Effects of cord blood element levels on neurodevelopment of preterm and full-term children: A cohort study / 环境与职业医学

Background Essential and non-essential elements have an important impact on the development of the central nervous system during fetal development. Due to their less developed brain, preterm infants are more sensitive to element exposure, and are high-risk groups of neurodevelopmental abnormalities. However, it is not clear whether the effects of element exposure in utero on postpartum neurodevelopment are different between full-term infants and preterm infants. Objective To evaluate the effects of element exposure levels during pregnancy on neurodevelopment of children aged 6-24 months (of corrected age), and compare the effects between preterm and full-term children. Methods A prospective study design was adopted and this study was conducted based on the Maoming Birth Cohort Study (MBCS) in Maoming City, Guangdong Province. Twenty elements in cord blood of 197 preterm infants and 297 full-term infants were measured, including 11 essential trace elements [vanadium (V), chromium (Cr), manganese (Mn), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), selenium (Se), strontium (Sr), tin (Sn), and iron (Fe)], and 9 non-essential trace elements [aluminum (Al), arsenic (As), thallium (Tl), lead (Pb), uranium (U), cerium (Ce), antimony (Sb), cadmium (Cd), and yttrium (Y)]. The neurodevelopment of the children at 6, 12, and 24 months were evaluated by the Ages and Stages Questionnaires-the Third Edition (ASQ-3). A generalized estimating equation (GEE) model was adopted to evaluate the associations between elements and neurodevelopment in full-term and preterm children separately. Results The positive rates of 10 elements (Mn, Cu, Zn, Se, Sr, Fe, Sb, Tl, Pb, and As) in cord blood were greater than 80%. Among the preterm birth children, the results of GEE analysis showed that after adjusting for the covariates, for each increase of interquartile range (IQR) in ln-transformed concentration, As was associated with problems/delay in the communication and problem-solving sub-scales, with the adjusted odds ratios (OR) and 95% confidence intervals (CI) of 1.36 (1.03-1.80) and 1.55 (1.10-2.20), respectively; the adjusted OR (95%CI) of problems/delay in the fine motor and problem-solving sub-scales were 1.44 (1.00-2.07) and 1.76 (1.09-2.84) for Sb, respectively; the adjusted OR (95%CI) of problems/delay in the communication sub-scale was 1.37 (1.09-1.74) for Se. No statistically significant associations between umbilical cord blood element concentrations and neurodevelopment indicators were observed among full-term children. The results of stratified analysis by sex showed that the associations between umbilical cord blood element concentrations and neurodevelopment problems/delay were only significant among female preterm children. Conclusion Exposures to As, Se, and Sb during pregnancy may increase the risk of neurodevelopment problems/delay in preterm children aged 6-24 months, and female seem to be more vulnerable.

Clonal evolution and clinical significance of trisomy 8 in acquired bone marrow failure / 中华血液学杂志

Objective@#To analyze clonal evolution and clinical significance of trisomy 8 in patients with acquired bone marrow failure.@*Methods@#The clinical data of 63 patients with acquired bone marrow failure accompanied with isolated trisomy 8 (+8) from June 2011 to September 2018 were analyzed retrospectively, the clonal evolution patterns and relationship with immmunosuppressive therapy were summarized.@*Results@#Totally 24 male and 39 female patients were enrolled, including 39 patients with aplastic anemia (AA) and 24 patients with relatively low-risk myelodysplastic syndrome (MDS) . Mean size of+8 clone in MDS patients[65% (15%-100%) ]was higher than that of AA patients[25% (4.8%-100%) , z=3.48, P=0.001]. The patients were was divided into three groups (<30%, 30%-<50%,and ≥50%) according to the proportion of+8 clone. There was significant difference among the three groups between AA[<30%:55.6% (20/36) ; 30-50%: 22.2% (8/36) ; ≥50%22.2% (8/36) ]and MDS patients[<30%:19.0% (4/21) ; 30%-<50%:19.0% (4/21) ; ≥50%61.9% (13/21) ] (P=0.007) . The proportion of AA patients with+8 clone <30% was significantly higher than that of MDS patients (P=0.002) ; and the proportion of AA patients with+8 clone ≥50%was significantly lower than that of MDS patients (P=0.002) . The median age of AA and MDS patients was respectively 28 (7-61) years old and 48.5 (16-72) years old. Moreover, there was no correlation between age and+8 clone size in AA or MDS (rs=0.109, P=0.125; rs=-0.022, P=0.924, respectively) . There was statistical difference in total iron binding capacity, transferrin and erythropoietin between high and low clone group of AA patients (P=0.016, P=0.046, P=0.012, respectively) , but no significant difference in MDS patients. The immunosuppressive therapy (IST) efficacy of AA and MDS patients was respectively 66.7% and 43.8% (P=0.125) . Comparing with initial clone size (27.3%) , the +8 clone size (45%) of AA patients was increased 1-2 year after IST, but no statistical difference (z=0.83, P=0.272) . Consistently, there was no significant change between initial clone size (72.5%) and 1-2 year clone size (70.5%) after IST in MDS patients. There was no significant difference in IST efficient rate between +8 clone size expansion and decline group of in AA patients at 0.5-<1, 1-2 and>2 years after IST. We found four dynamic evolution patterns of +8 clone, which were clone persistence (45%) , clone disappearance (30%) , clone emergence (10%) and clone recurrence (15%) .@*Conclusions@#AA patients had a low clone burden, while MDS patients had a high burden of +8 clone. The +8 clone of AA patients didn’t significantly expanded after IST, and the changes of +8 clone also had no effect on IST response.

Solution structure of the RNA recognition domain of METTL3-METTL14 N-methyladenosine methyltransferase

N-methyladenosine (mA), a ubiquitous RNA modification, is installed by METTL3-METTL14 complex. The structure of the heterodimeric complex between the methyltransferase domains (MTDs) of METTL3 and METTL14 has been previously determined. However, the MTDs alone possess no enzymatic activity. Here we present the solution structure for the zinc finger domain (ZFD) of METTL3, the inclusion of which fulfills the methyltransferase activity of METTL3-METTL14. We show that the ZFD specifically binds to an RNA containing 5'-GGACU-3' consensus sequence, but does not to one without. The ZFD thus serves as the target recognition domain, a structural feature previously shown for DNA methyltransferases, and cooperates with the MTDs of METTL3-METTL14 for catalysis. However, the interaction between the ZFD and the specific RNA is extremely weak, with the binding affinity at several hundred micromolar under physiological conditions. The ZFD contains two CCCH-type zinc fingers connected by an anti-parallel β-sheet. Mutational analysis and NMR titrations have mapped the functional interface to a contiguous surface. As a division of labor, the RNA-binding interface comprises basic residues from zinc finger 1 and hydrophobic residues from β-sheet and zinc finger 2. Further we show that the linker between the ZFD and MTD of METTL3 is flexible but partially folded, which may permit the cooperation between the two domains during catalysis. Together, the structural characterization of METTL3 ZFD paves the way to elucidate the atomic details of the entire process of RNA mA modification.

Structural Insights into N-methyladenosine (mA) Modification in the Transcriptome / 基因组蛋白质组与生物信息学报·英文版

More than 100 types of chemical modifications in RNA have been well documented. Recently, several modifications, such as N-methyladenosine (mA), have been detected in mRNA, opening the window into the realm of epitranscriptomics. The mA modification is the most abundant modification in mRNA and non-coding RNA (ncRNA). At the molecular level, mA affects almost all aspects of mRNA metabolism, including splicing, translation, and stability, as well as microRNA (miRNA) maturation, playing essential roles in a range of cellular processes. The mA modification is regulated by three classes of proteins generally referred to as the "writer" (adenosine methyltransferase), "eraser" (mA demethylating enzyme), and "reader" (mA-binding protein). The mA modification is reversibly installed and removed by writers and erasers, respectively. Readers, which are members of the YT521-B homology (YTH) family proteins, selectively bind to RNA and affect its fate in an mA-dependent manner. In this review, we summarize the structures of the functional proteins that modulate the mA modification, and provide our insights into the mA-mediated gene regulation.

Comparison of hemolytic characteristics among paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemia and hereditary spherocytosis / 中华血液学杂志

Objective@#To determine the valuable hemolytic characteristics in differential diagnosis of paroxysmal nocturnal hemoglobinuria (PNH), autoimmune hemolytic anemia (AIHA) and hereditary spherocytosis (HS).@*Method@#The clinical and hemolytic characteristics of 108 PNH patients, 127 AIHA patients and 172 HS patients diagnosed from January 1998 to April 2017 were compared.@*Results@#①Reticulocyte percentage (Ret%) of PNH patients [6.70% (0.14%-22.82%)] was significantly lower than that of AIHA [14.00%(0.10%-55.95%), P<0.001] and HS patients [11.83%(0.60%-57.39%), P<0.001]. The Ret% in PNH patients were significantly lower than those in AIHA and HS patients at the same levels of anemia, except for in mild anemia between PNH and AIHA patients. However, when comparing the Ret% between AIHA and HS patients, there was significant difference only in mild anemia [7.63%(1.87%-29.20%)% vs 11.20%(3.31%-22.44%), z=-2.165, P=0.030]. ②The level of TBIL in HS patients was significantly higher than that in AIHA and PNH patients [79.3 (11.2-244.0) μmol/L vs 57.6 (7.6-265.0) μmol/L, z=5.469, P<0.001; 79.3(11.2-244.0) μmol/L vs 26.2(4.6-217.7) μmol/L, z=-2.165, P<0.001], and the proportion of HS patients with TBIL more than 4 times the upper limit of normal (ULN) (64.1%) was significantly higher than that of AIHA (37.7%, χ2=19.896, P<0.001) and PNH patients (4.6%, P<0.001). ③The LDH level of PNH patients was significantly higher than that of AIHA and HS [1 500 (216-5 144) U/L vs 487 (29-3 516) U/L, z=-9.556, P<0.001; 1 500 (216-5 144) U/L vs 252 (132-663) U/L, z=-11.518, P<0.001], and the proportion of PNH patients with LDH more than 1 000 U/L (79.1%) was significantly higher than that of AIHA patients (13.0%, χ2=93.748, P<0.001) and HS patients (0, P<0.001). ④Splenomegaly occurred in 43.5% of PNH patients, including 16.0% with severe splenomegaly. In contrast, the occurrence of splenomegaly was 98.6% in AIHA patients and 100.0% in HS patients (P<0.001), and 63.0% of AIHA patients (P<0.001) and 90.4% of HS patients (P<0.001) were with severe splenomegaly. ⑤The prevalence of cholelithiasis in HS patients was up to 43.1%, significantly higher than that in AIHA patients (10.5%, P<0.001) and PNH patients (2.9%, P<0.001).@*Conclusion@#The comprehensive assessment of the five hemolytic characteristics is simplified, practical and efficient, with great clinical significance, providing specific indicators for differential diagnosis and efficient approach for making further work-up.

Comparison of age-based clinical and abnormal immune parameters in patients with Henoch-Schönlein purpura / 中华血液学杂志

Objective@#To explore age-based clinical and immune parameters in Henoch-Schönlein purpura (HSP) to determine clinically useful markers reflecting disease characteristic.@*Methods@#A cohort of 502 patients with HSP were enrolled into this retrospective study to evaluate their clinical and immune data.@*Results@#Majority HSP cases occurred at age ≤14 years and showed significant immune imbalances of ESR, CD3+ cells, CD4+ cells, CD3-CD16+CD56+ cells, CD4+/CD8+ cells, IgG, IgA, IgM, IgE, complements C3/C4 and ASO in the acute phase. Compared to patients aged >14 years, symptoms of joint were more frequent at disease onset in patients aged ≤14 years (20.8% vs 7.6%, χ2=13.547, P<0.001) , and involvement of digestive tract and joint were also more frequent (57.4% vs 33.8%, χ2=24.106, P<0.001; 55.9% vs 32.5%, χ2=23.768, P<0.001, respectively) , but not for involvement of kidney (21.4% vs 51.3%, χ2=42.440, P<0.001) . The patients aged ≤14 years had distinct immune state, reductions of CD3+ cells, CD4+ cells and IgG were more frequent than patients aged >14 years, also increase of ASO (33.1% vs 20.0%, χ2=6.656, P=0.010) , but not increase of IgA (2.6% vs 39.4%, χ2=15.582, P<0.001) . In addition, reduction of IgG and increase of IgE were positively associated with digestive tract involvement (P<0.001, P=0.001, respectively) , reduction of CD3+CD4+ cells and normal IgM were positively associated with joint involvement (P=0.004, P=0.003, respectively) , increase of CD3+CD8+ cells and normal CD3+ cells were positively associated with kidney involvement (P=0.032, P=0.014, respectively) .@*Conclusion@#HSP showed significant immune imbalance in the acute phase, patients between aged ≤14 and >14 years had distinct clinical and immune characteristic, and abnormal immune parameters were significantly associated with organ involvements.

Efficacy and safety of deferasirox in aplastic anemia patients with iron overload: a single arm, multi-center,prospective study in China / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the efficacy and safety of deferasirox in aplastic anemia (AA)patients with iron overload.</p><p><b>METHODS</b>A single arm, multi- center, prospective, open- label study was conducted to evaluate absolute change in serum ferritin (SF)from baseline to 12 months of deferasirox administration, initially at a dose of 20 mg·kg(-1)·d(-1), and the safety in 64 AA patients with iron overload.</p><p><b>RESULTS</b>All patients started their deferasirox treatment with a daily dose of 20 mg · kg(-1) ·d(-1). The mean actual dose was (18.6±3.60) mg · kg(-1)·d(-1). The median SF decreased from 4 924 (2 718- 6 765)μg/L at baseline (n=64) to 3 036 (1 474- 5 551)μg/L at 12 months (n=23) with the percentage change from baseline as 38%. A median SF decrease of 651 (126-2 125)μg/L was observed at the end of study in 23 patients who completed 12 months' treatment, the median SF level decreased by 1 167(580-4 806)μg/L [5 271(3 420-8 278)μg/L at baseline; 3 036(1 474-5 551)μg/L after 12 months' treatment; the percentage change from baseline as 42% ] after 12 months of deferasirox treatment. The most common adverse events (AEs) were increased serum creatinine levels (40.98%), gastrointestinal discomfort (40.98%), elevated liver transaminase (ALT: 21.31%; AST: 13.11%)and proteinuria (24.59%). The increased serum creatinine levels were reversible and non-progressive. Of 38 patients with concomitant cyclosporine use, 12(31.8%)patients had two consecutive values >ULN, 10(26.3%)patients had two consecutive values >1.33 baseline values, but only 1(2.6%)patient's serum creatinine increased more than 1.33 baseline values and exceeded ULN. For both AST and ALT, no patients experienced two post- baseline values >5 ×ULN or >10 × ULN during the whole study. In AA patients with low baseline PLT count (less than 50 × 10(9)/L), there was no decrease for median PLT level during 12 months' treatment period.</p><p><b>CONCLUSIONS</b>AA patients with iron overload could achieve satisfactory efficacy of iron chelation by deferasirox treatment. The drug was well tolerated with a clinically manageable safety profile and no major adverse events.</p>

Clinical characteristics and evolution of paroxysmal nocturnal hemoglobinuria clones in patients with acquired aplastic anemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the clinical characteristics, and the effect of paroxysmal nocturnal hemoglobinuria (PNH) clone size and its evolution on response and survival in aplastic anemia (AA) patients.</p><p><b>METHODS</b>The clinical data of 90 AA cases with PNH clones from 316 AA patients between January 2011 and September 2014 were retrospectively reviewed, their clinical characteristics were analyzed, and the influence of PNH clone evolution and size on response and survival were explored.</p><p><b>RESULTS</b>① Of 316 patients, 90 cases (28.5%) with PNH clones. Of 83 cases with long-term follow-up data available, the complete (CR) and partial response (PR) rates were 43.4% and 33.7% respectively, with the overall responsive rate of 77.1%. The 3-year and 5-year overall survival (OS)rates were 79.4% and 76.1% respectively. ② After immunosuppressive therapy (IST), the PNH clone changed from negative to positive in 24 cases, persistently positive PNH clones were observed in 22 cases, disappeared in 10 cases. There were no significant differences in terms of overall responsive rates, survival rates, absolute reticulocyte value, TBIL, IBIL and LDH among the three groups (P >0.05). Ten cases became AA-PNH after a median time of 15.6 months, no significant differences were found in overall responsive and survival rates between the 10 cases and the other 46 cases who were monitored for PNH clones (P values were 0.896, 0.688, respectively). ③ According to univariate analysis, age≥55, infection, VSAA, ANC <0.5 × 10(9)/L and absolute reticulocyte value <0.012 × 10(12)/L had significant influence on survival (P values were 0.026, 0.000, 0.001, 0.000 and 0.010, respectively). Cox regression model analysis identified that age, infection and ANC were independent prognostic factors affecting survival (P values were 0.050, 0.012 and 0.050, respectively). The PNH clone size had no significant influence on response and survival based on univariate and Cox analyses.</p><p><b>CONCLUSION</b>The PNH clone size and its evolution had no significant influence on response and survival.</p>

The gene mutation analysis of a Wiskott-Aldrich syndrome family with normal mean platelet volume / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the history of a Wiskott- Aldrich syndrome (WAS) family with normal mean platelet volume (MPV), analyse the WASP gene mutation of to better understand its clinical characteristics.</p><p><b>METHODS</b>A four- generation WAS family histories of 22 members were investigated. Peripheral blood samples were collected from propositus and his mother to analyse all exon mutations of WASP gene using sanger sequencing.</p><p><b>RESULTS</b>The MPV of both propositus and his elder brother were normal. The patient's clinical score was 5, antibodies to PM-Scl, PCNA and PO were positive with very high level of ASO, the patient co- suffered from autoimmune disease, anemia, abnormal renal function, fungal infection and scleritis. A homozygous mutation (C>T) was found at 173 bp of exon 2, corresponding to amino acids Pro (P) 58 abnormally changed to Leu (L). His mother was the carrier of the mutation. Of 112 blood diseases- related genes, mutation frequencies of CBL, CREBBP, DNM2 and ADAMTS13 were higher than normals.</p><p><b>CONCLUSION</b>This was the first report the phenotype 173C>T mutation of WASP without eczema, but with normal MPV and autoimmune disease in Chinese, WAS should be recognized earlier and diagnosed correctly by genomic methods.</p>

Salvage therapy for severe aplastic anemia after allogenenic hematopoietic cell transplant / 中华血液学杂志

<p><b>OBJECTIVE</b>To probe a practical salvage strategy for relapse or failure patients with severe aplastic anemia (SAA) after allogenenic hematopoietic cell transplant (allo-HSCT).</p><p><b>METHODS</b>The clinical characteristics and initial treatments of allo-HSCT, and the responses of a novel salvage therapy of cyclosporine alternately combined with levamisole (CsA & LMS regimen) plus danazol (DNZ) in 2 patients were reviewed and evaluated.</p><p><b>RESULTS</b>(1) Patient 1 achieved partial response (PR) at 3 months and complete response (CR) at 6 months after CsA & LMS regimen, respectively; Patient 2 also achieved PR 3 months and nearly CR at 6 months after the salvage therapy, respectively. (2) Increased numbers of T regulatory cells and colony forming unit-erythroid, burst-forming unit-erythroid, colony forming unit-granulocytes/macrophages after CsA & LMS regimen in both patients were observed.</p><p><b>CONCLUSION</b>This was the first report of successful salvage by a novel strategy of CsA & LMS regimen for relapse or failure patients with SAA after allo-HSCT.</p>

Relationship between serum parathyriod hormone level and renal anemia in patients with chronic kidney dis-ease / 中国基层医药

Objective To explore the relationship of serum parathyriod hormone ( PTH) level with renal ane-mia in patients with chronic kidney disease (CKD).Methods Serum levels of PTH,Hb,Hct,BUN,Cr were observed in 126 patients with CKD at stages 3-5,the changes of 42 patients in maintenance hemodialysis(MHD) with recombi-nant human erythropoietin (rhEPO) and calcitriol-1.25(OH)2D3 treatment for three months were determined. Results The serum PTH level was significantly increased in CKD patients at stage 3 and more in CKD patients at stage 4 and 5.There were positive relationship between blood PTH and BUN ,Cr(P<0.01),but a negative relation-ship between PTH and Ccr,Hb(P <0.01).42 patients of MHD treated with rhEPO,1.25(OH)2D3 after three months,according to the changes of HCT ,the effective rate was 73.8% and the ineffective rate was 26.2%.The PTH,Hb,HCT of the effective group had statistically significant differences compared with the ineffective group ( all P<0.01).Hb and Hct significantly increased and PTH significantly decreased in the effective group .Conclusion CKD patients had decreased renal function ,elevated blood PTH .High serum PTH might aggravate renal anemia and fail to respond to rhEPO.The high serum PTH corrected by using 1.25(OH)2D3 might improve renal anemia,with high plasma PTH correcting .

The diagnosis and management of isolated sphenoiditis in children / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#Analyzing the clinical manifestation, diagnosis and management of isolated sphenoiditis in children, retrospectively, was to get more information of the disease and to supply correct treatment early.@*METHOD@#The symptoms, signs and imaging data of seventeen cases with isolated sphenoiditis hospitalized in our department from June 2001 to January 2010 were analyzed retrospectively.@*RESULT@#Nine out of seventeen patients had the chief complaint of headache, three patients had blood in nasal discharge and had a fever, and five patients had postnasal drip with headache and a slight fever. The disease lasted for three months to one year. Five patients showed nasal discharge in rhinologic examination, one patient had solitary polyps in sphenoethmoid recess, eight patients had adenoid hypertrophy and the last three patients showed no positive signs. CT scan or MRI revealed opacification in sphenoid sinus. Eight patients received normative antibiotic therapy and were cured. The rest nine patients received endoscopic sinus surgery. The complaints relieved after the surgery and there was no signs of recurrence in 1 to 5 years of follow-up.@*CONCLUSION@#Headache can be the chief and unique symptom of isolated sphenoiditis in children, which was easy to misdiagnose and miss diagnosis. CT or MRI was the evidence of diagnosis. Antibiotic therapy could be used for acute sphenoiditis. Patients with chronic sphenoiditis should receive endoscopic sinus surgery as early as better. From supraturbinal to sphenoid sinus natural ostia is the best way in sphenoidotomy.