Structural characteristics and catalytic cycle of dihydroorotate dehydrogenase-a review / 生物工程学报

Dihydroorotate dehydrogenase is a flavin-dependent mitochondrial enzyme to catalyze the fourth step of the de novo synthesis of pyrimidine and to oxidize dihydroorotate to orotate. By selectively inhibiting dihydroorotate dehydrogenase, thereby inhibiting pyrimidine synthesis, the enzyme has been developed for the treatment of cancer, autoimmune diseases, bacterial or viral infections, parasitic diseases and so on. The development of inhibitory drugs requires a detailed understanding of the structural characteristics and catalytic cycle mechanism of dihydroorotate dehydrogenase. Therefore, this paper reviews these two aspects, and indicates perspectives of these inhibitors in clinical application.

Analysis of human intestinal nematode infections in Nanjing City from 2006 to 2015 / 中国血吸虫病防治杂志

Objective To analyze the epidemiological situation of human intestinal nematode infections in Nanjing City from 2006 to 2015,so as to provide the reference for formulating prevention and control measures. Methods The surveillance data of human intestinal nematode infections in Nanjing City from 2006 to 2015 were collected and analyzed statistically. Results From 2006 to 2015,98804 person-times of residents were surveyed in Nanjing City,and 465 person-times of residents were de-tected with intestinal nematode infections. The highest infection rate was in 2006(1.97%),and the lowest in 2013 and 2015 (both 0.05%). Moreover,the positive rate of human intestinal nematode infections showed a significantly declining trend in total (χ2=552.19,P<0.001). Meanwhile,the numbers of Ascaris lumbricoides,hookworm and Trichuris trichura cases were 329, 98 and 25 respectively,and the infection rates were 0.33%,0.10%and 0.03%respectively. Among them,443 cases had mild infection intensity (98.66%). There were 462 cases of single-infection (99.35%),and 3 of co-infection of two parasites (0.65%). From 2006 to 2015,92539 person-times of children under 12 years old were surveyed for Enterobius vermicularis in-fection and 352 cases were detected with E. vermicularis infection. Moreover,the positive rate showed a significantly decreasing trend in total(χ2=147.94,P<0.001). Conclusions The control effect of human intestinal nematode infections in Nanjing City is remarkable. However,the surveillance and health education in key groups still should be strengthened,and the preven-tion and control programs should be adjusted promptly to further consolidating the effectiveness of intestinal nematode disease prevention and control.

A Novel Functional Missense Mutation p.T219A in Type 1 Gaucher's Disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Gaucher's disease (GD) is an autosomal recessive disorder caused by a deficiency of acid β-glucosidase (glucocerebrosidase [GBA]) that results in the accumulation of glucocerebroside within macrophages. Many mutations have been reported to be associated with this disorder. This study aimed to discover more mutations and provide data for the genetic pattern of the gene, which will help the development of quick and accurate genetic diagnostic tools for this disease.</p><p><b>METHODS</b>Genomic DNA was obtained from peripheral blood leukocytes of the patient and Sanger sequencing is used to sequence GBA gene. Sequence alignments of mammalian β-GBA (GCase) and three-dimensional protein structure prediction of the mutation were made. A construct of this mutant and its compound heterozygous counterpart were used to measure GCase in vitro.</p><p><b>RESULTS</b>GCase is relatively conserved at p.T219A. This novel mutation differs from its wild-type in structure. Moreover, it also causes a reduction in GCase enzyme activity.</p><p><b>CONCLUSION</b>This novel mutation (c.655A>G, p.T219A) is a pathogenic missense mutation, which contributes to GD.</p>

Relationship between PPARγ2 Pro12Ala polymorphism and type 2 diabetes mellitus in Chinese Han population: a Meta-analysis / 中华预防医学杂志

<p><b>OBJECTIVE</b>To evaluate the relationship between peroxisome proliferator-activated receptor-γ2 (PPARγ2) Pro12Ala polymorphism and type 2 diabetes mellitus (T2DM) in Chinese Han population.</p><p><b>METHODS</b>PubMed, Chinese Biomedicine Database (CBM), China National Knowledge Infrastructure (CNKI) and Wanfang database were searched for all relevant articles investigating the association between PPARγ2 Pro12Ala polymorphism and T2DM that were available from January, 1990 to June, 2011. A total of 29 relevant articles were selected. A Meta-analysis was performed to estimate heterogeneity and the pooled odds ratio (OR) to evaluate the relationship between PPARγ2 Pro12Ala polymorphism and T2DM. The sensitivity analysis was also assessed.</p><p><b>RESULTS</b>A total of 21 qualified articles including 3870 patients with T2DM and 3333 healthy controls were analyzed in the study. The frequencies of the allele Ala12 in T2DM and control groups were 4.13% (320/7740) and 4.56% (304/6666), respectively. There were not heterogeneity (χ(2) = 25.96, P = 0.17) among the 21 qualified articles. The pooled OR (95%CI) value of the frequencies of the PPARγ2 genotype (PA + AA)/PP calculated by fixed effects model was 0.96 (0.81 - 1.14) (P = 0.64). There was not heterogeneity among the remaining articles after excluding the article with the largest weight and the article with larger frequencies of the allele Ala12 respectively (χ(2) values were 24.23, 16.87 respectively, both P values > 0.05). The pooled OR (95%CI) value of the frequencies of the PPARγ2 genotype (PA + AA)/PP of the remaining articles were 1.01 (0.84 - 1.21) and 1.07 (0.89 - 1.28) after excluding the article with the largest weight and the article with larger frequencies of the allele Ala12 (both P values > 0.05).</p><p><b>CONCLUSION</b>PPARγ2 Pro12Ala polymorphism was not associated with type 2 diabetes mellitus in Chinese Han population.</p>

Research on long-year-program medical students' pediatric clinical skill training methods / 中华医学教育探索杂志

To study the clinical skills training methods and formulate a training objective for pediatric long-year-program students, to let the students, through three years of training program, reach the clinical ability as a chief resident, with better laboratory research skills, teaching awareness and responsibility, and also with good comprehensive quality and excellent English, and finally become clinical talents with great potential and innovation, this report summarized our study results of training two terms of long-year-program pediatric graduates, who fully meeted the training objectives in the department's practice.

Treatment of childhood aplastic anemia with antithymocyte globulin, management of side effects and long-term follow-up / 中华儿科杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy of antithymocyte globulin (ATG) based immunosuppression therapy for childhood aplastic anemia, to reduce the adverse effects and to observe the long-term outcome.</p><p><b>METHOD</b>Thirty-five children with aplastic anemia (AA) were enrolled in this study. Six of the cases had very severe AA (VSAA), 11 had severe AA (SAA)-I, 8 had SAA-II and 10 had moderate AA (MAA). All these patients were treated with ATG plus Cyclosporin A (CSA). The following measures were taken during the ATG therapy: infection of the patients had been controlled before ATG treatment. Comprehensive anti-allergic measures were implemented. Close attention was paid to the hemorrhage related with platelet reduction caused by ATG and severe infection of the patients.</p><p><b>RESULT</b>Shortly after the ATG usage, all the patients had a significant decrease of absolute peripheral lymphoblast count by more than 60 percent. With a mean follow-up time of 28 months, the total effective rate was 77.14% (27/35), significant response rate was 57.14%(20/35). There was no significant difference among VSAA, SAA and MAA groups in the response rate. Adverse reactions included the following: (1) 48.6% (17/35) patients presented mild anaphylactoid reaction during the first day of ATG treatment; (2) 42.9%(15/35) cases presented serum sickness 5 - 11 days after the last dose of ATG with a mean duration of 3.6 days, all the patients were cured effectively with methylprednisolone; (3) 25.7% (9/35) patient's peripheral blood platelet count was reduced, might be caused by ATG, to below 10 × 10(9)/L, but no patient had severe hemorrhagic complication after platelet transfusion was performed; (4) 22.9%(8/35)of patients got infection within a month after ATG therapy, including 3 cases with clinical septicemia, all the 3 cases recovered after antibiotics treatment. There was no ATG treatment-related death in this series.</p><p><b>CONCLUSION</b>ATG is a very effective therapy for children with SAA and MAA. Comprehensive measures are needed to prevent and handle the side effects to avoid treatment-related death. Long-term supportive therapy and proper follow up contribute to the favourable outcomes of the patients.</p>

Relationship between the expression of the genes encoding the key enzymes for cytarabine metabolism and the pharmacokinetics of cytarabine in the treatment of childhood acute leukemia with high-dose cytarabine / 中华儿科杂志

<p><b>OBJECTIVE</b>It has been reported that high-dose cytarabine (HD-AraC) was very effective for childhood hematological malignancies, especially for improving the long-term survival of high-risk acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and T-cell lymphoid malignancies (T-ALL, T-cell non-Hodgkin's lymphoma). This study aimed to evaluate the pharmacokinetics of HD-AraC for childhood hematological malignancies, and the relationship between the expression of the genes coding the key enzymes for Ara-C metabolism with the outcome of the patients.</p><p><b>METHODS</b>The drug levels of Ara-C in plasma and cerebrospinal fluid were detected with HPLC while HD-AraC was used, the expression of deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA in human leukemia cell lines and the bone marrow cells were investigated in 48 cases of childhood hematological malignancies with RT-PCR methods, and the relationship between the expression of these enzymes mRNA and the outcome of the patients was analyzed.</p><p><b>RESULTS</b>(1) When HD-AraC was used, the plasma levels of Ara-C and Ara-U could be respectively about 50 times and 25 times higher than those obtained when the patients were treated with regular dose of Ara-C treatment, and the level of Ara-C in cerebrospinal fluid could reach about 10% of plasma level of Ara-C. (2) There were significantly different expressions of dCK mRNA in different childhood acute leukemia (AL) patients, which were markedly related to the chemotherapy results. The expression of dCK in ALL was much higher than that in AML and relapsed AL cases. There were no significant differences in expressions of dCK in T-ALL and B lineage ALL. (3) In vitro study found that the expressions of dCK and CDA mRNA did not change in leukemia cell lines incubated at different doses and times of Ara-C.</p><p><b>CONCLUSIONS</b>HD-AraC was a very effective protocol for childhood hematological malignancies for it could significantly elevate the plasma and cerebrospinal fluid drug levels. The expression of dCK may be an important factor in predicting the long-term outcomes of children with hematological malignancies. Good long-term outcomes of the childhood T-ALL could be achieved as the B lineage ALL had been treated with HD-AraC regimen. As the expression levels of dCK were much lower, it may be necessary for the treatment of AML with HD-AraC for consecutive three days.</p>

Natural history of moderate aplastic anemia in children and effects of immunosuppressive therapy / 中华儿科杂志

<p><b>OBJECTIVE</b>In contrast to severe aplastic anemia (SAA), the appropriate management of patients with moderate aplastic anemia (MAA) is unclear. Recently, it was reported that when childhood MAA was treated with supportive care alone, 2/3 of patients progressed to SAA, and therefore patients with MAA should be treated with immunosuppressive (IS) therapy in time. The present study aimed to review the natural history, the rate of progression to SAA and outcome of children with MAA seen at our institution over the past 12 years and to explore the relationship between the effectiveness of IS therapy and the immune mediated pathological mechanism.</p><p><b>METHODS</b>Seventy-one MAA patients were included in this study. At the first stage, thirty-six children with MAA were given IS therapy (IS group, antithymocyte globulin, ATG or cyclosporin-A, CSA). The therapeutic effects were evaluated and compared with those of 35 children with MAA who received the treatment of supportive care alone (androgens, control group). At the second stage, the patients with MAA progressed to SAA were given combined immunosuppressive (CIS) therapy (CIS group, a combination of ATG, CSA and high-dose immunoglobulin). Peripheral blood lymphocyte subsets levels were measured with a flow cytometer.</p><p><b>RESULTS</b>At the first stage, in the IS group, the percentage of overall and complete responders was 83.3% and 69.4%, respectively, which was significantly higher than that of the control group (34.3% and 17.1%). Twenty-three patients with MAA progressed to SAA. In the control group, 18 patients with MAA progressed to SAA. In the IS group, five patients with MAA progressed to SAA. The 17 patients with MAA who progressed to SAA were given combined immunosuppressive therapy. The percentage of overall and complete responders was 70.6% and 41.2%, respectively. The level of CD4(+), NK cell ratio decreased but the level of CD8(+) cell increased in MAA children before the treatment. The level of NK and CD4(+) cell was significantly higher in the IS group with the treatment than in the control group.</p><p><b>CONCLUSION</b>When childhood MAA is treated with supportive care alone, more than 50% of patients may progress to SAA. Immune mediated pathological mechanism of MAA might be the base of IS therapy. IS therapy is effective and safe for childhood MAA.CIS therapy given to patients with MAA that was progressed to SAA may also be effective.</p>

A study on the effect of Oncomelania hupensis hupensiss killed with niclosamide in China / 中华流行病学杂志

<p><b>OBJECTIVE</b>To study the effect of Oncomelania hupensis hupensis of niclosamide, and exploring the main influencing factors.</p><p><b>METHODS</b>The samples of Oncomelania hupensis hupensis were collected from 37 sampling sites in 33 counties of 10 provinces by means of stratified random sampling methods in accordance with the categories of Oncomelania hupensis hupensis habitats. Samples were randomly located into study group and control group. Oncomelania hupensis hupensis of the study group was marinated in different concentration liquor of niclosamide which was confected with water for 24 hours or 48 hours, then LC50 of niclosamide by which Oncomelania hupensis hupensis was killed and amount calculated. The influencing factors of the mortality of Oncomelania hupensis hupensis in the study group was statistically analyzed by 2 test and by multiple logistic regression using SPSS 13.0 statistical software.</p><p><b>RESULTS</b>The mortality of Oncomelania hupensis hupensis of the two test groups which were marinated in 0.5 mg/L liquor for 48 hours and 1.0 mg/L liquor for 24 hours was 100%. The effect of Oncomelania hupensis hupensis killed by niclosamide was markedly reduced along with the reduction of drug concentration. The average LC50 rates of niclosamide liquor by which Oncomelania hupensis hupensis killed for the 24 hours and 48 hours in the study group, were 0.0939 mg/L and 0.0625 mg/L, respectively. There was significant difference between the two test groups (chi(2) = 5.001, P <0.01) . In determinate range of concentration, the mortality of Oncomelania hupensis hupensis showed significant difference among the geographic types of habitat ( chi(2) = 4.264, P < 0.05). By means of multiple logistic regression using SPSS 13.0 statistical software, the estimate value of coefficient of regression on the influence factors, drug concentration, test time and the geographic types of habitat were 2. 047 ( OR = 5. 573), 0.263 ( OR = 2.924) and 0. 187- 0.210 ( OR = 1.969- 2. 560), respectively.</p><p><b>CONCLUSION</b>Niclosamide could kill Oncomelania hupensis hupensis effectively. The main influencing factors on the efficacy of niclosamide by which Oncomelania hupensis hupensis was killed, appeared to be drug concentration, time of testing and the geographic types of habitat.</p>

Effect of nutrient support on severe infant pneumonia / 中南大学学报(医学版)

OBJECTIVE@#To explore the effect of nutrient support on severe infant pneumonia.@*METHODS@#Prospective study was conducted on the outcome of 567 inpatients suffering from severe pneumonia in 13 hospitals randomly selected in Hunan. Twelve factors were surveyed and data analyzed by multiple logistic regression.@*RESULTS@#Malnnutrition, anemia and rickets were risk factors in severe pneumonia, and nutrient support had protective effect on severe pneumonia.@*CONCLUSION@#Nutrient support contributes to the positive outcome of severe infant pneumonia.

Reversal of multidrug resistance in leukemic cell line K562/AO2 by chlordelazine in vitro / 中华儿科杂志

<p><b>OBJECTIVE</b>Some recent studies revealed that phenthiazine might be able to reverse tumor cell drug-resistance. Chlorderazin belongs to the phenthiazine compounds. The study aimed to investigate the reversing effect and mechanism of chlorderazin on multidrug resistance of leukemic cell line K562/AO2.</p><p><b>METHODS</b>(1) The cytotoxicities of chlorderazin were assayed with the tetrazolium dye, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. (2) The reverse effect of chlorderazin on K562/AO2 cells was analyzed with MTT method. The multidrug resistance reversal index (RI) was equal to the ratio of control group IC(50)/test group half inhibition concentration IC(50). (3) The intracellular daunorubicin (DNR) concentrations were measured by the flow cytometry. (4) Mdr1 mRNA expression was detected by reverse transcription-polymerase chain reaction (RT-PCR). The ratio of mdr-1/beta-actin density was calculated.</p><p><b>RESULTS</b>(1) Chlorderazin 3 micro g/ml showed little toxicity to K562/AO2 cells and the suppression rate was less than 5%, so the concentration of 3 micro g/ml chlorderazin was selected as the experiment concentration. (2) The cytotoxicities of DNR to K562/AO2 were enhanced by 3 micro g/ml of chlorderazin (P < 0.05) and RI was 1.901. (3) Chlorderazin of 3 micro g/ml could increase the intracellular DNR accumulation significantly (P < 0.05), and the fluorescence staining by the flow cytometry was higher (250.95 +/- 18.96) than the control group (112.75 +/- 15.78) and shift right in K562/AO2 cells treated with chlorderazin, and the difference was significant (P < 0.05). (4) Chlorderazin has no significant influence to the expression level of mdr-1 mRNA. Both test group and control group showed a clear mdr-1 mRNA band located at the position of 157 kb. The ratios of mdr-1/beta-actin density were 0.414 +/- 0.012 in the test group and 0.447 +/- 0.027 in the control group, respectively, and the difference was not significant (P > 0.05).</p><p><b>CONCLUSION</b>Chlorderazin could reverse the multidrug resistance by increasing the intracellular DNR accumulation in K562/AO2 cells. The effects had no correlation to the mdr-1 gene. Further study is needed.</p>