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American Journal of Hematology May 2024
PubMed: 38817045
DOI: 10.1002/ajh.27386 -
Prenatal Diagnosis Jun 2024We evaluated fetal cardiovascular physiology and mode of cardiac failure in premature miniature piglets on a pumped artificial placenta (AP) circuit.
OBJECTIVES
We evaluated fetal cardiovascular physiology and mode of cardiac failure in premature miniature piglets on a pumped artificial placenta (AP) circuit.
METHODS
Fetal pigs were cannulated via the umbilical vessels and transitioned to an AP circuit composed of a centrifugal pump and neonatal oxygenator and maintained in a fluid-filled biobag. Echocardiographic studies were conducted to measure ventricular function, umbilical blood flow, and fluid status. In utero scans were used as control data.
RESULTS
AP fetuses (n = 13; 102±4d gestational age [term 115d]; 616 ± 139 g [g]; survival 46.4 ± 46.8 h) were tachycardic and hypertensive with initially supraphysiologic circuit flows. Increased myocardial wall thickness was observed. Signs of fetal hydrops were present in all piglets. Global longitudinal strain (GLS) measurements increased in the left ventricle (LV) after transition to the circuit. Right ventricle (RV) and LV strain rate decreased early during AP support compared with in utero measurements but recovered toward the end of the experiment. Fetuses supported for >24 h had similar RV GLS to in utero controls and significantly higher GLS compared to piglets surviving only up to 24 h.
CONCLUSIONS
Fetuses on a pump-supported AP circuit experienced an increase in afterload, and redistribution of blood flow between the AP and systemic circulations, associated with elevated end-diastolic filling pressures. This resulted in heart failure and hydrops. These preterm fetuses were unable to tolerate the hemodynamic changes associated with connection to the current AP circuit. To better mimic the physiology of the native placenta and preserve normal fetal cardiovascular physiology, further optimization of the circuit will be required.
Topics: Animals; Female; Swine; Pregnancy; Placenta; Echocardiography; Swine, Miniature; Artificial Organs; Heart Failure; Animals, Newborn; Cardiovascular Physiological Phenomena; Hydrops Fetalis
PubMed: 38809178
DOI: 10.1002/pd.6612 -
Taiwanese Journal of Obstetrics &... May 2024α-thalassemia is an autosomal recessive monogenic blood disorder, affecting up to 5% of the world's population. The occurrence rate of the disease in Vietnam varies up...
OBJECTIVES
α-thalassemia is an autosomal recessive monogenic blood disorder, affecting up to 5% of the world's population. The occurrence rate of the disease in Vietnam varies up to up to 51.5%, with high rate of mutation carriers, of couples consisting of two carriers at risk of bearing a child with fetal Hb Bart, which can develop into hydrops fetalis syndrome, threatening the well-being of the mother and the child. Our study aims to facilitate birth of healthy/asymptomatic children of α-thalassemia carrier couples who received reproductive service at our centre during the period of 2019-2022.
MATERIALS AND METHODS
89 couples at risks of having α-thalassemia offsprings requested IVF procedures and PGD at Post Hospital during 2019-2022 were recruited for investigation. Couple and additional family members' peripheral blood samples of couples and additional family members were subjected to haemoglobin electrophoresis, DNA extraction for α-thalassemia gene mutation detection and STRs linkage analysis. Data were observed and analysed on GeneMarker software.
RESULTS
91 cycles of PGD for α-thalassemia were carried out for 89 couples. α-thalassemia large deletion (--/αα) was the most common mutation identified in 88 couples, in which 4 cases also carried β-thalassemia point mutations. Combining results of PGS and PGD, 278/424 amplified embryos were transferable (HBA-mutation free or carriers of single heterozygous HBA mutation, without chromosomal abnormality). 64/89 couples have been transferred with the embryos (prioritizing mutation free ones over carriers), resulting in the birth of 36 α-thalassemia disease-free children, 17 ongoing pregnancies, and 11 with miscarriages.
CONCLUSION
Successful application of microsatellite-based method in PGD facilitated the birth of 36 healthy children and 17 ongoing pregnancies for 53/64 couples with embryo-transferred. All resulted clinical births displayed confirmation results in line with the PGD results, thus demonstrating the feasibility and credibility of the use of STR markers in PGD.
Topics: Humans; Preimplantation Diagnosis; alpha-Thalassemia; Female; Microsatellite Repeats; Pregnancy; Male; Adult; Vietnam; Heterozygote; Mutation; Fertilization in Vitro
PubMed: 38802201
DOI: 10.1016/j.tjog.2023.09.024 -
Molecular Genetics and Metabolism... Jun 2024Our study evaluated the association of the polymorphism rs724016 in the gene, previously associated with height in other populations, with predictors of height,...
OBJECTIVES
Our study evaluated the association of the polymorphism rs724016 in the gene, previously associated with height in other populations, with predictors of height, clinical outcomes, and laboratory parameters in sickle cell anemia (SCA).
METHODS
Cross-sectional study with individuals with SCA and aged between 3 and 20 years. Clinical, laboratory, molecular, and bone age (BA) data were evaluated. Levels of IGF-1 and IGFBP-3 were adjusted for BA, target height (TH) was calculated as the mean parental height standard deviation score (SDS), and predicted adult height (PAH) SDS was calculated using BA.
RESULTS
We evaluated 80 individuals with SCA. The homozygous genotype of the G allele of rs724016 was associated with a lower height SDS ( < 0.001) and, in a additive genetic model, was negatively associated with HbF levels ( = 0.016). Lower adjusted IGF-1 levels were associated with co-inheritance of alpha-thalassemia and with the absence of HU therapy. Elevated HbF levels were associated with a lower deficit in adjusted growth potential (TH minus PAH).
CONCLUSION
Our analysis shows that SNP rs724016 in the is associated with shorter height and lower HbF levels, an important modifier of SCA.
PubMed: 38800625
DOI: 10.1016/j.ymgmr.2024.101086 -
Clinica Chimica Acta; International... Jun 2024Thalassemia is one of the most common and damaging monogenic diseases in the world. It is caused by pathogenic variants of α- and/or β-globin genes, which disrupt the...
Thalassemia is one of the most common and damaging monogenic diseases in the world. It is caused by pathogenic variants of α- and/or β-globin genes, which disrupt the balance of these two protein chains and leads to α-thalassemia or β-thalassemia, respectively. Patients with α-thalassemia or β-thalassemia could exhibit a severe phenotype, with no simple and effective treatment. A three-tiered strategy of carrier screening, prenatal diagnosis and newborn screening has been established in China for the prevention and control of thalassemia, of which the first two parts have been studied thoroughly. The implementation of neonatal thalassemia screening is lagging, and the effectiveness of various screening programs has not yet been demonstrated. In this study, hemoglobin capillary electrophoresis (CE), hotspot testing method, and third-generation sequencing (TGS) were used in the variant detection of 2000 newborn samples, to assess the efficacy of these methods in neonatal thalassemia screening. Compared with CE (249, 12.45 %) and hotspot analysis (424, 21.2 %), CATSA detected the largest number of thalassemia variants (535, 26.75 %), which included 24 hotspot variants, increased copy number of α-globin gene, rare pathogenic variants, and three unreported potentially disease-causing variants. More importantly, CATSA directly determined the cis-trans relationship of variants in three newborns, which greatly shortens the clinical diagnosis time of thalassemia. CATSA showed a great advantage over other genetic tests and could become the most powerful technical support for the three-tiered prevention and control strategy of thalassemia.
Topics: Humans; Infant, Newborn; Neonatal Screening; Thalassemia; Alleles; Electrophoresis, Capillary; alpha-Globins; High-Throughput Nucleotide Sequencing
PubMed: 38796052
DOI: 10.1016/j.cca.2024.119749 -
International Journal of Molecular... May 2024Sickle cell nephropathy (SCN) is a common complication of sickle cell disease (SCD) that significantly contributes to morbidity and mortality. In addition to clinical... (Review)
Review
Sickle cell nephropathy (SCN) is a common complication of sickle cell disease (SCD) that significantly contributes to morbidity and mortality. In addition to clinical and life-style factors, genetic variants influence this risk. We performed a systematic review, searching five databases. Studies evaluating the effect of genetic modifiers on SCN were eligible. Twenty-eight studies (fair-to-good quality) were included: one genome-wide association study, twenty-six case-control studies, and one article combining both approaches. was significantly associated with albuminuria and hyperfiltration in children and with worse glomerular filtration in adults. On the other hand, alpha-thalassemia protected patients against albuminuria and hyperfiltration, while variants were protective against albuminuria alone. The long GT-tandem repeat polymorphism led to a lower glomerular filtration rate. No modifiers for the risk of hyposthenuria were identified. A genome-wide association approach identified three new loci for proteinuria (, , and ) and nine loci were linked with eGFR (, , , , , , , , and ). In conclusion, this systematic review supports the role of genetic modifiers in influencing the risk and progression of SCN. Incorporating and expanding this knowledge is crucial to improving the management and clinical outcomes of patients at risk.
Topics: Humans; Anemia, Sickle Cell; Genome-Wide Association Study; Genetic Predisposition to Disease; Kidney Diseases; Apolipoprotein L1; Disease Progression; Genes, Modifier; Glomerular Filtration Rate
PubMed: 38791464
DOI: 10.3390/ijms25105427 -
Human Antibodies 2024Tumor necrosis factor-α (TNFα) is a crucial physiologic regulator of immune responses, and several disorders have been associated with its dysregulation.
BACKGROUND
Tumor necrosis factor-α (TNFα) is a crucial physiologic regulator of immune responses, and several disorders have been associated with its dysregulation.
OBJECTIVE
This study aimed to understand TNFα gene expression in adult patients with liver and pancreas disorders and examine the impact of TNFα-238 genotypes on this population.
METHODS
At the Ibn Al-Baladi Hospital in Baghdad, blood samples were collected from forty patients who were diagnosed with beta thalassemia together with pancreatic disease, forty patients who were diagnosed with thalassemia together with liver disorder, and forty patients who were diagnosed with thalassemia without pancreas or liver disorder. For the purpose of establishing a control group, forty samples were collected from persons who were of the same age and gender and seemed to be in good health. All of these individuals were deemed to be older than 18 years old. Through the utilization of real-time polymerase chain reaction (PCR), the level of TNF-α gene expression was investigated and assessed. The T-ARMS-PCR method was performed for detection and genotyping of TNFα-238 in thalassemia patients and healthy control samples.
RESULTS
The result showed that TNF α gene expression assessment showed that group B (thalassemia patients with liver disorder) had higher folding than other groups while the lowest gene expression was in group D (as control group). Furthermore, the relationship between TNFα gene expressions folding with TNFα-238 genotypes in beta thalassemia major patients, discovered a considerable increase at GA genotype patients in TNFα gene expression level, followed by AA genotype compared to the GG genotype. Furthermore, the results of the current study showed an association between the presence of the mutant (A) allele whether heterozygous (GA) and homozygous (AA) with the TNF-α gene expression in thalassemia patients with liver and pancreatic disorders.
CONCLUSION
Based on the results, it can be concluded that there is a relationship between the presence of the mutant (A) allele, whether heterozygous (GA) or homozygous (AA) of TNF-α 238, and TNF-α gene expression in liver and pancreatic diseases as well as in patients with thalassemia.
Topics: Humans; beta-Thalassemia; Tumor Necrosis Factor-alpha; Adult; Male; Female; Iraq; Genotype; Liver Diseases; Pancreatic Diseases; Polymorphism, Single Nucleotide; Young Adult; Case-Control Studies; Gene Frequency; Gene Expression; Adolescent; Genetic Predisposition to Disease; Alleles
PubMed: 38788064
DOI: 10.3233/HAB-240022 -
BioRxiv : the Preprint Server For... May 2024Alpha-thalassemia is an autosomal recessive disease with increasing worldwide prevalence. The molecular basis is due to mutation or deletion of one or more duplicated...
Alpha-thalassemia is an autosomal recessive disease with increasing worldwide prevalence. The molecular basis is due to mutation or deletion of one or more duplicated α-globin genes, and disease severity is directly related to the number of allelic copies compromised. The most severe form, α-thalassemia major (αTM), results from loss of all four copies of α-globin and has historically resulted in fatality . However, transfusions now enable survival to birth. Postnatally, patients face challenges similar to β-thalassemia, including severe anemia and erythrotoxicity due to imbalance of β-globin and α-globin chains. While curative, hematopoietic stem cell transplantation (HSCT) is limited by donor availability and potential transplant-related complications. Despite progress in genome editing treatments for β-thalassemia, there is no analogous curative option for patients suffering from α-thalassemia. To address this, we designed a novel Cas9/AAV6-mediated genome editing strategy that integrates a functional α-globin gene into the β-globin locus in αTM patient-derived hematopoietic stem and progenitor cells (HSPCs). Incorporation of a truncated erythropoietin receptor transgene into the α-globin integration cassette dramatically increased erythropoietic output from edited HSPCs and led to the most robust production of α-globin, and consequently normal hemoglobin. By directing edited HSPCs toward increased production of clinically relevant RBCs instead of other divergent cell types, this approach has the potential to mitigate the limitations of traditional HSCT for the hemoglobinopathies, including low genome editing and low engraftment rates. These findings support development of a definitive autologous genome editing strategy that may be curative for α-thalassemia.
PubMed: 38766216
DOI: 10.1101/2023.09.01.555926 -
Obstetrical & Gynecological Survey May 2024Although the risk of parvovirus B19 infection during pregnancy and subsequent risk of adverse fetal outcome are low, understanding management practices is essential for... (Review)
Review
IMPORTANCE
Although the risk of parvovirus B19 infection during pregnancy and subsequent risk of adverse fetal outcome are low, understanding management practices is essential for proper treatment of fetuses with nonimmune hydrops fetalis. In addition, continued investigation into delivery management, breastfeeding recommendations, and congenital abnormalities associated with pregnancies complicated by parvovirus B19 infection is needed.
OBJECTIVE
This review describes the risks associated with parvovirus B19 infection during pregnancy and the management strategies for fetuses with vertically transmitted infections.
EVIDENCE ACQUISITION
Original articles were obtained from literature search in PubMed, Medline, and OVID; pertinent articles were reviewed.
RESULTS
Parvovirus B19 is a viral infection associated with negative pregnancy outcomes. Up to 50% of people of reproductive age are susceptible to the virus. The incidence of B19 in pregnancy is between 0.61% and 1.24%, and, overall, there is 30% risk of vertical transmission when infection is acquired during pregnancy. Although most pregnancies progress without negative outcomes, viral infection of the fetus may result in severe anemia, congestive heart failure, and hydrops fetalis. In addition, vertical transmission carries a 5% to 10% chance of fetal loss. In pregnancies affected by fetal B19 infection, Doppler examination of the middle cerebral artery peak systolic velocity should be initiated to surveil for fetal anemia. In the case of severe fetal anemia, standard fetal therapy involves an intrauterine transfusion of red blood cells with the goal of raising hematocrit levels to approximately 40% to 50% of total blood volume. One transfusion is usually sufficient, although continued surveillance may indicate the need for subsequent transfusions. There are fewer epidemiologic data concerning neonatal risks of congenital parvovirus, although case reports have shown that fetuses with severe anemia in utero may have persistent anemia, thrombocytopenia, and edema in the neonatal period.
CONCLUSIONS AND RELEVANCE
Parvovirus B19 is a common virus; seropositivity in the geriatric population reportedly reaches 85%. Within the pregnant population, up to 50% of patients have not previously been exposed to the virus and consequently lack protective immunity. Concern for parvovirus B19 infection in pregnancy largely surrounds the consequences of vertical transmission of the virus to the fetus. Should vertical transmission occur, the overall risk of fetal loss is between 5% and 10%. Thus, understanding the incidence, risks, and management strategies of pregnancies complicated by parvovirus B19 is essential to optimizing care and outcomes. Further, there is currently a gap in evidence regarding delivery management, breastfeeding recommendations, and the risks of congenital abnormalities in pregnancies complicated by parvovirus B19. Additional investigations into optimal delivery management, feeding plans, and recommended neonatal surveillance are needed in this cohort of patients.
Topics: Humans; Pregnancy; Female; Infectious Disease Transmission, Vertical; Pregnancy Complications, Infectious; Parvovirus B19, Human; Hydrops Fetalis; Parvoviridae Infections; Erythema Infectiosum; Pregnancy Outcome
PubMed: 38764205
DOI: 10.1097/OGX.0000000000001263