declare no
further conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35404391 | 1. Clin Infect Dis. 2022 Aug 24;75(1):e361-e367. doi: 10.1093/cid/ciac275.
Coronavirus Disease 2019 Disease Severity in Children Infected With the Omicron
Variant.
Butt AA(1)(2)(3), Dargham SR(4), Loka S(1), Shaik RM(1), Chemaitelly H(3)(4),
Tang P(5), Hasan MR(5), Coyle PV(1), Yassine HM(6)(7), Al-Khatib HA(6)(7),
Smatti MK(6)(7), Kaleeckal AH(1), Latif AN(1), Zaqout A(1), Almaslamani MA(1),
Al Khal A(1), Bertollini R(8), Abou-Samra AB(1), Abu-Raddad LJ(3)(4)(9).
Author information:
(1)Hamad Medical Corporation, Doha, Qatar.
(2)Department of Medicine, Weill Cornell Medicine, New York, New York and Doha,
Qatar.
(3)Department of Population Health Sciences, Weill Cornell Medicine, New York,
New York and Doha, Qatar.
(4)Infectious Disease Epidemiology Group, Weill Cornell Medicine-Qatar, Cornell
University, Doha, Qatar.
(5)Sidra Medicine, Doha, Qatar.
(6)Biomedical Research Center, Member of QU Health, Qatar University, Doha,
Qatar.
(7)Department of Biomedical Science, College of Health Sciences, Member of QU
Health, Qatar University, Doha, Qatar.
(8)Ministry of Public Health Qatar, Doha, Qatar.
(9)Department of Public Health, College of Health Sciences, QU Health, Qatar
University, Doha, Qatar.
SHORT SUMMARY: Severe acute respiratory syndrome coronavirus 2 infection from
the Omicron variant in children/adolescents is less severe than infection from
the Delta variant. Those 6 to <18 years also have less severe disease than those
<6 years old.
BACKGROUND: There are limited data assessing coronavirus 2019 (COVID-19) disease
severity in children/adolescents infected with the Omicron variant.
METHODS: We identified children and adolescents <18 years of age with severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with Delta and
propensity score-matched controls with Omicron variant infection from the
National COVID-19 Database in Qatar. Primary outcome was disease severity,
determined by hospital admission, admission to the intensive care unit (ICU), or
mechanical ventilation within 14 days of diagnosis, or death within 28 days.
RESULTS: Among 1735 cases with Delta variant infection between 1 June and 6
November 2021, and 32 635 cases with Omicron variant infection between 1 January
and 15 January 2022, who did not have prior infection and were not vaccinated,
we identified 985 propensity score-matched pairs. Among those who were Delta
infected, 84.2% had mild, 15.7% had moderate, and 0.1% had severe/critical
disease. Among those who were Omicron infected, 97.8% had mild, 2.2% had
moderate, and none had severe/critical disease (P < .001). Omicron variant
infection (vs Delta) was associated with significantly lower odds of moderate or
severe/critical disease (adjusted odds ratio [AOR], 0.12; 95% confidence
interval [CI], .07-.18). Those aged 6-11 and 12 to <18 years had lower odds of
developing moderate or severe/critical disease compared with those younger than
age 6 years (aOR, 0.47; 95% CI, .33-.66 for 6-11 year olds; aOR, 0.45; 95% CI,
.21-.94 for 12 to <18 year olds).
CONCLUSIONS: Omicron variant infection in children/adolescents is associated
with less severe disease than Delta variant infection as measured by
hospitalization rates and need for ICU care or mechanical ventilation. Those 6
to <18 years of age also have less severe disease than those <6 years old.
© The Author(s) 2022. Published by Oxford University Press on behalf of the
Infectious Diseases Society of America. All rights reserved. For permissions,
please e-mail: journals.permissions@oup.com.
DOI: 10.1093/cid/ciac275
PMCID: PMC9047187
PMID: 35404391 [Indexed for MEDLINE]
Conflict of interest statement: Potential conflicts of interest. A. A. B. has
received investigator-initiated grant funding from Gilead Sciences (to the
institution, Veterans Health Foundation of Pittsburgh) that is unrelated to the
work presented here. All other authors report no potential conflicts. All
authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of
Interest. Conflicts that the editors consider relevant to the content of the
manuscript have been disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/35869843 | 1. Clin Infect Dis. 2023 Feb 8;76(3):e172-e178. doi: 10.1093/cid/ciac571.
Clinical Characteristics and Outcomes of Immunocompromised Patients With
Coronavirus Disease 2019 Caused by the Omicron Variant: A Prospective,
Observational Study.
Malahe SRK(1)(2), Hoek RAS(2)(3), Dalm VASH(4)(5), Broers AEC(6), den Hoed
CM(2)(7), Manintveld OC(2)(8), Baan CC(1)(2), van Deuzen CM(9), Papageorgiou
G(10), Bax HI(9), Van Kampen JJ(11), Hellemons ME(2)(3), Kho MML(1)(2), de Vries
RD(11), Molenkamp R(11), Reinders MEJ(1)(2), Rijnders BJA(9).
Author information:
(1)Department of Internal Medicine, Erasmus University Medical Center,
Rotterdam, The Netherlands.
(2)Erasmus MC Transplant Institute, Erasmus University Medical Center,
Rotterdam, The Netherlands.
(3)Department of Pulmonary Medicine, Erasmus University Medical Center,
Rotterdam, The Netherlands.
(4)Department of Internal Medicine, Division of Allergy and Clinical Immunology,
Erasmus University Medical Center, Rotterdam, The Netherlands.
(5)Department of Immunology, Erasmus University Medical Center, Rotterdam, The
Netherlands.
(6)Department of Hematology, Erasmus Cancer Institute, Rotterdam, The
Netherlands.
(7)Department of Gastroenterology and Hepatology, Erasmus University Medical
Center, Rotterdam, The Netherlands.
(8)Department of Cardiology, Erasmus University Medical Center, Rotterdam, The
Netherlands.
(9)Department of Internal Medicine, Section of Infectious Diseases and
Department of Medical Microbiology and Infectious Diseases, Erasmus University
Medical Center, Rotterdam, The Netherlands.
(10)Department of Biostatistics and Department of Epidemiology, Erasmus
University Medical Center, Rotterdam, The Netherlands.
(11)Department of Viroscience, Erasmus University Medical Center, Rotterdam, The
Netherlands.
BACKGROUND: Illness after infection with the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) Omicron variant is less severe compared with previous
variants. Data on the disease burden in immunocompromised patients are lacking.
We investigated the clinical characteristics and outcomes of immunocompromised
patients with coronavirus disease 2019 (COVID-19) caused by Omicron.
METHODS: Organ transplant recipients, patients on anti-CD20 therapy, and
allogenic hematopoietic stem cell transplantation recipients infected with the
Omicron variant were included. Characteristics of consenting patients were
collected and patients were contacted regularly until symptom resolution. To
identify possible risk factors for hospitalization, a univariate logistic
analysis was performed.
RESULTS: 114 consecutive immunocompromised patients were enrolled. Eighty-nine
percent had previously received 3 mRNA vaccinations. While only 1 patient died,
23 (20%) were hospitalized for a median of 11 days. A low SARS-CoV-2
immunoglobulin G (IgG) antibody response (<300 BAU [binding antibody units]/mL)
at diagnosis, being older, being a lung transplant recipient, having more
comorbidities, and having a higher frailty score were associated with hospital
admission (all P < .01). At the end of follow-up, 25% had still not fully
recovered. Of the 23 hospitalized patients, 70% had a negative and 92% had a low
IgG (<300 BAU/mL) antibody response at admission. Sotrovimab was administered to
17 of these patients, and 1 died.
CONCLUSIONS: While the mortality in immunocompromised patients infected with
Omicron was low, hospital admission was frequent and the duration of symptoms
often prolonged. In addition to vaccination, other interventions are needed to
limit the morbidity from COVID-19 in immunocompromised patients.
© The Author(s) 2022. Published by Oxford University Press on behalf of
Infectious Diseases Society of America.
DOI: 10.1093/cid/ciac571
PMCID: PMC9384537
PMID: 35869843 [Indexed for MEDLINE]
Conflict of interest statement: Potential conflicts of interest. B. J. A. R. has
served on advisory boards of Roche and AstraZeneca. R. A. S. H. and O. C. M.
have served on the advisory board of AstraZeneca. V. A. S. H. D. received grants
from ZonMw (paid to their institution), Horizon 2020–Marie Curie Sklodowska
(paid to their institution), and Takeda (paid to their institution) and has
received payment from Takeda, Pharming, GSK, and CSL Behring paid to their
institution for lectures. M. M. L. K. has served on the advisory board of
Takeda. All other authors report no potential conflicts. All authors have
submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
Conflicts that the editors consider relevant to the content of the manuscript
have been disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/36224216 | 1. Nat Commun. 2022 Oct 12;13(1):6025. doi: 10.1038/s41467-022-33801-z.
Clinical phenotypes and outcomes associated with SARS-CoV-2 variant Omicron in
critically ill French patients with COVID-19.
de Prost N(1)(2)(3), Audureau E(3)(4)(5), Heming N(6), Gault E(7), Pham
T(2)(8)(9), Chaghouri A(10), de Montmollin N(11), Voiriot G(11), Morand-Joubert
L(12)(13), Joseph A(14), Chaix ML(15)(16), Préau S(17), Favory R(17), Guigon
A(18), Luyt CE(19)(20), Burrel S(12)(21), Mayaux J(19), Marot S(21), Roux
D(22)(23), Descamps D(24), Meireles S(25), Pène F(26), Rozenberg F(27), Contou
D(28), Henry A(29), Gaudry S(30), Brichler S(31), Timsit JF(32), Kimmoun
A(33)(34), Hartard C(35), Jandeaux LM(36)(37), Fafi-Kremer S(38), Gabarre P(39),
Emery M(40), Garcia-Sanchez C(41), Jochmans S(42), Pitsch A(43), Annane D(6),
Azoulay E(14), Mekontso Dessap A(1)(2)(3), Rodriguez C(3)(44)(45), Pawlotsky
JM(3)(44)(45), Fourati S(46)(47)(48).
Author information:
(1)Médecine Intensive Réanimation, Hôpitaux Universitaires Henri Mondor,
Assistance Publique-Hôpitaux de Paris (AP-HP), Créteil, France.
(2)Groupe de Recherche Clinique CARMAS, Université Paris-Est-Créteil (UPEC),
Créteil, France.
(3)Université Paris-Est-Créteil (UPEC), Créteil, France.
(4)Department of Public Health, Hôpitaux Universitaires Henri Mondor, Assistance
Publique-Hôpitaux de Paris (AP-HP), Créteil, France.
(5)IMRB INSERM U955, Team CEpiA, Créteil, France.
(6)Médecine Intensive Réanimation, Hôpital Raymond Poincaré, Assistance
Publique-Hôpitaux de Paris (AP-HP), Garches, France.
(7)Laboratoire de Virologie, Hôpital Ambroise Paré, Assistance Publique-Hôpitaux
de Paris (AP-HP), Boulogne, France.
(8)Service de Médecine Intensive-Réanimation, Assistance Publique-Hôpitaux de
Paris, Hôpital de Bicêtre, DMU 4 CORREVE Maladies du Cœur et des Vaisseaux, FHU
Sepsis, Le Kremlin-Bicêtre, France.
(9)Inserm U1018, Equipe d'Epidémiologie respiratoire intégrative, CESP, 94807,
Villejuif, France.
(10)Laboratoire de Virologie, Hôpital Paul Brousse, Assistance Publique-Hôpitaux
de Paris, Villejuif, France.
(11)Sorbonne Université, Centre de Recherche Saint-Antoine INSERM, Médecine
Intensive Réanimation, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris,
Paris, France.
(12)Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de
Santé Publique, Paris, France.
(13)Laboratoire de virologie, Hôpital Saint-Antoine, Assistance
Publique-Hôpitaux de Paris, F-75012, Paris, France.
(14)Médecine Intensive Réanimation, Hôpital Saint-Louis, Assistance
Publique-Hôpitaux de Paris, Paris, France.
(15)Université de Paris, Inserm HIPI, F-75010, Paris, France.
(16)Laboratoire de Virologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux
de Paris, F-75010, Paris, France.
(17)U1167-RID-AGE Facteurs de Risque et Déterminants Moléculaires des Maladies
Liées au Vieillissement, University Lille, Inserm, CHU Lille, Institut Pasteur
de Lille, F-59000, Lille, France.
(18)Service de virologie, CHU de Lille, F-59000, Lille, France.
(19)Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital
Pitié-Salpêtrière, Médecine Intensive Réanimation, Paris, France.
(20)INSERM UMRS_1166-iCAN, Institute of Cardiometabolism and Nutrition, Paris,
France.
(21)Département de Virologie, Hôpital Pitié-Salpêtrière, Assistance
Publique-Hôpitaux de Paris (AP-HP), Paris, France.
(22)Université de Paris, APHP, Hôpital Louis Mourier, DMU ESPRIT, Service de
Médecine Intensive Réanimation, Colombes, France.
(23)INSERM U1151, CNRS UMR 8253, Institut Necker-Enfants Malades (INEM),
Department of Immunology, Infectiology and Hematology, Paris, France.
(24)Université de Paris, IAME INSERM UMR 1137, Service de Virologie, Hôpital
Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France.
(25)Service de Réanimation médico-chirurgicale, Assistance Publique-Hôpitaux de
Paris, Hôpital Ambroise Paré, Boulogne, France.
(26)Médecine Intensive Réanimation, Hôpital Cochin, Assistance Publique-Hôpitaux
de Paris, Paris, France.
(27)Laboratoire de Virologie, Hôpital Cochin, Assistance Publique-Hôpitaux de
Paris, Paris, France.
(28)Service de Réanimation, Hôpital Victor Dupouy, Argenteuil, France.
(29)Service de Virologie, Hôpital Victor Dupouy, Argenteuil, France.
(30)Service de Réanimation, Hôpital Avicenne, Assistance Publique-Hôpitaux de
Paris, Bobigny, France.
(31)Laboratoire de Virologie, Hôpital Avicenne, Assistance Publique-Hôpitaux de
Paris, Bobigny, France.
(32)Service de Médecine Intensive Réanimation, Hôpital Bichat, Assistance
Publique-Hôpitaux de Paris, Paris, France.
(33)Université de Lorraine, CHRU de Nancy, Médecine Intensive et Réanimation
Brabois, Vandœuvre-lès-Nancy, France.
(34)INSERM U942 and U1116, F-CRIN-INIC RCT, Vandœuvre-lès-Nancy, France.
(35)Service de Virologie, CHRU de Nancy, Vandœuvre-lès-Nancy, France.
(36)INSERM (French National Institute of Health and Medical Research), UMR 1260,
Regenerative Nanomedicine (RNM), CRBS (Centre de Recherche en Biomédecine de
Strasbourg), FMTS (Fédération de Médecine Translationnelle de Strasbourg),
University of Strasbourg, Strasbourg, France.
(37)Department of Intensive Care (Service de Médecine Intensive - Réanimation),
Nouvel Hôpital Civil, Hôpital Universitaire de Strasbourg, Strasbourg, France.
(38)Service de Virologie, Nouvel Hôpital Civil, Hôpital Universitaire de
Strasbourg, Strasbourg, France.
(39)Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital
Saint-Antoine, Médecine Intensive Réanimation, 75571, Paris, Cedex 12, France.
(40)Service de Réanimation, Hôpital Saint-Camille, Bry-sur-Marne, France.
(41)Laboratoire de Biologie, Hôpital Saint-Camille, Bry-sur-Marne, France.
(42)Service de Réanimation Polyvalente, Hôpital Marc Jacquet, Melun, France.
(43)Laboratoire de Microbiologie, Hôpital Marc Jacquet, Melun, France.
(44)Department of Virology, Hôpitaux Universitaires Henri Mondor, Assistance
Publique-Hôpitaux de Paris, Créteil, France.
(45)INSERM U955, Team « Viruses, Hepatology, Cancer », Créteil, France.
(46)Université Paris-Est-Créteil (UPEC), Créteil, France. slim.fourati@aphp.fr.
(47)Department of Virology, Hôpitaux Universitaires Henri Mondor, Assistance
Publique-Hôpitaux de Paris, Créteil, France. slim.fourati@aphp.fr.
(48)INSERM U955, Team « Viruses, Hepatology, Cancer », Créteil, France.
slim.fourati@aphp.fr.
Erratum in
Nat Commun. 2022 Dec 7;13(1):7547. doi: 10.1038/s41467-022-34575-0.
Infection with SARS-CoV-2 variant Omicron is considered to be less severe than
infection with variant Delta, with rarer occurrence of severe disease requiring
intensive care. Little information is available on comorbid factors, clinical
conditions and specific viral mutational patterns associated with the severity
of variant Omicron infection. In this multicenter prospective cohort study,
patients consecutively admitted for severe COVID-19 in 20 intensive care units
in France between December 7th 2021 and May 1st 2022 were included. Among 259
patients, we show that the clinical phenotype of patients infected with variant
Omicron (n = 148) is different from that in those infected with variant Delta
(n = 111). We observe no significant relationship between Delta and Omicron
variant lineages/sublineages and 28-day mortality (adjusted odds ratio [95%
confidence interval] = 0.68 [0.35-1.32]; p = 0.253). Among Omicron-infected
patients, 43.2% are immunocompromised, most of whom have received two doses of
vaccine or more (85.9%) but display a poor humoral response to vaccination. The
mortality rate of immunocompromised patients infected with variant Omicron is
significantly higher than that of non-immunocompromised patients (46.9% vs
26.2%; p = 0.009). In patients infected with variant Omicron, there is no
association between specific sublineages (BA.1/BA.1.1 (n = 109) and BA.2
(n = 21)) or any viral genome polymorphisms/mutational profile and 28-day
mortality.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-33801-z
PMCID: PMC9555693
PMID: 36224216 [Indexed for MEDLINE]
Conflict of interest statement: S.F. has served as a speaker for
GlaxoSmithKline, Abbvie, and Abbott Diagnostics. J.-M.P. has served as an
advisor or speaker for Abbvie, Arbutus, Assembly Biosciences, Gilead and Merck.
E.A. has received fees for lectures from Alexion, Sanofi, Gilead and Pfizer. His
hospital has received research grant from Pfizer, MSD and Alexion. D.D. served
as an advisor for Gilead-Sciences, ViiV Health care, Janssen-Cilag et MSD. F.P.
served as an advisor for Gilead; he also received research grant from Alexion.
C.-E.L. received lecture fees from MSD, Aerogen, Advanzpharma, and BioMérieux,
outside the submitted work. J.-F.T. served as an advisor for pfizer, Gilead, BD,
Gilead, Merck; he also received research grant from Thermofischer, merck,
Pfizer, Biomerieux; lectures: pfizer, biomerieux BD, Merck, Shionoghi outside
the submitted work. Other authors have no conflict of interest to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/35313451 | 1. Med. 2022 Apr 8;3(4):262-268.e4. doi: 10.1016/j.medj.2022.03.004. Epub 2022
Mar 17.
Reduced pathogenicity of the SARS-CoV-2 omicron variant in hamsters.
McMahan K(1), Giffin V(1), Tostanoski LH(1), Chung B(1), Siamatu M(1), Suthar
MS(2), Halfmann P(3), Kawaoka Y(3), Piedra-Mora C(4), Jain N(4), Ducat S(4), Kar
S(5), Andersen H(5), Lewis MG(5), Martinot AJ(4), Barouch DH(1)(6).
Author information:
(1)Center for Virology and Vaccine Research, Beth Israel Deaconess Medical
Center, Boston, MA, USA.
(2)Emory Vaccine Center, Emory School of Medicine, Atlanta, GA, USA.
(3)Influenza Research Institute, University of Wisconsin, Madison, WI 53711,
USA.
(4)Tufts University Cummings School of Veterinary Medicine, North Grafton, MA,
USA.
(5)Bioqual, Rockville, MD 20852, USA.
(6)Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Omicron (B.1.1.529) variant has proven to be highly transmissible and has
outcompeted the Delta variant in many regions of the world. Early reports have
also suggested that Omicron may result in less severe clinical disease in
humans. Here, we show that Omicron is less pathogenic than prior SARS-CoV-2
variants in Syrian golden hamsters.
METHODS: Hamsters were inoculated with either SARS-CoV-2 Omicron or other
SARS-CoV-2 variants. Animals were followed for weight loss, and upper and lower
respiratory tract tissues were assessed for viral loads and histopathology.
FINDINGS: Infection of hamsters with the SARS-CoV-2 WA1/2020, Alpha, Beta, or
Delta strains led to 4%-10% weight loss by day 4 and 10%-17% weight loss by day
6. In contrast, infection of hamsters with two different Omicron challenge
stocks did not result in any detectable weight loss, even at high challenge
doses. Omicron infection led to substantial viral replication in both the upper
and lower respiratory tracts but demonstrated lower viral loads in lung
parenchyma and reduced pulmonary pathology compared with WA1/2020 infection.
CONCLUSIONS: These data suggest that the SARS-CoV-2 Omicron variant may result
in robust upper respiratory tract infection, but less severe lower respiratory
tract clinical disease, compared with prior SARS-CoV-2 variants.
FUNDING: Funding for this study was provided by NIH grant CA260476, the
Massachusetts Consortium for Pathogen Readiness, the Ragon Institute, and the
Musk Foundation.
© 2022 The Authors.
DOI: 10.1016/j.medj.2022.03.004
PMCID: PMC8926874
PMID: 35313451 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35225672 | 1. J Virol. 2022 Mar 23;96(6):e0207721. doi: 10.1128/jvi.02077-21. Epub 2022 Mar
23.
Omicron: What Makes the Latest SARS-CoV-2 Variant of Concern So Concerning?
Jung C(#)(1), Kmiec D(#)(2), Koepke L(#)(2), Zech F(#)(2), Jacob T(1), Sparrer
KMJ(2), Kirchhoff F(2).
Author information:
(1)Institute of Electrochemistry, Ulm University, Ulm, Germany.
(2)Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
(#)Contributed equally
Emerging strains of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19)
pandemic, that show increased transmission fitness and/or immune evasion are
classified as "variants of concern" (VOCs). Recently, a SARS-CoV-2 variant first
identified in November 2021 in South Africa has been recognized as a fifth VOC,
termed "Omicron." What makes this VOC so alarming is the high number of changes,
especially in the viral Spike protein, and accumulating evidence for increased
transmission efficiency and escape from neutralizing antibodies. In an amazingly
short time, the Omicron VOC has outcompeted the previously dominating Delta VOC.
However, it seems that the Omicron VOC is overall less pathogenic than other
SARS-CoV-2 VOCs. Here, we provide an overview of the mutations in the Omicron
genome and the resulting changes in viral proteins compared to other SARS-CoV-2
strains and discuss their potential functional consequences.
DOI: 10.1128/jvi.02077-21
PMCID: PMC8941872
PMID: 35225672 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36056686 | 1. Mil Med. 2023 Jul 22;188(7-8):e1552-e1557. doi: 10.1093/milmed/usac263.
SARS-CoV-2 Omicron Variant: Clinical Presentation and Occupational Implications
in Young and Healthy IDF Soldiers.
Akavian I(1), Nitzan I(1)(2), Talmy T(1), Nitecki M(1)(2), Gendler S(1), Besor
O(1).
Author information:
(1)Medical Corps, Israel Defense Forces, Ramat Gan 02149, Israel.
(2)Department of Military Medicine, Faculty of Medicine, Hebrew University,
Jerusalem 9574869, Israel.
INTRODUCTION: To this date, there is little known about the symptoms, their
duration, and occupational implications of Coronavirus disease (COVID-19) in the
military population. Decisions regarding implementing precaution measures are
based on data deriving from the general population. Moreover, the Omicron
variant seems to cause a disease with lesser severity than previous variants. We
aimed to describe the clinical presentation and estimate the loss of workdays
due to mild COVID-19 during an Omicron predominant wave among a young, healthy,
and mostly vaccinated military population.
MATERIALS AND METHODS: A cross-sectional, survey-based study among IDF soldiers
who replied to an online questionnaire following recovery from COVID-19. Data
included self-reported vaccination status, symptoms presentation and duration,
and service-related sick days. Student's t-test and chi-square test of
independence were used to compare differences in continuous and categorical
variables, respectively. A binary logistic regression analysis was performed to
estimate the odds ratio and 95% CIs for prolonged symptom duration (4 days and
above) by participants' characteristics. The IDF medical corps institutional
review board approved this study.
RESULTS: A total of 199 soldiers, with a mean age of 21.9 years, were included
in the study. Upper respiratory tract symptoms, headache, and constitutional
symptoms were found to be the most common among symptomatic soldiers. The median
reported time for inability to continue the daily routine, including work, was
5 days [Interquartile range (IQR), 0-10]. Median duration of symptoms was 4 days
(IQR, 0-10). In addition, women were found to have longer symptomatic disease
(odds ratio = 2.34; 95% CI, 1.20-4.52).
CONCLUSIONS: Our findings demonstrate that even among a young and fully
vaccinated population, COVID-19 caused by the Omicron variant may result in
substantial medical leave from military service, compared to common cold or
influenza virus infection. Our study sample was relatively small; however, the
response rate was high and our results shed light on the yet-to-be fully
characterized Omicron variant-related COVID-19. Despite the current common
perception of COVID-19 as a self-limiting mild disease with low burden of
symptoms, our findings show the potential occupational burden of infection with
COVID-19 on military units and their readiness and could be considered when
discussing public health restrictions and further steps taken to minimize
outbreaks ramifications.
© The Association of Military Surgeons of the United States 2022. All rights
reserved. For permissions, please e-mail: journals.permissions@oup.com.
DOI: 10.1093/milmed/usac263
PMCID: PMC9494320
PMID: 36056686 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35594069 | 1. Am J Physiol Heart Circ Physiol. 2022 Jul 1;323(1):H59-H64. doi:
10.1152/ajpheart.00189.2022. Epub 2022 May 20.
Impact of breakthrough COVID-19 cases during the omicron wave on vascular health
and cardiac autonomic function in young adults.
Skow RJ(1), Nandadeva D(1), Grotle AK(1), Stephens BY(1), Wright AN(1), Fadel
PJ(1).
Author information:
(1)Department of Kinesiology, The University of Texas at Arlington, Arlington,
Texas.
We and others have previously shown that COVID-19 results in vascular and
autonomic impairments in young adults. However, the newest variant of COVID-19
(Omicron) appears to have less severe complications. Therefore, we investigated
whether recent breakthrough infection with COVID-19 during the Omicron wave
impacts cardiovascular health in young adults. We hypothesized that measures of
vascular health and indices of cardiac autonomic function would be impaired in
those who had the Omicron variant of COVID-19 when compared with controls who
never had COVID-19. We studied 23 vaccinated adults who had COVID-19 after
December 25, 2021 (Omicron; age, 23 ± 3 yr; 14 females) within 6 wk of diagnosis
compared with 13 vaccinated adults who never had COVID-19 (age, 26 ± 4 yr; 7
females). Macro- and microvascular function were assessed using flow-mediated
dilation (FMD) and reactive hyperemia, respectively. Arterial stiffness was
determined as carotid-femoral pulse wave velocity (cfPWV) and augmentation index
(AIx). Heart rate (HR) variability and cardiac baroreflex sensitivity (BRS) were
assessed as indices of cardiac autonomic function. FMD was not different between
control (5.9 ± 2.8%) and Omicron (6.1 ± 2.3%; P = 0.544). Similarly, reactive
hyperemia (P = 0.884) and arterial stiffness were not different between groups
(e.g., cfPWV; control, 5.9 ± 0.6 m/s and Omicron, 5.7 ± 0.8 m/s; P = 0.367).
Finally, measures of HR variability and cardiac BRS were not different between
groups (all, P > 0.05). Collectively, these data suggest preserved vascular
health and cardiac autonomic function in young, otherwise healthy adults who had
breakthrough cases of COVID-19 during the Omicron wave.NEW & NOTEWORTHY We show
for the first time that breakthrough cases of COVID-19 during the Omicron wave
does not impact vascular health and cardiac autonomic function in young adults.
These are promising results considering earlier research showing impaired
vascular and autonomic function following previous variants of COVID-19.
Collectively, these data demonstrate that the recent Omicron variant is not
detrimental to cardiovascular health in young, otherwise healthy, vaccinated
adults.
DOI: 10.1152/ajpheart.00189.2022
PMCID: PMC9169822
PMID: 35594069 [Indexed for MEDLINE]
Conflict of interest statement: No conflicts of interest, financial or
otherwise, are declared by the authors. |
http://www.ncbi.nlm.nih.gov/pubmed/35961786 | 1. J Med Virol. 2022 Dec;94(12):5790-5801. doi: 10.1002/jmv.28066. Epub 2022 Aug
24.
Proportion of asymptomatic infection and nonsevere disease caused by SARS-CoV-2
Omicron variant: A systematic review and analysis.
Yu W(1), Guo Y(1), Zhang S(1), Kong Y(1), Shen Z(1)(2)(3), Zhang J(1)(2)(3).
Author information:
(1)Department of Infectious Diseases, Shanghai Key Laboratory of Infectious
Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious
Diseases and Biosecurity, National Medical Center for Infectious Diseases,
Huashan Hospital, Fudan University, Shanghai, China.
(2)Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical
College, Fudan University, Shanghai, China.
(3)Department of Infectious Diseases, Jing' An Branch of Huashan Hospital, Fudan
University, Shanghai, China.
SARS-CoV-2 Omicron variant seemed to cause milder disease compared to previous
predominated variants. We aimed to conduct a meta-analysis to assess the pooled
proportion of nonsevere disease and asymptomatic infection among COVID-19
patients infected with Omicron and Delta. We searched PubMed, Embase, Web of
Science, and China National Knowledge Infrastructure (CNKI) databases. We
included studies of SARS-CoV-2 Omicron infection from November 1, 2021, to April
18, 2022, and studies of Delta infection from October 1, 2020, to June 30, 2022.
Studies without corresponding data, with less than 50 patients, or obviously
biased concerning main outcome were excluded. Meta-analysis was performed in R
4.2.0 with the "meta" package. Subgroup analyses were conducted by study group
and vaccination status. The pooled proportion of asymptomatic infection and
nonsevere disease with Omicron were 25.5% (95% confidence interval [CI]
17.0%-38.2%) and 97.9% (95% CI 97.1%-98.7%), significantly higher than those of
Delta with 8.4% (95% CI 4.4%-16.2%) and 91.4% (95% CI 87.0%-96.0%). During
Omicron wave, children and adolescents had higher proportion of asymptomatic
infection, SOTR and the elderly had lower proportion of nonsevere disease,
vaccination of a booster dose contributed to higher proportion of both
asymptomatic infection and nonsevere disease. This study estimates the pooled
proportion of asymptomatic infection and nonsevere disease caused by SARS-CoV-2
Omicron compared to other predominant variants. The result has important
implications for future policy making.
© 2022 Wiley Periodicals LLC.
DOI: 10.1002/jmv.28066
PMCID: PMC9538850
PMID: 35961786 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35746768 | 1. Viruses. 2022 Jun 14;14(6):1297. doi: 10.3390/v14061297.
Clinical Severity of SARS-CoV-2 Omicron Variant Compared with Delta among
Hospitalized COVID-19 Patients in Belgium during Autumn and Winter Season
2021-2022.
Van Goethem N(1), Chung PYJ(1), Meurisse M(1), Vandromme M(1), De Mot L(1),
Brondeel R(1), Stouten V(1), Klamer S(1), Cuypers L(2), Braeye T(1), Catteau
L(1), Nevejan L(2), van Loenhout JAF(1), Blot K(1).
Author information:
(1)Scientific Directorate of Epidemiology and Public Health, Sciensano, J.
Wytsmanstraat 14, 1050 Brussels, Belgium.
(2)Clinical Department of Laboratory Medicine and National Reference Center for
Respiratory Pathogens, University Hospitals Leuven, 3000 Leuven, Belgium.
This retrospective multi-center matched cohort study assessed the risk for
severe COVID-19 (combination of severity indicators), intensive care unit (ICU)
admission, and in-hospital mortality in hospitalized patients when infected with
the Omicron variant compared to when infected with the Delta variant. The study
is based on a causal framework using individually-linked data from national
COVID-19 registries. The study population consisted of 954 COVID-19 patients (of
which, 445 were infected with Omicron) above 18 years old admitted to a Belgian
hospital during the autumn and winter season 2021-2022, and with available viral
genomic data. Patients were matched based on the hospital, whereas other
possible confounders (demographics, comorbidities, vaccination status,
socio-economic status, and ICU occupancy) were adjusted for by using a
multivariable logistic regression analysis. The estimated standardized risk for
severe COVID-19 and ICU admission in hospitalized patients was significantly
lower (RR = 0.63; 95% CI (0.30; 0.97) and RR = 0.56; 95% CI (0.14; 0.99),
respectively) when infected with the Omicron variant, whereas in-hospital
mortality was not significantly different according to the SARS-CoV-2 variant
(RR = 0.78, 95% CI (0.28-1.29)). This study demonstrates the added value of
integrated genomic and clinical surveillance to recognize the multifactorial
nature of COVID-19 pathogenesis.
DOI: 10.3390/v14061297
PMCID: PMC9227815
PMID: 35746768 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33423210 | 1. Clin Rev Allergy Immunol. 2021 Aug;61(1):66-76. doi:
10.1007/s12016-021-08832-x. Epub 2021 Jan 9.
Current and Prospective Targets of Pharmacologic Treatment of Hereditary
Angioedema Types 1 and 2.
Fijen LM(1), Bork K(2), Cohn DM(3).
Author information:
(1)Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam,
Amsterdam, Netherlands. l.m.fijen@amsterdamumc.nl.
(2)Department of Dermatology, University Medical Center, Johannes Gutenberg
University, Mainz, Germany.
(3)Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam,
Amsterdam, Netherlands.
Hereditary angioedema (HAE) is a rare disease that causes episodic attacks of
subcutaneous and submucosal edema, which can be painful, incapacitating, and
potentially fatal. These attacks are mediated by excessive bradykinin
production, as a result of uncontrolled activation of the plasma
kallikrein/kinin system, which is caused by a C1 esterase inhibitor deficiency
or dysfunction in HAE types 1 and 2, respectively. For many years, treatment
options were limited to therapies with substantial adverse effects, insufficient
efficacy, or difficult routes of administration. Increased insights in the
pathophysiology of HAE have paved the way for the development of new therapies
with fewer side effects. In the last two decades, several targeted novel
therapeutic strategies for HAE have been developed, for both long-term
prophylaxis and on demand treatment of acute attacks. This article reviews the
advances in the development of more effective and convenient treatment options
for HAE and their anticipated effects on morbidity, mortality, and quality of
life. The emergence of these improved treatment options will presumably change
current HAE guidelines, but adherence to these recommendations may become
restricted by high treatment costs. It will therefore be essential to determine
the indications and identify the patients that will benefit most from these
newest treatment generations. Ultimately, current preclinical research into gene
therapies may eventually lead the way towards curative treatment options for
HAE. In conclusion, an increasing shift towards the use of highly effective
long-term prophylaxis is anticipated, which should drastically abate the burden
on patients with hereditary angioedema.
© 2021. The Author(s).
DOI: 10.1007/s12016-021-08832-x
PMCID: PMC8282552
PMID: 33423210 [Indexed for MEDLINE]
Conflict of interest statement: K.B. has received grant research support and/or
speaker fees from CSL Behring and Shire (a Takeda company), outside the
submitted work. D.C. reports consultancy fees from BioCryst, CSL Behring,
Pharming, Pharvaris and Shire (a Takeda company), outside the submitted work.
L.F. declares no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36401022 | 1. Methods Mol Biol. 2023;2587:31-41. doi: 10.1007/978-1-0716-2772-3_2.
Viltolarsen: From Preclinical Studies to FDA Approval.
Roshmi RR(1), Yokota T(2)(3).
Author information:
(1)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, Canada.
(2)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, Canada. toshifum@ualberta.ca.
(3)The Friends of Garrett Cumming Research & Muscular Dystrophy Canada, HM
Toupin Neurological Science Research Chair, Edmonton, Canada.
toshifum@ualberta.ca.
Viltolarsen is a phosphorodiamidate morpholino antisense oligonucleotide (PMO)
designed to skip exon 53 of the DMD gene for the treatment of Duchenne muscular
dystrophy (DMD), one of the most common lethal genetic disorders characterized
by progressive degeneration of skeletal muscles and cardiomyopathy. It was
developed by Nippon Shinyaku in collaboration with the National Center of
Neurology and Psychiatry (NCNP) in Japan based on the preclinical studies
conducted in the DMD dog model at the NCNP. After showing hopeful results in
pre-clinical trials and several clinical trials across North America and Japan,
it received US Food and Drug Administration (FDA) approval for DMD in 2020.
Viltolarsen restores the reading frame of the DMD gene by skipping exon 53 and
produces a truncated but functional form of dystrophin. It can treat
approximately 8-10% of the DMD patient population. This paper aims to summarize
the development of viltolarsen from preclinical trials to clinical trials to,
finally, FDA approval, and discusses the challenges that come with fighting DMD
using antisense therapy.
© 2023. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-2772-3_2
PMID: 36401022 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31720560 | 1. Drugs Today (Barc). 2019 Oct;55(10):627-639. doi:
10.1358/dot.2019.55.10.3045038.
Viltolarsen for the treatment of Duchenne muscular dystrophy.
Roshmi RR(1), Yokota T(2).
Author information:
(1)Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.
(2)Department of Medical Genetics, University of Alberta and The Friends of
Garrett Cumming Research and Muscular Dystrophy Canada, HM Toupin Neurological
Science Research Chair, Edmonton, AB, Canada. toshifum@ualberta.ca.
Duchenne muscular dystrophy is the most common lethal X-linked genetic disorder,
characterized by progressive muscle loss, with cardiac and respiratory
complications. It is caused by a lack of dystrophin protein due to mutations in
the DMD gene, which can disrupt the reading frame of the dystrophin primary
transcript. Antisense oligonucleotides such as phosphorodiamidate morpholino
oligomers (PMOs) can induce exon skipping during pre-mRNA splicing and restore
the reading frame of the DMD primary transcript. The resulting dystrophin
protein is internally deleted but partially functional. Viltolarsen, also known
as NS-065/NCNP-01, is a PMO developed through comprehensive sequence
optimization and is designed to skip exon 53 on the DMD primary transcript.
Exclusion of exon 53 from the DMD primary transcript can treat 8-10% of DMD
patients worldwide. This review paper summarizes the mechanism of action,
pharmacokinetics and safety of viltolarsen from preclinical and clinical trials.
Copyright 2019 Clarivate Analytics.
DOI: 10.1358/dot.2019.55.10.3045038
PMID: 31720560 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32519222 | 1. Drugs. 2020 Jul;80(10):1027-1031. doi: 10.1007/s40265-020-01339-3.
Viltolarsen: First Approval.
Dhillon S(1).
Author information:
(1)Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New
Zealand. dru@adis.com.
Viltolarsen (Viltepso® in Japan) is a phosphorodiamidate morpholino antisense
oligonucleotide being developed by Nippon Shinyaku, in collaboration with the
National Center of Neurology and Psychiatry (NCNP), for the treatment of
Duchenne muscular dystrophy (DMD). Viltolarsen binds to exon 53 of the
dystrophin mRNA precursor and restores the amino acid open-reading frame by
skipping exon 53, resulting in the production of a shortened dystrophin protein
that contains essential functional portions. In March 2020, intravenous
viltolarsen received its first global approval in Japan for the treatment of DMD
in patients with confirmed deletion of the dystrophin gene that is amenable to
exon 53 skipping. Viltolarsen is under regulatory review in the USA and clinical
trials continue in the USA, Canada and globally. This article summarizes the
milestones in the development of viltolarsen leading to the first approval for
DMD.
DOI: 10.1007/s40265-020-01339-3
PMID: 32519222 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33285037 | 1. Ann Clin Transl Neurol. 2020 Dec;7(12):2393-2408. doi: 10.1002/acn3.51235.
Epub 2020 Dec 7.
Viltolarsen in Japanese Duchenne muscular dystrophy patients: A phase 1/2 study.
Komaki H(1), Takeshima Y(2), Matsumura T(3), Ozasa S(4), Funato M(5), Takeshita
E(6), Iwata Y(7), Yajima H(7), Egawa Y(8), Toramoto T(8), Tajima M(8), Takeda
S(9).
Author information:
(1)Translational Medical Center, National Center of Neurology and Psychiatry,
Kodaira, Tokyo, Japan.
(2)Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Hyogo,
Japan.
(3)Department of Neurology, National Hospital Organization Osaka Toneyama
Medical Center, Toyonaka, Osaka, Japan.
(4)Department of Pediatrics, Kumamoto University Hospital, Kumamoto, Kumamoto,
Japan.
(5)Department of Pediatrics, National Hospital Organization Nagara Medical
Center, Gifu, Japan.
(6)Department of Child Neurology, National Center of Neurology and Psychiatry,
National Center Hospital, Kodaira, Tokyo, Japan.
(7)Department of Rehabilitation, National Center of Neurology and Psychiatry,
National Center Hospital, Kodaira, Tokyo, Japan.
(8)Global Clinical Development Department, Nippon Shinyaku Co., Ltd., Kyoto,
Kyoto, Japan.
(9)National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
OBJECTIVE: The novel morpholino antisense oligonucleotide viltolarsen targets
exon 53 of the dystrophin gene, and could be an effective treatment for patients
with Duchenne muscular dystrophy (DMD). We investigated viltolarsen's ability to
induce dystrophin expression and examined its safety in DMD patients.
METHODS: In this open-label, multicenter, parallel-group, phase 1/2, exploratory
study, 16 ambulant and nonambulant males aged 5-12 years with DMD received
viltolarsen 40 or 80 mg/kg/week via intravenous infusion for 24 weeks. Primary
endpoints were dystrophin expression and exon 53 skipping levels.
RESULTS: In western blot analysis, mean changes in dystrophin expression (%
normal) from baseline to Weeks 12 and 24 were - 1.21 (P = 0.5136) and 1.46
(P = 0.1636), respectively, in the 40 mg/kg group, and 0.76 (P = 0.2367) and
4.81 (P = 0.0536), respectively, in the 80 mg/kg group. The increase in mean
dystrophin level at Weeks 12 and 24 was significant in the 80 mg/kg group
(2.78%; P = 0.0364). Patients receiving 80 mg/kg showed a higher mean exon 53
skipping level (42.4%) than those receiving 40 mg/kg (21.8%). All adverse events
were judged to be mild or moderate in intensity and none led to study
discontinuation.
INTERPRETATION: Treatment with viltolarsen 40 or 80 mg/kg elicited an increasing
trend in dystrophin expression and exon 53 skipping levels, and was safe and
well tolerated. The decline in motor function appeared less marked in patients
with higher dystrophin levels; this may warrant further investigation. This
study supports the potential clinical benefit of viltolarsen.
© 2020 The Authors. Annals of Clinical and Translational Neurology published by
Wiley Periodicals LLC on behalf of American Neurological Association.
DOI: 10.1002/acn3.51235
PMCID: PMC7732240
PMID: 33285037 [Indexed for MEDLINE]
Conflict of interest statement: H.K. has received grants from Taiho, Pfizer
Japan, Nippon Shinyaku, Daiichi Sankyo, Chugai, PTC Therapeutics; and personal
fees from Sarepta Therapeutics. Y.T. has received grants from Nippon Shinyaku;
and personal fees from Daiichi Sankyo and Biogen. T.M. has received grants from
Nippon Shinyaku. S.O. has received grants from Nippon Shinyaku, Biogen, and PTC
Therapeutics. M.F. has received grants from Nippon Shinyaku and Taiho. E.T. has
received grants from Taiho, Nippon Shinyaku, Daiichi Sankyo, and Takeda; and
personal fees from Pfizer Japan. Y.I. has received grants from Taiho, Nippon
Shinyaku, and Daiichi Sankyo; and personal fees from Astellas Pharma. H.Y. has
received grants from Taiho, Nippon Shinyaku, and Daiichi Sankyo; and personal
fees from Biogen. S.T. is an officer and board member of the National Center of
Neurology and Psychiatry; and has received grants from Nippon Shinyaku, Daiichi
Sankyo and The Noguchi Institute. Y.E., M.T., and T.T. are employees of Nippon
Shinyaku Co., Ltd. |
http://www.ncbi.nlm.nih.gov/pubmed/35043116 | 1. medRxiv [Preprint]. 2022 Jan 13:2022.01.12.22269179. doi:
10.1101/2022.01.12.22269179.
COVID infection severity in children under 5 years old before and after Omicron
emergence in the US.
Wang L(1)(2), Berger NA(2)(3), Kaelber DC(4), Davis PB(5), Volkow ND(6), Xu
R(1)(3).
Author information:
(1)Center for Artificial Intelligence in Drug Discovery, Case Western Reserve
University School of Medicine, Cleveland, OH, USA.
(2)Center for Science, Health, and Society, Case Western Reserve University
School of Medicine, Cleveland, OH, USA.
(3)Case Comprehensive Cancer Center, Case Western Reserve University School of
Medicine, Cleveland, OH, USA.
(4)The Center for Clinical Informatics Research and Education, The MetroHealth
System, Cleveland, OH, USA.
(5)Center for Community Health Integration, Case Western Reserve University
School of Medicine, Cleveland, OH, USA.
(6)National Institute on Drug Abuse, National Institutes of Health, Bethesda,
MD, USA.
IMPORTANCE: Pediatric SARS-CoV-2 infections and hospitalizations are rising in
the US and other countries after the emergence of Omicron variant. However data
on disease severity from Omicron compared with Delta in children under 5 in the
US is lacking.
OBJECTIVES: To compare severity of clinic outcomes in children under 5 who
contracted COVID infection for the first time before and after the emergence of
Omicron in the US.
DESIGN SETTING AND PARTICIPANTS: This is a retrospective cohort study of
electronic health record (EHR) data of 79,592 children under 5 who contracted
SARS-CoV-2 infection for the first time, including 7,201 infected between
12/26/2021-1/6/2022 when the Omicron predominated (Omicron cohort), 63,203
infected between 9/1/2021-11/15/2021 when the Delta predominated (Delta cohort),
and another 9,188 infected between 11/16/2021-11/30/2021 when the Delta
predominated but immediately before the Omicron variant was detected in the US
(Delta-2 cohort).
EXPOSURES: First time infection of SARS-CoV-2.
MAIN OUTCOMES AND MEASURES: After propensity-score matching, severity of COVID
infections including emergency department (ED) visits, hospitalizations,
intensive care unit (ICU) admissions, and mechanical ventilation use in the
3-day time-window following SARS-CoV-2 infection were compared between Omicron
and Delta cohorts, and between Delta-2 and Delta cohorts. Risk ratios, and 95%
confidence intervals (CI) were calculated.
RESULTS: Among 7,201 infected children in the Omicron cohort (average age, 1.49
± 1.42 years), 47.4% were female, 2.4% Asian, 26.1% Black, 13.7% Hispanic, and
44.0% White. Before propensity score matching, the Omicron cohort were younger
than the Delta cohort (average age 1.49 vs 1.73 years), comprised of more Black
children, and had fewer comorbidities. After propensity-score matching for
demographics, socio-economic determinants of health, comorbidities and
medications, risks for severe clinical outcomes in the Omicron cohort were
significantly lower than those in the Delta cohort: ED visits: 18.83% vs. 26.67%
(risk ratio or RR: 0.71 [0.66-0.75]); hospitalizations: 1.04% vs. 3.14% (RR:
0.33 [0.26-0.43]); ICU admissions: 0.14% vs. 0.43% (RR: 0.32 [0.16-0.66]);
mechanical ventilation: 0.33% vs. 1.15% (RR: 0.29 [0.18-0.46]). Control studies
comparing Delta-2 to Delta cohorts show no difference.
CONCLUSIONS AND RELEVANCE: For children under age 5, first time SARS-CoV-2
infections occurring when the Omicron predominated (prevalence >92%) was
associated with significantly less severe outcomes than first-time infections in
similar children when the Delta variant predominated.
DOI: 10.1101/2022.01.12.22269179
PMCID: PMC8764724
PMID: 35043116
Conflict of interest statement: Declaration of interests LW, NAB, PBD, DCK, NDV,
RX have no financial interests to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/32955503 | 1. J Vis Exp. 2020 May 7;(159). doi: 10.3791/60672.
Characterizing Exon Skipping Efficiency in DMD Patient Samples in Clinical
Trials of Antisense Oligonucleotides.
Nordin JZ(#)(1), Mizobe Y(#)(1), Nakamura H(2), Komaki H(3), Takeda S(1), Aoki
Y(4).
Author information:
(1)Department of Molecular Therapy, National Institute of Neuroscience, National
Center of Neurology and Psychiatry.
(2)Clinical Research Support Office, Translational Medical Center, National
Center of Neurology and Psychiatry.
(3)Department of Child Neurology, National Center Hospital, National Center of
Neurology and Psychiatry.
(4)Department of Molecular Therapy, National Institute of Neuroscience, National
Center of Neurology and Psychiatry; tsugu56@ncnp.go.jp.
(#)Contributed equally
Duchenne muscular dystrophy (DMD) is a degenerative muscle disease that causes
progressive loss of muscle mass, leading to premature death. The mutations often
cause a distorted reading frame and premature stop codons, resulting in an
almost total lack of dystrophin protein. The reading frame can be corrected
using antisense oligonucleotides (AONs) that induce exon skipping. The
morpholino AON viltolarsen (code name: NS-065/NCNP-01) has been shown to induce
exon 53 skipping, restoring the reading frame for patients with exon 52
deletions. We recently administered NS-065/NCNP-01 intravenously to DMD patients
in an exploratory investigator-initiated, first-in-human trial of
NS-065/NCNP-01. In this methods article, we present the molecular
characterization of dystrophin expression using Sanger sequencing, RT-PCR, and
western blotting in the clinical trial. The characterization of dystrophin
expression was fundamental in the study for showing the efficacy since no
functional outcome tests were performed.
DOI: 10.3791/60672
PMID: 32955503 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34418398 | 1. Lancet Neurol. 2021 Sep;20(9):709-720. doi: 10.1016/S1474-4422(21)00179-4.
Safety and efficacy of bexarotene in patients with relapsing-remitting multiple
sclerosis (CCMR One): a randomised, double-blind, placebo-controlled,
parallel-group, phase 2a study.
Brown JWL(1), Cunniffe NG(2), Prados F(3), Kanber B(4), Jones JL(5), Needham
E(5), Georgieva Z(5), Rog D(6), Pearson OR(7), Overell J(8), MacManus D(9),
Samson RS(9), Stutters J(9), Ffrench-Constant C(10), Gandini Wheeler-Kingshott
CAM(11), Moran C(12), Flynn PD(13), Michell AW(5), Franklin RJM(14), Chandran
S(15), Altmann DR(16), Chard DT(17), Connick P(10), Coles AJ(5).
Author information:
(1)Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK;
NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Queen Square
Institute of Neurology, University College London, London, UK; Clinical Outcomes
Research Unit, University of Melbourne, Melbourne, VIC, Australia.
(2)Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Electronic address: ngc26@cam.ac.uk.
(3)NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Queen Square
Institute of Neurology, University College London, London, UK; Centre for
Medical Image Computing, Department of Medical Physics and Biomedical
Engineering, University College London, London, UK; e-Health Center, Universitat
Oberta de Catalunya, Barcelona, Spain.
(4)NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Queen Square
Institute of Neurology, University College London, London, UK; Centre for
Medical Image Computing, Department of Medical Physics and Biomedical
Engineering, University College London, London, UK; National Institute for
Health Research Biomedical Research Centre, University College London Hospitals
NHS Foundation Trust and University College London, London, UK.
(5)Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
(6)Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation
Trust, Salford, UK.
(7)Department of Neurology, Swansea Bay University Health Board, Swansea, UK.
(8)Product Development Neuroscience, F Hoffmann-La Roche, Basel, Switzerland;
Institute of Neurological Sciences, University of Glasgow, Glasgow, UK.
(9)NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Queen Square
Institute of Neurology, University College London, London, UK.
(10)Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
(11)NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Queen Square
Institute of Neurology, University College London, London, UK; Brain
Connectivity Centre, IRCCS Mondino Foundation, Pavia, Italy; Department of Brain
and Behavioural Sciences, University of Pavia, Pavia, Italy.
(12)Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge,
Cambridge, UK.
(13)Division of Cardiovascular Medicine, Department of Medicine, University of
Cambridge, Cambridge, UK.
(14)Department of Clinical Neurosciences, University of Cambridge, Cambridge,
UK; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge,
Cambridge, UK.
(15)Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK;
UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.
(16)Medical Statistics Department, London School of Hygiene & Tropical Medicine,
London, UK.
(17)NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Queen Square
Institute of Neurology, University College London, London, UK; National
Institute for Health Research Biomedical Research Centre, University College
London Hospitals NHS Foundation Trust and University College London, London, UK.
Comment in
Lancet Neurol. 2021 Sep;20(9):686-687. doi: 10.1016/S1474-4422(21)00253-2.
BACKGROUND: Progressive disability in multiple sclerosis occurs because CNS
axons degenerate as a late consequence of demyelination. In animals, retinoic
acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the
safety and efficacy of a non-selective retinoid X receptor agonist in promoting
remyelination in people with multiple sclerosis.
METHODS: This randomised, double-blind, placebo-controlled, parallel-group,
phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple
sclerosis from two centres in the UK. Eligible participants were aged 18-50
years and had been receiving dimethyl fumarate for at least 6 months. Via a
web-based system run by an independent statistician, participants were randomly
assigned (1:1), by probability-weighted minimisation using four binary factors,
to receive 300 mg/m2 of body surface area per day of oral bexarotene or oral
placebo for 6 months. Participants, investigators, and outcome assessors were
masked to treatment allocation. MRI scans were done at baseline and at 6 months.
The primary safety outcome was the number of adverse events and withdrawals
attributable to bexarotene. The primary efficacy outcome was the patient-level
change in mean lesional magnetisation transfer ratio between baseline and month
6 for lesions that had a baseline magnetisation transfer ratio less than the
within-patient median. We analysed the primary safety outcome in the safety
population, which comprised participants who received at least one dose of their
allocated treatment. We analysed the primary efficacy outcome in the
intention-to-treat population, which comprised all patients who completed the
study. This study is registered in the ISRCTN Registry, 14265371, and has been
completed.
FINDINGS: Between Jan 17, 2017, and May 17, 2019, 52 participants were randomly
assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who
received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09];
159 events in total) than did participants who received placebo (1·63 [SD 1·50];
39 events in total). All bexarotene-treated participants had at least one
adverse event, which included central hypothyroidism (n=26 vs none on placebo),
hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo),
and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene
and two (8%) on placebo discontinued the study drug due to adverse events. One
episode of cholecystitis in a placebo-treated participant was the only serious
adverse event. The change in mean lesional magnetisation transfer ratio was not
different between the bexarotene group (0·25 percentage units [pu; SD 0·98]) and
the placebo group (0·09 pu [0·84]; adjusted bexarotene-placebo difference 0·16
pu, 95% CI -0·39 to 0·71; p=0·55).
INTERPRETATION: We do not recommend the use of bexarotene to treat patients with
multiple sclerosis because of its poor tolerability and negative primary
efficacy outcome. However, statistically significant effects were seen in some
exploratory MRI and electrophysiological analyses, suggesting that other
retinoid X receptor agonists might have small biological effects that could be
investigated in further studies.
FUNDING: Multiple Sclerosis Society of the United Kingdom.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1474-4422(21)00179-4
PMID: 34418398 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests JWLB reports personal
fees from Biogen for real-world evidence consultation, outside the submitted
work. NGC reports grants from the Multiple Sclerosis Society of the United
Kingdom, during the conduct of the study. JLJ reports grants and personal fees
from Sanofi, outside the submitted work. DR reports grants from Merck, Roche,
Biogen, MedDay, Sanofi Genzyme, Novartis, TG Therapeutics, and Mitsubishi, and
personal fees from Merck, Roche, Biogen, MedDay, Sanofi Genzyme, Novartis,
Janssen, and Celgene, outside the submitted work. ORP reports personal fees from
Biogen, Genzyme, Merck, Novartis, Celegene, and Roche, outside the submitted
work. JO reports grants from Hoffmann La-Roche, Biogen, Novartis, and Sanofi
Genzyme, personal fees from Hoffmann La-Roche, Biogen, Teva, Novartis, Celgene,
Medday Pharmaceuticals, EMD Serono, Sanofi Genzyme, Web MD Global, and Allergan,
and employment from Hoffmann La-Roche, outside the submitted work, and is a
shareholder of Hoffmann La-Roche. Cf-C reports grants from Roche, outside the
submitted work. CM reports personal fees from Sanofi, AstraZeneca, and Apitope,
and non-financial support from Sanofi and AstraZeneca, outside the submitted
work. RJMF reports grants from Biogen, and personal fees from Biogen, Frequency
Therapeutics, and Rewind Therapeutics, outside the submitted work. SC reports
funding from Phenotherapeutics, outside the submitted work. DTC reports grants
from the Multiple Sclerosis Society of the United Kingdom during the conduct of
the study, and personal fees from Biogen and Hoffmann-La Roche, grants from the
International Progressive MS Alliance and the Multiple Sclerosis Society of the
United Kingdom, and infrastructure support from the National Institute for
Health Research (NIHR) University College London Hospitals (UCLH) Biomedical
Research Centre, outside the submitted work. AJC reports grants from the
Multiple Sclerosis Society of the United Kingdom during the conduct of the
study. All other authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/33069164 | 1. Pediatr Res. 2022 Aug;92(2):396-402. doi: 10.1038/s41390-020-01201-y. Epub
2020 Oct 17.
Iron transport across the human placenta is regulated by hepcidin.
McDonald EA(1)(2), Gundogan F(3), Olveda RM(4), Bartnikas TB(5), Kurtis
JD(6)(5), Friedman JF(6)(7).
Author information:
(1)Center for International Health Research, Rhode Island Hospital, Providence,
RI, USA. Emily_McDonald@brown.edu.
(2)Department of Pediatrics, Alpert Medical School of Brown University,
Providence, RI, USA. Emily_McDonald@brown.edu.
(3)Department of Pathology, Women & Infants Hospital, Providence, RI, USA.
(4)Department of Immunology, Research Institute for Tropical Medicine, Manila,
Philippines.
(5)Department of Pathology & Laboratory Medicine, Alpert Medical School of Brown
University, Providence, RI, USA.
(6)Center for International Health Research, Rhode Island Hospital, Providence,
RI, USA.
(7)Department of Pediatrics, Alpert Medical School of Brown University,
Providence, RI, USA.
BACKGROUND: Transport of iron across the placenta is critical for appropriate
development of the fetus. Iron deficiency during pregnancy remains a major
public health concern, particularly in low- and middle-income countries, often
exacerbated by infectious diseases leading to altered iron trafficking via
inflammatory responses. Herein, we investigate the role of hepcidin, a master
regulator of iron homeostasis, on regulation of iron transport across
trophoblast cells.
METHODS: We utilized the Jeg-3 choriocarcinoma cell line for analysis of the
expression of transferrin receptor, ferritin, and ferroportin as well as the
export of 59Fe in the presence of hepcidin. Placental tissue from human term
pregnancies was utilized for immunohistochemistry.
RESULTS: Hepcidin treatment of Jeg-3 cells decreased the expression of
ferroportin and transferrin receptor (TfR) and reduced the cellular export of
iron. Lower expression of TfR on the syncytiotrophoblast was associated with the
highest levels of hepcidin in maternal circulation, and ferroportin expression
was positively associated with placental TfR. Placentas from
small-for-gestational-age newborns had significantly lower levels of ferroportin
and ferritin gene expression at delivery.
CONCLUSIONS: Our data suggest that hepcidin plays an important role in the
regulation of iron transport across the placenta, making it a critical link in
movement of iron into fetal circulation.
IMPACT: Hepcidin has a direct impact on iron transport across the human
placenta. This study provides the first evidence of direct regulation of iron
efflux from human trophoblast cells by hepcidin. These data extend our
understanding of iron transport across the maternal-fetal interface, a process
critical for fetal health and development.
© 2020. International Pediatric Research Foundation, Inc.
DOI: 10.1038/s41390-020-01201-y
PMCID: PMC8052381
PMID: 33069164 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICT OF INTEREST: The authors report no
conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34938127 | 1. Clin Pharmacol. 2021 Dec 16;13:235-242. doi: 10.2147/CPAA.S288842. eCollection
2021.
Pharmacological Profile of Viltolarsen for the Treatment of Duchenne Muscular
Dystrophy: A Japanese Experience.
Roshmi RR(1), Yokota T(1).
Author information:
(1)Department of Medical Genetics, University of Alberta, Edmonton, Alberta,
Canada.
Duchenne muscular dystrophy (DMD) is a fatal, X-linked recessive disorder
characterized by progressive muscle loss and cardiorespiratory complications.
Mutations in the DMD gene that eliminate the production of dystrophin protein
are the underlying causes of DMD. Viltolarsen is a drug of phosphorodiamidate
morpholino oligomer (PMO) chemistry, designed to skip exon 53 of the DMD gene.
It aims to produce truncated but partially functional dystrophin in DMD patients
and restore muscle function. Based on a preclinical study showing the ability of
antisense PMOs targeting the DMD gene to improve muscle function in a large
animal model, viltolarsen was developed by Nippon Shinyaku and the National
Center of Neurology and Psychiatry in Japan. Following clinical trials conducted
in Japan, Canada, and the United States showing significant improvements in
muscle function, viltolarsen was approved for medical use in Japan in March 2020
and the United States in August 2020, respectively. Viltolarsen is a
mutation-specific drug and will work for 8% of the persons with DMD who carry
mutations amenable to exon 53 skipping. This review summarizes the
pharmacological profile of viltolarsen, important clinical trials, and
challenges, focusing on the contribution of Japanese patients and researchers in
its development.
© 2021 Roshmi and Yokota.
DOI: 10.2147/CPAA.S288842
PMCID: PMC8688746
PMID: 34938127
Conflict of interest statement: TY is a co-founder and shareholder
of OligomicsTx Inc., which aims to commercialize antisense technology. The
authors report no other conflicts of interest in this work. |
http://www.ncbi.nlm.nih.gov/pubmed/32720970 | 1. J Bras Nefrol. 2020 Oct-Dec;42(4):437-447. doi:
10.1590/2175-8239-JBN-2019-0188.
Association between interleukin-6 gene polymorphism and iron regulation in
hemodialysis patients infected with HCV.
Ali YBM(1), Moussa SG(1), Shahen SM(1), Dewir MA(2), El-Sayed IH(3).
Author information:
(1)University of Sadat City, Genetic Engineering and Biotechnology Research
Institute (GEBR), Molecular Biology Department, Sadat City, Egypt.
(2)Desouk General Hospital, Hemodialysis Unit, Kafr El-Sheikh, Egypt.
(3)Kafr El-Sheikh University, Faulty of Science, Biochemistry Department, Kafr
El-Sheikh, Egypt.
BACKGROUNDS: Hepcidin is related to the pathogenesis of chronic renal failure
anemia, which is considered a chronic inflammatory state as well as HCV
infection. IL-6 stimulates the release of hepcidin from the liver, suppresses
intestinal iron uptake, and releases iron from internal stores.
METHOD: To detect the association between IL-6 gene polymorphism and anemia
markers, 80 hemodialysis (HD) patients [40 negative HCV HD patients and 40
positive HCV HD patients] were studied by routine chemistry and complete blood
count, in addition to the assessment of serum hepcidin, iron parameters [serum
iron and serum ferritin], and hepatitis C markers. IL-6 polymorphism -174G/C was
determined by MS-PCR, while IL-6 polymorphisms -597G/A and -572 G/C were
detected by PCR-SSP.
RESULTS: Hepcidin was non-significantly elevated in HCV-positive compared with
HCV-negative hemodialysis patients. A statistically significant difference was
detected between the negative and positive HCV HD patients in frequencies of
IL-6 -174 G/C and -597 G/A (P≤ 0.01 and P≤ 0.001, respectively). On the other
hand, a non-significant difference was reported between negative and positive
HCV HD patients in the frequencies of IL-6 -572 G/C.
CONCLUSIONS: Our study indicated that IL-6 -174 G/C and -597 G/A polymorphisms
may play a role in HCV susceptibility in HD patients. Additional prospective
studies on a larger population are needed to confirm our findings.
INTRODUÇÃO: A hepcidina está associada à patogênese da anemia por insuficiência
renal crônica, considerada um estado inflamatório crônico e também infecção por
HCV. A IL-6 estimula a liberação de hepcidina a partir do fígado, suprime a
captação intestinal de ferro e libera ferro das reservas internas.
MÉTODO: Para detectar a associação entre o polimorfismo do gene IL-6 e os
marcadores de anemia, 80 pacientes em hemodiálise (HD) [40 pacientes em HD,
negativos para HCV; e 40 em HD, positivos para HCV] foram avaliados por exames
químicos de rotina e hemograma completo, além da avaliação da hepcidina sérica,
parâmetros do ferro [ferro sérico e ferritina sérica] e marcadores de hepatite
C. O polimorfismo da IL-6 -174G/C foi determinado por MS-PCR, enquanto os
polimorfismos de IL-6 -597G/A e -572 G/C foram detectados por PCR-SSP.
RESULTADOS: A hepcidina não esteve significativamente elevada em pacientes com
HCV em comparação com pacientes em hemodiálise negativos para HCV. Uma diferença
estatisticamente significativa foi detectada entre os pacientes em HD HCV
negativos comparados aos positivos nas frequências de IL-6 -174 G/C e -597 G/A
(P≤ 0,01 e P≤ 0,001, respectivamente). Por outro lado, foi relatada uma
diferença não significativa entre pacientes em HD HCV negativos e positivos nas
frequências de IL-6 -572 G/C.
CONCLUSÕES: Nosso estudo indicou que os polimorfismos de IL-6 -174 G/C e -597
G/A podem desempenhar um papel na suscetibilidade ao HCV em pacientes em HD.
Ainda necessitamos de estudos prospectivos adicionais em uma população maior
para confirmar nossos achados.
DOI: 10.1590/2175-8239-JBN-2019-0188
PMCID: PMC7860661
PMID: 32720970 [Indexed for MEDLINE]
Conflict of interest statement: Conflict Of Interest The authors declare that
they have no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/21152835 | 1. Rev Assoc Med Bras (1992). 2010 Sep-Oct;56(5):596-9. doi:
10.1590/s0104-42302010000500024.
Hepcidin as a biochemical parameter for the assessment of iron deficiency
anemia.
[Article in English, Portuguese]
Lemos Ados R(1), Ismael LA, Boato CC, Borges MT, Rondó PH.
Author information:
(1)Faculdade de Ciências Farmacêuticas da Universidade de São Paulo, São Paulo,
SP, Brazil.
Iron deficiency anemia is the most prevalent nutritional disorder in the world.
Information on the metabolism of hepcidin and its possible significance as a
biochemical parameter in iron deficiency anemia is reported in this review,
which was based on a survey of the databases PubMed and LILACS for articles
published between 2006 and 2010 on hepcidin as a biomarker for the regulation of
iron metabolism. The literature search returned 35 studies published in
international journals and one study on the subject in a Brazilian journal.
Hepcidin production is homeostatically regulated by anemia and hypoxia. When
oxygen delivery is inadequate, hepcidin levels decrease. Consequently, more iron
is made available from the diet and from the storage pool in macrophages and
hepatocytes. Hepcidin binds to ferroportin, regulating iron release into plasma.
When hepcidin concentrations are low, ferroportin molecules are displayed on the
plasma membrane and release iron. When hepcidin levels increase, hepcidin binds
to ferroportin molecules inducing their internalization and degradation, and
iron release is decreased progressively. Apparently, the development of
diagnosis and therapy for anemia based on the bioindicator hepcidin may provide
a more effective approach. Epidemiological studies are needed to demonstrate the
relevance of hepcidin to the differential diagnosis of anemia, including
sampling protocols for analysis, with standardization similar to that used in
other biochemical assessments, and establishment of cutoff points for urinary
and plasma expression of this peptide.
DOI: 10.1590/s0104-42302010000500024
PMID: 21152835 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31723763 | 1. Hemasphere. 2018 Mar 28;2(2):e35. doi: 10.1097/HS9.0000000000000035.
eCollection 2018 Mar-Apr.
Erythroferrone: An Erythroid Regulator of Hepcidin and Iron Metabolism.
Coffey R(1), Ganz T(1).
Author information:
(1)Departments of Medicine and Pathology, University of California Los Angeles,
CA.
Iron homeostasis ensures adequate iron for biological processes while preventing
excessive iron accumulation, which can lead to tissue injury. In mammalian
systems, iron availability is controlled by the interaction of the
iron-regulatory hormone hepcidin with ferroportin, a molecule that functions
both as the hepcidin receptor as well as the sole known cellular exporter of
iron. By reducing iron export through ferroportin to blood plasma, hepcidin
inhibits the mobilization of iron from stores and the absorption of dietary
iron. Among the many processes requiring iron, erythropoiesis is the most
iron-intensive, consuming most iron circulating in blood plasma. Under
conditions of enhanced erythropoiesis, more iron is required to provide
developing erythroblasts with adequate iron for heme and hemoglobin synthesis.
Here the hormone erythroferrone, produced by erythroblasts, acts on hepatocytes
to suppress hepcidin production, and thereby increase dietary iron absorption
and mobilization from stores. This review focuses on the discovery of
erythroferrone and recent advances in understanding the role of this hormone in
the regulation of iron homeostasis during states of increased erythropoietic
demand. Gaps in our understanding of the role of erythroferrone are highlighted
for future study.
Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. on
behalf of the European Hematology Association.
DOI: 10.1097/HS9.0000000000000035
PMCID: PMC6745900
PMID: 31723763 |
http://www.ncbi.nlm.nih.gov/pubmed/24132807 | 1. Biofactors. 2014 Mar-Apr;40(2):206-14. doi: 10.1002/biof.1148. Epub 2013 Oct
17.
The regulation of iron transport.
Frazer DM(1), Anderson GJ.
Author information:
(1)Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute,
Brisbane, Qld, Australia.
Iron is an essential nutrient, but its concentration and distribution in the
body must be tightly controlled due to its inherent toxicity and insolubility in
aqueous solution. Living systems have successfully overcome these potential
limitations by evolving a range of iron binding proteins and transport systems
that effectively maintain iron in a nontoxic and soluble form for much, if not
all, of its time within the body. In the circulation, iron is transported to
target organs bound to the serum iron binding protein transferrin. Individual
cells modulate their uptake of transferrin-bound iron depending on their iron
requirements, using both transferrin receptor 1-dependent and independent
pathways. Once inside the cell, iron can be chaperoned to sites of need or, if
in excess, stored within ferritin. Iron is released from cells by the iron
export protein ferroportin1, which requires the ferroxidase activity of
ceruloplasmin or hephestin to load iron safely onto transferrin. The regulation
of iron export is controlled predominantly at the systemic level by the master
regulator of iron homeostasis hepcidin. Hepcidin, in turn, responds to changes
in body iron demand, making use of a range of regulatory mechanisms that center
on the bone morphogenetic protein signaling pathway. This review provides an
overview of recent advances in the field of iron metabolism and outlines the key
components of the iron transport and regulation systems.
© 2013 International Union of Biochemistry and Molecular Biology.
DOI: 10.1002/biof.1148
PMID: 24132807 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24739829 | 1. Indian J Pathol Microbiol. 2014 Jan-Mar;57(1):39-42. doi:
10.4103/0377-4929.130891.
What regulates hepcidin in poly-transfused β-Thalassemia Major: erythroid drive
or store drive?
Chauhan R(1), Sharma S, Chandra J.
Author information:
(1)Department of Pathology, Lady Hardinge Medical College and Kalawati Saran
Children's Hospital,New Delhi, India.
BACKGROUND: Hepcidin, a key regulator of iron homeostasis, is increased by iron
overload and inflammation while suppressed by hypoxia. In spite of iron overload
in β-Thalassemia Major (β-TM), a paradoxical decrease in hepcidin is observed.
AIM: To assess the opposing effects of enhanced erythropoiesis due to anemia and
iron overloading on hepcidin in β-TM patients.
SETTING AND DESIGN: This prospective observational study was done at our
tertiary care hospital.
MATERIALS AND METHODS: Eighty-three pediatric polytransfused (> 20 transfusions)
patients of β-TM were compared with 70 children who served as controls. Serum
assays for ferritin, transferrin receptors (sTfR) and hepcidin were performed.
STATISTICAL ANALYSIS: Independent Student t test was used to compare variables
between both the groups. A Pearson correlation coefficient was used to find any
correlation between ferritin, sTfR and hepcidin.
RESULTS: The mean value of hepcidin in β-TM children was 13.88±10.68 ng/ml
(range, 0.9-60 ng/ml) and showed significant negative correlation with sTfR (r =
-0.296, P < 0.0066). However, there was no correlation of hepcidin with
ferritin. Ferritin and sTfR were significantly elevated in β-TM children
compared to controls (P < 0.001). The mean serum hepcidin/ferritin index in the
study group (0.00552) was significantly lower (P value < 0.001) than the
controls (0.378) thus indicating inappropriate levels of hepcidin to iron
overload.
CONCLUSION: In polytransfused β-TM children increased iron demand dominates over
iron overload in regulating hepcidin. In spite of excessive iron load, the
inappropriate hepcidin levels may further contribute to iron overload enhancing
iron toxicity.
DOI: 10.4103/0377-4929.130891
PMID: 24739829 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23986220 | 1. Adv Clin Exp Med. 2013 Jul-Aug;22(4):585-91.
Hepcidin and its role in inflammatory bowel disease.
Dudkowiak R(1), Neubauer K, Poniewierka E.
Author information:
(1)Division of Dietetics, Department of Gastroenterology and Hepatology, Wroclaw
Medical University, Poland.
Anemia is one of the most common extraintestinal symptoms of inflammatory bowel
disease (IBD). The pathophysiology of anemia in IBD is complex. It may be
developed in the course of inflammation, intestinal bleeding or disorders of
iron absorption. Hepcidin, discovered in the year 2000, is an endogenous peptide
responsible for iron homeostasis. Recent data suggests that hepcidin is a major
mediator of anemia and plays a central role in iron homeostasis and metabolism.
This paper presents information about hepcidin structure and function,
mechanisms of the regulation of the synthesis and current data about the role of
this hormone in IBD-related anemia. Assessment of hepcidin levels in patients
with IBD may become a key element in the treatment of anemia in the near future.
PMID: 23986220 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28096133 | 1. Adv Nutr. 2017 Jan 17;8(1):126-136. doi: 10.3945/an.116.013961. Print 2017
Jan.
Regulation of the Iron Homeostatic Hormone Hepcidin.
Sangkhae V(1), Nemeth E(2).
Author information:
(1)Center for Iron Disorders, Department of Medicine, David Geffen School of
Medicine, University of California Los Angeles, Los Angeles, CA.
(2)Center for Iron Disorders, Department of Medicine, David Geffen School of
Medicine, University of California Los Angeles, Los Angeles, CA
enemeth@mednet.ucla.edu.
Iron is required for many biological processes but is also toxic in excess;
thus, body iron balance is maintained through sophisticated regulatory
mechanisms. The lack of a regulated iron excretory mechanism means that body
iron balance is controlled at the level of absorption from the diet. Iron
absorption is regulated by the hepatic peptide hormone hepcidin. Hepcidin also
controls iron release from cells that recycle or store iron, thus regulating
plasma iron concentrations. Hepcidin exerts its effects through its receptor,
the cellular iron exporter ferroportin. Important regulators of hepcidin, and
therefore of systemic iron homeostasis, include plasma iron concentrations, body
iron stores, infection and inflammation, and erythropoiesis. Disturbances in the
regulation of hepcidin contribute to the pathogenesis of many iron disorders:
hepcidin deficiency causes iron overload in hereditary hemochromatosis and
nontransfused β-thalassemia, whereas overproduction of hepcidin is associated
with iron-restricted anemias seen in patients with chronic kidney disease,
chronic inflammatory diseases, some cancers, and inherited iron-refractory iron
deficiency anemia. This review summarizes our current understanding of the
molecular mechanisms and signaling pathways involved in the control of hepcidin
synthesis in the liver, a principal determinant of plasma hepcidin
concentrations.
© 2017 American Society for Nutrition.
DOI: 10.3945/an.116.013961
PMCID: PMC5227985
PMID: 28096133 [Indexed for MEDLINE]
Conflict of interest statement: 3 Author disclosures: V Sangkhae, no conflicts
of interest. E Nemeth is a consultant to and stockholder of Intrinsic
LifeSciences, Merganser Biotech, and Silarus Therapeutics. |
http://www.ncbi.nlm.nih.gov/pubmed/24385536 | 1. Blood. 2014 Mar 6;123(10):1574-85. doi: 10.1182/blood-2013-07-515957. Epub
2014 Jan 2.
Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to
proliferative Ras/RAF and nutrient-dependent mTOR signaling.
Mleczko-Sanecka K(1), Roche F, da Silva AR, Call D, D'Alessio F, Ragab A,
Lapinski PE, Ummanni R, Korf U, Oakes C, Damm G, D'Alessandro LA, Klingmüller U,
King PD, Boutros M, Hentze MW, Muckenthaler MU.
Author information:
(1)Department of Pediatric Oncology, Hematology and Immunology, and.
Comment in
Blood. 2014 Mar 6;123(10):1433-4. doi: 10.1182/blood-2014-01-548594.
The hepatic hormone hepcidin is a key regulator of systemic iron metabolism. Its
expression is largely regulated by 2 signaling pathways: the "iron-regulated"
bone morphogenetic protein (BMP) and the inflammatory JAK-STAT pathways. To
obtain broader insights into cellular processes that modulate hepcidin
transcription and to provide a resource to identify novel genetic modifiers of
systemic iron homeostasis, we designed an RNA interference (RNAi) screen that
monitors hepcidin promoter activity after the knockdown of 19 599 genes in
hepatocarcinoma cells. Interestingly, many of the putative hepcidin activators
play roles in signal transduction, inflammation, or transcription, and affect
hepcidin transcription through BMP-responsive elements. Furthermore, our work
sheds light on new components of the transcriptional machinery that maintain
steady-state levels of hepcidin expression and its responses to the BMP- and
interleukin-6-triggered signals. Notably, we discover hepcidin suppression
mediated via components of Ras/RAF MAPK and mTOR signaling, linking hepcidin
transcriptional control to the pathways that respond to mitogen stimulation and
nutrient status. Thus using a combination of RNAi screening, reverse phase
protein arrays, and small molecules testing, we identify links between the
control of systemic iron homeostasis and critical liver processes such as
regeneration, response to injury, carcinogenesis, and nutrient metabolism.
DOI: 10.1182/blood-2013-07-515957
PMCID: PMC3945866
PMID: 24385536 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23722909 | 1. J Clin Invest. 2013 Jun;123(6):2337-43. doi: 10.1172/JCI67225. Epub 2013 Jun
3.
Iron regulation by hepcidin.
Zhao N(1), Zhang AS, Enns CA.
Author information:
(1)Department of Cell and Developmental Biology, Oregon Health and Science
University, Portland, Oregon 97239, USA.
Hepcidin is a key hormone that is involved in the control of iron homeostasis in
the body. Physiologically, hepcidin is controlled by iron stores, inflammation,
hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a
complex process that requires the coordination of multiple proteins, including
hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis
protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and
transferrin. Misregulation of hepcidin is found in many disease states, such as
the anemia of chronic disease, iron refractory iron deficiency anemia, cancer,
hereditary hemochromatosis, and ineffective erythropoiesis, such as
β-thalassemia. Thus, the regulation of hepcidin is the subject of interest for
the amelioration of the detrimental effects of either iron deficiency or
overload.
DOI: 10.1172/JCI67225
PMCID: PMC3668831
PMID: 23722909 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24293278 | 1. Int J Hematol. 2014 Jan;99(1):12-20. doi: 10.1007/s12185-013-1476-8. Epub 2013
Dec 1.
Hepcidin production in response to iron is controlled by monocyte-derived
humoral factors.
Sasaki Y(1), Shimonaka Y, Ikuta K, Hosoki T, Sasaki K, Torimoto Y, Kanada H,
Moriguchi Y, Kohgo Y.
Author information:
(1)Product Research Department, Kamakura Research Labs, Chugai Pharmaceutical
Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan,
sasaki.yusuke@chugai-pharm.co.jp.
Hepcidin, which is mainly produced by the liver, is the key regulator in iron
homeostasis. Hepcidin expression is up-regulated by iron loading in vivo, but
the mechanism underlying this process is not completely understood. In the
present study, we investigated the mechanism, following the hypothesis that
hepcidin production in response to iron loading is regulated by extra-hepatic
iron sensors. We measured serum hepcidin concentrations and iron indices in
Wistar rats treated with saccharated ferric oxide (SFO). Human hepatoma-derived
HepG2 cells were stimulated using SFO-administered rat sera, and co-cultured
with rat spleen cells, human monocyte-derived THP-1 cells, or human monocytes
with diferric transferrin (holo-Tf), and hepcidin concentrations in the
conditioned media were measured. SFO elevated rat serum hepcidin concentrations.
SFO-treated rat sera increased hepcidin production from HepG2 cells, and this
induction correlated with serum hepcidin levels, but not with iron indices.
Holo-Tf up-regulated hepcidin concentrations in media from HepG2 cells
co-cultured with rat spleen cells, THP-1 cells, or human monocytes with or
without cell-to-cell contacts, while holo-Tf did not up-regulate hepcidin from
HepG2 cells alone. Our results suggest the existence of humoral factors capable
of inducing hepcidin production that are secreted by extra-hepatic cells, such
as reticuloendothelial monocytes, in response to iron.
DOI: 10.1007/s12185-013-1476-8
PMID: 24293278 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31431773 | 1. J Pak Med Assoc. 2019 Aug;69(8):1170-1175.
Hepcidin: A key regulator of iron.
Saneela S(1), Iqbal R(1), Raza A(2), Qamar MF(3).
Author information:
(1)Department of Zoology, University of Gujrat, Gujrat Pakistan.
(2)Department of Zoology, Government College University Lahore, Pakistan.
(3)College of Veterinary and animal Sciences Jhang, Pakistan.
Hapcidin is the central regulator of iron homeostasis in the body. Primarily it
is extracted from urine. Hepcidin is a 25 amino acid long chain peptide.
Inflammation or iron overload greatly stimulate production of hepcidin by
hepatocytes. Recent evidences have revealed that mutations in the human
haemochromatosis (HFE) gene lead to deficiency of hepcidin which is responsible
for iron overload and contributing to haemochromatosis. Moreover, hepcidin plays
a key role in different types of anaemia, mainly anaemia of inflammation in
which concentration of hepcidin increases up to 100 folds. Its contribution to
renal disease, heart diseases, cancer and obesity-related disorders are also
observed. On the other hand, its role is quite inevitable in understanding
metastasis in certain cancers. By understanding the mechanism of hepcidin and
its pathological roles in blood and iron diseases could lead to new therapies.
PMID: 31431773 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17557118 | 1. J Clin Invest. 2007 Jul;117(7):1926-32. doi: 10.1172/JCI31370.
Regulation of iron homeostasis by the hypoxia-inducible transcription factors
(HIFs).
Peyssonnaux C(1), Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH,
Nizet V, Johnson RS.
Author information:
(1)Molecular Biology Section, Division of Biological Sciences, UCSD School of
Medicine, La Jolla, CA 92093-0377, USA.
Iron is essential for many biological processes, including oxygen delivery, and
its supply is tightly regulated. Hepcidin, a small peptide synthesized in the
liver, is a key regulator of iron absorption and homeostasis in mammals.
Hepcidin production is increased by iron overload and decreased by anemia and
hypoxia; but the molecular mechanisms that govern the hepcidin response to these
stimuli are not known. Here we establish that the von
Hippel-Lindau/hypoxia-inducible transcription factor (VHL/HIF) pathway is an
essential link between iron homeostasis and hepcidin regulation in vivo. Through
coordinate downregulation of hepcidin and upregulation of erythropoietin and
ferroportin, the VHL-HIF pathway mobilizes iron to support erythrocyte
production.
DOI: 10.1172/JCI31370
PMCID: PMC1884690
PMID: 17557118 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30798816 | 1. Vitam Horm. 2019;110:47-70. doi: 10.1016/bs.vh.2019.01.003. Epub 2019 Feb 6.
Signaling pathways regulating hepcidin.
Rishi G(1), Subramaniam VN(2).
Author information:
(1)The Liver Disease and Iron Disorders Research Group, Institute of Health and
Biomedical Innovation and School of Biomedical Sciences, Queensland University
of Technology (QUT), Brisbane, QLD, Australia.
(2)The Liver Disease and Iron Disorders Research Group, Institute of Health and
Biomedical Innovation and School of Biomedical Sciences, Queensland University
of Technology (QUT), Brisbane, QLD, Australia. Electronic address:
nathan.subramaniam@qut.edu.au.
Since its discovery in 2001, there have been a number of important discoveries
and findings that have increased our knowledge about the functioning of
hepcidin. Hepcidin, the master iron regulator has been shown to be regulated by
a number of physiological stimuli and their associated signaling pathways. This
chapter will summarize our current understanding of how these physiological
stimuli and downstream signaling molecules are involved in hepcidin modulation
and ultimately contribute to the regulation of systemic or local iron
homeostasis. The signaling pathways and molecules described here have been shown
to primarily affect hepcidin at a transcriptional level, but these
transcriptional changes correlate with changes in systemic iron levels as well,
supporting the functional effects of hepcidin regulation by these signaling
pathways.
© 2019 Elsevier Inc. All rights reserved.
DOI: 10.1016/bs.vh.2019.01.003
PMID: 30798816 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27905193 | 1. Cancer Med. 2017 Jan;6(1):120-128. doi: 10.1002/cam4.974. Epub 2016 Dec 1.
High pretransplant hepcidin levels are associated with poor overall survival and
delayed platelet engraftment after allogeneic hematopoietic stem cell
transplantation.
Sakamoto S(1), Kawabata H(1)(2), Kanda J(1), Uchiyama T(3), Mizumoto C(3),
Kitano T(1), Kondo T(1), Hishizawa M(1), Tomosugi N(4), Takaori-Kondo A(1).
Author information:
(1)Department of Hematology and Oncology, Graduate School of Medicine, Kyoto
University, Kyoto, Japan.
(2)Department of Hematology and Immunology, Kanazawa Medical University,
Uchinada-machi, Japan.
(3)Department of Hematology and Immunology, Japanese Red Cross Otsu Hospital,
Otsu, Japan.
(4)Division of Advanced Medicine, Medical Research Institute, Kanazawa Medical
University, Uchinada-machi, Japan.
Iron overload is considered a risk factor for mortality in patients with
hematopoietic malignancies. Hepcidin is a key regulator of systemic iron
balance. We previously reported dynamic changes of serum hepcidin-25 levels in
patients with hematologic malignancies after allogeneic hematopoietic stem cell
transplantation (allo-HSCT). In this study, we retrospectively analyzed the
association of pretransplant hepcidin-25 levels with overall survival (OS),
engraftment, and other clinical outcomes of allo-HSCT in patients with
hematologic malignancies. A total of 166 patients were divided into two groups
depending on their pretransplant serum hepcidin-25 levels; their median age was
49.5 years, and the median follow-up time was 46.8 months. At 3 years, the
patients in the high-hepcidin group had a significantly lower OS than those in
the low-hepcidin group (49.2 vs. 69.0%, respectively; P = 0.006). Multivariate
analysis revealed that pretransplant serum hepcidin-25 level, sex, and disease
status were independently associated with OS. The incidence of platelet
engraftment was significantly lower in the high-hepcidin group than in the
low-hepcidin group, whereas no significant differences were observed in
neutrophil and reticulocyte engraftments between these groups. Hence,
pretransplant serum hepcidin levels can be a marker for predicting delayed
platelet recovery after allo-HSCT.
© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
DOI: 10.1002/cam4.974
PMCID: PMC5269567
PMID: 27905193 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33820875 | 1. Aging (Albany NY). 2021 Apr 4;13(8):11296-11314. doi: 10.18632/aging.202817.
Epub 2021 Apr 4.
Hepcidin-induced reduction in iron content and PGC-1β expression negatively
regulates osteoclast differentiation to play a protective role in postmenopausal
osteoporosis.
Zhang H(1)(2), Wang A(1)(2), Shen G(1), Wang X(1)(2), Liu G(3), Yang F(1)(2),
Chen B(1)(4)(2), Wang M(2), Xu Y(1)(4)(2).
Author information:
(1)Department of Orthopaedics, The Second Affiliated Hospital of Soochow
University, Suzhou 215004, China.
(2)Institute of Osteoporosis Diagnosis and Treatments of Soochow University,
Suzhou 215004, China.
(3)Department of Orthopaedics, Suzhou TCM Hospital Affiliated to Nanjing
University of Chinese Medicine, Suzhou 215004, China.
(4)Osteoporosis Clinical Center, The Second Affiliated Hospital of Soochow
University, Suzhou 215004, China.
As a necessary trace element, iron is involved in many physiological processes.
Clinical and basic studies have found that disturbances in iron metabolism,
especially iron overload, might lead to bone loss and even be involved in
postmenopausal osteoporosis. Hepcidin is a key regulator of iron homeostasis.
However, the exact role of hepcidin in bone metabolism and the underlying
mechanism remain unknown. In this study, we found that in postmenopausal
osteoporosis cohort, the concentration of hepcidin in the serum was
significantly reduced and positively correlated with bone mineral density.
Ovariectomized (OVX) mice were then used to construct an osteoporosis model.
Hepcidin overexpression in these mice significantly improved bone mass and
rescued the phenotype of bone loss. Additionally, overexpression of hepcidin in
OVX mice greatly reduced the number and differentiation of osteoclasts in vivo
and in vitro. This study found that overexpression of hepcidin significantly
inhibited ROS production, mitochondrial biogenesis, and PGC-1β expression. These
data showed that hepcidin protected osteoporosis by reducing iron levels in bone
tissue, and in conjunction with PGC-1β, reduced ROS production and the number of
mitochondria, thus inhibiting osteoclast differentiation and bone absorption.
Hepcidin could provide new targets for the clinical treatment of postmenopausal
osteoporosis.
DOI: 10.18632/aging.202817
PMCID: PMC8109081
PMID: 33820875 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICTS OF INTEREST: The authors declare that
they have no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/12663437 | 1. Blood. 2003 Aug 1;102(3):783-8. doi: 10.1182/blood-2003-03-0672. Epub 2003 Mar
27.
Hepcidin, a key regulator of iron metabolism and mediator of anemia of
inflammation.
Ganz T(1).
Author information:
(1)Department of Medicine, David Geffen School of Medicine, 10833 Le Conte Ave,
CHS 37-055, University of California, Los Angeles, CA 90095-1690, USA.
tganz@mednet.ucla.edu
Human hepcidin, a 25-amino acid peptide made by hepatocytes, may be a new
mediator of innate immunity and the long-sought iron-regulatory hormone. The
synthesis of hepcidin is greatly stimulated by inflammation or by iron overload.
Evidence from transgenic mouse models indicates that hepcidin is the predominant
negative regulator of iron absorption in the small intestine, iron transport
across the placenta, and iron release from macrophages. The key role of hepcidin
is confirmed by the presence of nonsense mutations in the hepcidin gene,
homozygous in the affected members, in 2 families with severe juvenile
hemochromatosis. Recent evidence shows that deficient hepcidin response to iron
loading may contribute to iron overload even in the much milder common form of
hemochromatosis, from mutations in the HFE gene. In anemia of inflammation,
hepcidin production is increased up to 100-fold and this may account for the
defining feature of this condition, sequestration of iron in macrophages. The
discovery of hepcidin and its role in iron metabolism could lead to new
therapies for hemochromatosis and anemia of inflammation.
DOI: 10.1182/blood-2003-03-0672
PMID: 12663437 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32814342 | 1. Nature. 2020 Oct;586(7831):807-811. doi: 10.1038/s41586-020-2668-z. Epub 2020
Aug 19.
Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms.
Billesbølle CB(#)(1), Azumaya CM(#)(2), Kretsch RC(3)(4)(5)(6)(7), Powers
AS(3)(4)(5)(6)(8), Gonen S(2)(9)(10), Schneider S(11), Arvedson T(12), Dror
RO(3)(4)(5)(6)(7), Cheng Y(13)(14), Manglik A(15)(16).
Author information:
(1)Department of Pharmaceutical Chemistry, University of California, San
Francisco, San Francisco, CA, USA.
(2)Department of Biochemistry and Biophysics, University of California, San
Francisco, San Francisco, CA, USA.
(3)Department of Computer Science, Stanford University, Stanford, CA, USA.
(4)Department of Molecular and Cellular Physiology, Stanford University School
of Medicine, Stanford, CA, USA.
(5)Department of Structural Biology, Stanford University School of Medicine,
Stanford, CA, USA.
(6)Institute for Computational and Mathematical Engineering, Stanford
University, Stanford, CA, USA.
(7)Biophysics Program, Stanford University, Stanford, CA, USA.
(8)Department of Chemistry, Stanford University, Stanford, CA, USA.
(9)Howard Hughes Medical Institute, University of California San Francisco, San
Francisco, CA, USA.
(10)Department of Molecular Biology and Biochemistry, University of California,
Irvine, Biological Sciences III, Irvine, CA, USA.
(11)Institute of Biochemistry, Goethe University Frankfurt, Max-von-Laue-Straße
9, Frankfurt am Main, Germany.
(12)Department of Oncology Research, Amgen Inc., South San Francisco, CA, USA.
(13)Department of Biochemistry and Biophysics, University of California, San
Francisco, San Francisco, CA, USA. yifan.cheng@ucsf.edu.
(14)Howard Hughes Medical Institute, University of California San Francisco, San
Francisco, CA, USA. yifan.cheng@ucsf.edu.
(15)Department of Pharmaceutical Chemistry, University of California, San
Francisco, San Francisco, CA, USA. aashish.manglik@ucsf.edu.
(16)Department of Anesthesia and Perioperative Care, University of California,
San Francisco, San Francisco, CA, USA. aashish.manglik@ucsf.edu.
(#)Contributed equally
The serum level of iron in humans is tightly controlled by the action of the
hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin regulates
iron absorption and recycling by inducing the internalization and degradation of
ferroportin1. Aberrant ferroportin activity can lead to diseases of iron
overload, such as haemochromatosis, or iron limitation anaemias2. Here we
determine cryogenic electron microscopy structures of ferroportin in lipid
nanodiscs, both in the apo state and in complex with hepcidin and the iron
mimetic cobalt. These structures and accompanying molecular dynamics simulations
identify two metal-binding sites within the N and C domains of ferroportin.
Hepcidin binds ferroportin in an outward-open conformation and completely
occludes the iron efflux pathway to inhibit transport. The carboxy terminus of
hepcidin directly contacts the divalent metal in the ferroportin C domain.
Hepcidin binding to ferroportin is coupled to iron binding, with an 80-fold
increase in hepcidin affinity in the presence of iron. These results suggest a
model for hepcidin regulation of ferroportin, in which only ferroportin
molecules loaded with iron are targeted for degradation. More broadly, our
structural and functional insights may enable more targeted manipulation of the
hepcidin-ferroportin axis in disorders of iron homeostasis.
DOI: 10.1038/s41586-020-2668-z
PMCID: PMC7906036
PMID: 32814342 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests Tara Arvedson is employed by
Amgen and reports Amgen stock. The other authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/30374287 | 1. Front Neurosci. 2018 Oct 15;12:740. doi: 10.3389/fnins.2018.00740. eCollection
2018.
The Dual Role of Hepcidin in Brain Iron Load and Inflammation.
Vela D(1).
Author information:
(1)Department of Physiology, Faculty of Medicine, University of Pristina,
Pristina, Kosovo.
Hepcidin is the major regulator of systemic iron metabolism, while the role of
this peptide in the brain has just recently been elucidated. Studies suggest a
dual role of hepcidin in neuronal iron load and inflammation. This is important
since neuronal iron load and inflammation are pathophysiological processes
frequently associated with neurodegeneration. Furthermore, manipulation of
hepcidin activity has recently been used to recover neuronal damage due to brain
inflammation in animal models and cultured cells. Therefore, understanding the
mechanistic insights of hepcidin action in the brain is important to uncover its
role in treating neuronal damage in neurodegenerative diseases.
DOI: 10.3389/fnins.2018.00740
PMCID: PMC6196657
PMID: 30374287 |
http://www.ncbi.nlm.nih.gov/pubmed/17593032 | 1. Br J Haematol. 2007 Jul;138(2):253-62. doi: 10.1111/j.1365-2141.2007.06638.x.
Hepcidin, a key regulator of iron metabolism, is transcriptionally activated by
p53.
Weizer-Stern O(1), Adamsky K, Margalit O, Ashur-Fabian O, Givol D, Amariglio N,
Rechavi G.
Author information:
(1)Cancer Research Centre and Lily and Edmond Safra Children's Hospital, Sheba
Medical Centre and Sackler Medical School, Tel Aviv University, Tel Aviv,
Israel.
Hepcidin is an iron-regulatory protein that is upregulated in response to
increased iron or inflammatory stimuli. Hepcidin reduces serum iron and induces
iron sequestration in the reticuloendothelial macrophages - the hallmark of
anaemia of inflammation. Iron deprivation is used as a defense mechanism against
infection, and it also has a beneficial effect on the control of cancer. The
tumour-suppressor p53 transcriptionally regulates genes involved in growth
arrest, apoptosis and DNA repair, and perturbation of p53 pathways is a hallmark
of the majority of human cancers. This study inspected a role of p53 in the
transcriptional regulation of hepcidin. Based on preliminary bioinformatics
analysis, we identified a putative p53 response-element (p53RE) contained in the
hepcidin gene (HAMP) promoter. Chromatin immunoprecipitation (ChIP), reporter
assays and a temperature sensitive p53 cell-line system were used to demonstrate
p53 binding and activation of the hepcidin promoter. p53 bound to hepcidin p53RE
in vivo, andthis p53RE could confer p53-dependent transcriptional activation.
Activation of p53 increased hepcidin expression, while silencing of p53 resulted
in decreased hepcidin expression in human hepatoma cells. Taken together, these
results define HAMP as a novel transcriptional target of p53. We hypothesise
that hepcidin upregulation by p53 is part of a defence mechanism against cancer,
through iron deprivation. Hepcidin induction by p53 might be involved in the
pathogenesis of anaemia accompanying cancer.
DOI: 10.1111/j.1365-2141.2007.06638.x
PMID: 17593032 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21439478 | 1. Chem Biol. 2011 Mar 25;18(3):336-43. doi: 10.1016/j.chembiol.2010.12.009.
Understanding the structure/activity relationships of the iron regulatory
peptide hepcidin.
Clark RJ(1), Tan CC, Preza GC, Nemeth E, Ganz T, Craik DJ.
Author information:
(1)The University of Queensland, Institute for Molecular Bioscience, Brisbane,
Queensland 4072, Australia. richard.clark@uq.edu.au
The peptide hormone hepcidin is a key homeostatic regulator of iron metabolism
and involved in pathological regulation of iron in response to infection,
inflammation, hypoxia, and anemia. It acts by binding to the iron exporter
ferroportin, causing it to be internalized and degraded; however, little is
known about the structure/activity relationships of the interaction of hepcidin
with ferroportin. We show that there are key residues in the N-terminal region
of hepcidin that influence its interaction with ferroportin, and we explore the
structure/function relationships at these positions. A series of hepcidin
mutants in which disulfide bonds were replaced with diselenide bonds showed no
change in activity compared to native hepcidin. These results identify important
constraints for the development of hepcidin congeners for the treatment of
hereditary iron overload.
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.chembiol.2010.12.009
PMCID: PMC3073735
PMID: 21439478 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22968710 | 1. JPEN J Parenter Enteral Nutr. 2013 Sep;37(5):599-606. doi:
10.1177/0148607112459648. Epub 2012 Sep 11.
Iron metabolism in man.
von Drygalski A(1), Adamson JW.
Author information:
(1)University of California, Medical Offices South, 200 West Arbor Drive, #8651,
San Diego, CA 92103-8651, USA. avondrygalski@ucsd.edu
Iron metabolism in man is a highly regulated process designed to provide iron
for erythropoiesis, mitochondrial energy production, electron transport, and
cell proliferation. The mechanisms of iron handling also protect cells from the
deleterious effects of free iron, which can produce oxidative damage of
membranes, proteins, and lipids. Over the past decade, several important
molecules involved in iron homeostasis have been discovered, and their function
has expanded our understanding of iron trafficking under normal and pathological
conditions. Physiologic iron metabolism is strongly influenced by inflammation,
which clinically leads to anemia. Although hepcidin, a small circulating peptide
produced by the liver, has been found to be the key regulator of iron
trafficking, molecular pathways of iron sensing that control iron metabolism and
hepcidin production are still incompletely understood. With this review, we
provide an overview of the current understanding of iron metabolism, the
recently discovered regulators of iron trafficking, and a focus on the effects
of inflammation on the process.
DOI: 10.1177/0148607112459648
PMID: 22968710 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33567510 | 1. Biomedicines. 2021 Feb 8;9(2):164. doi: 10.3390/biomedicines9020164.
Pursuing Orally Bioavailable Hepcidin Analogues via Cyclic N-Methylated
Mini-Hepcidins.
Goncalves Monteiro D(1), van Dijk JWA(1), Aliyanto R(1), Fung E(2), Nemeth E(2),
Ganz T(2), Rosengren J(1), Clark RJ(1).
Author information:
(1)School of Biomedical Sciences, Faculty of Medicine, The University of
Queensland, Brisbane, QLD 4072, Australia.
(2)David Geffen School of Medicine, University of California, Los Angeles, CA
90095, USA.
The peptide hormone hepcidin is one of the key regulators of iron absorption,
plasma iron levels, and tissue iron distribution. Hepcidin functions by binding
to and inducing the internalisation and subsequent lysosomal degradation of
ferroportin, which reduces both iron absorption in the gut and export of iron
from storage to ultimately decrease systemic iron levels. The key interaction
motif in hepcidin has been localised to the highly conserved N-terminal region,
comprising the first nine amino acid residues, and has led to the development of
mini-hepcidin analogs that induce ferroportin internalisation and have improved
drug-like properties. In this work, we have investigated the use of head-to-tail
cyclisation and N-methylation of mini-hepcidin as a strategy to increase oral
bioavailability by reducing proteolytic degradation and enhancing membrane
permeability. We found that backbone cyclisation and N-methylation was
well-tolerated in the mini-hepcidin analogues, with the macrocylic analogues
often surpassing their linear counterparts in potency. Both macrocyclisation and
backbone N-methylation were found to improve the stability of the
mini-hepcidins, however, there was no effect on membrane-permeabilizing
activity.
DOI: 10.3390/biomedicines9020164
PMCID: PMC7915682
PMID: 33567510
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/12433676 | 1. Blood. 2003 Apr 1;101(7):2461-3. doi: 10.1182/blood-2002-10-3235. Epub 2002
Nov 14.
Hepcidin, a putative mediator of anemia of inflammation, is a type II
acute-phase protein.
Nemeth E(1), Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T.
Author information:
(1)Department of Medicine, David Geffen School of Medicine, and the West Los
Angeles Veterans Administration Hospital, University of California, Los Angeles
90095, USA.
Hepcidin is a liver-made peptide proposed to be a central regulator of
intestinal iron absorption and iron recycling by macrophages. In animal models,
hepcidin is induced by inflammation and iron loading, but its regulation in
humans has not been studied. We report that urinary excretion of hepcidin was
greatly increased in patients with iron overload, infections, or inflammatory
diseases. Hepcidin excretion correlated well with serum ferritin levels, which
are regulated by similar pathologic stimuli. In vitro iron loading of primary
human hepatocytes, however, unexpectedly down-regulated hepcidin mRNA,
suggesting that in vivo regulation of hepcidin expression by iron stores
involves complex indirect effects. Hepcidin mRNA was dramatically induced by
interleukin-6 (IL-6) in vitro, but not by IL-1 or tumor necrosis factor alpha
(TNF-alpha), demonstrating that human hepcidin is a type II acute-phase
reactant. The linkage of hepcidin induction to inflammation in humans supports
its proposed role as a key mediator of anemia of inflammation.
DOI: 10.1182/blood-2002-10-3235
PMID: 12433676 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21073997 | 1. Ann Pharm Fr. 2010 Nov;68(6):388-96. doi: 10.1016/j.pharma.2010.08.002. Epub
2010 Oct 14.
[Reversible metalation of a bis-disulfide analogue of the Cys*-X-Cys* hepcidin
binding site: structural characterisation of the related copper complex].
[Article in French]
Desbenoit N(1), Galardon E, Deschamps P, Roussel P, Vaulont S, Artaud I, Tomas
A.
Author information:
(1)UMR 8015/CNRS, laboratoire de cristallographie et RMN biologiques, université
Paris Descartes, 4 avenue de l'Observatoire, Paris cedex 06, France.
Hepcidin, a 25-amino-acid peptide secreted by the liver, distributed in the
plasma and excreted in urine, is a key central regulator of body iron
homeostasis. This hormone decreases export of cellular iron by binding to
ferroportin, an iron exporter present at the basolateral surface of enterocytes
and macrophages (the sites of dietary iron absorption and iron recycling,
respectively), inducing its internalization and degradation. Hepcidin contains
eight cysteine residues that form four disulfide bridges, which stabilize a
hairpin-shaped structure with two beta sheets. We noticed in the sequence of
hepcidin a Cys*-X-Cys* motif which can act as a metal binding site able to trap
iron and/or copper. We have tested this hypothesis using a pseudopeptidic
synthetic bis-disulfide analogue and we have shown that direct metalation of
such ligand leads to the formation of a copper(III) complex with the typical
N(2)S(2) donor set. This compound crystallizes in the orthorhombic system, space
group Imma. The Cu(III) configuration is square planar, built up from two
carboximado-N and two thiolato-S donors. This complex is converted back to the
bis-disulfide, with release of the copper salt, upon oxidation with iodine.
Copyright © 2010 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.pharma.2010.08.002
PMID: 21073997 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22776295 | 1. FEBS J. 2012 Sep;279(17):3166-75. doi: 10.1111/j.1742-4658.2012.08695.x. Epub
2012 Jul 25.
Efficient oxidative folding and site-specific labeling of human hepcidin to
study its interaction with receptor ferroportin.
Luo X(1), Jiang Q, Song G, Liu YL, Xu ZG, Guo ZY.
Author information:
(1)Institute of Protein Research, College of Life Sciences and Technology,
Tongji University, Shanghai, China.
Hepcidin is a small disulfide-rich peptide hormone that plays a key role in the
regulation of iron homeostasis by binding and mediating the degradation of the
cell membrane iron efflux transporter, ferroportin. Since it is a small peptide,
chemical synthesis is a suitable approach for the preparation of mature human
hepcidin. However, oxidative folding of synthetic hepcidin is extremely
difficult due to its high cysteine content and high aggregation propensity. To
improve its oxidative folding efficiency, we propose a reversible S-modification
approach. Introduction of eight negatively charged sulfonate moieties into
synthetic hepcidin significantly decreased its aggregation propensity and, under
optimized conditions, dramatically increased the refolding yield. The folded
hepcidin displayed a typical disulfide-constrained β-sheet structure and could
induce internalization of enhanced green fluorescent protein (EGFP) tagged
ferroportin in transfected HEK293 cells. In order to study interactions between
hepcidin and its receptor ferroportin, we propose a general approach for
site-specific labeling of synthetic hepcidin analogues by incorporation of an
L-propargylglycine during chemical synthesis. Following efficient oxidative
refolding, a hepcidin analogue with Met20 replaced by L-propargylglycine was
efficiently mono-labeled by a red fluorescent dye through click chemistry. The
labeled hepcidin was internalized into the transfected cells together with the
EGFP-tagged ferroportin, suggesting direct binding between hepcidin and
ferroportin. The labeled hepcidin was also a suitable tool to visualize
internalization of overexpressed or even endogenously expressed ferroportin
without tags. We anticipate that the present refolding and labeling approaches
could also be used for other synthetic peptides.
© 2012 The Authors Journal compilation © 2012 FEBS.
DOI: 10.1111/j.1742-4658.2012.08695.x
PMID: 22776295 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15314524 | 1. Curr Opin Hematol. 2004 Jul;11(4):251-4. doi:
10.1097/00062752-200407000-00004.
Hepcidin in iron metabolism.
Ganz T(1).
Author information:
(1)Departments of Medicine and Pathology, David Geffen School of Medicine
University of California, Los Angeles, California 90095-1690, USA.
tganz@mednet.ucla.edu
PURPOSE OF REVIEW: Hepcidin is a recently discovered hepatic peptide that
regulates intestinal iron absorption as well as maternal-fetal iron transport
across the placenta. It probably also affects the release of iron from hepatic
stores and from macrophages involved in the recycling of iron from hemoglobin.
Connecting iron metabolism to innate immunity, hepcidin is a key mediator of
hypoferremia of inflammation.
RECENT FINDINGS: The essential role of hepcidin in iron metabolism is being
elucidated through mouse and human genetics, biochemistry, and cell biology.
SUMMARY: Studies of hepcidin are leading to fundamental understanding of iron
homeostasis and pointing to potential treatments for hemochromatosis and anemia
of inflammation (anemia of chronic disease).
DOI: 10.1097/00062752-200407000-00004
PMID: 15314524 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17768112 | 1. Haematologica. 2007 Oct;92(10):1407-10. doi: 10.3324/haematol.11377.
Effects of plasma transfusion on hepcidin production in human congenital
hypotransferrinemia.
Trombini P(1), Coliva T, Nemeth E, Mariani R, Ganz T, Biondi A, Piperno A.
Author information:
(1)Department of Clinical Medicine and Centre for Diagnosis and Therapy of
Hemochromatosis, University of Milano-Bicocca, San Gerardo Hospital, Monza,
Milan, Italy.
Hepcidin is the key regulator of systemic iron homeostasis. We describe the
modulation of hepcidin production induced by plasma transfusions in a patient
with congenital hypotransferrinemia that offers a unique model in which to study
the mechanism of hepcidin regulation by iron and erythropoiesis. Urinary
hepcidin increased from zero at baseline, when hemoglobin and serum transferrin
was low, to a maximum of 98 ng/mg creatinine on day 60, and subsequently
decreased. Time-course of urinary hepcidin and serum transferrin concentration
suggests that hepcidin production is regulated by the combination of marrow iron
requirements and iron supply by transferrin.
DOI: 10.3324/haematol.11377
PMID: 17768112 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18936232 | 1. J Nutr. 2008 Nov;138(11):2284-8. doi: 10.3945/jn.108.096347.
Hepcidin regulation of iron transport.
Collins JF(1), Wessling-Resnick M, Knutson MD.
Author information:
(1)Department of Exercise and Nutrition Sciences, University at Buffalo, the
State University of New York, Buffalo, NY 14214, USA.
The discovery of hepcidin as a key regulator of iron homeostasis has advanced
our current knowledge of this field. Liver-derived hepcidin peptide is secreted
in response to iron and inflammation and interacts with the iron export protein
ferroportin. This review summarizes recent advances discussed at the Symposium.
A particular focus is on molecular interactions between hepcidin and
ferroportin, the regulation of hepcidin expression by iron and inflammation, and
emerging methods to measure serum hepcidin in human populations.
DOI: 10.3945/jn.108.096347
PMCID: PMC2764359
PMID: 18936232 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15797999 | 1. Blood. 2005 Jul 15;106(2):746-8. doi: 10.1182/blood-2004-12-4855. Epub 2005
Mar 29.
Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin
levels, and hepatic function.
Détivaud L(1), Nemeth E, Boudjema K, Turlin B, Troadec MB, Leroyer P, Ropert M,
Jacquelinet S, Courselaud B, Ganz T, Brissot P, Loréal O.
Author information:
(1)Institut National de la Sante et de la Recherche Medicale, Rennes, France.
Hepcidin, a key regulator of iron metabolism, is synthesized by the liver.
Hepcidin binds to the iron exporter ferroportin to regulate the release of iron
into plasma from macrophages, hepatocytes, and enterocytes. We analyzed liver
samples from patients undergoing hepatic surgery for cancer or receiving liver
transplants and analyzed correlations between clinical parameters and liver
hepcidin mRNA and urinary hepcidin concentrations. Despite the many potential
confounding influences, urinary hepcidin concentrations significantly correlated
with hepatic hepcidin mRNA concentrations, indicating that hepcidin
quantification in urine is a valid approach to evaluate hepcidin expression.
Moreover, we found in humans that hepcidin levels correlated with hepatic iron
stores and hemoglobin levels and may also be affected by hepatic dysfunction.
DOI: 10.1182/blood-2004-12-4855
PMID: 15797999 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30530987 | 1. J Clin Invest. 2019 Jan 2;129(1):72-74. doi: 10.1172/JCI125509. Epub 2018 Dec
10.
At the crossroads of oxygen and iron sensing: hepcidin control of HIF-2α.
Lee FS.
Comment on
J Clin Invest. 2019 Jan 2;129(1):336-348. doi: 10.1172/JCI122359.
Hepcidin is the master regulator of iron metabolism. It plays a key role in the
regulation of iron transport across the duodenal epithelium, which in turn is
dependent on the oxygen-regulated transcription factor hypoxia-inducible factor
2α (HIF-2α). In this issue of the JCI, Schwartz and colleagues show that
duodenal HIF-2α is itself regulated by hepcidin, thereby indicating that this
transcription factor is not only regulated by oxygen, but also by iron. This
work indicates that the crosstalk between liver hepcidin and intestinal HIF-2α
plays an important role during iron overload, systemic iron deficiency, and
anemia.
DOI: 10.1172/JCI125509
PMCID: PMC6307931
PMID: 30530987 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest: The author has declared
that no conflict of interest exists. |
http://www.ncbi.nlm.nih.gov/pubmed/24356737 | 1. Rev Med Chil. 2013 Jul;141(7):887-94. doi: 10.4067/S0034-98872013000700008.
[Hepcidin as a central mediator of anemia of chronic diseases associated with
obesity].
[Article in Spanish]
Villarroel H P(1), Arredondo O M(1), Olivares G M(1).
Author information:
(1)Laboratorio de Micronutriente, Instituto de Nutrición y Tecnología de los
Alimentos, Universidad de Chile, Santiago, Chile, pia.villarroel@inta.uchile.cl.
Recent evidence suggests that obesity-related inflammation may play a central
role in hepcidin regulation. Hepcidin is a key regulator ofiron homeostasis and
has now been suggested as a central mediator ofiron metabolism disorders
involved in the pathogenesis of anemia of chronic disease. In this review, we
focus on subclinical inflammation in obesity and its effect on hepcidin levels,
as the most plausible explanation for the relationship between anemia of chronic
disease and obesity.
DOI: 10.4067/S0034-98872013000700008
PMID: 24356737 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21136948 | 1. Proteomics Clin Appl. 2009 Nov;3(11):1256-64. doi: 10.1002/prca.200900112.
Heterogeneous expressions of hepcidin isoforms in hepatoma-derived cells
detected using simultaneous LC-MS/MS.
Hosoki T(1), Ikuta K, Shimonaka Y, Sasaki Y, Yasuno H, Sato K, Ohtake T, Sasaki
K, Torimoto Y, Saito K, Kohgo Y.
Author information:
(1)Division of Gastroenterology and Hematology/Oncology, Department of Medicine,
Asahikawa Medical College, Asahikawa, Japan.
Hepcidin, a key regulator of iron homeostasis, is known to have three isoforms:
hepcidin-20, -22, and -25. Hepcidin-25 is thought to be the major isoform and
the only one known to be involved in iron metabolism; the physiological roles of
other isoforms are poorly understood. Because of its involvement in the
pathophysiology of hereditary hemochromatosis and the anemia of chronic disease,
the regulatory mechanisms of hepcidin expression have been extensively
investigated, but most studies have been performed only at the transcriptional
level. Difficulty in detecting hepcidin has impeded in vitro research. In the
present study, we developed a novel method for simultaneous quantification of
hepcidin-20, -22, and -25 in the media from hepatoma-derived cell lines. Using
this method, we determined the expression patterns of hepcidin isoforms and the
patterns of responses to various stimuli in human hepatoma-derived cultured
cells. We found substantial differences among cell lines. In conclusion, a novel
method for simultaneous quantification of hepcidin isoforms is presented.
Heterogeneous expressions of hepcidin isoforms in human hepatoma-derived cells
were revealed by this method. We believe our method will facilitate quantitative
investigation of the role hepcidin plays in iron homeostasis.
Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/prca.200900112
PMID: 21136948 |
http://www.ncbi.nlm.nih.gov/pubmed/25852110 | 1. Neth J Med. 2015 Mar;73(3):108-18.
Hepcidin in chronic kidney disease: not an anaemia management tool, but
promising as a cardiovascular biomarker.
van der Weerd NC(1), Grooteman MP, Nubé MJ, ter Wee PM, Swinkels DW, Gaillard
CA.
Author information:
(1)Department of Internal Medicine, Division of Nephrology, Academic Medical
Center, University of Amsterdam, Amsterdam, The Netherlands.
Hepcidin is a key regulator of iron homeostasis and plays a role in the
pathogenesis of anaemia of chronic disease. Its levels are increased in patients
with chronic kidney disease (CKD) due to diminished renal clearance and an
inflammatory state. Increased hepcidin levels in CKD patients are supposed to be
responsible for functional iron deficiency in these patients and contribute to
renal anaemia and resistance to erythropoiesis-stimulating agents. Therefore,
hepcidin was purported to be useful as a management tool guiding treatment of
renal anaemia. Furthermore, since hepcidin is associated with iron accumulation
in macrophages in the vessel wall inducing oxidative stress and atherosclerosis,
it has been speculated that hepcidin might function as a biomarker of
cardiovascular disease. In this descriptive review, the merits of hepcidin with
respect to its role in the pathophysiology of renal anaemia in CKD patients, its
presumptive role as a practical diagnostic tool guiding management of renal
anaemia, and its possible usefulness as a prognostic biomarker will be
discussed.
PMID: 25852110 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19681654 | 1. Physiol Res. 2010;59(3):393-400. doi: 10.33549/physiolres.931759. Epub 2009
Aug 12.
Hepcidin expression in adipose tissue increases during cardiac surgery.
Vokurka M(1), Lacinová Z, Kremen J, Kopecký P, Bláha J, Pelinková K, Haluzík M,
Necas E.
Author information:
(1)Institute of Pathological Physiology, Center of Experimental Hematology,
First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
martin.vokurka@lf1.cuni.cz
Hepcidin, a key regulator of iron metabolism, plays a crucial role in the
pathogenesis of anemia of chronic disease. Although it is produced mainly in the
liver, its recently described expression in adipose tissue has been shown to be
enhanced in massive obesity due to chronic low-grade inflammation. Our objective
was to study the changes in hepcidin expression in adipose tissue during
acute-phase reaction. We measured hepcidin mRNA expression from isolated
subcutaneous and epicardial adipose tissue at the beginning and at the end of
the surgery. The expression of mRNAs for hepcidin and other iron-related genes
(transferrin receptor 1, divalent metal transporter 1, ferritin, ferroportin)
were measured by real-time RT-PCR. Hepcidin expression significantly increased
at the end of the surgery in subcutaneous but not in epicardial adipose tissue.
Apart from the increased levels of cytokines, the parameters of iron metabolism
showed typical inflammation-induced changes. We suggest that acute inflammatory
changes could affect the regulation of hepcidin expression in subcutaneous
adipose tissue and thus possibly contribute to inflammation-induced systemic
changes of iron metabolism.
DOI: 10.33549/physiolres.931759
PMID: 19681654 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16198622 | 1. Hepatol Res. 2005 Nov;33(3):198-205. doi: 10.1016/j.hepres.2005.08.005. Epub
2005 Sep 29.
Upregulation of hepcidin by interleukin-1beta in human hepatoma cell lines.
Inamura J(1), Ikuta K, Jimbo J, Shindo M, Sato K, Torimoto Y, Kohgo Y.
Author information:
(1)Third Department of Internal Medicine, Asahikawa Medical College, 2-1-1-1
Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan.
Anemia of chronic disease (ACD) is commonly observed in chronic inflammation,
although its pathogenesis is poorly understood. Hepcidin is thought to be a key
regulator in iron metabolism and has been implicated in ACD. Although the
induction of hepcidin by an inflammatory cytokine interleukin-6 (IL-6) seems to
have been confirmed, it is still controversial whether interleukin-1beta
(IL-1beta), also known as an inflammatory cytokine, regulates hepcidin
expression. We demonstrated that hepcidin mRNA was upregulated by IL-1beta in
human hepatoma-derived HuH-7 cells, particularly at low concentrations of
IL-1beta, while high concentrations of IL-6 were needed for the upregulation of
hepcidin mRNA. Therefore, IL-1beta might be more important for the upregulation
of hepcidin in physiological conditions than IL-6. Although IL-1beta induces
IL-6 production in hepatocytes, our data indicate that the effect of IL-1beta on
hepcidin expression is independent from that of IL-6. In conclusion, IL-1beta
might have an important role in ACD.
DOI: 10.1016/j.hepres.2005.08.005
PMID: 16198622 |
http://www.ncbi.nlm.nih.gov/pubmed/15886319 | 1. Blood. 2005 Sep 1;106(5):1864-6. doi: 10.1182/blood-2005-03-1159. Epub 2005
May 10.
Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in
humans injected with LPS.
Kemna E(1), Pickkers P, Nemeth E, van der Hoeven H, Swinkels D.
Author information:
(1)Department of Clinical Chemistry 564, Radboud University Nijmegen Medical
Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. e.kemna@akc.umcn.nl
Hepatic peptide hormone hepcidin is the key regulator of iron metabolism and the
mediator of anemia of inflammation. Previous studies indicated that
interleukin-6 (IL-6) mediates hepcidin increase and consequent hypoferremia
during inflammation. Here we used an in vivo human endotoxemia model to analyze
the effects of lipopolysaccharide (LPS) as a more upstream inflammation
activator. The temporal associations between plasma cytokines, hepcidin levels,
and serum iron parameters were studied in 10 healthy individuals after LPS
injection. IL-6 was dramatically induced within 3 hours after injection, and
urinary hepcidin peaked within 6 hours, followed by a significant decrease in
serum iron. Serum prohepcidin showed no significant change within a 22-hour time
frame. These in vivo human results confirm the importance of the IL-6-hepcidin
axis in the development of hypoferremia in inflammation and highlight the rapid
responsiveness of this iron regulatory system.
DOI: 10.1182/blood-2005-03-1159
PMID: 15886319 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23807042 | 1. Wien Klin Wochenschr. 2013 Aug;125(15-16):448-52. doi:
10.1007/s00508-013-0388-1. Epub 2013 Jun 27.
Relationship between hepcidin and ferritin in haemodialysed patients.
Sedlackova T(1), Racek J, Rajdl D, Kielberger L, Eiselt J, Malanova L, Babuska
V.
Author information:
(1)Institute of Clinical Biochemistry and Haematology, Charles University
Hospital in Pilsen, Czech Republic.
BACKGROUND: Hepcidin is a key regulator of iron metabolism. It binds to
ferroportin and causes the trapping of iron in cells, rendering it unavailable
for erythropoiesis. The synthesis of hepcidin is upregulated by high iron stores
and inflammation. Haemodialysed patients suffer from anaemia and impaired iron
management, the cause of which is multifactorial. Our aim was to describe the
relationship between hepcidin and other parameters of iron metabolism,
erythropoiesis, and inflammation.
PATIENTS, MATERIALS AND METHODS: Complete blood cell counts, hepcidin,
parameters of iron metabolism, and inflammation were measured in samples from
164 dialysed patients and 37 control healthy volunteers. Patients were
subdivided according to the time of dialysis session.
RESULTS: According to the time of haemodialysis, iron levels showed an
insignificant tendency for diurnal variability, whereas hepcidin levels were
markedly different. Non-parametric correlations showed a weak, but statistically
significant correlation between parameters of iron metabolism and inflammation
in the entire group of patients. No correlation was found between hepcidin and
other biochemical parameters in controls. Non-parametric correlations were also
performed in the time subgroups of patients.
CONCLUSION: It seems that the influence of inflammation on hepcidin levels in
haemodialysed patients is not crucial and other factors (e.g. hepcidin
retention) are involved.
DOI: 10.1007/s00508-013-0388-1
PMID: 23807042 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25782630 | 1. Exp Hematol. 2015 Jun;43(6):469-78.e6. doi: 10.1016/j.exphem.2015.03.001. Epub
2015 Mar 14.
Evidence that the expression of transferrin receptor 1 on erythroid marrow cells
mediates hepcidin suppression in the liver.
Keel SB(1), Doty R(1), Liu L(2), Nemeth E(3), Cherian S(4), Ganz T(3), Abkowitz
JL(5).
Author information:
(1)Division of Hematology, Department of Medicine, University of Washington,
Seattle, Washington, USA.
(2)Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
(3)Departments of Medicine and Pathology, David Geffen School of Medicine,
University of California, Los Angeles, California, USA.
(4)Department of Pathology, University of Washington, Seattle, Washington, USA.
(5)Division of Hematology, Department of Medicine, University of Washington,
Seattle, Washington, USA. Electronic address: janabk@u.washington.edu.
Hepcidin is the key regulator of iron absorption and recycling, and its
expression is suppressed by red blood cell production. When erythropoiesis is
expanded, hepcidin expression decreases. To gain insight into the stage of
erythroid differentiation at which the regulation might originate, we measured
serum hepcidin levels in archived pure red cell aplasia samples from patients
whose block in erythroid differentiation was well defined by hematopoietic
colony assays and marrow morphologic review. Hepcidin values are high or high
normal in pure red cell aplasia patients in whom erythropoiesis is inhibited
prior to the proerythroblast stage, but are suppressed in patients with excess
proerythroblasts and few later erythroid cells. These data suggest that the
suppressive effect of erythropoietic activity on hepcidin expression can arise
from proerythroblasts, the stage at which transferrin receptor 1 expression
peaks, prompting the hypothesis that transferrin receptor 1 expression on
erythroid precursors is a proximal mediator of the erythroid regulator of
hepcidin expression. Our characterization of erythropoiesis, iron status, and
hepcidin expression in mice with global or hematopoietic cell-specific
haploinsufficiency of transferrin receptor 1 provides initial supporting data
for this model. The regulation appears independent of erythroferrone and growth
differentiation factor 15, supporting the concept that several mechanisms signal
iron need in response to an expanded erythron.
Copyright © 2015 ISEH - International Society for Experimental Hematology.
Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.exphem.2015.03.001
PMCID: PMC4771411
PMID: 25782630 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23531037 | 1. BMC Nephrol. 2013 Mar 25;14:70. doi: 10.1186/1471-2369-14-70.
Tubular reabsorption and local production of urine hepcidin-25.
Peters HP(1), Laarakkers CM, Pickkers P, Masereeuw R, Boerman OC, Eek A,
Cornelissen EA, Swinkels DW, Wetzels JF.
Author information:
(1)Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
h.peters@nier.umcn.nl
BACKGROUND: Hepcidin is a central regulator of iron metabolism. Serum hepcidin
levels are increased in patients with renal insufficiency, which may contribute
to anemia. Urine hepcidin was found to be increased in some patients after
cardiac surgery, and these patients were less likely to develop acute kidney
injury. It has been suggested that urine hepcidin may protect by attenuating
heme-mediated injury, but processes involved in urine hepcidin excretion are
unknown.
METHODS: To assess the role of tubular reabsorption we compared fractional
excretion (FE) of hepcidin-25 with FE of β2-microglobulin (β(2)m) in 30 patients
with various degrees of tubular impairment due to chronic renal disease. To
prove that hepcidin is reabsorbed by the tubules in a megalin-dependent manner,
we measured urine hepcidin-1 in wild-type and kidney specific megalin-deficient
mice. Lastly, we evaluated FE of hepcidin-25 and β(2)m in 19 patients who
underwent cardiopulmonary bypass surgery. Hepcidin was measured by a mass
spectrometry assay (MS), whereas β(2)m was measured by ELISA.
RESULTS: In patients with chronic renal disease, FE of hepcidin-25 was strongly
correlated with FE of β(2)m (r = 0.93, P <0.01). In megalin-deficient mice,
urine hepcidin-1 was 7-fold increased compared to wild-type mice (p < 0.01)
indicating that proximal tubular reabsorption occurs in a megalin- dependent
manner. Following cardiac surgery, FE of hepcidin-25 increased despite a decline
in FE of β(2)m, potentially indicating local production at 12-24 hours.
CONCLUSIONS: Hepcidin-25 is reabsorbed by the renal tubules and increased urine
hepcidin-25 levels may reflect a reduction in tubular uptake. Uncoupling of FE
of hepcidin-25 and β(2)m in cardiac surgery patients suggests local production.
DOI: 10.1186/1471-2369-14-70
PMCID: PMC3623618
PMID: 23531037 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16497104 | 1. Physiol Res. 2006;55(6):667-674. doi: 10.33549/physiolres.930841.
Hepcidin mRNA levels in mouse liver respond to inhibition of erythropoiesis.
Vokurka M(1), Krijt J, Sulc K, Necas E.
Author information:
(1)Institute of Pathophysiology, First Faculty of Medicine, Charles University,
Prague, Czech Republic. mvoku@LF1.cuni.cz
Hepcidin, a key regulator of iron metabolism, decreases intestinal absorption of
iron and its release from macrophages. Iron, anemia, hypoxia, and inflammation
were reported to influence hepcidin expression. To investigate regulation of the
expression of hepcidin and other iron-related genes, we manipulated
erythropoietic activity in mice. Erythropoiesis was inhibited by irradiation or
posttransfusion polycythemia and stimulated by phenylhydrazine administration
and erythropoietin. Gene expression of hepcidin and other iron-related genes
(hemojuvelin, DMT1, ferroportin, transferrin receptors, ferritin) in the liver
was measured by the real-time polymerase chain reaction. Hepcidin expression
increased despite severe anemia when hematopoiesis was inhibited by irradiation.
Suppression of erythropoiesis by posttransfusion polycythemia or irradiation
also increased hepcidin mRNA levels. Compensated hemolysis induced by repeated
phenylhydrazine administration did not change hepcidin expression. The decrease
caused by exogenous erythropoeitin was blocked by postirradiation bone marrow
suppression. The hemolysis and anemia decrease hepcidin expression only when
erythropoiesis is functional; on the other hand, if erythropoiesis is blocked,
even severe anemia does not lead to a decrease of hepcidin expression, which is
indeed increased. We propose that hepcidin is exclusively sensitive to iron
utilization for erythropoiesis and hepatocyte iron balance, and these changes
are not sensed by other genes involved in the control of iron metabolism in the
liver.
DOI: 10.33549/physiolres.930841
PMID: 16497104 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28514781 | 1. Acta Haematol. 2017;137(4):220-236. doi: 10.1159/000471838. Epub 2017 May 18.
Hepcidin: Homeostasis and Diseases Related to Iron Metabolism.
Reichert CO(1), da Cunha J, Levy D, Maselli LMF, Bydlowski SP, Spada C.
Author information:
(1)Clinical Analysis Department, Health Sciences Center, Federal University of
Santa Catarina (UFSC), Florianópolis, Brazil.
Iron is an essential metal for cell survival that is regulated by the peptide
hormone hepcidin. However, its influence on certain diseases is directly related
to iron metabolism or secondary to underlying diseases. Genetic alterations
influence the serum hepcidin concentration, which can lead to an iron overload
in tissues, as observed in haemochromatosis, in which serum hepcidin or
defective hepcidin synthesis is observed. Another genetic imbalance of iron is
iron-refractory anaemia, in which serum concentrations of hepcidin are
increased, precluding the flow and efflux of extra- and intracellular iron.
During the pathogenesis of certain diseases, the resulting oxidative stress, as
well as the increase in inflammatory cytokines, influences the transcription of
the HAMP gene to generate a secondary anaemia due to the increase in the serum
concentration of hepcidin. To date, there is no available drug to inhibit or
enhance hepcidin transcription, mostly due to the cytotoxicity described in the
in vitro models. The proposed therapeutic targets are still in the early stages
of clinical trials. Some candidates are promising, such as heparin derivatives
and minihepcidins. This review describes the main pathways of systemic and
genetic regulation of hepcidin, as well as its influence on the disorders
related to iron metabolism.
© 2017 S. Karger AG, Basel.
DOI: 10.1159/000471838
PMID: 28514781 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31280251 | 1. Dev Period Med. 2019;23(2):137-141. doi:
10.34763/devperiodmed.20192302.137141.
The role of hepcidin in regulating iron homeostasis in selected diseases.
Radosz A(1), Obuchowicz A(1).
Author information:
(1)Chair and Department of Pediatrics in Bytom, The School of Health Sciences,
Medical University of Silesia, Katowice, Poland.
Iron is an element whose content in the human organism remains under strict
control not only due to its involvement in many life processes but also because
of its potential toxicity. The latest studies in iron metabolism, especially the
involvement of hepcidin, which is the main regulator of iron homeostasis,
broadened our knowledge in many medical fields (immunology, nephrology,
hematology, gastrology). The present paper is a review of the literature devoted
to the importance of hepcidin under selected conditions.
Żelazo jest pierwiastkiem, którego zawartość w organizmie podlega ścisłej
regulacji ze względu na jego niezbędny udział w licznych procesach życiowych,
ale również ze względu na potencjalny efekt toksyczny nadmiaru żelaza.
Współczesne dane na temat gospodarki żelazem, a zwłaszcza udziału w niej
głównego regulatora, jakim jest hepcydyna, wzbogaciły wiedzę w wielu dziedzinach
medycyny (immunologia, nefrologia, hematologia, gastrologia). Praca stanowi
przegląd piśmiennictwa dotyczącego znaczenia hepcydyny w wybranych stanach
chorobowych.
DOI: 10.34763/devperiodmed.20192302.137141
PMCID: PMC8522373
PMID: 31280251 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of interest Conflicts of
interest/Konflikt interesu The Authors declare no conflict of interest. Autorzy
pracy nie zgłaszają konfliktu interesów. |
http://www.ncbi.nlm.nih.gov/pubmed/35236842 | 1. NPJ Vaccines. 2022 Mar 2;7(1):31. doi: 10.1038/s41541-022-00453-5.
Use of analgesics/antipyretics in the management of symptoms associated with
COVID-19 vaccination.
Ooi EE(1)(2)(3), Dhar A(4), Petruschke R(5), Locht C(6), Buchy P(4), Low
JGH(7)(8).
Author information:
(1)Program in Emerging Infectious Diseases, Duke-National University of
Singapore Medical School, Singapore, Singapore. engeong.ooi@duke-nus.edu.sg.
(2)Yong Loo Lin School of Medicine, National University of Singapore, Singapore,
Singapore. engeong.ooi@duke-nus.edu.sg.
(3)Saw Swee Hock School of Public Health, National University of Singapore,
Singapore, Singapore. engeong.ooi@duke-nus.edu.sg.
(4)Medical Affairs, GlaxoSmithKline, Singapore, Singapore.
(5)Medical Affairs, GlaxoSmithKline, Warren, NJ, USA.
(6)Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR
8204 - CIIL - Center for Infection and Immunity of Lille, Lille, France.
(7)Program in Emerging Infectious Diseases, Duke-National University of
Singapore Medical School, Singapore, Singapore.
(8)Department of Infectious Diseases, Singapore General Hospital, Singapore,
Singapore.
COVID-19 vaccines are effective and important to control the ongoing pandemic,
but vaccine reactogenicity may contribute to poor uptake. Analgesics or
antipyretic medications are often used to alleviate vaccine side effects, but
their effect on immunogenicity remains uncertain. Few studies have assessed the
effect of analgesics/antipyretics on vaccine immunogenicity and reactogenicity.
Some studies revealed changes in certain immune response parameters
post-vaccination when analgesics/antipyretics were used either prophylactically
or therapeutically. Still, there is no evidence that these changes impact
vaccine efficacy. Specific data on the impact of analgesic/antipyretic
medications on immunogenicity of COVID-19 vaccines are limited. However,
available data from clinical trials of licensed vaccines, along with
recommendations from public health bodies around the world, should provide
reassurance to both healthcare professionals and vaccine recipients that
short-term use of analgesics/antipyretics at non-prescription doses is unlikely
to affect vaccine-induced immunity.
© 2022. The Author(s).
DOI: 10.1038/s41541-022-00453-5
PMCID: PMC8891349
PMID: 35236842
Conflict of interest statement: Eng Eong Ooi and Camille Locht have no potential
competing interests to declare. Arti Dhar, Richard Petruschke, and Philippe
Buchy are employees of GlaxoSmithKline. Jenny Guek Hong Low receives salary
support from the National Medical Research Council of Singapore. |
http://www.ncbi.nlm.nih.gov/pubmed/19249912 | 1. Physiol Res. 2010;59(1):53-59. doi: 10.33549/physiolres.931706. Epub 2009 Feb
27.
Hepcidin downregulation by repeated bleeding is not mediated by soluble
hemojuvelin.
Krijt J(1), Fujikura Y, Sefc L, Vokurka M, Hlobenová T, Necas E.
Author information:
(1)Institute of Pathophysiology and Center of Experimental Hematology, Charles
University in Prague, First Faculty of Medicine, Prague, Czech Republic.
jkri@lf1.cuni.cz
Hepcidin is a key regulator of iron homeostasis, while hemojuvelin is an
important component of the hepcidin regulation pathway. It has been recently
proposed that soluble hemojuvelin, produced from hemojuvelin by the protease
furin, decreases hepcidin expression. The aim of the presented study was to
examine the downregulation of hepcidin by chronic bleeding in hemojuvelin-mutant
mice. Male mice with targeted disruption of the hemojuvelin gene (Hjv-/- mice)
and wild-type littermates were maintained on an iron-deficient diet and
subjected to weekly phlebotomies for 7 weeks. Gene expression was examined by
real-time PCR. In wild type mice, repeated bleeding decreased hepcidin mRNA by
two orders of magnitude. In Hjv-/- mice, basal hepcidin expression was low;
however, repeated bleeding also decreased hepcidin mRNA content by an order of
magnitude. Phlebotomies reduced hepatic iron overload in Hjv-/- mice by 80 %.
Liver and muscle furin mRNA content was not significantly changed. No effect on
hepatic Tmprss6 mRNA content was observed. Results from the study indicate that
soluble hemojuvelin is not the sole factor responsible for hepcidin
downregulation. In addition, the presented data suggest that, under in vivo
conditions, tissue hypoxia does not transcriptionally regulate the activity of
furin or TMPRSS6 proteases.
DOI: 10.33549/physiolres.931706
PMID: 19249912 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19837254 | 1. Lancet. 2009 Oct 17;374(9698):1339-50. doi: 10.1016/S0140-6736(09)61208-3.
Effect of prophylactic paracetamol administration at time of vaccination on
febrile reactions and antibody responses in children: two open-label, randomised
controlled trials.
Prymula R(1), Siegrist CA, Chlibek R, Zemlickova H, Vackova M, Smetana J, Lommel
P, Kaliskova E, Borys D, Schuerman L.
Author information:
(1)Faculty of Military Health Sciences, University of Defence, Hradec Kralove,
Czech Republic. prymula@pmfhk.cz
Comment in
Lancet. 2009 Oct 17;374(9698):1305-6. doi: 10.1016/S0140-6736(09)61802-X.
J Pediatr. 2010 May;156(5):857-8. doi: 10.1016/j.jpeds.2010.02.054.
Evid Based Med. 2010 Apr;15(2):50-1. doi: 10.1136/ebm1049.
Evid Based Nurs. 2010 Jul;13(3):76-7. doi: 10.1136/ebn1057.
BACKGROUND: Although fever is part of the normal inflammatory process after
immunisation, prophylactic antipyretic drugs are sometimes recommended to allay
concerns of high fever and febrile convulsion. We assessed the effect of
prophylactic administration of paracetamol at vaccination on infant febrile
reaction rates and vaccine responses.
METHODS: In two consecutive (primary and booster) randomised, controlled,
open-label vaccination studies, 459 healthy infants were enrolled from ten
centres in the Czech Republic. Infants were randomly assigned with a
computer-generated randomisation list to receive three prophylactic paracetamol
doses every 6-8 h in the first 24 h (n=226) or no prophylactic paracetamol
(n=233) after each vaccination with a ten-valent pneumococcal non-typeable
Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) co-administered
with the hexavalent diphtheria-tetanus-3-component acellular pertussis-hepatitis
B-inactivated poliovirus types 1, 2, and 3-H influenzae type b
(DTPa-HBV-IPV/Hib) and oral human rotavirus vaccines. The primary objective in
both studies was the reduction in febrile reactions of 38.0 degrees C or greater
in the total vaccinated cohort. The second objective was assessment of
immunogenicity in the according-to-protocol cohort. These studies are registered
with ClinicalTrials.gov, numbers NCT00370318 and NCT00496015.
FINDINGS: Fever greater than 39.5 degrees C was uncommon in both groups (after
primary: one of 226 participants [<1%] in prophylactic paracetamol group vs
three of 233 [1%] in no prophylactic paracetamol group; after booster: three of
178 [2%] vs two of 172 [1%]). The percentage of children with temperature of 38
degrees C or greater after at least one dose was significantly lower in the
prophylactic paracetamol group (94/226 [42%] after primary vaccination and
64/178 [36%] after booster vaccination) than in the no prophylactic paracetamol
group (154/233 [66%] after primary vaccination and 100/172 [58%] after booster
vaccination). Antibody geometric mean concentrations (GMCs) were significantly
lower in the prophylactic paracetamol group than in the no prophylactic
paracetamol group after primary vaccination for all ten pneumococcal vaccine
serotypes, protein D, antipolyribosyl-ribitol phosphate, antidiphtheria,
antitetanus, and antipertactin. After boosting, lower antibody GMCs persisted in
the prophylactic paracetamol group for antitetanus, protein D, and all
pneumococcal serotypes apart from 19F.
INTERPRETATION: Although febrile reactions significantly decreased, prophylactic
administration of antipyretic drugs at the time of vaccination should not be
routinely recommended since antibody responses to several vaccine antigens were
reduced.
FUNDING: GlaxoSmithKline Biologicals (Belgium).
DOI: 10.1016/S0140-6736(09)61208-3
PMID: 19837254 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24897504 | 1. PLoS One. 2014 Jun 4;9(6):e98175. doi: 10.1371/journal.pone.0098175.
eCollection 2014.
Effects of prophylactic and therapeutic paracetamol treatment during vaccination
on hepatitis B antibody levels in adults: two open-label, randomized controlled
trials.
Doedée AM(1), Boland GJ(2), Pennings JL(3), de Klerk A(3), Berbers GA(4), van
der Klis FR(4), de Melker HE(4), van Loveren H(1), Janssen R(3).
Author information:
(1)Centre for Health Protection, National Institute for Public Health and the
Environment, Bilthoven, The Netherlands; Department of Toxicogenomics,
Maastricht University Medical Centre, Maastricht, The Netherlands.
(2)Medical Microbiology and Virology, University Medical Centre Utrecht,
Utrecht, The Netherlands.
(3)Centre for Health Protection, National Institute for Public Health and the
Environment, Bilthoven, The Netherlands.
(4)Centre for Immunology of Infectious Diseases and Vaccines, National Institute
for Public Health and the Environment, Bilthoven, The Netherlands.
Worldwide, paracetamol is administered as a remedy for complaints that occur
after vaccination. Recently published results indicate that paracetamol inhibits
the vaccination response in infants when given prior to vaccination. The goal of
this study was to establish whether paracetamol exerts similar effects in young
adults. In addition, the effect of timing of paracetamol intake was
investigated. In two randomized, controlled, open-label studies 496 healthy
young adults were randomly assigned to three groups. The study groups received
paracetamol for 24 hours starting at the time of (prophylactic use) - or 6 hours
after (therapeutic use) the primary (0 month) and first booster (1 month)
hepatitis B vaccination. The control group received no paracetamol. None of the
participants used paracetamol around the second booster (6 months) vaccination.
Anti-HBs levels were measured prior to and one month after the second booster
vaccination on ADVIA Centaur XP. One month after the second booster vaccination,
the anti-HBs level in the prophylactic paracetamol group was significantly lower
(p = 0.048) than the level in the control group (4257 mIU/mL vs. 5768 mIU/mL).
The anti-HBs level in the therapeutic paracetamol group (4958 mIU/mL) was not
different (p = 0.34) from the level in the control group. Only prophylactic
paracetamol treatment, and not therapeutic treatment, during vaccination has a
negative influence on the antibody concentration after hepatitis B vaccination
in adults. These findings prompt to consider therapeutic instead of prophylactic
treatment to ensure maximal vaccination efficacy and retain the possibility to
treat pain and fever after vaccination.
TRIAL REGISTRATION: Controlled-Trials.com ISRCTN03576945.
DOI: 10.1371/journal.pone.0098175
PMCID: PMC4045752
PMID: 24897504 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |