Numerical Disorders Research Articles

Bacterial, Fungal and Viral Infections in Patients with Hematological Malignancies: Investigation of CMV Reactivation as a Risk Factor

Reactivation of latent viruses such as human cytomegalovirus (CMV), as well as opportunistic infections associated with bacterial and fungal agents, cause serious clinical consequences in patients with hematological malignancies, which are characterized by both immunosuppressive drug use and functional and numerical disorders of immune system cells. In this study, it was aimed to investigate the association between CMV reactivation and the frequency of various simultaneous infections in adult patients with hematological malignancies. All CMV-DNA test results reported in the medical microbiology laboratory between November 2016 and February 2022 were retrospectively reviewed and the study group consisting of 270 adult patients with hematological malignancies was created. CMV-DNA follow-up results and clinical evaluations of these patients were examined and cases with CMV reactivation were determined. In the final stage, the possible association between CMV reactivation and the frequency of other infections identified by microbiological examination of patients' samples and radiological and clinical evaluations was investigated. Of 270 adult patients with hematological malignancies in the study group, 175 (64.8%) were male and 95 (35.2%) were female, and the mean age of the patients was 50.98 (±17.6). It was determined that 35.9% (97/270) of the patients had CMV reactivation during the follow-up period. The presence of 139 bacterial agents in 99 patients, 63 viral agents in 58 patients, and 56 fungal agents in 50 patients were determined. Bacterial infections were as follows according to the systems; 108 bacteremia (most frequently detected agent Escherichia coli; n=31, 28.7%), 21 urinary tract infections (most common cause E. coli; n=13, 61.9%), and 10 other bacterial infections. Fungal infections were as follows according to the systems; 36 respiratory tract infections (most common Aspergillus spp.; n=23, 63.9%), 6 fungemia (all Candida spp.), 14 other fungal infections (Candida spp.; n=11, and mucormycosis; n= 3). Viral infections were as follows, in order of frequency; hepatitis B (anti-HBc IgG seropositivity in 30 patients), COVID-19 (Coronavirus Disease-2019) in 14 patients, herpes simplex virus in 11 patients, herpes zoster in four patients, BK virus in three patients, and parvovirus B19 in one patient. CMV reactivation rates were found to be significantly higher in patients with fungal pneumonia, non-CMV viral reactivation, and bacterial bloodstream infection, p=0.046, p=0.003, and p=0.038, respectively. In the literature, CMV reactivation, risk factors associated with reactivation, and adverse clinical outcomes of CMV reactivation in patients with hematological malignancies have been investigated from many different aspects. However, additional pressures of CMV on the immune system and its negative effects on innate and adaptive immune responses and possible contributions of this situation to the development of other infections have not yet been studied in detail. We think that determining the possible effects of CMV reactivation on the development of opportunistic infections by comprehensive prospective studies may change antimicrobial therapy strategies in the management of CMV infections.

Treg cell abnormality and its potential treatments in patients with primary immune thrombocytopenia

AbstractPrimary immune thrombocytopenia (ITP) is an autoimmune heterogeneous disorder. T regulatory cells (Treg), play an important role in the pathogenesis of the disease. Numerical and functional disorders of Treg cells were both demonstrated in ITP. Thymocyte output decrease and instability of Treg cells contributed to the lower count of the cells. Several immune deregulatory defects of Treg cells further led to the disease's onset. Restoring Treg cells might have a therapeutic effect on ITP. New options focusing on increasing the number, or enhancing the immunomodulating function of Treg cells was reviewed in this manuscript.

Нарушения счетных навыков: обзор причин и нейропсихологических механизмов дискалькулии

The article presents a review of foreign studies on the numerical difficulties and numerical disorders. The main modern theories of the mechanisms underlying the difficulties and disorders of counting are reflected, various classifications of dyscalculia are compared, and the neuropsychological foundations of the brain organization of counting are analyzed according to foreign scientists. It is noted that in the world of psychological science, the issues of the causes and mechanisms of difficulties and disorders of counting are still insufficiently developed, and the results of empirical researches are contradictory. It is concluded that for further study of dyscalculia it is necessary to analyze the psychological structure of counting and its changes under the influence of learning, taking into account the structural and functional features of the brain organization of quantitative information processing.

Low-pass genome sequencing versus chromosomal microarray analysis: implementation in prenatal diagnosis

PurposeEmerging studies suggest that low-pass genome sequencing (GS) provides additional diagnostic yield of clinically significant copy-number variants (CNVs) compared with chromosomal microarray analysis (CMA). However, a prospective back-to-back comparison evaluating accuracy, efficacy, and incremental yield of low-pass GS compared with CMA is warranted. MethodsA total of 1023 women undergoing prenatal diagnosis were enrolled. Each sample was subjected to low-pass GS and CMA for CNV analysis in parallel. CNVs were classified according to guidelines of the American College of Medical Genetics and Genomics. ResultsLow-pass GS not only identified all 124 numerical disorders or pathogenic or likely pathogenic (P/LP) CNVs detected by CMA in 121 cases (11.8%, 121/1023), but also defined 17 additional and clinically relevant P/LP CNVs in 17 cases (1.7%, 17/1023). In addition, low-pass GS significantly reduced the technical repeat rate from 4.6% (47/1023) for CMA to 0.5% (5/1023) and required less DNA (50 ng) as input. ConclusionIn the context of prenatal diagnosis, low-pass GS identified additional and clinically significant information with enhanced resolution and increased sensitivity of detecting mosaicism as compared with the CMA platform used. This study provides strong evidence for applying low-pass GS as an alternative prenatal diagnostic test.

Chromosomal disorders in the fetus of pregnant woman from Aktau

The article presents the data of cytogenetic study on the fetal karyotype of 310 pregnantwomen from the city Aktau in 2013-2015. Chorionic biopsy and placental biopsy were carried out for248 pregnant women with amniocentesis in 18 cases and cordocentesis in 44 cases. Clinical indicators imposing invasive procedures to pregnant women at risk were maternal age factor, fetal ultrasoundmarkers, serum blood markers determined in pregnant women, the presence of children with multiplecongenital malformations, chromosomal pathologies, etc. Distribution frequencies of fetal chromosomalabnormalities have been determined based on clinical and laboratory studies. The highest frequency ofchromosomal abnormalities of the fetus was indicated in pregnant women with three salient indicators:the factor of the age of the pregnant woman, parameters of biochemical screening, and ultrasound markers. Chromosomal abnormalities of the fetus were detected in 94 (30.3%) pregnant women including 92cases (97.9%) represented by numerical chromosome disorders and 2 cases (2.1%) of structural disorders. Disorders of the autosome system were observed 9.4 times more often comparing to abnormalitiesin the sex chromosome system. Of the numerical chromosome abnormalities, a high specific weight isoccupied by trisomy of the 21-st chromosome which has reached 65.1%. A comparative analysis of thefrequencies of chromosomal abnormalities of the fetus of two port cities has demonstrated a 1.7-foldincrease in the city of Aktau (Kazakhstan) compared with the city of Murmansk (Russia), and the averagefrequencies of fetal karyotype anomalies have made up 19.6% and 11.6%, respectively. Higher level offrequencies for fetal karyotype anomalies in Aktau is possibly associated with unfavorable environmentalconditions in this city caused by the allocation of the oil and gas industry, the repository for tailing toxicand radioactive wastes, and abandoned uranium mines.Key words: karyotype, fetus, prenatal diagnosis, fetal chromosome disorders, ecological state ofurban agglomerations.

Genetic testing and pregnancy outcome of 337 fetuses with urinary system anomalies

To explore the genetic basis and pregnancy outcome of fetuses with urinary system anomalies. Ultrasonographic features, genetic testing and pregnancy outcomes of 337 fetuses with urinary system anomalies identified by prenatal ultrasonograhy were collected for analysis. Ultrasonographic features of the fetuses were mainly characterized by hydronephrosis or hydronephrosis, polycystic kidney disease, and renal dysplasia. Thirty four fetuses (10.1%) were found to harbor a genetic defect, including 14 numerical chromosomal disorders, 10 structural chromosomal aberrations, and 10 pathogenic copy number variations (CNVs). In 31 cases, the parents elected induced labor. For the 303 fetuses with negative findings, 142 were born by spontaneous delivery or Caesarean section, 48 cases underwent induced labor, 1 case had miscarriage, and the remaining 112 cases had unknown or missed pregnancy outcomes. Hydronephrosis or hydronephrosis, polycystic kidney disease, and renal dysplasia are the most common findings among fetuses with urinary system anomalies. Approximately 10.1% of such fetuses are positive by genetic testing.

An Analysis of Cytogenetic and Clinical Phenotype of Klinefelter Syndrome Over 17 Years

Background: Clinical phenotype in Klinefelter syndrome (KS) shows utmost contrariety according to the genetic presentation. The karyotype 47, XXY is one of the commonest types of sex chromosomal abnormality in males presenting with infertility, hypogonadism, small penis, gynaecomastia and tall stature. Cytogenetic study is the only way to differentiate between chromosomal abnormality and other androgen deficiency disorders. The aim of this study was to investigate cytogenetic and phenotypic profile of Klinefelter syndrome in a group of referred patients with suspected genetic disorders.Methods: This observational study was carried out at the Cytogenetic Laboratory of the Department of Immunology BIRDEM General Hospital for a period of seventeen years from 2000 to 2016. A total of 9,216 patients suspected for different chromosomal abnormalities (e.g. numerical chromosomal disorders, primary amenorrhoea, ambiguous genitalia etc.) were included in this study referred by physicians of various discipline from different areas of Bangladesh. From the patients referred for cytogenetic study, detailed family history and physical findings were noted. Complete genetic examination and pedigree construction was done to exclude non-chromosomal causes of anomalies. For cytogenetic analysis, peripheral lymphocyte culture by the standard method using the G-banding technique was employed.Results: In this study 1.67% (154) of referred patients were diagnosed as Klinefelter syndrome in cytogenetic study and most of them were diagnosed in their adulthood between 20-29 years of age. Classical cytogenetic form of KS-47, XXY (87%) were most common followed by other mosaic and supernumerary X chromosome aneuploidy. Most of the patients presented with tall stature (61.7%) followed by other features such as gynaecomastia (45.5%), eunuchoid skeleton (29.8%), sexual dysfunction (34.41%), small penis (22.7%), and delayed development of secondary sex characteristics (22.7%).Conclusion: Diagnosis of Klinefelter syndrome in early age before puberty is needed to be differentiated from other related disorders and thereby improving the quality of life by providing appropriate and timely treatment. Therefore, we have to focus to improve our overall capacity to diagnose genetic disorders for proper interventionBirdem Med J 2018; 8(2): 126-131

Ecological assessment of numerical skills in adults suffering from stroke

The present study first assesses calculation skills and number processing in patients suffering from cerebrovascular disease patients with Ecological Assessment Battery of Number (EABN), the only French test standardised and validated. Second, relationship between disorders-related lesions and brain lesion lateralization, and formal analytical testing and cognitive disorders were evaluated. Patients suffering from a stroke were included in three departments of physical and rehabilitation medicine. Inclusion criteria entailed having a stroke, over 18 years, and exempt from prior neurologic or psychiatric disease. The systematic assessment included: EABN, a formal analytical test: Évaluation clinique des aptitudes numériques (ECAN), an evaluation of speech processing (Boston Diagnostic Aphasia Examination = BDAE), a cognitive assessment (Montreal Cognitive Assessment = MOCA), and assessment of independence (Functional Independence Measure = FIM). We studied the link between variables through multivariate analyses. Non-parametric group comparisons were also conducted. Out of 48 strokes included, 36 showed left brain damage (LBD) (75%) and 10 right brain damage (RBD) (20.8%). Mean age was 59.2 years, mean duration after stroke was 8.5 months. 62.5% of subjects showed a pathological score on EABN. LBD patients were significantly more impaired ( P = 0.0089) and slower ( P = 0.0003) than RBD patients for all tests, especially for transcoding tests ( P = 0.0025). The total EABN score was correlated to the ECAN ( P < 0.0001), what accounts for its sensitivity to capture numerical skills disorders. The correlation found with the language functions ( P < 0.0001) was partly explained by the difficulties of LBD patients. Finally MOCA and MIF were correlated with the total score of the EABN ( P = 0.0009 and 0.004, respectively). The EABN is a robust promising tool that enable promote more systematic screening for calculation impairment in patients with a brain damage, (in particularly those with LBL left brain lesion) and assess its major impact on everyday life activity. This tool allows us to distinguish differences in performances according to differences in locations of the brain lesion. Therefore, it seems important to assess the number processing and calculation skills in clinical practice of all LBD patients, in addition to the formal cognitive assessment.

Numerical chromosome disorders in the common marmoset (Callithrix jacchus) – comparison between two captive colonies

Chromosomal analyses were performed for marmosets from two colonies - Deutsches Primatenzentrum (DPZ) and Biomedical Primate Research Centre (BPRC). Chlorine-based disinfectants are used in DPZ; no chemical disinfection is applied in BPRC. The rates of chromosomal non-disjunction, polyploidy and endoreduplication were investigated after G-banding. For DPZ monkeys, the mean rates of non-disjunction were 7.6% for bone marrow and 11.3% for lymphocytes. The polyploidy level was 2.5% in bone marrow and 0.8% in blood. Frequency of endoreduplication in bone marrow and in leucocytes was 0.5% and 0.8%, respectively. For BPRC, the rate of non-disjunction in leucocytes (1.3%) was significantly lower than that for DPZ; the polyploidy rate (0.2%) in blood was lower than that in DPZ; endoreduplication was not observed. The levels of chromosomal disorders are elevated for DPZ colony. We suggest that the increased rate of chromosomal disorders in DPZ marmosets can be related to the chemical disinfection of their environment.

Application of microsatellite loci on the chromosome X for rapid prenatal detection of the chromosome X numerical abnormalities

AimTo determine the value of short-tandem repeat markers on the chromosome X (X-STR) for prenatal diagnostics of the chromosome X numerical disorders.MethodsWe investigated the genetic variability of 5 X-markers (DXS9895, DXS6810, DXS6803, GATA172D05, and HPRTB) in 183 healthy Croatian individuals (90 men and 93 women). We also tested 13 patients with X chromosome disorders (Turner syndrome – 6 cases; Klinefelter syndrome – 5 cases, and Triple X syndrome – 2 cases). The analysis was performed using polymerase chain reaction amplification with specific primers and electrophoresis on a polyacrylamide gel. The study was performed in 2010.ResultsOur sample showed no significant differences in allelic frequencies of the investigated X-markers from other European populations. A set of 5 X-STR markers was sufficiently informative for a successful determination of the chromosome X numerical abnormalities.ConclusionSince no false positive or negative results were observed, diagnostic value of the investigated X-STR loci for prenatal detection of chromosome X numerical disorders was confirmed. Our study represents an important step toward an improved prenatal diagnostics in Croatia.

Evidence-based information guides to rare chromosome disorders for families and professionals

The purpose of this project is to develop reliable, relevant, accurate leaflets for affected families and health (and other) professionals that fill an information gap about rare chromosome disorders. In 2003 Unique surveyed information materials published in the UK about specific rare chromosome disorders: for over 93% of members, no accessible disorder-specific information was available. Unique asked families what they most wanted to know at diagnosis and what questions remained unanswered. Unique prioritised 66 disorders according to frequency on its database (7,140 member families at February 2010) and absence of existing information accessible to families. Information was compiled from the medical literature, from Unique’s database and from detailed surveys sent to member families. Draft texts were reviewed for accuracy by Unique’s medical adviser and by medical and genetics professional experts in the specific disorders. Photographically illustrated draft leaflets were vetted for content by families. By early 2010, leaflets have been developed on 113 rare chromosome disorders including numerical and structural disorders, subtelomere deletions, mosaic disorders, emerging microdeletion and microduplication syndromes and a broad range of less common diagnoses. Twenty-one leaflets have been translated into at least one European language. Many more leaflets are in preparation or planned. Leaflets are available free to families and the professionals who work with them either in print format or online from Unique’s website at http://www.rarechromo.org. The leaflets improve families’ understanding and acceptance of a rare chromosome disorder and help diminish the acute stress and anxiety associated with diagnosis. They are also proving to be a useful resource for professionals, including health professionals in clinic.

Generation of Valpha14 NKT cells in vitro from hematopoietic precursors residing in bone marrow and peripheral blood.

We previously reported the generation of Valpha14 invariant TCR+ (Valpha14i) NK1.1+ natural killer T (NKT) cells in the cytokine-activated suspension culture of murine fetal liver cells. In this study, we attempted to apply this finding to the induction of Valpha14i NKT cell differentiation in the culture of hematopoietic precursors residing in bone marrow or peripheral blood. Preferential generation of NKT cells was found in the culture of Thy-1(+)-depleted bone marrow cells in the presence of culture supernatant from Con A-stimulated spleen T cells and a combination of recombinant IL-3, IL-4, IL-7 and GM-CSF. NKT cell development from peripheral blood hematopoietic precursors was induced when they were cultured on stromal cell monolayers prepared from Thy-1(+)-depleted bone marrow or fetal liver cells, suggesting that certain environments derived from hematopoietic organs are required for the induction of NKT cells from precursors in vitro. A significant fraction of NKT cells generated in the culture were positive for staining with CD1-alpha-galactosylceramide tetramer, indicating that Valpha14i NKT cells were the major subset among the NKT cells. The present methods for obtaining NKT cells in the culture of bone marrow or peripheral blood cells are applicable to the treatment of patients suffering from diseases with numerical and functional disorders of NKT cells.

Number Processing and Calculation – Normative Data from Healthy Adults

Despite the high incidence of numerical deficits in neurological patients, little attention has been paid to the development of diagnostic tools. In fact, most of the published reports on acquired numerical disorders, whether single case or group studies, do not refer to standardised measures of performance providing little, if any, control data specifically collected for the examination. In this study we present data of 282 healthy controls of different age groups and educational levels in a new battery of Number Processing and Calculation (NPC). The NPC battery includes a total of 35 tasks, assessing different counting abilities, various aspects of number comprehension (such as parity and magnitude judgements), numerical transcoding, calculation, arithmetic reasoning and conceptual knowledge. Special attention is paid to the assessment of different calculation abilities, including simple fact retrieval, rule based processing, mental calculation and written calculation in all four operations. Moreover, text problem solving is assessed as well as the understanding of arithmetic principles. Thus, the NPC battery differs from the EC 301 battery proposed by Deloche et al., 1994 (Dellatolas, Deloche, Basso, & Claros-Salinas, 2001) and allows a more fine grained diagnosis which is relevant for planning targeted interventions. The battery is easy to administer and does not require special materials or equipment.

X chromosome dosage by quantitative fluorescent PCR and rapid prenatal diagnosis of sex chromosome aneuploidies.

During the past few years, rapid prenatal diagnosis of chromosome aneuploidies has been successfully achieved by quantitative fluorescent PCR (QF-PCR) amplification of chromosome-specific small tandem repeats (STR). This approach has proven to be very useful in clinical settings, since it allows the detection of major numerical disorders in a few hours after sampling. For the detection of Turner's syndrome (45,X), several highly polymorphic STR on the X chromosome are needed in order to reduce the likelihood that a normal female might be homozygous for all sequences and, consequently, that the test could fail to discriminate between samples retrieved from a Turner's and a normal female fetus. Here we report a new method for rapid and accurate detection of X chromosome copy number in prenatal samples that does not depend on STR heterozygosity. The test is based on QF-PCR amplification of the X-linked HPRT together with the autosomal D21S1411 used as internal control for quantification. In the course of this study, this assay allowed the prenatal diagnosis of a rare case of a normal female homozygous for four selected highly polymorphic X chromosome STR, as well as the assessment of the normal chromosome complement of a fetus homozygous for five chromosome 21 markers.

Interphase-FISH-Test als Schnelltest für Trisomien im Fruchtwasser - Ergebnisse einer prospektiven Untersuchung*

Specific DNA probes allow rapid prenatal diagnosis of numerical chromosome disorders (chromosomes 13, 18, 21, X, Y) by FISH on interphase nuclei. The diagnostic reliability is presently under evaluation. In a period of 1.5 years a total 1126 amniotic fluid samples was investigated by FISH compared to standard cytogenetic analysis. The success rate was 93 percent (< or = 30 nuclei) and 84% (< or = 50 nuclei). An abnormal karyotype was detected by FISH in 27 of 28 successfully hybridised samples, including trisomy 21 [16], trisomy 13 [4], trisomy 18 [4], aberrations of sex chromosomes [4]. Two cases with clinically relevant cytogenetic abnormalities were in principle not detectable by FISH. One false-negative finding was observed, possibly arising from maternal cell contamination of the sample. 6% of all samples, respectively 23% of the bloody samples were contaminated by maternal cells (more than 10%). Maternal contamination represents the most important limitation of the diagnostic reliability in routine practice.

Rapid detection of chromosome aneuploidies by quantitative fluorescence PCR: first application on 247 chorionic villus samples

We report the results of the first major study of applying quantitative fluorescence polymerase chain reaction (QF-PCR) assays for the detection of major chromosome numerical disorders. The QF-PCR tests were...

The Prevention of Genetic Disease and Mental Retardation

During the past two decades, progress in understanding some genetic defects responsible for many physical and mental debilities has been impressive. It is now recognized, for example, that mental retardation occurs in appreciable numbers of humans with numerical and structural chromosome disorders (Down syndrome, cri-du-chat syndrome, etc). In other individuals, a single gene abnormality such as phenolketonuria has been identified at birth, and treatment can now be initiated to preserve life and reduce the debility. With other diseases, such as mucopolysaccharide storage disease, a specific biochemical defect may be identified, but satisfactory treatment is not yet available. In still other abnormalities, the causes are understood poorly and no treatment exists. It is now even possible to identify several single gene diseases in the 16- to 20-week-old fetus by means of biochemical studies on cells obtained by amniocentesis; in addition, all gross chromosome disorders can be recognized prenatally. However, these