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The Annals of Pharmacotherapy Oct 2023This article reviews the published data encompassing the development, pharmacology, efficacy, and safety of brincidofovir, a nucleotide analogue DNA polymerase inhibitor... (Review)
Review
OBJECTIVE
This article reviews the published data encompassing the development, pharmacology, efficacy, and safety of brincidofovir, a nucleotide analogue DNA polymerase inhibitor developed for the treatment of smallpox.
DATA SOURCES
A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from inception up to December 2022, using terms , and .
STUDY SELECTION AND DATA EXTRACTION
Data were limited to studies published in English language, which evaluated the efficacy and safety of brincidofovir.
DATA SYNTHESIS
Two surrogate animal models were included in the Food and Drug Administration's (FDA) decision to approve brincidofovir: ectromelia virus in mice and rabbitpox in rabbits. Phases 2 and 3 studies established safety for approval. Brincidofovir biweekly for the treatment of disseminated adenovirus disease resulted in all-cause mortality, ranging from 13.8% to 29%. In a study for cytomegalovirus prophylaxis, patients with clinically significant cytomegalovirus infection through week 24 posttransplant was 51.2% with brincidofovir and 52.3% with placebo.
CONCLUSIONS
Brincidofovir adds a second oral agent to treat smallpox, with a different mechanism of action than tecovirimat. In the event of a smallpox outbreak, prompt treatment will be necessary to contain its spread. Brincidofovir shows efficacy in surrogate animal models. In healthy volunteers and individuals treated, or used as prophylaxis, for cytomegalovirus or adenovirus, the primary adverse events were gastrointestinal in addition to transient hepatotoxicity. Additionally, excessive deaths were observed in hematopoietic cell transplant patients receiving it as cytomegalovirus prophylaxis, requiring a black box warning.
Topics: Humans; Rabbits; Animals; Mice; Smallpox; Hematopoietic Stem Cell Transplantation; Antiviral Agents; Disease Models, Animal; Variola virus; Cytosine; Cytomegalovirus
PubMed: 36688308
DOI: 10.1177/10600280231151751 -
The Journal of the Royal College of... May 2024Six decades ago the world learned that thalidomide, a seemingly non-toxic sedative and hypnotic, caused severe birth defects including the flipper-like deformity of the...
Six decades ago the world learned that thalidomide, a seemingly non-toxic sedative and hypnotic, caused severe birth defects including the flipper-like deformity of the arms known as phocomelia. When thalidomide was tested against placebo by the trialist Louis Lasagna in 1960 (while the drug was banned from the U.S. marketplace), he found the 100-mg dosage equivalent to placebo, as well as greatly inferior to the 200-mg dosage, in producing sleep. Even as these findings were made known, a 100-mg dose of thalidomide was in general use as a sleep aid for pregnant women. It appears that unbeknownst to themselves, an untold number of pregnant women around the world who were prescribed thalidomide incurred the risks of a teratogen in return for the benefits of a sugar pill.
PubMed: 38807349
DOI: 10.1177/14782715241258503 -
Fetal and Pediatric Pathology 2024Phocomelia is a congenital limb deformity in which the proximal part of the upper or lower limb does not develop. Occasionally the malformed limb may be located...
Phocomelia is a congenital limb deformity in which the proximal part of the upper or lower limb does not develop. Occasionally the malformed limb may be located ectopically. We present a frontal phocomelia in a three-year-old girl with right-hand phocomelia and thoracoschisis. The patient's arm was connected directly from the front of the chest, with a rudimentary thumb and two fingers. The truncated arm was not functional. The acromioclavicular joint was abnormal and ectopic, the limb articulated with the medial side of sternum. The thoracoschisis manifested as eventration of the right liver lobe and right side of chest wall. Ectopic phocomelia can be associated with thoracoschisis, it can be nonfunctional, and can articulate with the sternum.
Topics: Female; Humans; Child, Preschool; Ectromelia; Limb Deformities, Congenital; Thoracic Wall; Liver; Extremities
PubMed: 37715664
DOI: 10.1080/15513815.2023.2258417 -
Simultaneous femoral and tibial lengthening for severe limb length discrepancy in fibular hemimelia.Journal of Orthopaedic Surgery and... Nov 2023Fibular Hemimelia (FH) is the most common longitudinal limb deficiency. Significant limb length discrepancy (LLD) will necessitate long treatment times and multiple... (Review)
Review
BACKGROUND
Fibular Hemimelia (FH) is the most common longitudinal limb deficiency. Significant limb length discrepancy (LLD) will necessitate long treatment times and multiple settings to compensate for LLD when associated with femoral shortening. This study evaluates the outcome of simultaneous femoral and tibial lengthening using the Ilizarov frame.
METHODS
This retrospective study included the cases of 12 children with severe limb length discrepancy caused by combined FH and ipsilateral femoral shortening from May 2015 to August 2022. The total LLD ranged from 7 to 14.5 cm. All patients underwent single-session femoral and tibial lengthening using the Ilizarov ring external fixator technique. Additional procedures were performed in the same setting, including Achilles tendon lengthening, fibular anlage excision, peroneal tendons lengthening, and iliotibial band release. Follow-up ranged from 2 to 4 years.
RESULTS
The planned limb lengthening was achieved in ten cases (83%). No cases of joint subluxation or dislocation were encountered. No neurovascular injury has occurred during the treatment course. In all cases, the bone healing index was better on the femoral side than on the tibia. Poor regeneration and deformity of the tibia occurred in two cases (16.6%).
CONCLUSION
Simultaneous femoral and tibial lengthening using the Ilizarov fixator is a relatively safe procedure with the result of correction of total LLD in one session in a shorter time and less morbidity.
Topics: Child; Humans; Tibia; Ectromelia; Retrospective Studies; Fibula; Bone Lengthening; Ilizarov Technique; Leg Length Inequality; Leg; Treatment Outcome
PubMed: 37936235
DOI: 10.1186/s13018-023-04229-y -
Comparative Medicine Oct 2023Four strains of experimentally naïve mice (NOD. Cg- Il2rg /SzJ [NSG], NOD. Cg- /SzJ [NRG], B6.129S(Cg)-/J [STAT1 ], and B6.129S7- /J[IFNγR ] housed in a barrier...
Four strains of experimentally naïve mice (NOD. Cg- Il2rg /SzJ [NSG], NOD. Cg- /SzJ [NRG], B6.129S(Cg)-/J [STAT1 ], and B6.129S7- /J[IFNγR ] housed in a barrier facility developed unusual and seemingly unrelated clinical signs. Young NSG/NRG mice ( = 49, mean age = 4 ± 0.4 mo) exhibited nonspecific clinical signs of moderate-to-severe lethargy, hunched posture, decreased body condition, and pallor. In contrast to the NSG/NRG mice, the STAT1 and IFNγ R mice ( = 5) developed large subcutaneous abscesses on the head and neck. These mice were euthanized, and samples were collected for culture. NSG/NRG mice had moderate-markedly enlarged livers (20 of 49, 40%) and spleens (17 of 49, 35%). The livers contained multiple, variably-sized, tan regions throughout all lobes. Histology revealed necrotizing hepatitis (13 of 17, 77%), splenic and hepatic extramedullary hematopoiesis (17 of 17, 100%), glomerular histiocytosis (6 of 17, 35%), and metritis (6 of 11, 55%) with perivascular inflammation, suggesting hematogenous spread Differentials for these lesions included mouse hepatitis virus, ectromelia virus, spp., and was cultured from liver lesions and subcutaneous abscesses and confirmed with 16S ribosomal RNA sequencing. After completing systematic testing of the environment, failure of the water autoclave cycle was suspected as the cause of the outbreak. To address the situation, individually ventilated racks were sanitized and new breeders were purchased; these actions dramatically reduced infections. The current literature contains few reports of infections in immunocompromised mice, and its typical presentation is torticollis and rolling. infection is a potential differential for subcutaneous abscesses, hepatitis, and splenomegaly in immunocompromised mice. Careful monitoring of sterilization techniques is essential to prevent such infections in a barrier facility.
Topics: Animals; Mice; Abscess; Burkholderia gladioli; Burkholderia Infections; Hepatitis; Mice, Inbred NOD; Mice, SCID
PubMed: 38087404
DOI: 10.30802/AALAS-CM-23-000016 -
The Journal of Hand Surgery, European... Dec 2023In this study, we studied historical case notes to examine nomenclature of congenital upper limb anomalies and explore the changes in terminologies over time. Original...
In this study, we studied historical case notes to examine nomenclature of congenital upper limb anomalies and explore the changes in terminologies over time. Original diagnoses were reclassified according to previously published classifications and the most recent Oberg, Manske and Tonkin system. Two hundred and thirty-eight case notes were obtained from the period 1961-1991. Hand plate malformations where the diagnosis was obvious or traumatic defects, were excluded. Eighty-six cases (106 extremities) were finally included where an ambiguous diagnosis, such as 'congenital absence' was initially given. None of the re-classifications matched the original diagnoses except for cleft hand and radial dysplasia ( = 31). Eighteen phocomelia-type limbs were re-classifiable when seen as a continuum of longitudinal deficiency, but not as an intercalary deficit. This study provided further insights into the evolving nature of nomenclature in congenital upper limb anomalies, especially for the condition of phocomelia. IV.
Topics: Humans; Upper Extremity Deformities, Congenital; Ectromelia; Hand Deformities, Congenital; Syndrome; Upper Extremity
PubMed: 36927201
DOI: 10.1177/17531934231160400 -
The Iowa Orthopaedic Journal 2024Fibular hemimelia is the most common congenital long bone deficiency. It is often associated with femoral and tibial deficiencies which result in a clinically evident...
BACKGROUND
Fibular hemimelia is the most common congenital long bone deficiency. It is often associated with femoral and tibial deficiencies which result in a clinically evident leg length discrepancy. The primary soft tissue concern is ACL/PCL deficiency. If treatment includes bony lengthening, joint stability is imperative to avoid complications. In this study, we detail a novel technique for long bone lengthening and ACL reconstruction in a single, cohesive surgery. This consolidates the need for multiple procedures and offers improved limb length symmetry and knee stability for this patient population. Clinical outcomes of pediatric patients with hemimelia who underwent either femoral or tibial lengthening with PRECICE® nail and concomitant ACL reconstruction are presented.
METHODS
After IRB approval, we identified five patients with complex fibular hemimelia who underwent ACL reconstruction and concomitant lengthening with at least two years of follow-up. Two patients (40%) presented with congenital short femur, and three (60%) with congenital short tibia. In each case, ACL reconstruction and either femoral or tibial guided growth via PRECICE® nail were performed. Operative techniques involving both soft tissue and bony methodology are described in detail.
RESULTS
All patients had objective improvement in knee stability as assessed both intra and post operatively, as well as successful intermedullary lengthening without complications related to joint stability. Three patients had minor complications unrelated to joint stability that did not interfere with overall result.
CONCLUSION
Fibular hemimelia associated with hypoplasia of bony and soft tissue structures can be successfully addressed with concomitant ligamentous reconstruction at the time of implantation of lengthening devices. This addresses knee instability and reduces both number of operative procedures and potential complications related to joint instability while pursuing bony lengthening. .
Topics: Humans; Retrospective Studies; Ectromelia; Male; Female; Fibula; Child; Anterior Cruciate Ligament Reconstruction; Bone Lengthening; Treatment Outcome; Adolescent; Tibia; Femur
PubMed: 38919371
DOI: No ID Found -
Voprosy Virusologii Jul 2023Following the successful eradication of smallpox, mass vaccination against this disease was discontinued in 1980. The unvaccinated population continues to be at risk of...
INTRODUCTION
Following the successful eradication of smallpox, mass vaccination against this disease was discontinued in 1980. The unvaccinated population continues to be at risk of infection due to military use of variola virus or exposure to monkeypox virus in Africa and non-endemic areas. In cases of these diseases, rapid diagnosis is of great importance, since the promptness and effectiveness of therapeutic and quarantine measures depend on it. The aim of work is to develop a kit of reagents for enzyme-linked immunosorbent assay (ELISA) for fast and highly sensitive detection of orthopoxviruses (OPV) in clinical samples.
MATERIALS AND METHODS
The efficiency of virus detection was evaluated by single-stage ELISA in the cryolisate of CV-1 cell culture samples infected with vaccinia, cowpox, rabbitpox, and ectromelia viruses, as well as in clinical samples of infected rabbits and mice.
RESULTS
The method of rapid ELISA was shown to allow the detection of OPV in crude viral samples in the range of 5.0 1025.0 103 PFU/ml, and in clinical samples with a viral load exceeding 5 103 PFU/ml.
CONCLUSIONS
The assay involves a minimum number of operations and can be performed within 45 minutes, which makes it possible to use it in conditions of a high level of biosecurity. Rapid ELISA method was developed using polyclonal antibodies, which significantly simplifies and reduces the cost of manufacturing a diagnostic system.
Topics: Rabbits; Animals; Mice; Orthopoxvirus; Vaccinia virus; Variola virus; Ectromelia virus; Enzyme-Linked Immunosorbent Assay
PubMed: 37436415
DOI: 10.36233/0507-4088-178 -
Cells Dec 2023Conventional dendritic cells (cDCs) are innate immune cells that play a pivotal role in inducing antiviral adaptive immune responses due to their extraordinary ability...
Conventional dendritic cells (cDCs) are innate immune cells that play a pivotal role in inducing antiviral adaptive immune responses due to their extraordinary ability to prime and polarize naïve T cells into different effector T helper (Th) subsets. The two major subpopulations of cDCs, cDC1 (CD8α in mice and CD141 in human) and cDC2 (CD11b in mice and CD1c in human), can preferentially polarize T cells toward a Th1 and Th2 phenotype, respectively. During infection with ectromelia virus (ECTV), an orthopoxvirus from the family, the timing and activation of an appropriate Th immune response contributes to the resistance (Th1) or susceptibility (Th2) of inbred mouse strains to the lethal form of mousepox. Due to the high plasticity and diverse properties of cDC subpopulations in regulating the quality of a specific immune response, in the present study we compared the ability of splenic cDC1 and cDC2 originating from different ECTV-infected mouse strains to mature, activate, and polarize the Th immune response during mousepox. Our results demonstrated that during early stages of mousepox, both cDC subsets from resistant C57BL/6 and susceptible BALB/c mice were activated upon in vivo ECTV infection. These cells exhibited elevated levels of surface MHC class I and II, and co-stimulatory molecules and showed enhanced potential to produce cytokines. However, both cDC subsets from BALB/c mice displayed a higher maturation status than that of their counterparts from C57BL/6 mice. Despite their higher activation status, cDC1 and cDC2 from susceptible mice produced low amounts of Th1-polarizing cytokines, including IL-12 and IFN-γ, and the ability of these cells to stimulate the proliferation and Th1 polarization of allogeneic CD4 T cells was severely compromised. In contrast, both cDC subsets from resistant mice produced significant amounts of Th1-polarizing cytokines and demonstrated greater capability in differentiating allogeneic T cells into Th1 cells compared to cDCs from BALB/c mice. Collectively, our results indicate that in the early stages of mousepox, splenic cDC subpopulations from the resistant mouse strain can better elicit a Th1 cell-mediated response than the susceptible strain can, probably contributing to the induction of the protective immune responses necessary for the control of virus dissemination and for survival from ECTV challenge.
Topics: Humans; Animals; Mice; Mice, Inbred C57BL; Ectromelia, Infectious; Poxviridae Infections; Cytokines; Dendritic Cells
PubMed: 38201217
DOI: 10.3390/cells13010013