scholarly journals Why Remdesivir Failed: Preclinical Assumptions Overestimate the Clinical Efficacy of Remdesivir for COVID-19 and Ebola

2021 ◽  
Author(s):  
Victoria C. Yan ◽  
Florian L. Muller
Keyword(s):  
Clinical Efficacy ◽  
Species Differences ◽  
Clinical Performance ◽  
Drug Efficacy ◽  
Control Groups ◽  
Preclinical Data ◽  
Clinically Significant ◽  
Investigational Agents ◽  
And Control

Remdesivir is a nucleoside monophosphoramidate prodrug that has been FDA-approved for COVID-19. However, the clinical efficacy of remdesivir for COVID-19 remains contentious, as several trials have not found statistically significant differences in either time to clinical improvement or mortality between remdesivir-treated and control groups. Similarly, the inability for remdesivir to provide a clinically significant benefit above other investigational agents in patients with Ebola contrasts with strong, curative preclinical data generated in rhesus macaque models. For both COVID-19 and Ebola, significant discordance between the robust preclinical data and remdesivir’s lackluster clinical performance have left many puzzled. Here, we critically evaluate the assumptions of the models underlying remdesivir’s promising preclinical data and show that such assumptions over-predict efficacy and minimize toxicity of remdesivir in humans. Had the limitations of in vitro drug efficacy testing and species differences in drug metabolism been considered, the underwhelming clinical performance of remdesivir for both COVID-19 and Ebola would have been fully anticipated.

Growth and Development of Children Conceived by In Vitro Fertilization

PEDIATRICS ◽  
1992 ◽  
Vol 90 (3) ◽  
pp. 424-429
Author(s):  
Joseph M. Brandes ◽  
Joseph Itzkovits ◽  
Anat Scher ◽  
Miriam Sarid ◽  
Israel Thaler ◽  
...  
Keyword(s):  
Birth Weight ◽  
In Vitro Fertilization ◽  
Gestational Age ◽  
Head Circumference ◽  
Healthy Population ◽  
Control Groups ◽  
Vitro Fertilization ◽  
General Physical ◽  
And Control

To assess the physical and mental development of infants born after in vitro fertilization (IVF), we performed a general physical and developmental examination (Bayley and Stanford-Binet scales) on a cohort of 116 IVF children, conceived and born at our institution between February 1985 and March 1989, and on 116 non-IVF matched controls. Study and control groups were each composed of 66 singletons, 19 pairs of twins and 4 sets of triplets, whose age at examination ranged from 12 to 45 months. The developmental indices of IVF infants were within the normal range and did not differ from those of their matched controls. The indices were positively correlated to gestational age, birth weight, head circumference at birth and at examination, and mother's education. Mean birth weight, gestational age, and birth weight percentile of IVF infants were lower than the mean of the healthy population. Mean percentiles of weight and length at examination (mean age 22.4 months) were equally low but did not differ from those of the matched controls. However, mean percentiles of head circumference at birth and at examination compare well with the normal mean, both in IVF and control groups. Twins and triplets (IVF and controls) had significantly lower physical and mental indices as compared to singletons.

scholarly journals Effects of two different deep digital flexor tenotomy techniques on distal articular angles of equine cadaver forelimbs

2012 ◽  
Vol 42 (11) ◽  
pp. 2005-2010
Author(s):  
Antonio Cezar de Oliveira Dearo ◽  
Vitor Bruno Bianconi Rosa ◽  
Peter Reichmann ◽  
Milton Luis Ribeiro de Oliveira
Keyword(s):  
Quantitative Data ◽  
Statistical Significance ◽  
Surgical Approaches ◽  
Control Groups ◽  
Before And After ◽  
Distal Interphalangeal ◽  
The Difference ◽  
And Control ◽  
Flexor Tenotomy

Deep digital flexor (DDF) tenotomy is a technique employed for years to treat selected disorders of the musculoskeletal system in horses. Although two different surgical approaches (i.e. mid-metacarpal and pastern) have been described for performing the procedure, in vitro quantitative data regarding the modifications induced by either technique on the distal articular angles is lacking. Therefore, the purpose of the study reported here was to investigate the viability of a proposed biomechanical system of induced-traction used to compare the two DDF tenotomy techniques by measuring the distal articular angles of equine cadaver forelimbs. Ten pairs of forelimbs were collected and mounted to a biomechanical system developed to apply traction at the toe level. Dorsal articular angles of the metacarpophalangeal (MP), proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints were determined by geometric lines on radiographs taken before and after performing each technique. Comparisons between each tenotomy group and its own control, for each joint, and between the two tenotomy groups using as variable the difference between the tenotomy and control groups were tested. Despite the lack of statistical significance, the DDF tenotomy technique at the pastern level produced extension, to a lesser and greater extent, of the PIP and DIP joints, respectively when compared to the mid-metacarpal level. No remarkable differences could be observed for the MP joint. The developed traction-induced biomechanical construct seemed to be effective in producing valuable quantitative estimations of the distal articular angles of equine cadaver forelimbs subjected to different DDF tenotomy techniques.

scholarly journals The Accuracy and Reliability of Tooth Shade Selection Using Different Instrumental Techniques: An In Vitro Study

Sensors ◽  
2021 ◽  
Vol 21 (22) ◽  
pp. 7490
Author(s):  
Nattapong Sirintawat ◽  
Tanyaporn Leelaratrungruang ◽  
Pongsakorn Poovarodom ◽  
Sirichai Kiattavorncharoen ◽  
Parinya Amornsettachai
Keyword(s):  
Intraclass Correlation ◽  
In Vitro Study ◽  
Control Group ◽  
Intraoral Scanner ◽  
Control Groups ◽  
B Values ◽  
Cie Lab ◽  
And Control ◽  
Shade Selection

This study aimed to investigate and compare the reliability and accuracy of tooth shade selection in the model using 30 milled crowns via five methods: (1) digital single-lens reflex (DSLR) camera with twin flash (TF) and polarized filter (DSLR + TF), (2) DSLR camera with a ring flash (RF) and polarized filter (DSLR + RF), (3) smartphone camera with light corrector and polarized filter (SMART), (4) intraoral scanner (IOS), and (5) spectrophotometer (SPEC). These methods were compared with the control group or manufacturer’s shade. The CIE Lab values (L, a, and b values) were obtained from five of the methods to indicate the color of the tooth. Adobe Photoshop was used to generate CIE Lab values from the digital photographs. The reliability was calculated from the intraclass correlation based on two repetitions. The accuracy was calculated from; (a) ΔE calculated by the formula comparing each method to the control group, (b) study and control groups were analyzed by using the Kruskal–Wallis test, and (c) the relationship between study and control groups were calculated using Spearman’s correlation. The reliability of the intraclass correlation of L, a, and b values obtained from the five methods showed satisfactory correlations ranging from 0.732–0.996, 0.887–0.994, and 0.884–0.999, respectively. The ΔE from all groups had statistically significant differences when compared to the border of clinical acceptance (ΔE = 6.8). The ΔE from DSLR + TF, DSLR + RF, SMART, and SPEC were higher than clinical acceptance (ΔE > 6.8), whereas the ΔE from IOS was 5.96 and all of the L, a, and b values were not statistically significantly different from the manufacturer’s shade (p < 0.01). The ΔE of the DSLR + RF group showed the least accuracy (ΔE = 19.98), whereas the ∆E of DSLR + TF, SMART, and SPEC showed similar accuracy ∆E (ΔE = 10.90, 10.57, and 11.57, respectively). The DSLR camera combined with a ring flash system and polarized filter provided the least accuracy. The intraoral scanner provided the highest accuracy. However, tooth shade selection deserves the combination of various techniques and a professional learning curve to establish the most accurate outcome.

scholarly journals Evaluation of Apical Sealing Ability of Four Different Sealers using Centrifuging Dye Penetration Method: An in vitro Study

2012 ◽  
Vol 13 (6) ◽  
pp. 830-833
Author(s):  
Romel Joseph
Keyword(s):  
In Vitro Study ◽  
Blue Dye ◽  
Control Groups ◽  
Root Canals ◽  
Dye Penetration ◽  
Gutta Percha ◽  
Sealing Ability ◽  
Ah Plus ◽  
And Control

ABSTRACT Aim The aim of this in vitro study was to evaluate the apical seal obtained with four root canal sealers AH 26, Sealapex, Endoflas FS and AH Plus, with lateral condensation. Materials and methods Sixty root canals were prepared using the step-back technique. The specimens were divided into four experimental groups of 12 teeth and two control groups of 12 teeth. The experimental groups were obturated by laterally condensed gutta-percha with one of the tested sealers and control groups were obturated without any sealer. Methylene blue dye penetration with centrifuging method was used to evaluate the apical sealing ability. The quantitative apical leakage of each specimen was measured after 2 weeks. Results The results showed no significant differences between all groups except between AH Plus and Endoflas FS (<0.05). AH Plus showed significantly less leakage than Endoflas FS. Conclusion AH Plus showed the least leakage compared to AH 26, Sealapex and Endoflas FS. How to cite this article Joseph R, Singh S. Evaluation of Apical Sealing Ability of Four Different Sealers using Centrifuging Dye Penetration Method: An in vitro Study. J Contemp Dent Pract 2012;13(6):830-833.

scholarly journals Use of oocytes selected by brilliant cresyl blue staining enhances rabbit cloned embryo development in vitro

Zygote ◽  
2019 ◽  
Vol 27 (3) ◽  
pp. 166-172 ◽  
Author(s):  
Linying Jia ◽  
Bo Ding ◽  
Chong Shen ◽  
Shiwei Luo ◽  
Yanru Zhang ◽  
...  
Keyword(s):  
Cell Mass ◽  
Developmental Competence ◽  
Blue Staining ◽  
Control Group ◽  
Control Groups ◽  
Brilliant Cresyl Blue ◽  
Positive Group ◽  
Cresyl Blue ◽  
And Control

SummaryRabbits play an important role in people’s lives due to their high nutritional value and high-quality hair that can be used as raw material for textiles. Furthermore, rabbits are an important animal model for human disease, as genome-edited animals are particularly valuable for studying gene functions and pathogenesis. Somatic cell nuclear transfer (SCNT) is an important technique for producing genome-edited animals and it has great value in saving endangered species and in clone stem cell therapy. However, the low efficiency of SCNT limits its application, with the selection of suitable rabbit oocytes being crucial to its success. In the present study, we collected oocytes from ovarian follicles and stained them with 26 μM brilliant cresyl blue (BCB). We then matured the oocytes in vitro and used them for SCNT. Comparison of the BCB-positive oocytes with BCB-negative oocytes and the control group showed that the BCB-positive group had a significantly higher maturation rate (81.4% vs. 48.9% and 65.3% for the negative and control groups, respectively), cleavage rate (86.6% vs. 67.9% and 77.9%), blastocyst rate (30.5% vs. 12.8% and 19.6%), total number of blastocysts (90±7.5 vs. 65.3±6.3 and 67.5±5.7), and inner cell mass (ICM)/ trophectoderm (TE) index (42.3±4.2 vs. 30.2±2.1 and 33.9±5.1) (P<0.05). The BCB-positive group had a significantly lower apoptosis index (2.1±0.6 vs. 8.2±0.9 and 6.7±1.1 for the negative and control groups, respectively) (P<0.05). These findings demonstrate that BCB-positive oocytes have a higher maturation ability and developmental competence in vitro, indicating that BCB staining is a reliable method for selecting oocytes to enhance the efficiency of SCNT.

Production of good-quality blastocyst embryos following IVF of ovine oocytes vitrified at the germinal vesicle stage using a cryoloop

2013 ◽  
Vol 25 (8) ◽  
pp. 1204 ◽  
Author(s):  
Adel R. Moawad ◽  
Jie Zhu ◽  
Inchul Choi ◽  
Dasari Amarnath ◽  
Wenchao Chen ◽  
...  
Keyword(s):  
Germinal Vesicle ◽  
Blastocyst Stage ◽  
Control Groups ◽  
Blastocyst Development ◽  
Chromosome Configuration ◽  
Nuclear Maturation ◽  
Chromatin Configuration ◽  
And Control ◽  
First Time

The cryopreservation of immature oocytes at the germinal vesicle (GV) stage would create an easily accessible, non-seasonal source of female gametes for research and reproduction. The present study investigated the ability of ovine oocytes vitrified at the GV stage using a cryoloop to be subsequently matured, fertilised and cultured in vitro to blastocyst-stage embryos. Selected cumulus–oocyte complexes obtained from mature ewes at the time of death were randomly divided into vitrified, toxicity and control groups. Following vitrification and warming, viable oocytes were matured in vitro for 24 h. Matured oocytes were either evaluated for nuclear maturation, spindle and chromosome configuration or fertilised and cultured in vitro for 7 days. No significant differences were observed in the frequencies of IVM (oocytes at the MII stage), oocytes with normal spindle and chromatin configuration and fertilised oocytes among the three groups. Cleavage at 24 and 48 h post insemination was significantly decreased (P < 0.01) in vitrified oocytes. No significant differences were observed in the proportion of blastocyst development between vitrified and control groups (29.4% v. 45.1%, respectively). No significant differences were observed in total cell numbers, the number of apoptotic nuclei or the proportion of diploid embryos among the three groups. In conclusion, we report for the first time that ovine oocytes vitrified at the GV stage using a cryoloop have the ability to be matured, fertilised and subsequently developed in vitro to produce good-quality blastocyst embryos at frequencies comparable to those obtained using fresh oocytes.

scholarly journals Differential effect of L-thyroxine on phospholipid biosynthesis in mitochondria and microsomal fraction

1980 ◽  
Vol 186 (1) ◽  
pp. 127-133 ◽  
Author(s):  
J M Pasquini ◽  
I Faryna de Raveglia ◽  
N Capitman ◽  
E F Soto
Keyword(s):  
Differential Effect ◽  
Microsomal Fraction ◽  
Liver Mitochondria ◽  
Subcellular Fractions ◽  
Control Groups ◽  
Adult Rats ◽  
And Control ◽  
Isolated Liver ◽  
Normal Controls

1. The action of L-thyroxine on the incorporation of radioactive choline or CDP-choline into phosphatidylcholine in vitro was explored in liver and brain microsomal fraction and mitochondria obtained from young adult rats. 2. In liver mitochondria isolated from animals treated with L-thyroxine (40 mg/kg body wt. during 6 days), the incorporation of both radioactive precursors into phosphatidylcholine was significantly decreased compared with normal controls, whereas in the total homogenate and in the microsomal fraction the incorporation was similar in the experimental and control groups. In subcellular fractions isolated from brain, the incorporation of precursors was similar in L-thyroxine-treated and normal animals. 3. Liver mitochondria isolated from normal animals incubated in vitro with CDP-choline, in the presence of different concentrations of L-thyroxine, showed also a marked decrease in the incorporation of label into phosphatidylcholine, whereas no significant changes were found in the total homogenate and in the microsomal fraction compared with control experiments. 4. The differential effect of L-thyroxine on the incorporation of radioactive precursors into phosphatidylcholine of isolated liver subcellular fractions gives further support to the hypothesis that liver mitochondria can independently synthesize part of their own phospholipids. 5. Possible mechanisms of the action of the hormone at the mitochondrial level are discussed.

Distinct Hemostatic Profile of Leukocytes in Essential Thrombocythemia (ET) Carrying the JAK2 V617F Mutation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 378-378 ◽  
Author(s):  
Anna Falanga ◽  
Marina Marchetti ◽  
Donatella Balducci ◽  
Alfonso Vignoli ◽  
Laura Russo ◽  
...  
Keyword(s):  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Specific Marker ◽  
Control Groups ◽  
Jak2 Mutation ◽  
Mutation Carriers ◽  
Mixed Aggregates ◽  
Platelet Aggregates ◽  
And Control

Abstract The pathogenesis of the thrombotic diathesis of patients with ET is not completely clarified. Activation of polymorphonuclear leukocyte (PMN) occurs in these patients and is associated with a hypercoagulable state and increased number of circulating platelet/PMN aggregates. Further, increased procoagulant Tissue Factor (TF) expression in ET PMN is also reported. Recently, a gain-of-function JAK2 mutation (V617F) has been described in a high proportion of bcr/abl-negative myeloproliferative disorders. Specifically, in subjects with ET the mutation is present in about 50% of cases and retrospective data suggest an association with a higher rate of complications, including thrombosis. Aim of this study was to evaluate whether ET patients carrying the JAK2 mutation possess PMN with different hemostatic characteristics compared to ET subjects without JAK2 mutation and healthy controls. Twenty ET patients, 10 with and 10 without JAK2 mutation (median age: 50 years, range 32–61; platelet count: median 782 x 109/L, range 474–1,565 x 109/L), not receiving cytoreductive therapy (classified as low risk group), were included in the study; 16 age matched healthy subjects acted as controls. Expression of CD11b, TF and fibrinogen on PMN surface as well as PMN-platelet mixed aggregates (defined as the percentage of CD11b-positive PMN co-expressing a platelet-specific marker, i.e. CD42b or CD62P) were evaluated by whole blood flow-cytometry in both basal condition and after in vitro PMN stimulation by f-MLP. In washed isolated PMN samples the level of TF-mRNA was determined by RT-PCR. In basal conditions, significantly (p&lt;0.01) increased levels of PMN/platelet aggregates (both CD42 and CD62P pos. PMN) compared to controls were found, independently from JAK2 mutation. Differently, PMN from JAK2 mutation carriers expressed significantly higher surface TF (18.2±9 %pos. cells) and fibrinogen (12.3±7 %pos. cells) antigens compared to non-carrier (TF: 11.6±5 %; fibrinogen: 7.2±2 %pos. cells) and control subjects (TF: 11.1±3 %; fibrinogen: 7.1±3 %pos. cells). In vitro stimulation with f-MLP increased the proportion of platelet/PMN aggregates (CD11b/CD42 and CD11b/CD62P) in all ET patients and controls. However, in JAK2 mutation carriers the levels of both CD62P and CD42b positive PMN were significantly greater than those of non-carrier ET patients and controls (p&lt;0.05). Similarly, TF and fibrinogen levels on stimulated PMN surface were more elevated in the JAK2 mutation positive group compared to both the mutation negative and control groups. The analysis of PMN TF-mRNA showed a significantly higher expression in the whole ET patient group compared to controls, independently from the presence of JAK2 mutation. In conclusions, these data indicate that the expression of JAK2 mutation in ET patients may confer to PMN a different hemostatic phenotype in terms of increased interaction with platelets and increased expression of surface TF and fibrinogen, suggesting a new link of this mutation with a prothrombotic status.

scholarly journals Effect of crotamine, a cell-penetrating peptide, on blastocyst production and gene expression of in vitro fertilized bovine embryos

Zygote ◽  
2014 ◽  
Vol 24 (1) ◽  
pp. 48-57 ◽  
Author(s):  
Iana S. Campelo ◽  
Alexsandra F. Pereira ◽  
Agostinho S. Alcântara-Neto ◽  
Natalia G. Canel ◽  
Joanna M.G. Souza-Fabjan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Control Group ◽  
Cell Penetrating Peptide ◽  
Mrna Levels ◽  
Bovine Embryos ◽  
Control Groups ◽  
Cell Penetrating ◽  
A Cell ◽  
And Control

SummaryThe present study investigated the effects of crotamine, a cell-penetrating peptide from rattlesnake venom, at different exposure times and concentrations, on both developmental competence and gene expression (ATP1A1, AQP3, GLUT1 and GLUT3) of in vitro fertilized (IVF) bovine embryos. In Experiment 1, presumptive zygotes were exposed to 0.1 μM crotamine for 6, 12 or 24 h and control groups (vehicle and IVF) were included. In Experiment 2, presumptive zygotes were exposed to 0 (vehicle), 0.1, 1 and 10 μM crotamine for 24 h. Additionally, to visualize crotamine uptake, embryos were exposed to rhodamine B-labelled crotamine and subjected to confocal microscopy. In Experiment 1, no difference (P > 0.05) was observed among different exposure times and control groups for cleavage and blastocyst rates and total cells number per blastocyst. Within each exposure time, mRNA levels were similar (P > 0.05) in embryos cultured with or without crotamine. In Experiment 2, concentrations as high as 10 μM crotamine did not affect (P > 0.05) the blastocyst rate. Crotamine at 0.1 and 10 μM did not alter mRNA levels when compared with the control (P > 0.05). Remarkably, only 1 μM crotamine decreased both ATP1A1 and AQP3 expression levels relative to the control group (P < 0.05). Also, it was possible to visualize the intracellular localization of crotamine. These results indicate that crotamine can translocate intact IVF bovine embryos and its application in the culture medium is possible at concentrations from 0.1–10 μM for 6–24 h.

The effect of nerve growth factor on nuclear progression of porcine oocytes during in vitro maturation and embryo development

2005 ◽  
Vol 53 (1) ◽  
pp. 91-101 ◽  
Author(s):  
Ágnes Bali Papp ◽  
T. Somfai ◽  
Mabel Tartaglione ◽  
Erika Varga ◽  
J. C. Gardon
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
In Vitro Maturation ◽  
Developmental Competence ◽  
Control Groups ◽  
Cell Stage ◽  
Nerve Growth ◽  
Morula Stage ◽  
And Control

The present study examined the effect of nerve growth factor (NGF) on in vitro maturation (IVM), in vitro fertilisation (IVF) and subsequent embryonic development of porcine oocytes. Cumulus-oocyte complexes were cultured with or without 1.0 ng/ml NGF for 40 h. After IVF, they were cultured in vitro for 6 days. After 10 and 20 h of IVM, there was no difference in nuclear status between the NGF-treated and control oocytes. Significant differences were detected in nuclear progression of oocytes matured in the presence or absence of NGF at 30 h of culture. A higher proportion of NGF-treated oocytes were at M-II stage compared to the control. Nevertheless, at the end of the 40-h IVM period, there was no difference in the proportion of M-II stage oocytes between the NGF-treated and control groups. NGF in IVM medium did not influence the developmental competence of putative embryos. Most embryos remained at the 2- to 4-cell stage; however, a significant amount of embryos reached the morula stage both in the NGF and the control groups. These results suggest that NGF during IVM accelerates nuclear progression of porcine oocytes by enhancing the post-diakinetic events of meiosis.

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