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Frontiers in Pediatrics 2022Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a prevalent condition worldwide and is caused by loss-of-function mutations in the G6PD gene. Individuals with... (Review)
Review
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a prevalent condition worldwide and is caused by loss-of-function mutations in the G6PD gene. Individuals with deficiency are more susceptible to oxidative stress which leads to the classical, acute hemolytic anemia (favism). However, G6PD deficiency in newborn infants presents with an increased risk of hyperbilirubinemia, that may rapidly escalate to result in bilirubin induced neurologic dysfunction (BIND). Often with no overt signs of hemolysis, G6PD deficiency in the neonatal period appears to be different in the pathophysiology from favism. This review discusses and compares the mechanistic pathways involved in these two clinical presentations of this enzyme disorder. In contrast to the membrane disruption of red blood cells and Heinz bodies formation in favism, G6PD deficiency causing jaundice is perhaps attributed to the disruption of oxidant-antioxidant balance, impaired recycling of peroxiredoxin 2, thus affecting bilirubin clearance. Screening for G6PD deficiency and close monitoring of affected infants are important aspects in neonatal care to prevent kernicterus, a permanent and devastating neurological damage. WHO recommends screening for G6PD activity of all infants in countries with high prevalence of this deficiency. The traditional fluorescent spot test as a screening tool, although low in cost, misses a significant proportion of cases with moderate deficiency or the partially deficient, heterozygote females. Some newer and emerging laboratory tests and diagnostic methods will be discussed while developments in genomics and proteomics contribute to increasing studies that spatially profile genetic mutations within the protein structure that could predict their functional and structural effects. In this review, several known variants of G6PD are highlighted based on the location of the mutation and amino acid replacement. These could provide insights on why some variants may cause a higher degree of phenotypic severity compared to others. Further studies are needed to elucidate the predisposition of some variants toward certain clinical manifestations, particularly neonatal hyperbilirubinemia, and how some variants increase in severity when co-inherited with other blood- or bilirubin-related genetic disorders.
PubMed: 35685917
DOI: 10.3389/fped.2022.875877 -
International Journal of Laboratory... Dec 2022
Topics: Humans; Heinz Bodies; COVID-19; Erythrocytes; Hematologic Tests
PubMed: 35751427
DOI: 10.1111/ijlh.13926 -
Nature Communications Dec 2022Mechanisms by which specific histone modifications regulate distinct gene networks remain little understood. We investigated how H3K79me2, a modification catalyzed by...
Mechanisms by which specific histone modifications regulate distinct gene networks remain little understood. We investigated how H3K79me2, a modification catalyzed by DOT1L and previously considered a general transcriptional activation mark, regulates gene expression during cardiogenesis. Embryonic cardiomyocyte ablation of Dot1l revealed that H3K79me2 does not act as a general transcriptional activator, but rather regulates highly specific transcriptional networks at two critical cardiogenic junctures: embryonic cardiogenesis, where it was particularly important for left ventricle-specific genes, and postnatal cardiomyocyte cell cycle withdrawal, with Dot1L mutants having more mononuclear cardiomyocytes and prolonged cardiomyocyte cell cycle activity. Mechanistic analyses revealed that H3K79me2 in two distinct domains, gene bodies and regulatory elements, synergized to promote expression of genes activated by DOT1L. Surprisingly, H3K79me2 in specific regulatory elements also contributed to silencing genes usually not expressed in cardiomyocytes. These results reveal mechanisms by which DOT1L successively regulates left ventricle specification and cardiomyocyte cell cycle withdrawal.
Topics: Gene Regulatory Networks; Cell Division; Cell Cycle; Myocytes, Cardiac; Heart Ventricles
PubMed: 36460641
DOI: 10.1038/s41467-022-35070-2 -
Annals of Oncology : Official Journal... Aug 2010Drug development traditionally has relied upon the complementary contributions of clinicians and scientists at academic institutions and at pharmaceutical companies.... (Review)
Review
BACKGROUND
Drug development traditionally has relied upon the complementary contributions of clinicians and scientists at academic institutions and at pharmaceutical companies. Greater regulatory burdens, increased bureaucratic requirements, restricted reimbursement, and spiralling research and development costs are exerting pressure on the drug development pipeline. The result is a de-emphasis of exploratory research, particularly independent academic research, despite its proven value in identifying new drug targets and developing innovative cancer therapies.
DESIGN
An expert panel assembled by the Biotherapy Development Association-a nonprofit international forum for academic and industry researchers, patients, and government regulatory and postregulatory agencies-examined the growing schism between academia and industry and identified several causes of declining academic research.
RESULTS
The authors propose solutions to sustain investigator-initiated research and provide a new model whereby expert organisations provide a forum for academia and industry to plan studies within a regulatory framework to support licensure/authorisation and reimbursement for new molecularly targeted agents and biomarkers.
CONCLUSIONS
Investigator-initiated trials have led to the discovery and development of innovative, safe, and effective cancer treatments. To ensure that such research continues, action will be required on the parts of legislative and regulatory bodies, industry, universities, patient advocacy organisations, and preclinical and clinical academic scientists.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Neoplasms; Research Personnel
PubMed: 20133383
DOI: 10.1093/annonc/mdq018 -
Frontiers in Molecular Biosciences 2022RNA is a vital biomolecule, the function of which is tightly spatiotemporally regulated. RNA organelles are biological structures that either membrane-less or surrounded... (Review)
Review
RNA is a vital biomolecule, the function of which is tightly spatiotemporally regulated. RNA organelles are biological structures that either membrane-less or surrounded by membrane. They are produced by the all the cells and indulge in vital cellular mechanisms. They include the intracellular RNA granules and the extracellular exosomes. RNA granules play an essential role in intracellular regulation of RNA localization, stability and translation. Aberrant regulation of RNA is connected to disease development. For example, in microsatellite diseases such as CXG repeat expansion disorders, the mutant CXG repeat RNA's localization and function are affected. RNA is not only transported intracellularly but can also be transported between cells exosomes. The loading of the exosomes is regulated by RNA-protein complexes, and recent studies show that cytosolic RNA granules and exosomes share common content. Intracellular RNA granules and exosome loading may therefore be related. Exosomes can also transfer pathogenic molecules of CXG diseases from cell to cell, thereby driving disease progression. Both intracellular RNA granules and extracellular RNA vesicles may serve as a source for diagnostic and treatment strategies. In therapeutic approaches, pharmaceutical agents may be loaded into exosomes which then transport them to the desired cells/tissues. This is a promising target specific treatment strategy with few side effects. With respect to diagnostics, disease-specific content of exosomes, e.g., RNA-signatures, can serve as attractive biomarker of central nervous system diseases detecting early physiological disturbances, even before symptoms of neurodegeneration appear and irreparable damage to the nervous system occurs. In this review, we summarize the known function of cytoplasmic RNA granules and extracellular vesicles, as well as their role and dysfunction in CXG repeat expansion disorders. We also provide a summary of established protocols for the isolation and characterization of both cytoplasmic and extracellular RNA organelles.
PubMed: 36589236
DOI: 10.3389/fmolb.2022.1000932 -
Biophysical Journal Mar 2020Hemoglobin functions as a tetrameric oxygen transport protein, with each subunit containing a heme cofactor. Its denaturation, either in vivo or in vitro, involves...
Hemoglobin functions as a tetrameric oxygen transport protein, with each subunit containing a heme cofactor. Its denaturation, either in vivo or in vitro, involves autoxidation to methemoglobin, followed by cofactor loss and globin unfolding. We have proposed a global disassembly scheme for human methemoglobin, linking hemin (ferric protoporphyrin IX) disassociation and apoprotein unfolding pathways. The model is based on the evaluation of circular dichroism and visible absorbance measurements of guanidine-hydrochloride-induced disassembly of methemoglobin and previous measurements of apohemoglobin unfolding. The populations of holointermediates and equilibrium disassembly parameters were estimated quantitatively for adult and fetal hemoglobins. The key stages are characterized by hexacoordinated hemichrome intermediates, which are important for preventing hemin disassociation from partially unfolded, molten globular species during early disassembly and late-stage assembly events. Both unfolding experiments and independent small angle x-ray scattering measurements demonstrate that heme disassociation leads to the loss of tetrameric structural integrity. Our model predicts that after autoxidation, dimeric and monomeric hemichrome intermediates occur along the disassembly pathway inside red cells, where the hemoglobin concentration is very high. This prediction suggests why misassembled hemoglobins often get trapped as hemichromes that accumulate into insoluble Heinz bodies in the red cells of patients with unstable hemoglobinopathies. These Heinz bodies become deposited on the cell membranes and can lead to hemolysis. Alternatively, when acellular hemoglobin is diluted into blood plasma after red cell lysis, the disassembly pathway appears to be dominated by early hemin disassociation events, which leads to the generation of higher fractions of unfolded apo subunits and free hemin, which are known to damage the integrity of blood vessel walls. Thus, our model provides explanations of the pathophysiology of hemoglobinopathies and other disease states associated with unstable globins and red cell lysis and also insights into the factors governing hemoglobin assembly during erythropoiesis.
Topics: Erythrocytes; Heme; Hemoglobins; Hemolysis; Humans; Methemoglobin
PubMed: 32075750
DOI: 10.1016/j.bpj.2020.01.031 -
Journal of Feline Medicine and Surgery Aug 2022This study aimed to compare the analgesic effect between carprofen and grapiprant every 12 or 24 h on postoperative pain in cats undergoing ovariohysterectomy, in...
OBJECTIVES
This study aimed to compare the analgesic effect between carprofen and grapiprant every 12 or 24 h on postoperative pain in cats undergoing ovariohysterectomy, in addition to the effects on the hematological, biochemical and urinalysis variables.
METHODS
A total of 32 female cats were randomly divided into three groups, according to the treatment administered with the first dose given orally 90 mins before surgery, as follows: CAR (cats received 4 mg/kg carprofen, n = 11); GRA1 (cats received 2 mg/kg grapiprant, n = 10); and GRA2 (cats received 2 mg/kg grapiprant q12h, n = 11). Pain was assessed by UNESP-Botucatu Multidimensional Composite Pain Scale (UNESP) and Glasgow Feline Composite Measure Pain Scale (GLASGOW) for cats preoperatively (baseline) and at 1, 3, 6, 8, 12 and 24 h after extubation. Venous blood was collected at baseline, and 12 and 24 h after the administration of carprofen or grapiprant to perform a complete blood count (CBC), the percentage of Heinz bodies and serum biochemistry (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, creatinine and urea). Urinalysis was performed at baseline and 24 h after extubation. Glucose levels were evaluated at baseline and 1 h postoperatively.
RESULTS
Pain scores were not significantly different among groups in both scales, although pain was higher at 3 h in comparison with 24 h in all groups. In the GRA1 and GRA2 groups, 67% (14/21) of cats needed rescue analgesia compared with 18% (2/11) in the CAR group. Glucose increased from baseline to 1 h in the GRA1 and GRA2 groups. None of the CBC, serum biochemistry and urinalysis variables differed among groups.
CONCLUSIONS AND RELEVANCE
Grapiprant did not promote adequate analgesia during the first 3 h postoperatively in cats undergoing ovariohysterectomy compared with carprofen, and no benefits were observed by administering grapiprant every 12 h.
Topics: Analgesics; Animals; Carbazoles; Cat Diseases; Cats; Female; Glucose; Hysterectomy; Imidazoles; Ovariectomy; Pain, Postoperative; Pyridines; Sulfonylurea Compounds; Urinalysis
PubMed: 35531962
DOI: 10.1177/1098612X221097935 -
British Journal of Industrial Medicine Oct 1957
Topics: Azo Compounds; Coloring Agents; Erythrocytes; Heinz Bodies; Hematologic Tests; Organic Chemicals
PubMed: 13471874
DOI: 10.1136/oem.14.4.275 -
Canadian Medical Association Journal Apr 1972The hematological features of phenacetin-induced hemolytic anemia are presented in order to make the physician aware of the abnormalities which suggest the use of an...
The hematological features of phenacetin-induced hemolytic anemia are presented in order to make the physician aware of the abnormalities which suggest the use of an oxidant drug. The presence of "bitten out" red cells is the commonest initial clue to the existence of drug-induced hemolytic anemia. The diagnosis is confirmed by the demonstration of Heinz bodies and sulfhemoglobinemia. Early recognition of this form of drug-abuse may avert the development or progression of analgesic nephropathy.
Topics: Adult; Aged; Anemia, Hemolytic; Erythrocytes; Female; Glucosephosphate Dehydrogenase; Glutathione; Glutathione Reductase; Glycolysis; Heinz Bodies; Hemoglobins; Humans; Male; Methemoglobin; Middle Aged; Phenacetin; Stomach Ulcer; Sulfhemoglobin
PubMed: 5016923
DOI: No ID Found