Hematologic Dysfunction Research Articles

Toxic Effects of Cobalt on Erythroid Progenitor Cells.

Cobalt is a crucial trace element that widely exists in natural environments and is necessary for normal physiological function. However, excessive cobalt exposure leads to various adverse health effects, especially hematological and endocrine dysfunctions. Here, we investigated the toxicity of cobalt on early erythropoiesis by using ex vivo cultured erythroid progenitor cells (EPCs). We exposed EPCs to cobalt chloride (CoCl2) and observed that their proliferation was significantly reduced after treatment with 50 μM CoCl2 for 3 days and 10 μM CoCl2 for 4 days. Furthermore, CoCl2 exposure reduced the proportion of S phase cells and induced apoptosis of EPCs in a dose-dependent manner (20-100 μM). Notably, further studies revealed that CoCl2 exposure inhibited the expression and phosphorylation of the erythroid proliferation master gene c-Kit. During EPC differentiation, treatment with CoCl2 hindered the enucleation of erythrocytes. Consistent with these findings, the RNA-seq results revealed that CoCl2 treatment inhibited the expression of several genes related to both proliferation and differentiation. The gene responsible for nucleoprotein export during enucleation, Xpo7, was also downregulated. Gene ontology analysis revealed that CoCl2 treatment inhibited a variety of biological processes, including DNA replication and ribosome synthesis. In summary, we demonstrated that sustained excessive CoCl2 exposure impaired the function of the EPCs.

Perioperative Management of Patients with Preeclampsia: A Comprehensive Review.

Preeclampsia is a common condition of pregnancy characterized by hypertension complicated by cerebral, cardiac, hepatic, renal, hematologic, and placental dysfunction. Patients with preeclampsia frequently undergo cesarean delivery, the most common major surgical procedure in the world. They represent a high-risk perioperative cohort suffering significant preventable morbidity and mortality. This review focuses on the anesthesiologist's role, through a perioperative lens, in reducing maternal complications through management of hypertension and strategies for preserving the function of the brain, heart, liver, kidney, hematologic and coagulation systems, and placenta in patients with preeclampsia undergoing cesarean delivery. Preeclampsia-specific resuscitation, individualized fluid administration, safe neuraxial and general anesthesia, and management of intraoperative bleeding are discussed along with strategies for postoperative analgesia, thromboprophylaxis, and antihypertensive agents in patients who breastfeed. This review discusses recently recognized postoperative deterioration in maternal mental health, the possibility of myocardial injury after cesarean delivery, and the need for long-term cardiometabolic follow-up.

P04 A vexing case of polymyalgia rheumatica

Abstract Introduction VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described autoinflammatory condition characterised by somatic mutations in the UBA1 gene, resulting in significant morbidity. Disease presentation can mimic several rheumatological conditions, delaying diagnosis and appropriate management. This case report presents the clinical course of a patient with a complex history of musculoskeletal symptoms and systemic inflammation, first diagnosed with polymyalgia rheumatica (PMR), who was later identified as having VEXAS syndrome almost six years after first referral to the rheumatology clinic. It illustrates the importance of considering rare autoinflammatory conditions in patients with atypical presentations of common rheumatological disorders. Case description A 76-year-old gentleman was referred from the haematology clinic where he had undergone investigation for pancytopenia and raised inflammatory markers. Initial investigations under the haematology team revealed normal CT chest, abdomen and pelvis, unremarkable bone marrow biopsy and cytogenetics. He presented with muscle stiffness and proximal limb girdle pain. Additional symptoms included fatigue and a diffuse non-specific erythematous rash. There was no significant past medical history and he was previously very fit and active. Rheumatology investigations were normal, apart from persistently elevated inflammatory markers (ESR 86 mm/h and CRP 70 mg/L). A diagnosis of polymyalgia rheumatica was made and prednisolone 15 mg was started. Although he initially had a good response to this, he continued to experience significant inflammatory and constitutional symptoms. These included small joint polyarthritis, night sweats and weight loss. He was pancytopenic with associated reduced exercise tolerance, requiring transfusions and erythropoietin. To exclude other differentials, a repeat bone marrow biopsy was performed. This revealed dysplasia likely secondary to underlying inflammation, although no clonal abnormalities or vacuoles were detected. MRI right hand showed synovitis, and he was therefore treated for myalgic-onset rheumatoid arthritis. Prednisolone dose was increased temporarily and methotrexate was added, resulting in temporary improvement of his ESR 16 mm/h and CRP 25 mg/L. The patient continued to have ongoing constitutional symptoms and developed new ataxia. Further investigations, including MRI head, gastroscopy and Whipple’s PCR were all normal. Repeat CT chest, abdomen and pelvis and PET-CT were unremarkable. His symptoms and inflammatory markers were responsive to steroids. Given his symptoms and macrocytosis, he was tested for ubiquitin-activating enzyme UBA1 gene which was positive, confirming the diagnosis of VEXAS syndrome. Methotrexate was stopped due to worsening cytopenia, prednisolone continued and tocilizumab started. He showed significant improvement in pancytopenia and symptoms following initiation of tocilizumab. Discussion VEXAS is characterised by somatic mutations in the UBA1 gene; its pathogenesis leads to malfunctioning methionine-41, an enzyme that initiates ubiquitylation. This leads to increased activation of innate immune pathways and induces systemic inflammation, manifesting in a variable clinical presentation. This variability makes the diagnosis challenging and leads to a median diagnostic delay of 5.5 years, similar to our patient’s six-year delay. Our patient was initially managed as PMR due to his clinical presentation and lack of an obvious alternative diagnosis. This misdiagnosis is not unique. Often, patients later diagnosed with VEXAS are first managed as either inflammatory conditions, notably polychondritis, vasculitis or Sweet’s syndrome, or myelodysplastic syndrome (MDS). VEXAS is hallmarked by haematological dysfunction as much as it is by inflammatory features. In fact, our patient’s first signs included a mild cytopenia which later developed into a progressive macrocytic anaemia. This is classical of VEXAS. Other haematological manifestations include thrombotic events and MDS, with minimal response to EPO-stimulating agents as seen here. His ongoing deterioration triggered an alternative diagnosis to be sought. VEXAS is unusual as an autoinflammatory disease: its causative mechanism is a somatic mutation acquired later in life. Its diagnosis can be confirmed by inactivation of the x-linked UBA1 gene. This case highlights the need for UBA1 testing when dealing with an unexplained inflammatory phenotype, especially in men with cytopenia, multiorgan autoinflammation or MDS-like features. VEXAS presents a management challenge. The term ‘haeamatoinflammatory’ has been created to reflect its unique nature, warranting input from both specialist teams as well as the wider MDT. Key learning points • VEXAS should be considered as a differential when dealing with unexplained inflammatory symptoms, especially in men, multiorgan autoinflammation, vasculitis and/or MDS-like features. • VEXAS is often progressive and transfusion-dependence is associated with a poorer prognosis. A macrocytic anaemia is a prominent feature of the condition. • The absence or low proportion of vacuoles in bone marrow should not prevent us from testing for VEXAS if clinically indicated. • No established protocols for VEXAS yet exist. Haematological management is supportive. Anti-inflammatory treatment is based on collective observed evidence, including the use of tocilizumbab (anti-IL6) and janus kinase (JAK) inhibitors. Allogenic haemopoietic stem cell transplantation has been successful in few patients and may represent an option for patients with severe disease.

Haematology and histology studies on Moringa oleifera leaves and bark extracts in streptozotocin-induced diabetic albino rats

Alterations in haematological parameters are frequently observed in individuals with diabetes mellitus (DM). Oxidative stress has been identified as a contributing factor in the pathogenesis of organ damage and haematological dysfunction associated with DM. As a result, the potential positive impact of Moringa oleifera, a medicinal plant known for its antioxidant properties, on haematological parameters and kidney function in diabetic rats was investigated. A total of thirty-five rats were divided into seven groups, each consisting of five rats. Group I was administered only distilled water, while groups II to VII were induced with a single dose of 60mg/kg streptozotocin intraperitoneally. Subsequently, groups II to VI were treated with 150 mg/kg Moringa oleifera leaf methanol extract, 150 mg/kg Moringa oleifera bark methanol extract, 300 mg/kg Moringa oleifera leaf, 300 mg/kg Moringa oleifera bark, and metformin, respectively. The results showed positive modulation to most of the haematology parameters evaluated except neutrophils and lymphocytes by the treatments. The leaf extract showed a more significant modulation of platelets than other treatments. The histology of the kidney showed normal structure for all the treatments. Moringa oleifera especially the leaf extract is promising in the treatment of DM

The Ambivalence of Post COVID-19 Vaccination Responses in Humans.

The Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has prompted a massive global vaccination campaign, leading to the rapid development and deployment of several vaccines. Various COVID-19 vaccines are under different phases of clinical trials and include the whole virus or its parts like DNA, mRNA, or protein subunits administered directly or through vectors. Beginning in 2020, a few mRNA (Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273) and adenovirus-based (AstraZeneca ChAdOx1-S and the Janssen Ad26.COV2.S) vaccines were recommended by WHO for emergency use before the completion of the phase 3 and 4 trials. These vaccines were mostly administered in two or three doses at a defined frequency between the two doses. While these vaccines, mainly based on viral nucleic acids or protein conferred protection against the progression of SARS-CoV-2 infection into severe COVID-19, and prevented death due to the disease, their use has also been accompanied by a plethora of side effects. Common side effects include localized reactions such as pain at the injection site, as well as systemic reactions like fever, fatigue, and headache. These symptoms are generally mild to moderate and resolve within a few days. However, rare but more serious side effects have been reported, including allergic reactions such as anaphylaxis and, in some cases, myocarditis or pericarditis, particularly in younger males. Ongoing surveillance and research efforts continue to refine the understanding of these adverse effects, providing critical insights into the risk-benefit profile of COVID-19 vaccines. Nonetheless, the overall safety profile supports the continued use of these vaccines in combating the pandemic, with regulatory agencies and health organizations emphasizing the importance of vaccination in preventing COVID-19's severe outcomes. In this review, we describe different types of COVID-19 vaccines and summarize various adverse effects due to autoimmune and inflammatory response(s) manifesting predominantly as cardiac, hematological, neurological, and psychological dysfunctions. The incidence, clinical presentation, risk factors, diagnosis, and management of different adverse effects and possible mechanisms contributing to these effects are discussed. The review highlights the potential ambivalence of human response post-COVID-19 vaccination and necessitates the need to mitigate the adverse side effects.

A case of VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic) syndrome presenting as progressive multisystem involvement with parenchymal infiltrates following infection with Epstein Barr virus

AbstractVEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, and somatic) syndrome is a rare multisystem disease affecting predominantly males over 50 and manifesting as widespread progressive inflammatory sequelae and haematological dysfunction. We describe a patient who presented with systemic symptoms of fevers, night sweats and weight loss, and developed progressive inflammatory sequelae including cutaneous lesions, haematological dysfunction, lymphadenopathy, migratory inflammatory arthropathies, with new pulmonary infiltrates, following infection with Epstein Barr Virus. Laboratory investigations, bronchoscopy, bone marrow biopsy and imaging were consistent with an inflammatory aetiology. The constellation of organ system involvement, laboratory, biopsy, and imaging results were suspicious for VEXAS syndrome, and this diagnosis was confirmed by identification of a somatic mutation in the UBA1 gene following extensive exclusion of infectious and autoimmune causes. Interestingly the onset of the VEXAS syndrome coincided with serological confirmation of Epstein Barr Virus raising the importance of further exploration into the underlying aetiology of VEXAS syndrome.

SBDS Gene Mutation Increases ROS Production and Causes DNA Damage as Well as Oxidation of Mitochondrial Membranes in the Murine Myeloid Cell Line 32Dcl3.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease caused by mutation in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. SDS has a variety of clinical features, including exocrine pancreatic insufficiency and hematological dysfunction. Neutropenia is the most common symptom in patients with SDS. SDS is also associated with an elevated risk of developing myelodysplastic syndromes and acute myeloid leukemia. The SBDS protein is involved in ribosome biogenesis, ribosomal RNA metabolism, stabilization of mitotic spindles and cellular stress responses, yet the function of SBDS in detail is still incompletely understood. Considering the diverse function of SBDS, the effect of SBDS seems to be different in different cells and tissues. In this study, we established myeloid cell line 32Dcl3 with a common pathogenic SBDS variant on both alleles in intron 2, 258 + 2T > C, and examined the cellular damage that resulted. We found that the protein synthesis was markedly decreased in the mutant cells. Furthermore, reactive oxygen species (ROS) production was increased, and oxidation of the mitochondrial membrane lipids and DNA damage were induced. These findings provide new insights into the cellular and molecular pathology caused by SBDS deficiency in myeloid cells.

Assessment of serum proprotein convertase subtilisin/kexin type 9 in pediatric sepsis syndrome

Sepsis is a life-threatening condition that arises when the body's response to infection causes injury to its tissues and organs. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme released in response to the drop in cholesterol level occurring in sepsis. Our study aimed to evaluate the prognostic role of serum Proprotein convertase subtilisin/kexin type 9 (PCSK9) level in children with sepsis and severe sepsis. Sixty children were included in this study. They were divided into two groups: 30 children in the sepsis group and 30 in the severe sepsis group. Another 30 apparently healthy children were included as a control group. Blood samples were withdrawn from all included children for complete blood count (CBC), renal function tests (RFT), liver function tests (LFT), LDL-cholesterol (LDL-C), blood culture, and serum PCSK9. In this study, PCSK9 and LDL-C were higher in the two sepsis groups than in the control group (p < 0.05). They were also higher in the severe sepsis group than the sepsis group and in the non-survivors than in the survivors (p < 0.05). PCSK9 was positively correlated with length of hospital stay in surviving children (r = 0.67, p = 0.001) and had predicted significant hematological dysfunction (adjusted B = − 96.95, p = 0.03). In conclusion, the PCSK9 assay can be used as a biomarker for bad prognosis in children suffering from clinical sepsis.

Clonal Hematopoiesis in Patients With Neuroendocrine Tumor Treated With Lutetium-177 and the Risk of Thrombocytopenia: A Prospective Study.

Thrombocytopenia is a relatively common dose-limiting toxicity during peptide receptor radionuclide therapy (PRRT) in patients with NET. Although uncommon, some patients develop persistent cytopenia and eventually therapy-related myeloid neoplasm (t-MN), which has a dismal prognosis. As the indications for PRRT are expanding, it is important to investigate factors that may predict cytopenias during/after PRRT. We prospectively evaluated the prevalence of clonal hematopoiesis (CH) and cytopenia in patients with NET undergoing PRRT. Patients with metastatic NET with plan to receive four cycles of lutetium-177 were enrolled. CH was evaluated before PRRT using a panel of 220 genes with a targeted depth of ≥1,000×. Patients were followed during PRRT and every 3 months thereafter. Of 37 patients enrolled, the median age was 68 years and 51.4% were male. Previous treatment exposures included alkylating agents in 30%, platinum agents in 8%, and external radiation in 13%. CH was detected in 35.1% using a variant allele frequency (VAF) cutoff of ≥2% and 45.9% with a VAF of ≥1%. The most common mutations were in age-related genes (DNMT3A, TET2). CH was not associated with anemia or neutropenia; however, it was associated with lower platelet count at baseline and more time spent in a thrombocytopenic state during/after PRRT. Five patients had bone marrow biopsies (BMBs) because of sustained hematologic dysfunction post-PRRT, and of those, diagnoses included clonal cytopenia of undetermined significance (CCUS) in three and idiopathic cytopenia of undetermined significance (ICUS) in two. CH is present in 35.1% of patients with NET and is associated with thrombocytopenia risk during PRRT. Future studies with long-term follow-up will delineate whether CH might be a predictor for higher risk of t-MN after PRRT.

The frequency and timing of sepsis-associated coagulopathy in the neonatal intensive care unit.

Sepsis is a common cause of morbidity and mortality in the neonatal intensive care unit (NICU). The frequency and severity of sepsis-associated coagulopathy as well as its relationship to illness severity are unclear. We performed a single-center, retrospective, observational cohort study of all infants admitted to the University of Florida Health (UF Health), level IV NICU between January 1st 2012 to March 1st 2020 to measure the frequency of sepsis-associated coagulopathy as well as its temporal relationship to critical illness in the NICU population. All clinical data in the electronic health record were extracted and deposited into an integrated data repository that was used for this work. We identified 225 new sepsis episodes in 216 patients. An evaluation for sepsis-associated coagulopathy was performed in 96 (43%) episodes. Gram-negative pathogen, nSOFA score at evaluation, and mortality were greater among episodes that included a coagulopathy evaluation compared with those that did not. Abnormal coagulation results were common (271/339 evaluations; 80%) and were predominantly prothrombin times. Intervention (plasma or cryoprecipitate) followed a minority (84/271; 31%) of abnormal results, occurred in 40/96 (42%) episodes that were often associated with >1 intervention (29/40; 73%), and coincided with thrombocytopenia in 37/40 (93%) and platelet transfusion in 27/40 (68%). Shapley Additive Explanations modeling demonstrated strong predictive performance for the composite outcome of death and/or treatment for coagulopathy in neonates (f1 score 0.8, area under receiver operating characteristic curve 0.83 for those with abnormal coagulation values). The three most important features influencing the composite outcome of death or treatment for coagulopathy included administration of vasoactive medications, hematologic dysfunction assessed by the maximum nSOFA platelet score, and early sepsis (≤72 h after birth). A coagulopathy evaluation was performed in a minority of NICU patients with sepsis and was associated with greater illness severity and mortality. Abnormal results were common but infrequently associated with intervention, and intervention was contemporaneous with thrombocytopenia. The most important feature that influenced the composite outcome of death or treatment for coagulopathy was the administration of vasoactive-inotropic medications. These data help to identify NICU patients at risk of sepsis-associated coagulopathy.

Characteristics of patients with newly diagnosed hematological malignancies referred for echocardiography.

The importance of cardio-hemato-oncology programs is increasing. The main aim of the study was to identify all coexisting cardiovascular disorders in patients with new hematological malignancies referred for echocardiography during baseline evaluation before anticancer therapy. The study was based on 900 echocardiographic examinations performed within 12 months at the Institute of Hematology and Transfusion Medicine in Poland: 669 tests (74.3%) were dedicated to hemato-oncology patients at the different stages of cancer therapy, however almost a third of the tests (277, 30.8%) were part of a baseline evaluation before starting first line anticancer therapy due to newly diagnosed hematological malignancies. The group of 277 patients with new hematological malignancies (138 women, 49.82%) with a median age of 66 years (interquartile range: 53-72 years) was included in the main analyses. The three most frequent new histopathological diagnoses were: non-Hodgkin lymphoma (63 cases; 22.74%), acute myeloid leukaemia (47 cases; 16.97%), and multiple myeloma (45 cases; 16.25%). The three most common clinical cardiology disorders were arterial hypertension (in 133 patients, 48.01%), arrhythmias (48 patients, 17.33%), and heart failure (39 patients, 14.08%). Among 48 patients with arrhythmias there were 22 cases with atrial fibrillation. The most frequently detected echocardiographic abnormality was Left Atrial Volume Index >34 ml/m2 which was present in 108 of 277 patients (38.99%) and associated with a significantly greater chance of concomitant diagnosis of arrhythmias (OR=1.98; p=0.048) especially atrial fibrillation (OR=3.39; p=0.025). The second most common echocardiographic finding was diastolic dysfunction 2nd or 3rd degree revealed in 43 patients (15.52%) and associated with a greater chance of simultaneous diagnosis of heart failure (OR=8.32; p<0.0001) or arrhythmias (OR=4.44; p<0.0001) including atrial fibrillation (OR=5.40; p=0.0003). In patients with newly diagnosed hematological malignancies left ventricular diastolic dysfunction is a common abnormality in echocardiography and may determine diagnoses of heart failure or arrhythmias.

Effect of Thyroid Dysfunctions on Complete Blood Count in Almatama Town-Sudan

Background: Thyroid hormones have a crucial role in the metabolism and proliferation of blood cells. Thyroid dysfunction causes different outcomes on blood cells such as anemia, erythrocytosis, leukopenia, thrombocytopenia, and in rare cases causes’ pancytopenia. It also alters RBC indices including MCV, MCH, MCHC, and RDW. Objectives: This is a cross-sectional descriptive study conducted in Almatama town during the period from September 2021 to January 2022, aimed to assess the effects of hypothyroidism and hyperthyroidism on blood cell count and RBC indices. Materials and Methods: Fifty patients with thyroid disease (24 hyperthyroidism, 26 hypothyroidism) and 20 healthy subjects served as controls. Whole venous blood samples were collected in EDTA anticoagulant container, mixed well, transferred to the laboratory according to standard procedures to avoid contamination, and then automatically counted for complete blood counts. Results: RBCs, HB, MCV, MCHC, and MCH, had statistically insignificant results in thyroid patients when compared with the control group (P. value 0.225,0.077,0.235,0.498,0.626) respectively. In hyperthyroid RBCs, HB, PCV, MCV, and MCH were statistically insignificant (P. value 0.388,0.951,0.123,0.575,0.148) respectively, and a statistically significant MCHC (P. value 0.0020). In hypothyroid HB, PCV, and MCH were, statistically significant (P. value 0.001,0.010,0.029) respectively, RBCs, MCV, and MCHC were, statistically insignificant (P. value 0.166,0.107,0.125) respectively. Conclusions: The hematological parameters were affected by thyroid disease, In case of patients with unknown hematological dysfunctions, must be evaluated for thyroid hormones. The follow-up of patients with thyroid disorders should have the complete blood count and patients diagnosed with anemia should be considered for thyroid conditions before iron treatment. Cases of anemia that resist therapy should be investigated for the case of thyroid dysfunction.

Adult-onset combined methylmalonic acidemia and hyperhomocysteinemia, cblC type with aortic dissection and acute kidney injury: a case report

BackgroundCombined methylmalonic acidemia (MMA) and hyperhomocysteinemia, cobalamin C (cblC) type, also named cblC deficiency is a rare autosomal recessive genetic metabolic disease. It progressively causes neurological, hematologic, renal and other system dysfunction. The clinical manifestations are relatively different due to the onset time of disease.Case presentationThis report describes a rare case of a 26 year old man with cblC deficiency who developed life-threatening aortic dissection and acute kidney injury (AKI) and showed neuropsychiatric symptoms with elevated serum homocysteine and methylmalonic aciduria. After emergent operation and intramuscular cobalamin supplementation therapy, the male recovered from aortic dissection, neurological disorder and AKI. Finally, two previously published compound heterozygous variants, c.482G > A (p.R161Q) and c.658_660del (p.K220del) in the MMACHC gene were detected in this patient and he was confirmed to have cblC deficiency.ConclusionsPoor cognizance of presenting symptoms and biochemical features of adult onset cblC disease may cause delayed diagnosis and management. This case is the first to depict a case of adult-onset cblC deficiency with aortic dissection. This clinical finding may contribute to the diagnosis of cblC deficiency.

Haematological, biochemical, enzymological changes and mitochondrial dysfunction of liver in freshwater climbing perch Anabas testudineus during their acute and chronic exposure to sodium fluoride

Anthropogenic activities are increasing fluoride concentration in watercourses. The present study focuses on the sublethal toxicity of sodium fluoride during sub-chronic and chronic time periods in the freshwater fish Anabas testudineus. The 96-hour LC50 value for fluoride was found to be 616.50 mg/L. Excessive mucous production and hyper excitability, followed by loss of balance, were seen in fish under acute fluoride exposure. Significant reduction in yield and specific growth rate of fish were assessed at 15, 30 and 45-days exposure intervals. Different bio-indicators like Hepatosomatic-index, Gonadosomatic-index and fecundity were reduced significantly in fish exposed to 10% (61.6 mg/L) and 20% (123.2 mg/L) of 96 h of LC50 values of fluoride in comparison to control. Toxicant concentrations directly correlated with parameter lowering. Fluoride exposure increased plasma glucose, creatinine, AST, and ALT and reduced total RBC, haemoglobin content, Hct (%), plasma protein, and cholesterol. Moreover, fluoride exposure significantly reduces the mitochondrial membrane potential in liver. This may result in metabolic depression, haematological, biochemical, and enzymological stress. The in-silico structural analysis predicts that fluoride may impede cytochrome c oxidase of the electron transport system, hence inhibiting mitochondrial functionality. These findings collectively highlight the urgent need for stringent regulation and monitoring of fluoride levels in freshwater ecosystems, as the subchronic and chronic effects observed in A. testudineus may have broader implications for aquatic ecosystems.

Assessment of Organ Dysfunction and Underlying Causes in Maternal Near-miss Cases at Health Care Facilities in Doiwala Block of District Dehradun - A Retrospective Study.

The extent of maternal morbidity is a good gauge of a nation's maternal health care system. Maternal near-miss (MNM) cases need to be reviewed because they can indirectly contribute significantly to reducing the maternal mortality ratio in India. MNM cases can provide useful information in this context. Such women who survive these life-threatening conditions arising from complications during pregnancy, childbirth and post partum (42 days) share many commonalities with those who die because of such complications. To assess the organ dysfunction and the underlying causes, associated/contributory factors associated with "maternal near-miss" cases in pregnant, in labor, post-partum women (upto42 days) in the health care facilities of Doiwala block, district Dehradun. The present study was conducted over a period of 6 months under the Department of Community and Family Medicine, All India Institute of Medical Sciences, Rishikesh. The cross-sectional study included the medical record files of all pregnant women attending the Department of Obstetrics and Gynecology, in the selected healthcare facilities of Doiwala block, district Dehradun. This study was conducted as per the WHO criteria for "near-miss" by using convenience sampling for the selection of healthcare facilities. The medical record files of all women who were pregnant, in labor, or who had delivered or aborted up to 42 days were included from a period of 01.06.2021 - 31.05.2022. It was found that Out of the women with maternal near-miss (n=91), the majority of women had coagulation /hematological dysfunction (n=45, 49.4%), followed by neurologic dysfunction (n=15, 16.4%), cardio-vascular dysfunction (n=11, 12%). Out of the total women with a maternal near-miss (n = 91), 10 women underwent multiple organ dysfunctions. Of the total 91 maternal near-miss cases, the underlying cause of near-miss was obstetric hemorrhage in almost half the participants (n=45, 49.5%) followed by hypertensive disorders (n=36, 39.5%). Eleven women had a pregnancy with abortive outcomes (12%) and 7 women had pregnancy-related infection. It was also seen that, out of 91 near-miss women, the leading contributory /associated cause was Anemia (n=89, 97.8%) followed by women having a history of previous cesarean section (n=63, 69.2%). Sixteen women had prolonged /obstructed labor (n = 16, 17.58%). Pregnancy should be a positive experience for every woman of childbearing age. A better understanding of pregnancy-related conditions enables early detection of complications and prevents the conversion of mild to moderate maternal morbidity outcomes to severe maternal outcomes with long-term health implications or death. There are already effective measures in place to reduce maternal and newborn mortality and morbidity.

Metabolic Programming of Hematopoietic Stem Cell Function By Prenatal Folate

Hematopoietic stem cells (HSCs) are programmed by metabolic changes resulting in alterations to HSC function. Here, we discovered that varying prenatal folate status metabolically programs HSCs during development and affects adult HSC self-renewal and engraftment potential into adulthood. Folate status varies greatly in the global population based on nutritional intake, common genetic polymorphisms, and widespread supplementation. Folate-derived one-carbon metabolism (OCM) regulates cellular methylation, de novo nucleotide biosynthesis and mitochondrial metabolism, processes critical to HSC function and establishment. Despite immense therapeutic potential, there is limited understanding of mechanisms driving HSC developmental programming. We hypothesize that varying prenatal folate status affects risk for hematologic dysfunction by developmentally programming HSCs. To test how prenatal folate modulated HSC function, female mice were assigned to one of three experimental diets to model population-wide folate consumption: 0mg/kg (deficient, FD), 2mg/kg (control, FC) and 8mg/kg (supplemented, FS). Profiling of fetal liver (FL) hematopoietic cells revealed that FD diet caused expansion of long term (LT)-HSCs that was propagated across the hematopoietic hierarchy, including myeloid and lymphoid progenitors and mature myeloid cells. In contrast, FS decreased FL cell output. We next determined if these changes were driven by metabolic activity. FD fetal HSPCs exhibited higher mitochondrial membrane potential and lower glycolytic activity, whereas FS fetal HSPCs displayed both higher glycolytic activity and oxygen consumption despite impaired production of downstream hematopoietic cells. Together, these data suggest that HSPC metabolic programming initiates during fetal development and is folate-dose dependent. To determine if prenatal folate programs hematopoiesis into adulthood, we quantified bone marrow (BM) hematopoietic cells in adult offspring after weaning onto standard chow. Surprisingly, FD expanded lymphoid progenitors in adult offspring with no impact on mature lymphoid cell output. In contrast, FS diet expanded myeloid and lymphoid progenitors in the BM as well as downstream mature cells, including monocytes and B-cells. To determine if these effects were HSC cell-intrinsic, we performed competitive transplantation assays of LT-HSCs isolated from adult offspring. FD offspring HSCs showed worse engraftment by chimerism across all peripheral blood (PB) populations compared to FC. In comparison, FS offspring HSCs showed enhanced total cellular output by donor cells/uL across all PB mature lineages except platelets. Secondary whole BM transplantation revealed that FS HSCs retained enhanced total cellular output and superior engraftment compared to FC, whereas FD HSCs demonstrated complete exhaustion. These data indicate that adult HSC function is programmed by prenatal folate status. To investigate molecular alterations driving metabolic programming of adult hematopoiesis by prenatal folate, we performed single-cell RNA sequencing (Scseq) and metabolomics on adult offspring HSPCs. Scseq analysis revealed most differential gene expression (DE) in HSC clusters, with less DE in progenitors. Re-clustering of all HSCs revealed distinct heterogeneity within this population, where both FD and FS HSCs were identified as distinct clusters compared to FC. Metabolomic profiling further suggested that FD HSCs exhibited signs of mitochondrial dysfunction through, 1) accumulating glucose and lactate suggesting reliance on glycolysis and, 2) accumulating succinate and glutamine suggesting complex II impairment and inadequate utilization of mitochondrial metabolism. Surprisingly, the same changes associated with mitochondrial dysfunction in FD HSCs persisted downstream into lymphoid-biased multipotent progenitors. In contrast, limited metabolic changes were observed in FS HSCs, suggesting alternative pathways for sustained programming. These changes indicate that FD and FS offspring have distinct metabolic programming. Together, our data suggest that prenatal folate status programs hematopoietic stem cell function into adulthood and is driven by alterations to metabolic activity. Ongoing studies examine how prenatal folate status affects the adult hematological and immune response to challenge.

Clinical, epidemiological and laboratory characteristics of cases of Covid-19-related maternal near miss and death at referral units in northeastern Brazil: a cohort study

Objective: Covid-19 poses a major risk during pregnancy and postpartum, resulting in an increase in maternal mortality worldwide, including in Brazil; however, little research has been conducted into cases of a near miss. This study aimed to describe the frequency of COVID-19-related near miss and deaths during pregnancy or in the postpartum in referral centers in northeastern Brazil, as well as the clinical, epidemiological, and laboratory characteristics of the women who experienced a severe maternal outcome. Methods: A retrospective and prospective cohort study was performed between April 2020 and June 2021 with hospitalized pregnant and postpartum women with a diagnosis of COVID-19 confirmed by real-time polymerase chain reaction (RT-PCR). Data from five tertiary hospitals in northeastern Brazil were evaluated. Descriptive statistical analysis was performed using Epi Info, version 7.2.5.0. Results: A total of 463 patients were included. Of these, 64 (14% of the sample) had a severe maternal outcome, with 42 cases of near miss (9%) and 22 maternal deaths (5%). Patients who had a severe maternal outcome were predominantly young (median age 30 years) and 65.6% were black or brown-skinned. The women had between 6 and 16 years of schooling; 45.3% had a stable partner; 81.3% were pregnant at the time of admission to the study; and 76.6% required a Cesarean section. The great majority (82.8%) had severe acute respiratory syndrome (SARS). Other complications included hypertensive syndromes (40.6%), pneumonia (37.5%), urinary tract infections (29.7%), acute renal failure (25.0%) and postpartum hemorrhage (21.9%). Sepsis developed in 18.8% of cases, neurological dysfunction in 15.6%, and hepatic dysfunction and septic shock in 14.1% of cases each. The relative frequency of admission to an intensive care unit was 87.5%, while 67.2% of the patients required assisted mechanical ventilation, and 54.7% required noninvasive ventilation. Antibiotics were prescribed in 93.8% of cases and corticosteroids in 71.9%, while blood transfusion was required in 25.0% of cases and renal replacement therapy in 15.6%. Therapeutic anticoagulants were administered to 12.5% of the patients. Of the patients who had a severe maternal outcome, the frequency of respiratory dysfunction was 93.8%, with 50.0% developing neurological dysfunction and 37.5% cardiovascular dysfunction. Hematological dysfunction was found in 29.7%, renal dysfunction in 18.8%, and uterine dysfunction in 14.1%. Hepatic dysfunction occurred in 7.8% of the sample. The near-miss ratio for Covid-19 was 1.6/1000 live births and the maternal mortality ratio for Covid-19 was 84.8/100,000 live births, with a mortality index of 34.4% in the sample. Conclusion: This study revealed a low Covid-19-related maternal near miss (MNM) ratio of 1.6/1000 live births and a high Covid-19-related maternal mortality ratio (MMR) of 84.81/100,000 live births. The mortality index was also high. Most of the patients were admitted while pregnant, were young, married and black or brown-skinned, and none had completed university education. The majority had SARS and required admission to an intensive care unit and mechanical ventilation. Most were submitted to a Cesarean section.

Spectrum of diabetes mellitus in patients with Shwachman-Diamond syndrome: case report and review of the literature

BackgroundShwachman-Diamond syndrome (SDS) is a rare congenital disorder caused by mutations in the SBDS gene and characterized by exocrine pancreatic deficiency, hematologic dysfunction, and skeletal growth failure. Although the hematologic features and characteristics of the somatic disorders commonly associated with SDS are well known, emerging data from case reports and patient registries suggest that SDS may also be associated with an increased risk of diabetes mellitus. However, currently available data on SDS-associated diabetes are limited and do not allow conclusions regarding prevalence and incidence rates, clinical course, and outcomes.Case presentationHere we report the case of a 5-year-old girl with SDS who underwent bone marrow transplantation at the age of 3 months and developed autoantibody-positive type 1 diabetes mellitus at the age of 1.8 years. The manifestation and course of diabetes development were mild, complicated by concurrent spontaneous episodes of hypoglycemia even before the onset of antidiabetic treatment. Currently, adequate metabolic control can be achieved by dietary intervention.ConclusionsConsidering that the SBDS protein regulates mitosis and ribosomal biosynthesis and that its suppression may cause immunologic instability and chronic inflammation, this case provides insight into the phenotype of rare Shwachman-Diamond syndrome-associated diabetes mellitus, which may be characterized by significant age-dependent differences in clinical course.

Non-alcoholic fatty liver disease in a pediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant: a case report and systematic literature review.

Familial hypobetalipoproteinemia (FHBL) is an autosomal semi-dominant disorder usually caused by variants in the APOB gene that frequently interferes with protein length. Clinical manifestations include malabsorption, non-alcoholic fatty liver disease, low levels of lipid-soluble vitamins, and neurological, endocrine, and hematological dysfunction. Genomic DNA was isolated from the blood samples of the pediatric patient with hypocholesterolemia and his parents and brother. Next-generation sequencing (NGS) was performed, and an expanded dyslipidemia panel was employed for genetic analysis. In addition, a systematic review of the literature on FHBL heterozygous patients was performed. Genetic investigation revealed the presence of a heterozygous variant in the APOB (NM_000384.3) gene c.6624dup[=], which changes the open reading frame and leads to early termination of translation into the p.Leu2209IlefsTer5 protein (NP_000375.3). The identified variant was not previously reported. Familial segregation analysis confirmed the variant in the mother of the subject, who also has a low level of low-density lipoprotein and non-alcoholic fatty liver disease. We have introduced therapy that includes limiting fats in the diet and adding lipid-soluble vitamins E, A, K, and D and calcium carbonate. We reported 35 individuals with APOB gene variations linked to FHBL in the systematic review. We have identified a novel pathogenic variant in the APOB gene causing FHBL in pediatric patients with hypocholesterolemia and fatty liver disease. This case illustrates the importance of genetic testing for dyslipidemias in patients with significant decreases in plasma cholesterol as we can avoid damaging neurological and ophthalmological effects by sufficient vitamin supplementation and regular follow-ups.

Recent advances in understanding the impact of infection and inflammation on hematopoietic stem and progenitor cells

Just over one decade ago, it was discovered that hematopoietic stem cells (HSCs) could directly respond to inflammatory cytokines by mounting a proliferative response thought to mediate the emergency production of mature blood cells. In the intervening years, we have gained mechanistic insight into this so-called activation process and have started to learn such a response may come at a cost in terms of ultimately resulting in HSC exhaustion and hematologic dysfunction. In this review article, we report the progress we have made in understanding the interplay between infection, inflammation and HSCs during the funding period of the Collaborative Research Center 873 “Maintenance and Differentiation of Stem Cells in Development and Disease”, and place this work within the context of recent output by others working within this field.