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1.
Article in Chinese | WPRIM | ID: wpr-828722

ABSTRACT

OBJECTIVE@#To study the clinical features and genetic mutations of children with Shwachman-Diamond syndrome (SDS) and malignant myeloid transformation.@*METHODS@#Next-generation sequencing was used to analyze the gene mutations in 11 SDS children with malignant myeloid transformation, and their clinical features and genetic mutations were analyzed.@*RESULTS@#Of the 11 children with SDS, 9 (82%) presented with refractory cytopenia of childhood (RCC), 1 (9%) had myelodysplastic syndrome with excess blasts (MDS-EB), and 1 (9%) had acute myeloid leukemia with myelodysplasia-related changes (AML-MRC). The median age of onset of malignant myeloid transformation was 48 months (ranged 7 months to 14 years). Of the 11 children, 45% had abnormalities in the hematological system alone. Mutations of the SBDS gene were detected in all 11 children, among whom 5 (45%) had c.258+2T>C homozygous mutation and 3 (27%) had c.184A>T+c.258+2T>C compound heterozygous mutation. The new mutations of the SBDS gene, c.634_635insAACATACCTGT+c.637_638delGA and c.8T>C, were rated as "pathogenic" and "possibly pathogenic" respectively. The 3-year predicted overall survival rates of children transformed to RCC and MDS-EB/AML-MRC were 100% and 0% respectively (P=0.001).@*CONCLUSIONS@#SDS children may have hematological system symptoms as the only manifestation, which needs to be taken seriously in clinical practice. The type of malignant transformation is associated with prognosis.


Subject(s)
Adolescent , Child , Child, Preschool , Exocrine Pancreatic Insufficiency , Humans , Infant , Leukemia, Myeloid, Acute , Mutation , Myelodysplastic Syndromes , Shwachman-Diamond Syndrome
2.
Journal of Experimental Hematology ; (6): 1831-1836, 2020.
Article in Chinese | WPRIM | ID: wpr-879979

ABSTRACT

OBJECTIVE@#To investigate the consistency between FCM and PCR on the detecting of MRD in TCF3-PBX1@*METHODS@#55 cases of paediatric TCF3-PBX1@*RESULTS@#Among the 55 children with TCF3-PBX1@*CONCLUSION@#The detection result of MRD in TCF3-PBX1 detect by FCM and PCR shows better consistency. MRD positivity detected by FCM at the end of induction therapy (day 33) predicts a high risk of relapse in TCF3-PBX1 ALL patients.


Subject(s)
Adolescent , Bone Marrow , Child , Child, Preschool , Female , Humans , Male , Neoplasm, Residual , Oncogene Proteins, Fusion/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Prognosis , Recurrence
3.
Article in Chinese | WPRIM | ID: wpr-774051

ABSTRACT

OBJECTIVE@#To study the clinical features of Wiskott-Aldrich syndrome (WAS) in children.@*METHODS@#A retrospective analysis was performed for the clinical data of 13 children with WAS.@*RESULTS@#All 13 children were boys, with a median age of onset of 3 months (range 1-48 months) and a median age of 24 months (range 1-60 months) at the time of diagnosis. Of the 13 children, only 3 had typical WAS and the remaining 10 children had X-linked thrombocytopenia (XLT). The mean WAS score was 2 (range 1-3), the mean platelet count was 20.5×10/L [range (13-46)×10/L], and the mean platelet volume was 8.1 fl (range 6.7-12.1 fl). Lymphocyte subsets and immunoglobulins were measured for 4 children, among whom 1 (25%) had a reduction in both the percentage of CD3T cells per lymphocyte and lymphocyte per nuclear cells, 1(25%) had a reduction in CD3CD56 NK cells. Among these 4 children, 1 (25%) had an increase in IgG, 2 (50%) had a reduction in IgM, 1 (25%) had a reduction in IgA, and 4 (100%) had an increase in IgE. A total of 14 gene mutations belonging to 13 types were found in 13 children, among which there were 9 missense mutations (65%), 2 splicing mutations (14%), 2 nonsense mutation (14%), and 1 frameshift mutation (7%). The median follow-up time was 39 months (range 3-62 months), and all 13 children survived.@*CONCLUSIONS@#Children with WAS often have a young age of onset, and most of them are boys. Major clinical features include thrombocytopenia with a reduction in platelet volume. Missense mutation is the main type of gene mutation.


Subject(s)
Child, Preschool , Humans , Infant , Male , Mutation , Retrospective Studies , Thrombocytopenia , Wiskott-Aldrich Syndrome , Wiskott-Aldrich Syndrome Protein
4.
Article in Chinese | WPRIM | ID: wpr-775064

ABSTRACT

OBJECTIVE@#To study the clinical features and gene mutation spectrum of children with sideroblastic anemia (SA) and the clinical value of targeted next-generation sequencing in the molecular diagnosis of children with SA.@*METHODS@#Clinical data were collected from 36 children with SA. Targeted next-generation sequencing was used to detect mutations in SA-related pathogenic genes and genes associated with heme synthesis and mitochondrial iron metabolism. The association between genotype and clinical phenotype was analyzed.@*RESULTS@#Of the 36 patients, 32 had congenital sideroblastic anemia (CSA) and 4 had myelodysplastic syndrome with ring sideroblasts (MDS-RS). Mutations in CSA-related genes were detected in 19 children (19/36, 53%), among whom 9 (47%) had ALAS2 mutation, 4 (21%) had SLC25A38 mutation, and 6 (32%) had mitochondrial fragment deletion. No pathogenic gene mutation was detected in 4 children with MDS-RS. Among the 19 mutations, 89% (17/19) were known mutations and 11% (2/19) were novel mutations. The novel mutation of the ALAS2 gene c.1153A>T(p.I385F) was rated as "possibly pathogenic" and the novel mutation of the SLC25A38 gene c.175C>T(p.Q59X) was rated as "pathogenic".@*CONCLUSIONS@#ALAS2 and SLC25A38 gene mutations are commonly seen in children with CSA, but mitochondrial gene fragment deletion also accounts for a relatively high proportion. For children with hypoplastic anemia occurring in infancy, mitochondrial disease should be considered.


Subject(s)
5-Aminolevulinate Synthetase , Anemia, Sideroblastic , Genetics , Child , Genetic Diseases, X-Linked , Humans , Mitochondrial Membrane Transport Proteins , Mutation , Myelodysplastic Syndromes , Phenotype
5.
Article in Chinese | WPRIM | ID: wpr-690084

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the value of multiparameter flow cytometry (MFC) and flow cytometric scoring system (FCSS) in the diagnosis and prognostic evaluation of childhood myelodysplastic syndrome (MDS).</p><p><b>METHODS</b>A retrospective analysis was performed for the clinical data of 42 children who were diagnosed with MDS. MFC was performed to investigate the phenotype and proportion of each lineage of bone marrow cells. The correlations of FCSS score with MDS type, International Prognostic Scoring System (IPSS) score, and revised IPSS (IPSS-R) score were analyzed.</p><p><b>RESULTS</b>Of all the 42 children, 20 (48%) had an increase in abnormal marrow blasts, 19 (45%) had a lymphoid/myeloid ratio of >1, 14 (33%) had abnormal cross-lineage expression of lymphoid antigens in myeloid cells, 8 (19%) had abnormal CD13/CD16 differentiation antigens, 5 (12%) had abnormal expression of CD56, 3 (7%) had reduced or increased side scatter of granulocytes, 3 (7%) had reduced expression of CD36 in nucleated red blood cells, 2 (5%) had reduced expression of CD71 in nucleated red blood cells, 1 (2%) had absent expression of CD33 in myeloid cells, 1 (2%) had reduced or absent expression of CD11b in granulocytes, and 1 (2%) had absent expression of CD56 and CD14 in monocytes. There were significant differences in the median overall survival time and event-free survival time among the low-, medium-, and high-risk FCSS groups (P<0.05). Among the low-, medium-, and high-risk FCSS groups, the low-risk FCSS group had the highest 2-year overall survival rate, while there was no significant difference between the medium- and high-risk FCSS groups (P>0.05). The three groups had a 2-year event-free survival rate of 95%, 60%, and 46% respectively (P<0.05). FCSS score was positively correlated with MDS type, IPSS score, and IPSS-R score (P<0.05).</p><p><b>CONCLUSIONS</b>MFC and FCSS help with the diagnosis and prognostic evaluation of childhood MDS.</p>

6.
Article in Chinese | WPRIM | ID: wpr-351407

ABSTRACT

<p><b>OBJECTIVE</b>To evaluate the clinical characteristics and risk factors of clonal evolution after immunosuppressive therapy (IST) in children with severe/very severe aplastic anemia (SAA/VSAA).</p><p><b>METHODS</b>The clinical data of 231 children with newly-diagnosed SAA/VSAA who received IST were retrospectively studied. The incidence and risk factors of clonal evolution after IST were analyzed.</p><p><b>RESULTS</b>The 5-year overall survival rate of the 231 patients was 82.7%. Except for 18 cases of early deaths, 213 patients were evaluated for IST efficacy. Among the 231 patients, cytogenetic abnormalities for at least two chromosome metaphase were detectable in 14 (7.4%) patients, and PNH clones were detectable in either peripheral red blood cells or neutrophils for 95 patients. Among the 213 patients evaluated for IST efficacy, 15 patients experienced clonal evolution after IST. Five patients had PNH and trisomy 8 which were defined as favorable progressions, and ten patients experienced monosomy 7 and MDS/AML as unfavorable progressions. The 5-year accumulative incidence of favorable and unfavorable progression were (2.2±2.2)% and (4.8±3.3)%, respectively. Until the last follow-up, 100% (5/5) of patients with favorable progressions and 50% (5/10) of patients with unfavorable progressions survived. WBC>3.5×10/L, CD3T cell percentage>80%, dosage of antithymocyte globulin >3.0 mg/(kg·d) and no response to IST were related to unfavorable progressions by univariate analysis. Cox multivariate analysis revealed that an increased CD3T cell percentage (>80%) and no response to IST were independent risk factors for unfavorable progressions.</p><p><b>CONCLUSIONS</b>The children with SAA/VSAA who have an increased CD3T cell percentage at diagnosis or have no response to IST are in high risks of unfavorable progressions.</p>


Subject(s)
Adolescent , Anemia, Aplastic , Drug Therapy , Genetics , Allergy and Immunology , Mortality , Child , Child, Preschool , Chromosome Aberrations , Clonal Evolution , Female , Humans , Immunosuppressive Agents , Therapeutic Uses , Infant , Male , Proportional Hazards Models , Retrospective Studies
7.
Article in Chinese | WPRIM | ID: wpr-259612

ABSTRACT

<p><b>OBJECTIVE</b>To analysze genotype and measure telomere length in two Chinese patients with dyskeratosis congenita(DC).</p><p><b>METHODS</b>The peripleral blood DNA was extracted in two patients characterized by mucocutaneous abnormalities (abnormal nails, lacy reticulated skin pigmentation, and oral leukoplakia), bone marrow failure, DC genes were amplified by polymerase chain reaction (PCR), including DKC1, TERT, TERC, TINF2, NOP10, NHP2, then DNA sequencing was performed for abnormal exons. Lymphocyte telomere length was measured by flow cytometry-fluorescence in situ hybridization(Flow-FISH).</p><p><b>RESULTS</b>Abnormal peaks were found in exon 6 of TINF2 gene of the two patients and a 811C→T transition in TINF2 gene in one patient. DNA sequencing showed a 848C→A transition in TINF2 gene in another patient. Relative telomere length was remarkable less than that of normal children with same age.</p><p><b>CONCLUSIONS</b>Physician should think about DC if the young patients with mucocutaneous abnormalities and marrow failure. Early detection of related genes and measurernant of tolomere length may contribute to avoid misdiagnosis. TINF2 c.811C→T (Q271X) and TINF2 c.848C→A (P283H) exist in the two patients, it is reported in China for the first time.</p>


Subject(s)
Base Sequence , Bone Marrow , China , Dyskeratosis Congenita , Exons , Genotype , Humans , In Situ Hybridization, Fluorescence , Polymerase Chain Reaction , Sequence Analysis, DNA , Telomere , Telomere-Binding Proteins
8.
Article in Chinese | WPRIM | ID: wpr-289478

ABSTRACT

<p><b>OBJECTIVE</b>To study the clinical features of patients with refractory cytopenia of childhood (RCC).</p><p><b>METHODS</b>The clinical data of 1 420 children (0-14 years old) with an initial diagnosis of non-severe aplastic anemia between January 1990 and June 2013 were retrospectively analyzed. Bone marrow cell morphology and histopathology were re-evaluated, and the patients were re-classified using the criteria proposed in the 2008 edition of the World Health Organization classification of RCC in hematopoietic and lymphoid tumor tissues. The clinical outcomes were followed up every 3-6 months.</p><p><b>RESULTS</b>Among all the 1 420 cases, 152 (10.7%) were reassessed as RCC. Patients with RCC had a lower level of hemoglobin and a higher percentage of fetal hemoglobin than those with non-severe aplastic anemia. Of the patients with RCC, 21.5% showed abnormal karyotypes at diagnosis. The median follow-up period for all patients was 36 months (ranging from 1 to 283 months). The rates of complete response, partial response, and no response to cyclosporine and androgen treatment in RCC patients were 19.0%, 26.7%, and 54.3%, respectively. The 5- and 10-year prospective overall survival rates of RCC patients were 87.9% and 72.4%, respectively. The 5- and 10-year prospective clonal evolution rates were 15.3% and 20.0%, respectively. The 2-year prospective incidence of newly diagnosed karyotype abnormality after the initial diagnosis was 3.6%. The 5- and 10-year prospective leukemia transformation rates were 10.0% and 20.0%, respectively.</p><p><b>CONCLUSIONS</b>RCC shows clinical features similar to adult myelodysplastic syndrome. Children with RCC have a poor prognosis, an increased risk of transformation to leukemia, and a low response rate to cyclosporine treatment.</p>


Subject(s)
Adolescent , Child , Child, Preschool , Clonal Evolution , Female , Humans , Infant , Infant, Newborn , Male , Myelodysplastic Syndromes , Drug Therapy , Mortality , Pancytopenia , Drug Therapy , Mortality , Prognosis , Retrospective Studies
9.
Article in Chinese | WPRIM | ID: wpr-357299

ABSTRACT

<p><b>OBJECTIVE</b>To ovaluate the prognostic value of prednisone response in treatment regimes of children with acute lymphoblastic leukemia.</p><p><b>METHODS</b>A total of 598 newly diagnosed ALL patients were enrolled and received prednisone pre-treatment. Based on the peripheral lymphoblast count on day 8, these patients were divided into 2 groups: prednisone good response (PGR) and prednisone poor response (PPR). PPR patients were classified into high risk group immediately and then received intensed chemotherapy. The all enrolled patients were followed up and the clinical features and treatment outcomes of the two groups were analyzed.</p><p><b>RESULTS</b>Compared with PGR group, PPR group had different characteristics. They were older in age and had higher initial white blood cell count (P<0.05). T-cell ALL (T-ALL) and Philadelphia chromosome positive ALL (Ph+ ALL) were frequent in PPR group (P<0.05). Event-free survival (EFS) rate of PPR group was significantly lower than that of PGR group (P<0.05). 2 year event-free survival(EFS) rate of PGR group was (88.3±1.5)%, while the 2-year EFS rate of PPR group was (58.4±5.3)%. 5 year EFS rates of PGR and PPR were (80.8±2.1)% and (53.4±6.0)%, respectively. The EFS rate of PPR group was falling rapidly within 2 years. PPR group had higher relapse rate, and most relapses occurred within 18 months (P<0.05). PPR group had more high incidence of minimal residual disease (MRD) both on day 33 and on week 12 (P<0.05). No significant difference of EFS and relapse time was found between PPR and high risk PGR patients (P>0.05). In multi-variate regression analysis, the PPR, the presence of BCR-ABL1 and MLL were significantly unfavorable factors (P<0.05).</p><p><b>CONCLUSION</b>Prednisone response has been confirmed to be still great prognostic value and PPR children patients have poor outcomes generally. It is likely that the response to prednisone does not make much sense to high risk ALL patients.</p>


Subject(s)
Disease-Free Survival , Humans , Multivariate Analysis , Neoplasm, Residual , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Prednisone , Prognosis , Recurrence , Treatment Outcome
10.
Article in Chinese | WPRIM | ID: wpr-332710

ABSTRACT

This study was aimed to explore the pathogenesis of type III familial hemophagocytic lymphohistiocytosis (FHL3) via susceptibility gene UNC13D involving in homologous recombination repair (HRR) of DNA double-strand break (DSB). By means of DNA homologous recombination repair, the change of homologous recombination repair rate of normal control cells and DR-U2OS cells after down-regulation of UNC13D was detected; the UNC13D gene related function was explored. The results showed that DR-U2OS cells displayed a significant reduction in homologous recombination repair of DNA DSB after siRNA knockdown of UNC13D, compared to its normal control cell counterparts (P < 0.05), suggesting that UNC13D was involved in DNA double-stranded breakage repair. It is concluded that UNC13D gene mutation may be involved in the pathogenesis of FHL3 via its dual effects of both the cytotoxic granule exocytosis and decrease of homologous recombination repair rate after the DNA double-strand break, therefore, providing a new theoretical basis to reveal the pathogenesis of FHL3.


Subject(s)
DNA Breaks, Double-Stranded , DNA-Binding Proteins , Genetics , Humans , Lymphohistiocytosis, Hemophagocytic , Classification , Genetics , Membrane Proteins , Genetics , Recombinational DNA Repair
11.
Chinese Journal of Pediatrics ; (12): 178-182, 2013.
Article in Chinese | WPRIM | ID: wpr-359775

ABSTRACT

<p><b>OBJECTIVE</b>To study the clinical and laboratory characteristics of cases with warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome.</p><p><b>METHOD</b>An 11-year-old boy was diagnosed as WHIM syndrome and CXCR4 gene mutation analysis was performed.</p><p><b>RESULT</b>Since 3 years of age, the patient had recurrent fever and persistent cough. Since 6 years of age, he had warts on his fingers, the warts increased gradually. His complete blood count showed: white blood cell (WBC) 0.65×10(9)/L, neutrophil 0.15×10(9)/L, hemoglobin 116 g/L, platelet 200×10(9)/L, reticulocyte 0.62%. Results of serum biochemical tests: total protein (TP) 72.2 g/L (reference value 60 - 80 g/L), albumin 20.4 g/L (reference value 20 - 35 g/L), gammaglobulin 20.4 g/L (reference value 20 - 35 g/L). IgG 5.56 g/L (reference value 7.51 - 15.6 g/L), IgA 0.48 g/L (reference value 0.82 - 4.53 g/L), IgM 0.29 g/L (reference value 0.46 - 3.04 g/L). Peripheral blood lymphocyte subsets: CD3(+)T lymphocyte 43.6% (reference value 64.01% - 75.95%), CD19(+)B lymphocyte 1.00% (reference value 9.02% - 14.1%). Bone marrow smears showed that many of the neutrophils had a reactive appearance, with cytoplasmic vacuolation. Most neutrophils had hypersegmentation with four or five nuclear lobules. In some cells, the filaments connecting the nuclear lobes were long. CXCR4 mutation was detected.</p><p><b>CONCLUSION</b>WHIM syndrome is a rare immunodeficiency disorder with an autosomal-dominant pattern of inheritance. The disease is less progressive, and may accompany the patients' whole life.</p>


Subject(s)
Agranulocytosis , Genetics , Pathology , Amino Acid Sequence , Child , Humans , Immunoglobulins , Blood , Immunohistochemistry , Immunologic Deficiency Syndromes , Genetics , Pathology , Leukocyte Count , Male , Mutation , Receptors, CXCR4 , Genetics , Warts , Genetics , Pathology
12.
Journal of Experimental Hematology ; (6): 1099-1102, 2012.
Article in Chinese | WPRIM | ID: wpr-278427

ABSTRACT

This study was purposed to investigate the diagnostic value of fluorescence in situ hybridization (FISH) technique for the childhood acute myeloid leukemia (AML). The medical data of 179 children with AML (aged ≤ 16 years) were retrospectively studied, who were initially diagnosed in our hospital from April 2005 to April 2010. Through the analysis of the results of FISH, chromosome banding analysis and polymerase chain reaction, the difference and complementarity between FISH and other 2 methods for detecting the fusion genes were explored. The results indicated that the detection rate of genetic abnormality with FISH was higher. The PML/RARα probe was used in 27 AML-M3 patients, 22 out of whom were evaluated as PML/RARα positive. The AML1/ETO probe was used in 24 AML-M2b patients and all of them were evaluated as AML1/ETO positive. The CBFβ/MYH11 probe was used in 4 AML-M4Eo patients and all of them were evaluated as CBFβ/MYH11 positive. It is concluded that FISH is a sensitive method for detecting fusion genes and the results of FISH have a good correlation with the chromosome banding analysis and polymerase chain reaction. The combination of FISH with other 2 methods improves the detection rate of genetic abnormality, which is useful for the diagnosis and typing of childhood AML.


Subject(s)
Adolescent , Child , Child, Preschool , Female , Humans , In Situ Hybridization, Fluorescence , Infant , Karyotyping , Leukemia, Myeloid, Acute , Diagnosis , Genetics , Male , Retrospective Studies
13.
Journal of Experimental Hematology ; (6): 1297-1301, 2012.
Article in Chinese | WPRIM | ID: wpr-278386

ABSTRACT

Within the past few years, the invention of next-generation sequencing has revealed several new genes associated with tumor formation and development, for example DNMT3a. This gene is an independent prognostic factor for acute myeloid leukemia (AML). The objective of this study was to analyze the DNMT3a mutation in childhood AML in a single center. PCR amplification of the entire coding region of DNMT3a was performed using 23 overlapping primer pairs in 57 patients who were diagnosed in Blood Disease Hospital of Chinese Academy of Medical Sciences, then the directly sequencing was underwent. The results showed that no DNMT3a mutation was found in these patients including the hotspot R882. But AML1/ETO mutation was found in 10 patients, CBFB/MYH11 mutation in 3 patients, PML/RARa mutation in 13 patients, FLT3/ITD mutation in 5 patients, FLT3/TKD mutation in 1 patient, PML/RARa and FLT3/TKD mutation coexisted in 2 patients. It is concluded that DNMT3a mutations are rare in childhood AML, and different mechanisms of myeloid leukemogenesis between childhood and adults maybe involved.


Subject(s)
Adolescent , Base Sequence , Child , Child, Preschool , DNA (Cytosine-5-)-Methyltransferases , Genetics , DNA Mutational Analysis , Female , Humans , Infant , Karyotyping , Leukemia, Myeloid, Acute , Genetics , Male , Mutation
14.
Article in Chinese | WPRIM | ID: wpr-313914

ABSTRACT

In order to investigate the epidemiology of childhood acute leukemia (CAL), such as onset age and time, risk factor, subtypes distribution and genetics, 1236 CAL patients admitted in blood disease hospital of Chinese Academy of Medical Sciences for treatment from April 2004 to April 2010 were analyzed retrospectively. The results showed that the sex ratio of ALL and AML patients were 1.80:1 and 1.73:1 respectively; the average peak age of incidence lasted from 2 to 6 years with the median age of 6 years, while the ALL peak age of incidence lasted from 2 to 5 years but AML showed no significant peak age of incidence. Winter, especially January was the peak time for both onset and birth. Among all the 631 ALL patients who had already been immunophenotyped, B-ALL patients accounted for 83%, T-ALL patients accounted for 9%. Among 361 AML patients, sub-leukemia phenotype from M(0) to M(7) accounted for 0.3%, 2.2%, 29.8%, 20.9%, 8.1%, 25.2%, 4.1% and 4.6% respectively. Among 631 pediatric ALL patients who had been examined by using molecular biology technique, the positive rate of TEL/AML1, BCR/ABL, MLL and E2A/PBX1 were 23%, 7.4%, 4.1%, 2.1% respectively. Among 361 pediatric AML patients who had been examined by using molecular biology technique, 19% of the patients showed positive AML1/ETO fusion gene, 18% of the patients showed positive PML/RARα fusion gene, while 4.2% of patients showed positive CBFβ/MYH11. It is concluded that the onset of pediatric acute leukemia is influenced by age, season, environment and different genetic background.


Subject(s)
Age of Onset , Child , Child, Preschool , Female , Humans , Leukemia , Epidemiology , Leukemia, Myeloid, Acute , Epidemiology , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Epidemiology , Retrospective Studies
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