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Marija Marjanovic,1 Vesna Stojanov,1,2 Ivan Marjanovic,2,3 Gordana Vukcevic-Milosevic,1 Nenad Radivojevic,1 Dragan Matic1,2 1Clinic for Cardiology, University Clinical Centre of Serbia, Belgrade, Serbia; 2Faculty of Medicine, University of Belgrade, Belgrade, Serbia; 3Ophthalmology Clinic, University Clinical Centre of Serbia, Belgrade, SerbiaCorrespondence: Dragan Matic, Clinic for Cardiology, University Clinical Centre of Serbia, Dr Koste Todorovi&cacute;a 8, Belgrade, 11000, Serbia, Tel +381 63 208 975, Email dragan4m@gmail.comPurpose: The aim of this study was to use non-invasive impedance cardiography (ICG) to determine the hemodynamic status of patients with grade 1 and grade 2 hypertension in relation to gender and age.Patients and Methods: We analyse prospectively collected data of 158 patients with grade 1 or grade 2 arterial hypertension. Patients were grouped according to age: 1) < 50 years and 2) ≥ 50 years. Hemodynamic status of patients was assessed by using non-invasive ICG. For the purpose of this study two hemodynamic parameters were used: a) systemic vascular resistance index (SVRI) and b) left cardiac work index (LCWI). The primary endpoint was the hemodynamic status of patients. The secondary endpoint was hypertension-mediated organ damage.Results: Increased SVRI was assessed in 80% of patients, more common in the ≥ 50 years group than in the < 50 years group (88.5% vs 64.8%; p < 0.01). The occurrence of increased systemic vascular resistance correlates hierarchically with increasing age. Elevated LCWI (hypervolemia and/or hyperinotropy) was present in 63% of patients, more often in males than females (70.3% vs 57.1%; p < 0.05) as well in those < 50 years than in older patients (70.4% vs 59.6%; p < 0.05). Patients with diabetes were less likely to have hypervolemia/hyperinotropy than those without diabetes (46.7% vs 67.2%; p < 0.01). Hypervolemia/hyperinotropy (46.7%) and hypovolemia/hypoinotropy (43.3%) were present in a similar percentage of diabetic patients. Left ventricular hypertrophy was found in 30 patients (19%). Patients with left ventricular hypertrophy were more commonly male (66.7% vs 42.2%; p = 0.016) and had increased systemic vascular resistance (96.7% vs 77.3%; p = 0.015) compared to the patients without left ventricular hypertrophy. Hypertensive retinopathy grade III was found in 14 patients (8.9%). Elevated daytime systolic pressure, diabetes and increased age are independent predictors of grade III hypertensive retinopathy. Patients with reduced renal function had higher mean systolic blood pressure (p < 0.05), were more commonly male (p < 0.01) and older (p < 0.01) than those without reduced renal function.Conclusion: Although there are certain correlations between hemodynamic disorders and age and gender, specific hemodynamic status of an individual patient with hypertension cannot reliably be predicted on the basis of age and gender. The measurement of hemodynamic parameters by ICG can guide the clinician to select appropriate antihypertensive therapy to the patients’ hemodynamic pathophysiologic condition.Keywords: hypertension, hemodynamics, impedance cardiography

Long non-coding RNAs (lncRNAs) play complex roles at multiple levels of gene regulation, thus modulating key cellular processes involved in the pathogenesis and progression of cancer. Aberrant expression of lncRNAs has been reported in various malignancies, including chronic lymphocytic leukemia (CLL). We investigated the expression of lnc-IRF2-3 and lnc-KIAA1755-4 in peripheral blood mononuclear cells of 112 previously untreated CLL patients by quantitative reverse-transcriptase polymerase chain reaction. Both lncRNAs were found to be overexpressed in CLL samples in comparison to healthy controls, and their high levels were associated with adverse clinico-biological characteristics of patients at diagnosis. High lnc-IRF2-3 expression was associated with high leukocyte and lymphocyte counts, high β2-microglobulin, advanced Binet stage, unfavorable cytogenetics, CD38-positivity and IGHV -unmutated status. Regarding lnc-KIAA1755-4, its high expression was associated with high leukocyte count, lymphocyte count, β2-microglobulin, lactate dehydrogenase and low hemoglobin, as well as with IGHV -unmutated status. In addition, we observed shorter time to first treatment and overall survival of patients expressing high levels of both lncRNAs in comparison to low-expressing patients. In summary, our study showed that high lnc-IRF2-3 and lnc-KIAA1755-4 expression at diagnosis predicts poor survival in CLL. The mechanisms of their upregulation, as well as their specific targets in CLL cells, remain to be elucidated.

Background: Childhood epilepsies are caused by heterogeneous underlying disorders where approximately 40% of the origins of epilepsy can be attributed to genetic factors. The application of next-generation sequencing (NGS) has revolutionized molecular diagnostics and has enabled the identification of disease-causing genes and variants in childhood epilepsies. The objective of this study was to use NGS to identify variants in patients with childhood epilepsy, to expand the variant spectrum and discover potential therapeutic targets., Methods: In our study, 55 children with epilepsy of unknown etiology were analyzed by combining clinical-exome and whole-exome sequencing. Novel variants were characterized using various in silico algorithms for pathogenicity and structure prediction., Results: The molecular genetic cause of epilepsy was identified in 28 patients and the overall diagnostic success rate was 50.9%. We identified variants in 22 different genes associated with epilepsy that correlate well with the described phenotype. SCN1A gene variants were found in five unrelated patients, while ALDH7A1 and KCNQ2 gene variants were found twice. In the other 19 genes, variants were found only in a single patient. This includes genes such as ASH1L, CSNK2B, RHOBTB2, and SLC13A5, which have only recently been associated with epilepsy. Almost half of diagnosed patients (46.4%) carried novel variants. Interestingly, we identified variants in ALDH7A1, KCNQ2, PNPO, SCN1A, and SCN2A resulting in gene-directed therapy decisions for 11 children from our study, including four children who all carried novel SCN1A genetic variants., Conclusions: Described novel variants will contribute to a better understanding of the European genetic landscape, while insights into the genotype-phenotype correlation will contribute to a better understanding of childhood epilepsies worldwide. Given the expansion of molecular-based approaches, each newly identified genetic variant could become a potential therapeutic target., (© 2024. The Author(s).)

Introduction: Childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can be traced back to birth using leukemic clone-specific immunoglobulin heavy chain (IGH) rearrangements, implying prenatal origin of this disease., Methods: We retrospectively analyzed neonatal blood spots (Guthrie cards) of 24 patients with childhood BCP-ALL aged 1-9.6 years (median 3.1 years) for the presence of clonotypic IGH rearrangements identified in diagnostic bone marrow samples. Based on the sequences of IGH rearrangements, 2 patient-specific primers were designed for each patient and used in semi-nested polymerase chain reaction for the detection of preleukemic clones at birth., Results: Clonotypic IGH rearrangements were detected in neonatal blood spots of 54.2% of patients (13/24). In two cases with double IGH rearrangements detected at diagnosis, only one rearrangement was present at birth, while in the third case both leukemic rearrangements were detected in neonatal blood. Guthrie card-positive findings were significantly more frequent in children ≤5 years of age than in older children (p = 0.011). Regarding patients' characteristics at birth and at diagnosis, Guthrie card-positivity was not associated with sex, birth weight and mother's age, as well as with white blood cell count, percentage of bone marrow blasts, immunophenotype and the presence of ETV6/RUNX1 and TCF3/PBX1 fusion genes at diagnosis., Conclusion: Our study confirms that a large proportion of childhood BCP-ALL originates in utero, regardless of the molecular subtype defined by chromosomal aberrations. The observed trend toward younger age at diagnosis in Guthrie card-positive versus Guthrie card-negative patients implies that the age at diagnosis depends on the presence of preleukemic clone at birth, as well as on the timing of postnatal transforming genetic events., (© 2023 John Wiley & Sons Ltd.)

Dysregulated expression of the long non-coding RNA MALAT1 has been implicated in the pathogenesis and progression of a variety of cancers, including hematological malignancies, but it has been poorly investigated in chronic lymphocytic leukemia (CLL). In this study, the expression of MALAT1 was measured using a quantitative reverse-transcriptase polymerase chain reaction in the peripheral blood mononuclear cells of 114 unselected, newly diagnosed CLL patients in order to analyze its association with clinical, laboratory, and molecular patients' characteristics at diagnosis, as well as its prognostic relevance. MALAT1 was found to be upregulated in CLL patients in comparison to healthy controls, and expression levels were not related to age, leukocyte, lymphocyte and platelet count, serum β2-microglobulin, and IGHV somatic hypermutational status. On the other hand, high MALAT1 expression was associated with several favorable prognostic markers (high hemoglobin, low serum lactate dehydrogenase, earlier clinical stages, CD38-negative status), but also with unfavorable cytogenetics. Furthermore, an association between high MALAT1 levels and longer time to first treatment and overall survival in IGHV -unmutated CLL subtype was observed. In summary, our results imply that high MALAT1 expression at diagnosis may be a predictor of better prognosis and point to MALAT1 expression profiling as a candidate biomarker potentially useful in clinical practice.