scholarly journals Hematologic and systemic metabolic alterations due to Mediterranean type II G6PD deficiency in a novel murine model

2021 ◽  
Author(s):  
Angelo D'Alessandro ◽  
Heather L Howie ◽  
Ariel M Hay ◽  
Karolina H Dziewulska ◽  
Benjamin Brown ◽  
...  
Keyword(s):  
G6pd Deficiency ◽  
Oxidant Stress ◽  
Multiple Organ ◽  
Severe Form ◽  
Missense Mutations ◽  
Human Sequence ◽  
Organ Systems ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Promoter Mutations ◽  
Altered Lipid

Deficiency of Glucose 6 phosphate dehydrogenase (G6PD) is the single most common enzymopathy, present in approximately 400 million humans (e.g. 5% of humans). Its prevalence is hypothesized to be due to conferring resistance to malaria. However, G6PD deficiency also results in hemolytic sequelae from oxidant stress. Moreover, G6PD deficiency is associated with kidney disease, diabetes, pulmonary hypertension, immunological defects, and neurodegenerative diseases. To date, the only available mouse models have decreased levels of G6PD due to promoter mutations, but with stable G6PD. However, human G6PD mutations are missense mutations that result in decreased enzymatic stability. As such, this results in very low activity in red blood cells and platelets that cannot synthesize new protein. To generate a more accurate model, the human sequence for a severe form of G6PD deficiency (Med -) was knocked into the murine G6PD locus. As predicted, G6PD levels were extremely low in RBCs and deficient mice have increased hemolytic sequalae to oxidant stress. G6PD levels were mildly decreased in non-erythroid organs, consistent with what has been observed in humans. Juxtaposition of G6PD deficient and wild-type mice revealed altered lipid metabolism in multiple organ systems. Together, these findings both establish a new mouse model of G6PD deficiency that more accurately reflects human G6PD deficiency and also advance our basic understanding of altered metabolism in this setting.

scholarly journals Glucose-6-phosphate dehydrogenase deficiency in the Han Chinese population: molecular characterization and genotype–phenotype association throughout an activity distribution

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ying He ◽  
Yinhui Zhang ◽  
Xionghao Chen ◽  
Qiong Wang ◽  
Lifen Ling ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
G6pd Deficiency ◽  
National Level ◽  
Gene Mutations ◽  
Single Mutation ◽  
Missense Mutations ◽  
Severe Deficiency ◽  
Compound Mutation ◽  
Normal Males ◽  
Glucose 6 Phosphate Dehydrogenase

Abstract Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common hereditary disorder in China. The existing prevalence and molecular epidemiology of G6PD deficiency in China were geographically limited. In this study, the spectrum of G6PD gene mutations was well characterized in a large and diverse population all over the country; and the correlation of genotype and enzyme activity phenotype was explored for the first time. The results showed that the overall prevalence of G6PD deficiency in China was 2.10% at the national level. The top six common mutations were c.1388 G>A, c.1376 G>T, c.95 A>G, c.392 G>T, c.871 G>A and c.1024 C>T, accounting for more than 90% of G6PD deficient alleles. Compound mutation patterns were frequently observed in females with severe deficiency. The distribution of G6PD activities depended on the type of mutation patterns and genders. Hemizygote, homozygote, and compound heterozygote were predominantly associated with severe G6PD deficiency, whereas heterozygotes with single mutation mainly presented moderate enzyme deficiency. A significant gap between G6PD activities in hemizygous and normal males was observed, and yet, the overall distribution of that in females carrying missense mutations was a continuum from G6PD severely deficient to normal. This is the first report of discussing the association between G6PD genetic variants in the Chinese and enzyme activity phenotypes.

scholarly journals Excess release of ferriheme in G6PD-deficient erythrocytes: possible cause of hemolysis and resistance to malaria

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 331-333 ◽  
Author(s):  
SK Janney ◽  
JJ Joist ◽  
CD Fitch
Keyword(s):  
G6pd Deficiency ◽  
Oxidant Stress ◽  
Spectrophotometric Assay ◽  
Erythrocyte Membranes ◽  
Selective Toxicity ◽  
Initial Concentration ◽  
Us Government ◽  
Government Work ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Possible Cause

Abstract Hemoglobin in glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes is abnormally vulnerable to oxidative denaturation, which may release ferriheme, a known cytolytic agent. We found 13.3 nmol of ferriheme in G6PD-deficient erythrocyte membranes (per gram of total erythrocyte hemoglobin) using a spectrophotometric assay, as compared to 9.8 in normal membranes (P less than .05). After incubation of erythrocytes with 250 mumol/L menadione, an oxidant drug, the values increased by 37.4 nmol in G6PD-deficient membranes and by 26 in normal membranes (P less than .005), indicating increased hemoglobin denaturation. To verify that hemoglobin denaturation in G6PD-deficient erythrocytes releases ferriheme in a form available to interact with other ligands, [14C]-chloroquine binding to intact erythrocytes was measured. With an initial concentration of 5 mumol/L chloroquine in a medium containing no menadione, an excess of 14.8 nmol of chloroquine was bound in G6PD-deficient erythrocytes (per gram of hemoglobin) as compared to normal erythrocytes (P less than .005). In the presence of 250 mumol/L menadione, chloroquine binding increased by 17.9 nmol in G6PD-deficient and by 7.2 in normal erythrocytes (P less than .005). These results indicate that ferriheme becomes available to interact with endogenous ligands and, thus, to mediate menadione-induced hemolysis in patients with G6PD deficiency. Furthermore, the increase in ferriheme may mediate the selective toxicity of menadione for Plasmodium falciparum parasites growing in G6PD-deficient erythrocytes. Ferriheme release in response to the intraerythrocytic oxidant stress introduced by malaria parasites also may account for the resistance to malaria afforded by G6PD deficiency. This is a US government work. There are no restrictions on its use.

scholarly journals Excess release of ferriheme in G6PD-deficient erythrocytes: possible cause of hemolysis and resistance to malaria

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 331-333
Author(s):  
SK Janney ◽  
JJ Joist ◽  
CD Fitch
Keyword(s):  
G6pd Deficiency ◽  
Oxidant Stress ◽  
Spectrophotometric Assay ◽  
Erythrocyte Membranes ◽  
Selective Toxicity ◽  
Initial Concentration ◽  
Us Government ◽  
Government Work ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Possible Cause

Hemoglobin in glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes is abnormally vulnerable to oxidative denaturation, which may release ferriheme, a known cytolytic agent. We found 13.3 nmol of ferriheme in G6PD-deficient erythrocyte membranes (per gram of total erythrocyte hemoglobin) using a spectrophotometric assay, as compared to 9.8 in normal membranes (P less than .05). After incubation of erythrocytes with 250 mumol/L menadione, an oxidant drug, the values increased by 37.4 nmol in G6PD-deficient membranes and by 26 in normal membranes (P less than .005), indicating increased hemoglobin denaturation. To verify that hemoglobin denaturation in G6PD-deficient erythrocytes releases ferriheme in a form available to interact with other ligands, [14C]-chloroquine binding to intact erythrocytes was measured. With an initial concentration of 5 mumol/L chloroquine in a medium containing no menadione, an excess of 14.8 nmol of chloroquine was bound in G6PD-deficient erythrocytes (per gram of hemoglobin) as compared to normal erythrocytes (P less than .005). In the presence of 250 mumol/L menadione, chloroquine binding increased by 17.9 nmol in G6PD-deficient and by 7.2 in normal erythrocytes (P less than .005). These results indicate that ferriheme becomes available to interact with endogenous ligands and, thus, to mediate menadione-induced hemolysis in patients with G6PD deficiency. Furthermore, the increase in ferriheme may mediate the selective toxicity of menadione for Plasmodium falciparum parasites growing in G6PD-deficient erythrocytes. Ferriheme release in response to the intraerythrocytic oxidant stress introduced by malaria parasites also may account for the resistance to malaria afforded by G6PD deficiency. This is a US government work. There are no restrictions on its use.

scholarly journals Glucose-6-phosphate dehydrogenase deficiency

Blood ◽  
2020 ◽  
Vol 136 (11) ◽  
pp. 1225-1240 ◽  
Author(s):  
Lucio Luzzatto ◽  
Mwashungi Ally ◽  
Rosario Notaro
Keyword(s):  
Hemolytic Anemia ◽  
G6pd Deficiency ◽  
Point Of Care ◽  
Diagnostic Procedures ◽  
Missense Mutations ◽  
The Stability ◽  
Almost All ◽  
Inherited Mutations ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Point Of Care Tests

Abstract Glucose 6-phosphate dehydrogenase (G6PD) deficiency is 1 of the commonest human enzymopathies, caused by inherited mutations of the X-linked gene G6PD. G6PD deficiency makes red cells highly vulnerable to oxidative damage, and therefore susceptible to hemolysis. Over 200 G6PD mutations are known: approximately one-half are polymorphic and therefore common in various populations. Some 500 million persons with any of these mutations are mostly asymptomatic throughout their lifetime; however, any of them may develop acute and sometimes very severe hemolytic anemia when triggered by ingestion of fava beans, by any of a number of drugs (for example, primaquine, rasburicase), or, more rarely, by infection. Approximately one-half of the G6PD mutations are instead sporadic: rare patients with these mutations present with chronic nonspherocytic hemolytic anemia. Almost all G6PD mutations are missense mutations, causing amino acid replacements that entail deficiency of G6PD enzyme activity: they compromise the stability of the protein, the catalytic activity is decreased, or a combination of both mechanisms occurs. Thus, genotype-phenotype correlations have been reasonably well clarified in many cases. G6PD deficiency correlates remarkably, in its geographic distribution, with past/present malaria endemicity: indeed, it is a unique example of an X-linked human polymorphism balanced through protection of heterozygotes from malaria mortality. Acute hemolytic anemia can be managed effectively provided it is promptly diagnosed. Reliable diagnostic procedures are available, with point-of-care tests becoming increasingly important where primaquine and its recently introduced analog tafenoquine are required for the elimination of malaria.

scholarly journals Hemolysis in children with Glucose-6-Phosphate Dehydrogenase deficiency after ingestion of fava beans; facts predicting severity

2020 ◽  
Vol 6 (6) ◽  
Author(s):  
Hasanein Habeeb Ghali
Keyword(s):  
G6pd Deficiency ◽  
Severe Form ◽  
P Value ◽  
Fava Bean ◽  
Younger Age ◽  
Medical City ◽  
History Of ◽  
Fava Beans ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Children Welfare

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an enzymatic disorder of red blood cells causes acute haemolysis after exposure to certain offending agents including ingestion of fava beans. This problem represents a major health issue for Iraqis, especially during the fava bean harvesting season. This study aimed to assess the demographic, clinical and biochemical characteristics as predictors of haemolysis after ingesting fava beans. Methods: A cross-sectional study was undertaken. A total of 57 patients with G6PD deficiency were recruited from the Emergency Department of Children Welfare Teaching Hospital, Medical City. Data were collected using a specially designed form. A purposive sampling method was used to recruit 57 patients 49 males and 8 females who were visiting the pediatric emergency department from March to May 2017 with a presentation of acute hemolytic episode of G6PD. Patients were classified into mild or severe haemolysis groups based on their haemoglobin level at the time of admission. Results: Younger age group patients tend to present with the severe form of hemolysis (3.59 years with a P value of 0.001). No significant gender susceptibility between both types of hemolysis. The urban area based living individuals tend to present with mild hemolysis while those from rural areas tends to present with more severe episodes of hemolysis (P value 0.001). There was a significant correlation between the type of fava bean ingestion (fresh or dried) and the severity of hemolysis, those who presented with more severe hemolysis usually had a history of ingestion of fresh type of fava bean. Eight individuals of severe type recorded previous episodes of hemolysis while three individuals of the mild type recorded previous episodes (P value 0.001). Family history of G6PD was significant in 88.2% of individuals with the severe form (P value 0.005). Conclusions: This study is aimed to report several factors that might predict the severity of hemolysis among patients with G6PD deficiency. Younger age, residence in a rural region, ingestion of fresh fava beans, and history of frequent hemolysis incidents are predictors of developing severe hemolysis among children admitted to the emergency room of Children Welfare Teaching Hospital in Medical City/Baghdad.

Microprobe analysis of inclusion bodies related to two benzofuran derivatives

1987 ◽  
Vol 45 ◽  
pp. 672-673
Author(s):  
T. L. Benning ◽  
P. Ingram ◽  
J. D. Shelburne
Keyword(s):  
Inclusion Bodies ◽  
Uranyl Acetate ◽  
Multiple Organ ◽  
High Dose ◽  
En Bloc ◽  
Tissue Samples ◽  
Transmission Electron ◽  
Organ Systems ◽  
Dense Inclusion ◽  
Melanin Complex

Two benzofuran derivatives, chlorpromazine and amiodarone, are known to produce inclusion bodies in human tissues. Prolonged high dose chlorpromazine therapy causes hyperpigmentation of the skin with electron-dense inclusion bodies present in dermal histiocytes and endothelial cells ultrastructurally. The nature of the deposits is not known although a drug-melanin complex has been hypothesized. Amiodarone may also cause cutaneous hyperpigmentation and lamellar lysosomal inclusion bodies have been demonstrated within the cells of multiple organ systems. These lamellar bodies are believed to be the product of an amiodarone-induced phospholipid storage disorder. We performed transmission electron microscopy (TEM) and energy dispersive x-ray microanalysis (EDXA) on tissue samples from patients treated with these drugs, attempting to detect the sulfur atom of chlorpromazine and the iodine atom of amiodarone within their respective inclusion bodies.A skin biopsy from a patient with hyperpigmentation due to prolonged chlorpromazine therapy was fixed in 4% glutaraldehyde and processed without osmium tetroxide or en bloc uranyl acetate for Epon embedding.

Impairment Rating and Spinal Cord Injuries: Revisiting the Guides

2010 ◽  
Vol 15 (3) ◽  
pp. 1-7
Author(s):  
Richard T. Katz
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injuries ◽  
Functional Independence ◽  
Outcome Data ◽  
Multiple Organ ◽  
Loss Of Function ◽  
Sixth Edition ◽  
Organ Systems ◽  
Cord Injury ◽  
Impairment Ratings

Abstract This article addresses some criticisms of the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) by comparing previously published outcome data from a group of complete spinal cord injury (SCI) persons with impairment ratings for a corresponding level of injury calculated using the AMA Guides, Sixth Edition. Results of the comparison show that impairment ratings using the sixth edition scale poorly with the level of impairments of activities of daily living (ADL) in SCI patients as assessed by the Functional Independence Measure (FIM) motor scale and the extended FIM motor scale. Because of the combinations of multiple impairments, the AMA Guides potentially overrates the impairment of paraplegics compared with that of quadriplegics. The use and applicability of the Combined Values formula should be further investigated, and complete loss of function of two upper extremities seems consistent with levels of quadriplegia using the SCI model. Some aspects of the AMA Guides contain inconsistencies. The concept of diminishing impairment values is not easily translated between specific losses of function per organ system and “overall” loss of ADLs involving multiple organ systems, and the notion of “catastrophic thresholds” involving multiple organ systems may support the understanding that variations in rating may exist in higher rating cases such as those that involve an SCI.

Renal Manifestations of Tuberous Sclerosis Complex

2020 ◽  
Vol 7 (3) ◽  
pp. 5-19
Author(s):  
Nikhil Nair ◽  
Ronith Chakraborty ◽  
Zubin Mahajan ◽  
Aditya Sharma ◽  
Sidarth Sethi ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Gene Disruption ◽  
Treatment Guidelines ◽  
Renal Cysts ◽  
Skin Lesions ◽  
Multiple Organ ◽  
Tsc2 Gene ◽  
Genetic Condition ◽  
Organ Systems

Tuberous sclerosis complex (TSC) is a genetic condition caused by a mutation in either the TSC1 or TSC2 gene. Disruption of either of these genes leads to impaired production of hamartin or tuberin proteins, leading to the manifestation of skin lesions, tumors and seizures. TSC can manifests in multiple organ systems with the cutaneous and renal systems being the most commonly affected. These manifestations can secondarily lead to the development of hypertension, chronic kidney disease, and neurocognitive declines. The renal pathologies most commonly seen in TSC are angiomyolipoma, renal cysts and less commonly, oncocytomas. In this review, we highlight the current understanding on the renal manifestations of TSC along with current diagnosis and treatment guidelines.

scholarly journals Attenuation of COVID-19-induced cytokine storm in a young male patient with severe respiratory and neurological symptoms

2021 ◽  
Author(s):  
Christian Muschitz ◽  
Anita Trummert ◽  
Theresa Berent ◽  
Norbert Laimer ◽  
Lukas Knoblich ◽  
...  
Keyword(s):  
Decision Making ◽  
Male Patient ◽  
Young Male ◽  
Standard Of Care ◽  
Multiple Organ ◽  
Cytokine Storm ◽  
Invasive Ventilation ◽  
Organ Systems ◽  
The Central Nervous System

SummarySevere acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), produces protean manifestations and causes indiscriminate havoc in multiple organ systems. This rapid and vast production of proinflammatory cytokines contributes to a condition termed cytokine storm. A 35-year-old, otherwise healthy, employed, male patient was tested positive for COVID-19. He was admitted to the hospital on disease day 10 due to retarded verbal reactions and progressive delirium. On account of these conditions and the need for noninvasive/invasive ventilation, a combination treatment with baricitinib and remdesivir in conjunction with standard of care was initiated. The cytokine storm was rapidly blocked, leading to a vast pulmonary recovery with retarded recovery of the central nervous system. We conclude that the rapid blockade of the COVID-19-induced cytokine storm should be considered of avail as a principle of careful decision-making for effective recovery.

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