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Proceedings of the National Academy of... Feb 2022Viral causes of pneumonia pose constant threats to global public health, but there are no specific treatments currently available for the condition. Antivirals are...
Viral causes of pneumonia pose constant threats to global public health, but there are no specific treatments currently available for the condition. Antivirals are ineffective when administered late after the onset of symptoms. Pneumonia is caused by an exaggerated inflammatory cytokine response to infection, but tissue necrosis and damage caused by virus also contribute to lung pathology. We hypothesized that viral pneumonia can be treated effectively if both virus and inflammation are simultaneously targeted. Combined treatment with the antiviral drug cidofovir and etanercept, which targets tumor necrosis factor (TNF), down-regulated nuclear factor kappa B-signaling and effectively reduced morbidity and mortality during respiratory ectromelia virus (ECTV) infection in mice even when treatment was initiated after onset of clinical signs. Treatment with cidofovir alone reduced viral load, but animals died from severe lung pathology. Treatment with etanercept had no effect on viral load but diminished levels of inflammatory cytokines and chemokines including TNF, IL-6, IL-1β, IL-12p40, TGF-β, and CCL5 and dampened activation of the STAT3 cytokine-signaling pathway, which transduces signals from multiple cytokines implicated in lung pathology. Consequently, combined treatment with a STAT3 inhibitor and cidofovir was effective in improving clinical disease and lung pathology in ECTV-infected mice. Thus, the simultaneous targeting of virus and a specific inflammatory cytokine or cytokine-signaling pathway is effective in the treatment of pneumonia. This approach might be applicable to pneumonia caused by emerging and re-emerging viruses, like seasonal and pandemic influenza A virus strains and severe acute respiratory syndrome coronavirus 2.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Cell Line; Chlorocebus aethiops; Cidofovir; Cytokines; Drug Evaluation, Preclinical; Drug Therapy, Combination; Ectromelia virus; Etanercept; Female; Lung; Mice, Inbred C57BL; NF-kappa B; Pneumonia, Viral; STAT3 Transcription Factor; Signal Transduction; Tumor Necrosis Factor-alpha; Viral Load; Mice
PubMed: 35177474
DOI: 10.1073/pnas.2112725119 -
Annals of the New York Academy of... Dec 2017Postaxial limb hypoplasia (PALH) is a group of nonhereditary diseases with congenital lower limb deficiency affecting the fibular ray, including fibular hemimelia,... (Review)
Review
Postaxial limb hypoplasia (PALH) is a group of nonhereditary diseases with congenital lower limb deficiency affecting the fibular ray, including fibular hemimelia, proximal femoral focal deficiency, and tarsal coalition. The etiology and the developmental biology of the anomaly are still not fully understood. Here, we review the previous classification systems, present the clinical features, and discuss the developmental biology of PALH.
Topics: Ectromelia; Fibula; Genetic Predisposition to Disease; Humans; Limb Deformities, Congenital; Musculoskeletal Development; Mutation; Signal Transduction
PubMed: 28990185
DOI: 10.1111/nyas.13440 -
Human Heredity 2012There is increasing evidence that rare variants play a role in some complex traits, but their analysis is not straightforward. Locus-based tests become necessary due to...
OBJECTIVES
There is increasing evidence that rare variants play a role in some complex traits, but their analysis is not straightforward. Locus-based tests become necessary due to low power in rare variant single-point association analyses. In addition, variant quality scores are available for sequencing data, but are rarely taken into account. Here, we propose two locus-based methods that incorporate variant quality scores: a regression-based collapsing approach and an allele-matching method.
METHODS
Using simulated sequencing data we compare 4 locus-based tests of trait association under different scenarios of data quality. We test two collapsing-based approaches and two allele-matching-based approaches, taking into account variant quality scores and ignoring variant quality scores. We implement the collapsing and allele-matching approaches accounting for variant quality in the freely available ARIEL and AMELIA software.
RESULTS
The incorporation of variant quality scores in locus-based association tests has power advantages over weighting each variant equally. The allele-matching methods are robust to the presence of both protective and risk variants in a locus, while collapsing methods exhibit a dramatic loss of power in this scenario.
CONCLUSIONS
The incorporation of variant quality scores should be a standard protocol when performing locus-based association analysis on sequencing data. The ARIEL and AMELIA software implement collapsing and allele-matching locus association analysis methods, respectively, that allow the incorporation of variant quality scores.
Topics: Alleles; Computer Simulation; Genetic Association Studies; Genetic Variation; Genotype; Humans; Logistic Models; Software
PubMed: 22441326
DOI: 10.1159/000336982 -
Medicine Dec 2018Sirenomelia is a very rare congenital malformation and characterized by fused lower extremities, oligohydramnios, renal agenesis, absent urinary tract and external... (Review)
Review
RATIONALE
Sirenomelia is a very rare congenital malformation and characterized by fused lower extremities, oligohydramnios, renal agenesis, absent urinary tract and external genitalia, single umbilical artery, and imperforate anus. Ultrasonography is an optimal method for prenatal screening and diagnosis of sirenomelia. The incidence of sirenomelia in the twin pregnancy is extremely low.
PATIENT CONCERNS
We reported a case of 1 twin with sirenomelia in dichorionic-diamniotic twin pregnancy after in vitro fertilization and embryo transfer.
DIAGNOSES
The sirenomelia twin was diagnosed at the 2nd trimester by ultrasonic examination and complicated with oligohydramnios and a single umbilical artery, another twin was normal.
INTERVENTIONS
A regular and careful antenatal care was conducted. The parents refused to examine the chromosome of sirenomelia twin, and the chromosomal microarray analysis of the amniotic fluid sample was only achieved in the normal anatomy twin after extensively counseled by the multi-disciplinary team.
OUTCOMES
At 34+2 gestational weeks, the demise of the malformed twin occurred, while fetal heart rate monitoring of the normal twin was abnormal, and an emergency cesarean section was performed. A healthy male baby was delivered with Apgar scores of 10 and 10 at 1 and 5 minutes, respectively. The mother and the baby were followed up and are in good health until now.
CONCLUSION
Sirenomelia is a lethal condition in the perinatal period. Early antenatal diagnosis is very important. Voluntary selective termination of sirenomelia 1 in twin pregnancy may be advised. Expecting parents should be counseled by the multidisciplinary team about the management and prognosis of the sirenomelia.
Topics: Abortion, Spontaneous; Adult; Diseases in Twins; Ectromelia; Embryo Transfer; Fatal Outcome; Female; Fertilization in Vitro; Humans; Infant, Newborn; Male; Oligohydramnios; Pregnancy; Pregnancy, Twin; Ultrasonography, Prenatal
PubMed: 30572488
DOI: 10.1097/MD.0000000000013672 -
Viruses Aug 2017Taterapox virus (TATV), which was isolated from an African gerbil () in 1975, is the most closely related virus to variola; however, only the original report has...
Taterapox virus (TATV), which was isolated from an African gerbil () in 1975, is the most closely related virus to variola; however, only the original report has examined its virology. We have evaluated the tropism of TATV in vivo in small animals. We found that TATV does not infect , a species of African dormouse, but does induce seroconversion in the Mongolian gerbil () and in mice; however, in wild-type mice and gerbils, the virus produces an unapparent infection. Following intranasal and footpad inoculations with 1 × 10⁶ plaque forming units (PFU) of TATV, immunocompromised mice showed signs of disease but did not die; however, SCID mice were susceptible to intranasal and footpad infections with 100% mortality observed by Day 35 and Day 54, respectively. We show that death is unlikely to be a result of the virus mutating to have increased virulence and that SCID mice are capable of transmitting TATV to C57BL/6 and C57BL/6 animals; however, transmission did not occur from TATV inoculated wild-type or mice. Comparisons with ectromelia (the etiological agent of mousepox) suggest that TATV behaves differently both at the site of inoculation and in the immune response that it triggers.
Topics: Animals; Antiviral Agents; Disease Models, Animal; Ectromelia virus; Ectromelia, Infectious; Host Specificity; Mice; Mice, Inbred C57BL; Mice, SCID; Orthopoxvirus; Poxviridae Infections; STAT1 Transcription Factor; Viral Tropism
PubMed: 28763036
DOI: 10.3390/v9080203 -
Cell Reports Nov 2022Inflammatory monocytes (iMOs) and B cells are the main targets of the poxvirus ectromelia virus (ECTV) in the lymph nodes of mice and play distinct roles in surviving...
Inflammatory monocytes (iMOs) and B cells are the main targets of the poxvirus ectromelia virus (ECTV) in the lymph nodes of mice and play distinct roles in surviving the infection. Infected and bystander iMOs control ECTV's systemic spread, preventing early death, while B cells make antibodies that eliminate ECTV. Our work demonstrates that within an infected animal that survives ECTV infection, intrinsic and bystander infection of iMOs and B cells differentially control the transcription of genes important for immune cell function and, perhaps, cell identity. Bystander cells upregulate metabolism, antigen presentation, and interferon-stimulated genes. Infected cells downregulate many cell-type-specific genes and upregulate transcripts typical of non-immune cells. Bystander (Bys) and infected (Inf) iMOs non-redundantly contribute to the cytokine milieu and the interferon response. Furthermore, we uncover how type I interferon (IFN-I) or IFN-γ signaling differentially regulates immune pathways in Inf and Bys iMOs and that, at steady state, IFN-I primes iMOs for rapid IFN-I production and antigen presentation.
Topics: Animals; Mice; Monocytes; Poxviridae; Ectromelia, Infectious; Ectromelia virus; Antiviral Agents; Interferon Type I
PubMed: 36417857
DOI: 10.1016/j.celrep.2022.111676 -
Journal of Medical Genetics Sep 1993
Topics: Abnormalities, Multiple; Adolescent; Amenorrhea; Ectromelia; Female; Genes, Recessive; Humans; Pelvic Bones; Syndrome; Uterus
PubMed: 8411080
DOI: 10.1136/jmg.30.9.797-a -
Disease Models & Mechanisms May 2011Sirenomelia, also known as sirenomelia sequence, is a severe malformation of the lower body characterized by fusion of the legs and a variable combination of visceral... (Review)
Review
Sirenomelia, also known as sirenomelia sequence, is a severe malformation of the lower body characterized by fusion of the legs and a variable combination of visceral abnormalities. The causes of this malformation remain unknown, although the discovery that it can have a genetic basis in mice represents an important step towards the understanding of its pathogenesis. Sirenomelia occurs in mice lacking Cyp26a1, an enzyme that degrades retinoic acid (RA), and in mice that develop with reduced bone morphogenetic protein (Bmp) signaling in the caudal embryonic region. The phenotypes of these mutant mice suggest that sirenomelia in humans is associated with an excess of RA signaling and a deficit in Bmp signaling in the caudal body. Clinical studies of sirenomelia have given rise to two main pathogenic hypotheses. The first hypothesis, based on the aberrant abdominal and umbilical vascular pattern of affected individuals, postulates a primary vascular defect that leaves the caudal part of the embryo hypoperfused. The second hypothesis, based on the overall malformation of the caudal body, postulates a primary defect in the generation of the mesoderm. This review gathers experimental and clinical information on sirenomelia together with the necessary background to understand how deviations from normal development of the caudal part of the embryo might lead to this multisystemic malformation.
Topics: Animals; Disease Models, Animal; Ectromelia; Humans; Limb Deformities, Congenital; Lower Extremity Deformities, Congenital; Models, Biological; Phenotype
PubMed: 21504909
DOI: 10.1242/dmm.007732 -
G3 (Bethesda, Md.) Feb 2022Roberts syndrome (RBS) is a multispectrum developmental disorder characterized by severe limb, craniofacial, and organ abnormalities and often intellectual disabilities....
Roberts syndrome (RBS) is a multispectrum developmental disorder characterized by severe limb, craniofacial, and organ abnormalities and often intellectual disabilities. The genetic basis of RBS is rooted in loss-of-function mutations in the essential N-acetyltransferase ESCO2 which is conserved from yeast (Eco1/Ctf7) to humans. ESCO2/Eco1 regulate many cellular processes that impact chromatin structure, chromosome transmission, gene expression, and repair of the genome. The etiology of RBS remains contentious with current models that include transcriptional dysregulation or mitotic failure. Here, we report evidence that supports an emerging model rooted in defective DNA damage responses. First, the results reveal that redox stress is elevated in both eco1 and cohesion factor Saccharomyces cerevisiae mutant cells. Second, we provide evidence that Eco1 and cohesion factors are required for the repair of oxidative DNA damage such that ECO1 and cohesin gene mutations result in reduced cell viability and hyperactivation of DNA damage checkpoints that occur in response to oxidative stress. Moreover, we show that mutation of ECO1 is solely sufficient to induce endogenous redox stress and sensitizes mutant cells to exogenous genotoxic challenges. Remarkably, antioxidant treatment desensitizes eco1 mutant cells to a range of DNA damaging agents, raising the possibility that modulating the cellular redox state may represent an important avenue of treatment for RBS and tumors that bear ESCO2 mutations.
Topics: Acetyltransferases; Cell Cycle Proteins; Chromatids; Chromosomal Proteins, Non-Histone; Craniofacial Abnormalities; Ectromelia; Humans; Hypertelorism; Nuclear Proteins; Oxidation-Reduction; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 34897432
DOI: 10.1093/g3journal/jkab426 -
Saudi Medical Journal Dec 2014To describe cases of sirenomelia and severe caudal regression syndrome (CRS), to report the prevalence of sirenomelia, and compare our findings with the literature.
OBJECTIVE
To describe cases of sirenomelia and severe caudal regression syndrome (CRS), to report the prevalence of sirenomelia, and compare our findings with the literature.
METHODS
Retrospective data was retrieved from the medical records of infants with the diagnosis of sirenomelia and CRS and their mothers from 1989 to 2010 (22 years) at the Security Forces Hospital, Riyadh, Saudi Arabia. A perinatologist, neonatologist, pediatric neurologist, and radiologist ascertained the diagnoses. The cases were identified as part of a study of neural tube defects during that period. A literature search was conducted using MEDLINE.
RESULTS
During the 22-year study period, the total number of deliveries was 124,933 out of whom, 4 patients with sirenomelia, and 2 patients with severe forms of CRS were identified. All the patients with sirenomelia had single umbilical artery, and none were the infant of a diabetic mother. One patient was a twin, and another was one of triplets. The 2 patients with CRS were sisters, their mother suffered from type II diabetes mellitus and morbid obesity on insulin, and neither of them had a single umbilical artery. Other associated anomalies with sirenomelia included an absent radius, thumb, and index finger in one patient, Potter's syndrome, abnormal ribs, microphthalmia, congenital heart disease, hypoplastic lungs, and diaphragmatic hernia.
CONCLUSION
The prevalence of sirenomelia (3.2 per 100,000) is high compared with the international prevalence of one per 100,000. Both cases of CRS were infants of type II diabetic mother with poor control, supporting the strong correlation of CRS and maternal diabetes.
Topics: Abnormalities, Multiple; Diabetes Mellitus, Type 2; Ectromelia; Female; Humans; Infant, Newborn; Male; Meningocele; Pregnancy; Pregnancy Complications; Prevalence; Retrospective Studies; Sacrococcygeal Region; Saudi Arabia
PubMed: 25551110
DOI: No ID Found