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PubMed2002

Genetic imbalances in progressed B-cell chronic lymphocytic leukemia and transformed large-cell lymphoma (Richter's syndrome).

Chromosomal imbalances were examined by comparative genomic hybridization in 30 cases of B-cell chronic lymphocytic leukemia (CLL) at diagnosis, in sequential samples from 17 of these patients, and in 6 large B-cell lymphomas transformed from CLL [Richter's syndrome (RS)] with no available previous sample. The most common imbalances in CLL at diagnosis were gains in chromosome 12 (30%), and losses in chromosomes 13 (17%), 17p (17%), 8p (7%), 11q (7%), and 14q (7%). The analysis of sequential samples showed an increased number of chromosomal imbalances in 6 of 10 (60%) patients with clinical progression and in 2 patients with stable stage C disease. No karyotypic evolution was observed in four cases with stable stage A disease and in one RS clonally unrelated to the previous CLL. Gains of 2pter, and 7pter, and losses of 8p, 11q, and 17p were recurrent alterations associated with karyotype progression. RS showed a higher number of gains, losses, total alterations, and losses of 8p and chromosome 9 than CLL at diagnosis. 17p losses were associated with p53 gene mutations and with a significantly higher number of chromosomal imbalances than tumors with normal chromosome 17 profile. However, no relationship was observed between 9p deletions and p16(INK4a) gene alterations. Losses of 17p and an increased number of losses at diagnosis were significantly associated with a shorter survival. These findings indicate that CLL has frequent chromosomal imbalances, which may increase during the progression of the disease and transformation into large cell lymphoma. Genetic alterations detected by comparative genomic hybridization may also be of prognostic significance.

Chromosome Aberrations↗
PubMed1989

Fatal cutaneous T cell lymphoma in a child with atopic dermatitis.

The development of a fatal cutaneous T cell lymphoma in a child with atopic disease is presented. From very early childhood the patient had classic atopic dermatitis, and at age 13 developed lymphoma-like skin tumors. The diagnosis--based on immunohistologic criteria--was initially difficult to establish, but cytogenetic and DNA studies of the dermal infiltrate supported the clinical suspicion of malignancy. In addition, the T cell receptor beta chain gene showed a clonal rearrangement pattern both in skin and in lymph node, suggesting malignancy. Whether the malignant evolution in our patient took place primarily in the skin or in the lymph nodes is difficult to decide. Further examination of the association between atopic dermatitis and cutaneous T cell lymphoma may lead to insights into both disorders.

Adolescent↗
PubMed2000

Monoclonality or oligoclonality of human herpesvirus 8 terminal repeat sequences in Kaposi's sarcoma and other diseases.

BACKGROUND: Infection with human herpesvirus 8 (HHV8), also termed Kaposi's sarcoma (KS)-associated herpesvirus, is associated with all forms of KS, with primary effusion lymphoma (PEL), and with some forms of multicentric Castleman's disease (MCD), but the pathogenic role of HHV8 in these tumors and the clonal nature of KS are still unclear. The purpose of this study was to examine whether the number of terminal repeats (TRs) contained in the fused TR region of HHV8 could be used as a marker of clonality in HHV8-associated tumors. METHODS: Pulsed-field gel electrophoresis (PFGE) and multiple-probe Southern blot analysis of the HHV8 TR region were performed on high-molecular-weight DNA obtained from tumoral KS, PEL, and MCD lesions. RESULTS: These analysis showed that the fused TR region contains a large but variable number of TR units (ranging from 16 to 75) and that the viral genome is present as extrachromosomal circular DNA in these tumors in vivo, with occasional ladders of heterogeneous linear termini reflecting lytic replication. All PEL tumors and PEL-derived cell lines as well as some KS tumors contained monoclonal or oligoclonal fused TR fragments; however, the TR region appeared polyclonal in MCD tumors and in a few KS lesions. CONCLUSION: Several KS and PEL lesions are monoclonal expansions of a single infected cell, suggesting that HHV8 infection precedes tumor growth and thus supporting an etiologic role of latent HHV8 in these proliferations. Our finding that nodular KS lesions display all possible patterns of clonality supports the model according to which KS begins as a polyclonal disease with subsequent evolution to a monoclonal process.

Adult↗
PubMed2006

Retreatment with rabbit anti-thymocyte globulin and ciclosporin for patients with relapsed or refractory severe aplastic anaemia.

The management of patients with severe aplastic anaemia (SAA) who do not have a matched sibling donor and fail a course of horse anti-thymocyte globulin (h-ATG)/ciclosporin (CsA) is uncertain. Repeated courses of ATG-based immunosuppression are often employed; in children and increasingly in adults, alternative donor haematopoietic stem cell transplantation is an option. We analysed the success rate of retreatment with rabbit ATG (r-ATG)/CsA in 43 patients treated at our institution in the last 5 years; 22 were refractory (20 adults; two children) to h-ATG/CsA-based regimens and 21 (17 adults; four children) had relapsed after h-ATG/CsA-based regimens. The overall response rate was 30% in patients who were refractory to h-ATG and 65% in patients who had relapsed following h-ATG. The 1000-d survival in patients who responded to r-ATG was 90% compared with 65% in non-responders. Six patients developed a clonal haematological disorder; two were responders, two were non-responders and in two the evolution occurred before the response could be assessed at 3 months following r-ATG. Thirteen patients died; three were responders, six were non-responders and four patients died prior to 3 months when response was assessed. In our study, the response rate in refractory patients was inferior to what has been previously reported.

Adolescent↗
PubMed2001

The ecology of genetically diverse infections.

Microparasite infections often consist of genetically distinct clonal lineages. Ecological interactions between these lineages within hosts can influence disease severity, epidemiology, and evolution. Many medical and veterinary interventions have an impact on genetic diversity within infections, but there is little understanding of the long-term consequences of such interventions for public and animal health. Indeed, much of the theory in this area is based on assumptions contradicted by the available data.

Animals↗
PubMed2026

Genomic characterization of KPC-2 and NDM coproducing carbapenem-resistant Klebsiella pneumoniae in a hospital: discovery of ST1869 clone and a novel hybrid plasmid.

UNLABELLED: To characterize the plasmid architecture and molecular background of KPC-NDM coproducing carbapenem-resistant Klebsiella pneumoniae (KN-CRKP) in a South China hospital. Five KN-CRKP isolates were collected, including three from one patient. All underwent Illumina sequencing; two (ST11 and ST1869) additionally had Nanopore sequencing. Antimicrobial susceptibility testing strain sequence types, conjugation assays, resistance gene profiling, plasmid typing, genetic structure comparison, core-genome single nucleotide polymorphisms (SNPs) analysis, and plasmid clustering were performed. All isolates exhibited an imipenem minimum inhibitory concentration (MIC) of ≥128 µg/mL and harbored multiple resistance genes. One isolate (1/5) belonged to ST1869 and co-harbored blaKPC-2 and blaNDM-5. The blaNDM-5-carrying plasmid was a novel IncI1/X3 fusion plasmid that also carried blaCMY-42. Unlike several IncX3 plasmids carrying blaNDM in publicly available KN-CRKP genomes from South China, this IncI1/X3 hybrid lacked a complete conjugative transfer system. ST11 was the predominant clone (4/5), co-harboring blaKPC-2 and blaNDM-1. A rare genetic structure, ΔISKpn6-blaKPC-2-ISKpn28, was identified on IncFII plasmids carrying blaKPC-2. Plasmid clustering analysis of 126 comparative KN-CRKP genomes showed diverse sequence types and plasmid backgrounds associated with the KPC/NDM co-production pattern. The observed plasmid diversity and structural variation in KN-CRKP support continued genomic surveillance, with particular attention to the ST1869 clone, the novel IncI1/X3 hybrid plasmid harboring blaNDM-5 and blaCMY-42, and the rare "ΔISKpn6-blaKPC-2-ISKpn28" genetic structure. Expanded genomic data on KN-CRKP are needed to further elucidate its resistance mechanisms and plasmid evolutionary trajectories. IMPORTANCE: The co-production of KPC and NDM carbapenemases in Klebsiella pneumoniae poses a formidable threat to clinical antimicrobial therapy, as these enzymes confer resistance to virtually all β-lactam agents, including carbapenems. Here, we report novel genomic features of KN-CRKP in South China, including the emergence of the ST1869 clone, a unique IncI1/X3 hybrid plasmid harboring blaNDM-5 and blaCMY-42, and the rare ΔISKpn6-blaKPC-2-ISKpn28 genetic structure. These findings substantially expand current understanding of plasmid evolution and resistance gene dissemination in this region. The identification of diverse resistance mechanisms and clonal backgrounds supports enhanced genomic surveillance and infection-control awareness for pan-resistant Enterobacterales.

Plasmids↗
PubMed1995

Chromosomal deletions in myelodysplasia.

There are two major classes of genes implicated in human tumorigenesis, the oncogenes and the tumour suppressor genes. In haematological malignancies most emphasis has been placed upon the recurring translocations in which the juxtaposition of two gene sequences has resulted in the activation of an oncogene. Chromosomal loss rather than translocation is the most frequent karyotypic abnormality in the myelodysplastic syndromes, a heterogeneous group of clonal malignant blood disorders characterised by dyshaematopoiesis and/or impaired maturation of haemopoietic cells with frequent evolution to acute leukaemia. Recent attention has focused on the loss of genetic material as a result of chromosomal monosomy or deletion in the myelodysplastic syndromes. The most frequently reported deletions in these myeloid syndromes are of chromosomes 5, 20 and 7. Deletions of chromosomes 11, 12, and 13, although more rarely observed, are also characteristics of the myelodysplastic syndromes. It is probable that the deleted chromosomal bands give the location for as yet unidentified myeloid specific tumour suppressor loci and there is considerable interest in the cloning of these genes. This review discusses the three most frequently observed deletions in MDS; 7q deletion, 5q deletion and 20q deletion taking into account recent evidence on the respective critical regions of gene loss and the role of candidate genes.

Animals↗
PubMedDate not supplied

[Association of the cytogenetic pattern and latero-cervical metastasis of laryngeal cancer].

Although solid tumors, in particular carcinomas, play a much larger part in human morbidity and mortality than hematological neoplasias do, much less is known about the cytogenetic abnormalities that characterize them. Numerous classification schemes have been used in the subdivision of human tumors. Most often the tumors are classified according to the presumed cell of origin (epithelial, mesenchymal, neurogenic or germ cell tumors), their benignity or malignancy, differentiation features and histological growth pattern or anatomical site or organ of origin. In the following discussion, we analyse 12 cases of squamous cell carcinoma of the larynx. All teh sample were karyotyped using a direct chromosome analysis method. The method reported was highly successful and in several types of tumors showed the possibility of obtaining good banded metaphases. The purpose of this research was to attempt to define the chromosomal pattern of laryngeal carcinomas and, consequently, to correlated, it to histological grading and clinical evolution. In all the cases studied we found several chromosomal anomalies. In five of them clonal anomalies, such as the loss of chromosome 4; Robertsonian translocation t(13,14); rearrangement of chromosome 1 and chromosome 17 and the presence of similar markers, were observed. The characterization of the markers was made with an IN SITU hybridization technique using specific probes, followed also in order to define two particular markers involving chromosome 1 and t(13,14). We did not reveal a correlation between histological grading and karyotype, but we did find a correlation between tumor ploidy and latero-cervical metastases. The most important result seems to correlate the presence of latero-cervical metastases with a hypodiploid cell line (with less than 46 chromosomes) in the primary tumor. This could be an index of the ability of the tumor to invade the latero-cervical lymph nodes. If this correlation is confirmed, conservative neck dissection could be limited to N0 patients with a hypodiploid pattern. In conclusion, we feel that, if confirmed, the results of this research, may be widely applied in clinical medicine.

Carcinoma, Squamous Cell↗
PubMed2006

Evidence for recombination in Mycobacterium tuberculosis.

Due to its mostly isolated living environment, Mycobacterium tuberculosis is generally believed to be highly clonal, and thus recombination between different strains must be rare and is not critical for the survival of the species. To investigate the roles recombination could have possibly played in the evolution of M. tuberculosis, an analysis was conducted on previously determined genotypes of 36 synonymous single nucleotide polymorphisms (SNPs) in 3,320 M. tuberculosis isolates. The results confirmed the predominant clonal structure of the M. tuberculosis population. However, recombination between different strains was also suggested. To further resolve the issue, 175 intergenic SNPs and 234 synonymous SNPs were genotyped in 37 selected representative strains. A clear mosaic polymorphic pattern ahead of the MT0105 locus encoding a PPE (Pro-Pro-Glu) protein was obtained, which is most likely a result of recombination hot spot. Given that PPE proteins are thought to be critical in host-pathogen interactions, we hypothesize that recombination has been influential in the history of M. tuberculosis and possibly a major contributor to the diversity observed ahead of the MT0105 locus.

Antigens, Bacterial↗
PubMed2000

Oligoclonality of early lesions of the urothelium as determined by microdissection-supported genetic analysis.

AIM: To contribute to the ongoing discussion of clonality of human urothelial cancer it was considered a valuable approach to analyze multiple areas from cystectomy specimens for deletions of chromosomes known to be involved early in bladder cancer development. MATERIAL AND METHODS: Thus, in 86 biopsies of 4 human cystectomies with different histological findings (maximal diagnosis: pT1G2, pTaG3, pT2G2, normal) loss of heterozygosity (LOH) was investigated as a deletion marker using markers of chromosomes 8p, 9p, 9q and 17p. Findings were compared to histology of the lesion. RESULTS: Findings indicate: (1) no changes in the markers investigated in the bladder with histologically normal urothelium in contrast to detection of LOH in normal urothelium of tumour-bearing bladders; (2) an accumulation of the number of LOH with increasing malignancy of lesions within one bladder, and (3) indications of oligoclonal neoplastic lesions in two of the urinary bladders investigated. CONCLUSIONS: The investigation of multiple lesions within one bladder presents a snapshot of genetic changes in differently advanced tumour stages. The hypotheses of tumour evolution and oligoclonality as derived from our LOH data need to be supported by deletion-independent clonality studies as X-chromosomal inactivation analysis.

Carcinoma in Situ↗
PubMed2006

Evidence for alternative candidate genes near RB1 involved in clonal expansion of in situ urothelial neoplasia.

In this paper, we present whole-organ histologic and genetic mapping studies using hypervariable DNA markers on chromosome 13 and then integrate the recombination- and single-nucleotide polymorphic sites (SNPs)-based deletion maps with the annotated genome sequence. Using bladders resected from patients with invasive urothelial carcinoma, we studied allelic patterns of 40 microsatellite markers mapping to all regions of chromosome 13 and 79 SNPs located within the 13q14 region containing the RB1 gene. A whole-organ histologic and genetic mapping strategy was used to identify the evolution of allelic losses on chromosome 13 during the progression of bladder neoplasia. Markers mapping to chromosomal regions involved in clonal expansion of preneoplastic intraurothelial lesions were subsequently tested in 25 tumors and 21 voided urine samples of patients with bladder cancer. Four clusters of allelic losses mapping to distinct regions of chromosome 13 were identified. Markers mapping to the 13q14 region that is flanked by D13S263 and D13S276, which contains the RB1 gene, showed allelic losses associated with early clonal expansion of intraurothelial neoplasia. Such losses could be identified in approximately 32% bladder tumor tissue samples and 38% of voided urines from patients with bladder cancer. The integration of distribution patterns of clonal allelic losses revealed by the microsatellite markers with those obtained by genotyping of SNPs disclosed that the loss within an approximately 4-Mb segment centered around RB1 may represent an incipient event in bladder neoplasia. However, the inactivation of RB1 occurred later and was associated with the onset of severe dysplasia/carcinoma in situ. Our studies provide evidence for the presence of critical alternative candidate genes mapping to the 13q14 region that are involved in clonal expansion of neoplasia within the bladder antecedent to the inactivation of the RB1 gene.

Aged↗
PubMed2005

Rearrangements of IgH, TCRD and TCRG genes as clonality marker of childhood acute lymphoblastic leukemia.

AIM: Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements are excellent patient-specific targets for clonality studies and monitoring of acute lymphoblastic leukemia (ALL). THE AIMS of the study were to select the optimum panel of primers, evaluate incidence of particular types of monoclonal and oligoclonal gene rearrangements and observe alteration of rearrangement profile between diagnosis of ALL and subsequent relapse(s). METHODS: We used polymerase chain reaction (PCR) for amplification of junctional region of rearranged IgH, TCRD and TCRG genes in combination with heteroduplex analysis in polyacrylamide gel. RESULTS: TCRD gene rearrangements were detected in 64%, TCRG - in 45%, and IgH - in 79% of B-precursor ALL patients. For patients with T-ALL, TCRD gene rearrangements were found in 47%, TCRG gene - in 66%, and IgH - in 19% of cases. Evaluation of biallelic and oligoclonal rearrangements was performed in the study. The highest incidence of oligoclonal rearrangements - 25% was shown for IgH gene in patients with B-precursor ALL. Seven pair cases of patients with de novo leukemia and relapses were analyzed and revealed subclonal deviation in rearrangements of IgH or TCR genes during disease evolution. CONCLUSION: We propose a panel of 13 types of rearrangements (primer pairs) sufficient for tumor cell clonality detection in 96% of patients with ALL. Applications of PCR-based analysis of rearranged IgH, TCRD and TCRG genes for discrimination of mono- and oligoclonality and identification of the origin of relapse were demonstrated.

Child↗
PubMed2001

exl, an exchangeable genetic island in Neisseria meningitidis.

The genetic structure and evolution of a novel exchangeable meningococcal genomic island was defined for the important human pathogen Neisseria meningitidis. In 125 meningococcal strains tested, one of three unrelated nucleotide sequences, designated exl (exchangeable locus), was found between a gene required for heme utilization, hemO, and col, encoding a putative Escherichia coli collagenase homologue. The 5' boundary of each exl cassette was the stop codon of hemO, whereas the 3' boundary was delineated by a 33-bp repeat containing neisserial uptake sequences located downstream of col. One of the three alternative exl cassettes contained the meningococcal hemoglobin receptor gene, hmbR (exl3). In other meningococcal strains, hmbR was absent from the genome and was replaced by either a nucleotide sequence containing a novel open reading frame, exl2, or a cassette containing exl3. The proteins encoded by exl2 and exl3 had no significant amino acid homology to HmbR but contained six motifs that are also present in the lipoprotein components of the lactoferrin (LbpB), transferrin (TbpB), and hemoglobin-haptoglobin (HpuA) uptake systems. To determine the evolutionary relationships among meningococci carrying hmbR, exl2, or exl3, isolates representing 92 electrophoretic types were examined. hmbR was found throughout the population structure of N. meningitidis (genetic distance, >0.425), whereas exl2 and exl3 were found in clonal groups at genetic distances of <0.2. The commensal neisserial species were identified as reservoirs for all of the exl cassettes found in meningococci. The structure of these cassettes and their correlation with clonal groups emphasize the extensive gene pool and frequent horizontal DNA transfer events that contribute to the evolution and virulence of N. meningitidis.

Amino Acid Sequence↗
PubMed2006

Clonal interference and the periodic selection of new beneficial mutations in Escherichia coli.

The conventional model of adaptation in asexual populations implies sequential fixation of new beneficial mutations via rare selective sweeps that purge all variation and preserve the clonal genotype. However, in large populations multiple beneficial mutations may co-occur, causing competition among them, a phenomenon called "clonal interference." Clonal interference is thus expected to lead to longer fixation times and larger fitness effects of mutations that ultimately become fixed, as well as to a genetically more diverse population. Here, we study the significance of clonal interference in populations consisting of mixtures of differently marked wild-type and mutator strains of Escherichia coli that adapt to a minimal-glucose environment for 400 generations. We monitored marker frequencies during evolution and measured the competitive fitness of random clones from each marker state after evolution. The results demonstrate the presence of multiple beneficial mutations in these populations and slower and more erratic invasion of mutants than expected by the conventional model, showing the signature of clonal interference. We found that a consequence of clonal interference is that fitness estimates derived from invasion trajectories were less than half the magnitude of direct estimates from competition experiments, thus revealing fundamental problems with this fitness measure. These results force a reevaluation of the conventional model of periodic selection for asexual microbes.

Cloning, Molecular↗
PubMed2002

Sex releases the speed limit on evolution.

Explaining the evolutionary maintenance of sex remains a key problem in evolutionary biology. One potential benefit of sex is that it may allow a more rapid adaptive response when environmental conditions change, by increasing the efficiency with which selection can fix beneficial mutations. Here I show that sex can increase the rate of adaptation in the facultatively sexual single-celled chlorophyte Chlamydomonas reinhardtii, but that the benefits of sex depend crucially on the size of the population that is adapting: sex has a marked effect in large populations but little effect in small populations. Several mechanisms have been proposed to explain the benefits of sex in a novel environment, including stochastic effects in small populations, clonal interference and epistasis between beneficial alleles. These results indicate that clonal interference is important in this system.

Adaptation, Physiological↗
PubMed1999

A distinctive composite lymphoma consisting of clonally related mantle cell lymphoma and follicle center cell lymphoma.

Although follicle center cell lymphoma and mantle cell lymphoma are both B cell non-Hodgkin's lymphomas (NHL), they are regarded as separate entities with distinct clinical, morphological, immunophenotypic and molecular characteristics. To our knowledge, the coexistence of these 2 lymphomas in the same patient has never been reported. We describe a 70-year-old woman with a long-standing history of follicle center cell lymphoma, cytological grade I, who subsequently developed a composite lymphoma consisting of well-demarcated foci of persistent follicle center cell lymphoma surrounded by mantle cell lymphoma. This morphological interpretation was supported by the presence of both bcl-1 and bcl-2 gene rearrangements, which are molecular genetic hallmarks of mantle cell lymphoma and follicle center cell lymphoma, respectively. Polymerase chain reaction (PCR) analysis for rearranged immunoglobulin heavy chain (IgH) genes showed a dominant band identical in size in microdissected tumor cells of the follicle center cell and mantle cell lymphomas. Cloning and sequence analysis of the PCR products revealed a common clone-specific IgH gene rearrangement in these 2 lymphomas. These findings suggest that this composite lymphoma represents the unusual evolution of a malignant B-cell clone that resulted in the development of 2 morphologically distinct but clonally related B-cell NHLs. These findings also show the importance of integrating morphological, immunophenotypic, and molecular data to enhance our understanding of the complex pathogenic interrelationships in lymphomagenesis.

Aged↗
PubMed1998

Differential genome analysis of bacteria by genomic subtractive hybridization and pulsed field gel electrophoresis.

A comprehensive analysis of the differences between the genomes of two closely related bacterial strains should give insight into the molecular basis of their individual phenotypic and genotypic characteristics. Here we present an integrative approach including two different strategies for the thorough investigation of genomic divergence. We have combined two techniques including genomic subtractive hybridization and comparative genome mapping by pulsed field gel electrophoresis (PFGE) techniques. The subtractive method for which a protocol is given herein results in the production of a library of specific DNA sequence tags present only in one strain, while the construction of macrorestriction maps of the bacterial chromosomes yields data about the overall genome organization and the arrangement and distance of gene loci. Comparison of the physical and genetic maps and determination of the map positions of the strain-specific DNA sequences reveals gross chromosomal modifications, insertions or deletions of additional genetic material, and transpositional events. The further investigation of the strain-specific regions yields information about the nature and origin of the acquired DNA and their influence on the evolution of the individual bacterial genome. The two methods were applied to differential genome analysis of clonal divergence in Pseudomonas aeruginosa choosing two clone C isolates from diverse habitats.

Chromosomes, Bacterial↗
PubMedDate not supplied

Hematopoietic stem cells in aplastic anemia.

Profound cytopenia involving all blood lineages, a hallmark of aplastic anemia (AA), can result in devastating morbidity and high mortality. Although various etiologies and distinct pathophysiologic mechanisms may be involved, a profound defect in the stem cell compartment is a unifying feature in most patients with AA. As a stem cell disease, AA is very instructive and provides insights into the function and quantity of normal hematopoietic stem cells and their ability to regenerate. Pathophysiologically, understanding of AA may reveal mechanisms as to the evolution of other related bone marrow failure syndromes such as paroxysmal nocturnal hemoglobinuria and myelodysplasia-clonal diseases of hematopoiesis associated with defective stem cells. Conversely, constitutional forms of AA occurring in association with Fanconi anemia and dyskeratosis congenita demonstrate the role of specific genes and pathways in the dysfunction of the stem cells leading to the failure of the stem cell compartment. The acquired mechanisms resulting in depletion of stem cells in AA may involve fundamental pathways such as apoptosis and senescence as well as exhaustion of proliferative capacity or excessive differentiation. Inherent in the paucity of the bone marrow in AA, the study of the stem cells in AA has been very difficult due to their natural rarity and disease-specific contraction of the stem cell pool. Despite these scientific challenges, laboratory studies and systematic clinical observation provide valuable information of significance beyond its specific application to AA.

Anemia, Aplastic↗