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Polish Archives of Internal Medicine Jun 2024
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Polycythemia Vera; Primary Myelofibrosis; Male; Disease Progression; Aged; Myelodysplastic Syndromes; Middle Aged
PubMed: 38656083
DOI: 10.20452/pamw.16735 -
Heliyon Apr 2024As common abnormal conditions in clinical practice, hypoxemia and respiratory failure are mainly caused by various respiratory diseases. However, other causes are easily...
BACKGROUND
As common abnormal conditions in clinical practice, hypoxemia and respiratory failure are mainly caused by various respiratory diseases. However, other causes are easily overlooked but deserve more attention from doctors.
CASE PRESENTATION
A 44-year-old man presented with dyspnea for 10 years. In the early stage, his dyspnea was mild without hypoxemia, and he was misdiagnosed with polycythemia vera due to elevated hemoglobin level. He later developed to respiratory failure but he did not have weakness in his extremities. The positional difference in pulmonary function tests and arterial blood gas analysis led us to identify the respiratory muscle dysfunction. Fatty infiltration of the thigh muscle found by magnetic resonance imaging and muscle biopsies gave us more clues to the causes of diaphragmatic dysfunction. Finally, in combination with his family history and the results of whole exome sequencing, he was diagnosed with hereditary myopathy with early respiratory failure (HMERF, OMIM 603689) caused by a variant in the titin gene ().
CONCLUSIONS
We have identified a Chinese family with HMERF due to genetic variants in NM_001256850.1: c.90272C > T, p. Pro30091Leu, located at g.179410829A > G on chromosome 2 (GRCh37) which may be specifically associated with the diagrammatic dysfunction. And hyperhemoglobinemia could serve as a potential sign for the early identification of HMERF.
PubMed: 38655354
DOI: 10.1016/j.heliyon.2024.e29637 -
Scientific Reports Apr 2024BCR::ABL1-negative myeloproliferative neoplasms are hematopoietic disorders characterized by panmyelosis. JAK2 V617F is a frequent variant in these diseases and often...
BCR::ABL1-negative myeloproliferative neoplasms are hematopoietic disorders characterized by panmyelosis. JAK2 V617F is a frequent variant in these diseases and often occurs in the 46/1 haplotype. The G allele of rs10974944 has been shown to be associated with this variant, specifically its acquisition, correlations with familial cases, and laboratory alterations. This study evaluated the association between the 46/1 haplotype and JAK2 V617F in patients with myeloproliferative neoplasms in a population from the Brazilian Amazon. Clinical, laboratory and molecular sequencing analyses were considered. Carriers of the G allele of rs10974944 with polycythemia vera showed an increase in mean corpuscular volume and mean corpuscular hemoglobin, while in those with essential thrombocythemia, there was an elevation in red blood cells, hematocrit, and hemoglobin. Associations were observed between rs10974944 and the JAK2 V617F, in which the G allele (OR 3.4; p < 0.0001) and GG genotype (OR 4.9; p = 0.0016) were associated with JAK2 V617F + and an increase in variant allele frequency (GG: OR 15.8; p = < 0.0001; G: OR 6.0; p = 0.0002). These results suggest an association between rs10974944 (G) and a status for JAK2 V617F, JAK2 V617F + _VAF ≥ 50%, and laboratory alterations in the erythroid lineage.
Topics: Humans; Brazil; Female; Male; Janus Kinase 2; Middle Aged; Myeloproliferative Disorders; Polymorphism, Single Nucleotide; Aged; Adult; Gene Frequency; Alleles; Haplotypes; Polycythemia Vera; Genotype; Genetic Predisposition to Disease; Aged, 80 and over
PubMed: 38654055
DOI: 10.1038/s41598-024-60090-x -
JCI Insight Apr 2024Manganese is an essential yet potentially toxic metal. Initially reported in 2012, mutations in SLC30A10 are the first known inherited cause of manganese excess....
Manganese is an essential yet potentially toxic metal. Initially reported in 2012, mutations in SLC30A10 are the first known inherited cause of manganese excess. SLC30A10 is an apical membrane protein that exports manganese from hepatocytes into bile and from enterocytes into the lumen of the gastrointestinal tract. SLC30A10 deficiency results in impaired gastrointestinal manganese excretion, leading to manganese excess, neurologic deficits, liver cirrhosis, polycythemia, and erythropoietin excess. Neurologic and liver disease are attributed to manganese toxicity. Polycythemia is attributed to erythropoietin excess. The goal of this study was to determine the basis of erythropoietin excess in SLC30A10 deficiency. Here, we demonstrate that transcription factors hypoxia-inducible factor 1a (Hif1a) and 2a (Hif2a), key mediators of the cellular response to hypoxia, are both upregulated in livers of Slc30a10-deficient mice. Hepatic Hif2a deficiency corrected erythropoietin expression and polycythemia and attenuated aberrant hepatic gene expression in Slc30a10-deficient mice, while hepatic Hif1a deficiency had no discernible impact. Hepatic Hif2a deficiency also attenuated manganese excess, though the underlying cause of this is not clear at this time. Overall, our results indicate that hepatic HIF2 is a key determinant of pathophysiology in SLC30A10 deficiency and expand our understanding of the contribution of HIFs to human disease.
Topics: Animals; Polycythemia; Mice; Basic Helix-Loop-Helix Transcription Factors; Liver; Manganese; Hypoxia-Inducible Factor 1, alpha Subunit; Humans; Cation Transport Proteins; Erythropoietin; Mice, Knockout; Male; Hepatocytes
PubMed: 38652538
DOI: 10.1172/jci.insight.169738 -
Annals of Hematology Jun 2024Janus kinase 2 (JAK2) V617F mutation is present in most patients with polycythemia vera (PV). One persistently puzzling aspect unresolved is the association between... (Meta-Analysis)
Meta-Analysis
Janus kinase 2 (JAK2) V617F mutation is present in most patients with polycythemia vera (PV). One persistently puzzling aspect unresolved is the association between JAK2V617F allele burden (also known as variant allele frequency) and the relevant clinical characteristics. Numerous studies have reported associations between allele burden and both hematologic and clinical features. While there are strong indications linking high allele burden in PV patients with symptoms and clinical characteristics, not all associations are definitive, and disparate and contradictory findings have been reported. Hence, this study aimed to synthesize existing data from the literature to better understand the association between JAK2V617F allele burden and relevant clinical correlates. Out of the 1,851 studies identified, 39 studies provided evidence related to the association between JAK2V617F allele burden and clinical correlates, and 21 studies were included in meta-analyses. Meta-analyses of correlation demonstrated that leucocyte and erythrocyte counts were significantly and positively correlated with JAK2V617F allele burden, whereas platelet count was not. Meta-analyses of standardized mean difference demonstrated that leucocyte and hematocrit were significantly higher in patients with higher JAK2V617F allele burden, whereas platelet count was significantly lower. Meta-analyses of odds ratio demonstrated that patients who had higher JAK2V617F allele burden had a significantly greater odds ratio for developing pruritus, splenomegaly, thrombosis, myelofibrosis, and acute myeloid leukemia. Our study integrates data from approximately 5,462 patients, contributing insights into the association between JAK2V617F allele burden and various hematological parameters, symptomatic manifestations, and complications. However, varied methods of data presentation and statistical analyses prevented the execution of high-quality meta-analyses.
Topics: Polycythemia Vera; Janus Kinase 2; Humans; Alleles; Gene Frequency; Amino Acid Substitution; Mutation, Missense
PubMed: 38652240
DOI: 10.1007/s00277-024-05754-4 -
Clinical Cancer Research : An Official... Jun 2024ARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell...
PURPOSE
ARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell carcinoma (ccRCC). The aims of this Phase 1 study (AROHIF21001) were to evaluate safety, tolerability, pharmacokinetics, and establish a recommended Phase 2 dose.
PATIENTS AND METHODS
Subjects with ccRCC and progressive disease after at least 2 prior therapies that included VEGF and immune checkpoint inhibitors were progressively enrolled into dose-escalation cohorts of ARO-HIF2 administered intravenously at 225, 525, or 1,050 mg weekly.
RESULTS
Twenty-six subjects received ARO-HIF2. The most common treatment emergent adverse events (AE) irrespective of causality were fatigue (50.0%), dizziness (26.9%), dyspnea (23.1%), and nausea (23.1%). Four subjects (15.4%) had treatment-related serious AEs. AEs of special interest included neuropathy, hypoxia, and dyspnea. ARO-HIF2 was almost completely cleared from plasma circulation within 48 hours with minimal renal clearance. Reductions in HIF2α were observed between pre- and post-dosing tumor biopsies, but the magnitude was quite variable. The objective response rate was 7.7% and the disease control rate was 38.5%. Responses were accompanied by ARO-HIF2 uptake in tumor cells, HIF2α downregulation, as well as rapid suppression of tumor produced erythropoietin (EPO) in a patient with paraneoplastic polycythemia.
CONCLUSIONS
ARO-HIF2 downregulated HIF2α in advanced ccRCC-inhibiting tumor growth in a subset of subjects. Further development was hampered by off-target neurotoxicity and low response rate. This study provides proof of concept that siRNA can target tumors in a specific manner.
Topics: Humans; Carcinoma, Renal Cell; Basic Helix-Loop-Helix Transcription Factors; Male; Female; Middle Aged; Aged; Kidney Neoplasms; RNA, Small Interfering; Adult; RNA Interference; Antineoplastic Agents; Aged, 80 and over
PubMed: 38652038
DOI: 10.1158/1078-0432.CCR-23-3029 -
Cureus Mar 2024We conducted a retrospective observational cohort study between 2020 and 2023 in 26 patients with type 1 and type 2 diabetes mellitus (DM) who were using 3-4 injections...
The Discrepancy Between Hemoglobin A1c and Glucose Management Indicators in 26 Patients Treated With Continuous Glucose Monitoring in an Internal Medicine Residency Clinic.
We conducted a retrospective observational cohort study between 2020 and 2023 in 26 patients with type 1 and type 2 diabetes mellitus (DM) who were using 3-4 injections per day of insulin and were monitored by continuous glucose monitoring (CGM). The goal of this retrospective observational cohort study is to compare these two metrics in an internal medicine community primary care residency clinic. We used CGM devices, Dexcom G6 and G7, and Freestyle Libre 3. The goal was to compare the patient's hemoglobin A1c (HbA1c) taken during their clinic visit by phlebotomy as a marker for diabetic control with an estimated HbA1c glucose management indicator (GMI) derived from the 30-day CGM readings. HbA1c is derived from the blood, while the GMI value is derived from the interstitial fluid. Both parameters were taken within 30 days of each other. GMI was taken in the last 30 days. We excluded patients with known anemia, chronic kidney disease, polycythemia, cirrhosis of the liver, or metabolic dysfunction associated with steatohepatitis (MASH) because disease states can affect the measured HbA1c. Also, pregnant and African American patients were excluded. We concluded the measured HbA1c was 0.34% (4 mmol/mol) higher than the CGM-derived GMI. The relationship between factors that affect glycemic control was discussed in the article, as well as the future utilization of them in improving diabetic control and management. As the use of CGM continues to grow, addressing differences between laboratory-measured HbA1c and CGM-derived GMI is critical.
PubMed: 38650779
DOI: 10.7759/cureus.56768 -
Cytometry. Part B, Clinical Cytometry Apr 2024Thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF), prefibrotic/early (pre-PMF), and overt fibrotic PMF (overt PMF) are classical...
Thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF), prefibrotic/early (pre-PMF), and overt fibrotic PMF (overt PMF) are classical Philadelphia-Negative (Ph-negative) myeloproliferative neoplasms (MPNs). Differentiating between these types based on morphology and molecular markers is challenging. This study aims to clarify the application of flow cytometry in the diagnosis and differential diagnosis of classical MPNs. This study retrospectively analyzed the immunophenotypes, clinical characteristics, and laboratory findings of 211 Ph-negative MPN patients, including ET, PV, pre-PMF, overt PMF, and 47 controls. Compared to ET and PV, PMF differed in white blood cells, hemoglobin, blast cells in the peripheral blood, abnormal karyotype, and WT1 gene expression. PMF also differed from controls in CD34 cells, granulocyte phenotype, monocyte phenotype, percentage of plasma cells, and dendritic cells. Notably, the PMF group had a significantly lower plasma cell percentage compared with other groups. A lasso and random forest model select five variables (CD34CD19cells and CD34CD38 cells on CD34cells, CD13CD11b cells in granulocytes, CD38CD19plasma, and CD123HLA-DRbasophils), which identify PMF with a sensitivity and specificity of 90%. Simultaneously, a classification and regression tree model was constructed using the percentage of CD34CD38 on CD34 cells and platelet counts to distinguish between ET and pre-PMF, with accuracies of 94.3% and 83.9%, respectively. Flow immunophenotyping aids in diagnosing PMF and differentiating between ET and PV. It also helps distinguish pre-PMF from ET and guides treatment decisions.
PubMed: 38647185
DOI: 10.1002/cyto.b.22173 -
The Journal of Applied Laboratory... Apr 2024The most frequently ordered laboratory test worldwide is the complete blood count (CBC).
BACKGROUND
The most frequently ordered laboratory test worldwide is the complete blood count (CBC).
CONTENT
In this primer, the red blood cell test components of the CBC are introduced, followed by a discussion of the laboratory evaluation of anemia and polycythemia.
SUMMARY
As clinical chemists are increasingly tasked to direct laboratories outside of the traditional clinical chemistry sections such as hematology, expertise must be developed. This review article is a dedication to that effort.
PubMed: 38646908
DOI: 10.1093/jalm/jfae031 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... Mar 2024To investigate the prevalence and influencing factors of isolated diastolic hypertension (IDH) in the Tibetan population in Tibet and to provide some evidence for the...
OBJECTIVE
To investigate the prevalence and influencing factors of isolated diastolic hypertension (IDH) in the Tibetan population in Tibet and to provide some evidence for the prevention and control of hypertension and other related diseases in high-altitude areas.
METHODS
A multistage stratified whole-group random sampling method was used to enroll participants from Ngari Prefecture, Nagqu City, Shannan City, and Lhasa City, Tibet. A total of 3918 native Tibetans with complete data were enrolled in the survey between June 2020 and August 2023. The participants were aged from 18 to 80. The demographic data, life habits, and chronic disease prevalence of the participants were collected. Fasting venous blood samples were collected to perform the routine blood tests and blood biochemistry tests. The prevalence of IDH in subgroups with different characteristics was analyzed and the influencing factors were analyzed by multivariate logistic regression, accordingly. The predictive value of influencing factors on the prevalence of IDH was analyzed by the receiver operating characteristic (ROC) curve and the findings were compared with those of the previous prediction models for IDH.
RESULTS
The prevalence of hypertension in the participants was 33.7% (=1321), among which, 395 had IDH, accounting for 29.9% of the hypertensive patients. The results of multivariate regression showed that age, heart rate, body mass index, waist circumference, hemoglobin, and low-density lipoprotein cholesterol were associated with risks of developing IDH (<0.05). The area under the ROC curve () was 0.71, which indicated improved accuracy for predicting the risks for IDH in comparison with previous predictive models for IDH. Among the influencing factors, BMI showed the best predictive value for IDH risks.
CONCLUSION
The prevalence of IDH is high among Tibetans in Tibet, suggesting the necessity for rational allocation of health resources in accordance. Compared with the previous IDH prediction models, the model proposed in this study is more suited for the Tibetan population. Targeted interventions should be carried out for the high-risk populations, such as young and middle-aged adults and populations suffering from overweight/obesity, central obesity, high-altitude polycythemia, and dyslipidemia, so as to effectively control the occurrence and development of IDH.
Topics: Humans; Tibet; Middle Aged; Prevalence; Hypertension; Adult; Male; Female; Aged; Risk Factors; Adolescent; Altitude; Young Adult; Aged, 80 and over; Body Mass Index
PubMed: 38645841
DOI: 10.12182/20240360501