[Clinical features and follow-up study on 55 patients with adolescence-onset methylmalonic acidemia].

Objective: To investigate the clinical features and outcomes of adolescence-onset methylmalonic acidemia (MMA) and explore preventive strategies. Methods: This was a retrospective case analysis of the phenotypes, genotypes and prognoses of adolescence-onset MMA patients. There were 55 patients diagnosed in Peking University First Hospital from January 2002 to June 2023, the data of symptoms, signs, laboratory results, gene variations, and outcomes was collected. The follow-ups were done through WeChat, telephone, or clinic visits every 3 to 6 months. Results: Among the 55 patients, 31 were males and 24 were females. The median age of onset was 12 years old (range 10-18 yearsold). They visited clinics at Tanner stages 2 to 5 with typical secondary sexual characteristics. Nine cases (16%) were trigged by infection and 5 cases (9%) were triggered by insidious exercises. The period from onset to diagnosis was between 2 months and 6 years. Forty-five cases (82%) had neuropsychiatric symptoms as the main symptoms, followed by cardiovascular symptoms in 12 cases (22%), kidney damage in 7 cases (13%), and eye disease in 12 cases (22%). Fifty-four cases (98%) had the biochemical characteristics of methylmalonic acidemia combined with homocysteinemia, and 1 case (2%) had the isolated methylmalonic acidemia. Genetic diagnosis was obtained in 54 cases, with 20 variants identified in MMACHC gene and 2 in MMUT gene. In 53 children with MMACHC gene mutation,1 case had dual gene variants of PRDX1 and MMACHC, with 105 alleles. The top 5 frequent variants in MMACHC were c.482G>A in 39 alleles (37%), c.609G>A in 17 alleles (16%), c.658_660delAAG in 11 alleles (10%), c.80A>G in 10 alleles (10%), c.567dupT and c.394C>T both are 4 alleles (4%). All patients recovered using cobalamin, L-carnitine, betaine, and symptomatic therapy, and 54 patients (98%) returned to school or work. Conclusions: Patients with adolescence-onset MMA may triggered by fatigue or infection. The diagnosis is often delayed due to non-specific symptoms. Metabolic and genetic tests are crucial for a definite diagnosis. Treatment with cobalamin, L-carnitine, and betaine can effectively reverse the prognosis of MMA in adolescence-onset patients.

[Association between high-sensitivity C-reactive protein and both cardiovascular, total mortality events in middle-aged Chinese adults].

Objective: To estimate the association between high-sensitivity C-reactive protein (hs-CRP) and cardiovascular events as well as all-cause mortality events. Methods: During 2009- 2010, out of the 11 623 individuals, 1 000 participants aged 35-64 years, were recruited and divided into 12 age-groups, to have received a study on CVD risk factors. Information on the risk factors of cardiovascular diseases was also collected. Fasting blood sample was gathered for all the participants, with hs-CRP tested. Participants in 7 out of the 12 sites were followed, with 6.21 years (36 075 person-years) as the median follow-up period. Cardiovascular and all-cause mortality events were collected. A total of 6 177 participants had been followed after excluding participants who had baseline infections, or did not take hs-CRP test/physical examination at the baseline. Finally, 5 984 participants were included for analysis. Participants were categorized into three groups based on the hs-CRP (mg/L) values: <1, 1-3 and >3, respectively. Cox proportional hazards regression model was used to analyze the relationships between hs-CRP with cardiovascular events or all-cause mortality events, after adjusting for confounding factors. Results: Mean age of the participants was 50.2 years. The incidence rates of cardiovascular disease events were 3.6/1 000 person-years, 7.1/1 000 person-years,and 10.4/1 000 person-years among three groups and 3.0/1 000 person-years, 5.7/1 000 person-years, 9.1/1 000 person-years for all-cause mortality events, respectively. After adjusting for confounding factors, the hazard risks (HR) for cardiovascular events were 1.33 (95%CI: 0.95-1.84) in the hs-CRP 1-3 mg/L group and 1.76 (95%CI: 1.20-2.60) in the hs-CRP>3 mg/L group when comparing with the hs-CRP<1 mg/L group (trend test P=0.003). The HRs for all-cause mortality events were 1.76 (95%CI: 1.23-2.54) and 2.64 (95%CI: 1.74-4.01) (trend test P<0.001), respectively. Conclusion: Hs-CRP appeared an independent predictor for cardiovascular events and all-cause mortality events.

Plasma exchange parameter selection and safety observation of children with severe ricinism.

The aim of this study was to investigate the selection of plasma exchange (PE) parameters and the safety of children with severe ricinism. The PE parameters and heparin dosage in 7 children with severe ricinism were recorded, and changes in the patients' vital signs and coagulation function were monitored before and after PE. All patients successfully completed PE. The speed of blood flow was 50-80 mL/min, speed of exchange flow was 600-800 mL/h, and isolating rate of blood plasma was 12.5-19.05%. Transmembrane pressure was stable at approximately 100 mmHg, and venous pressure was stable at approximately 95 mmHg. The first dose of heparin was 0.39 ± 0.04 mg/kg, and the maintaining heparin dose was 0.40 ± 0.05 to 0.22 ± 0.03 mg·kg(-1)·h(-1). During the PE process, mean arterial pressure, heart rate, respiratory rate, and pulse oxygen saturation were steady. After PE, the activated partial thromboplastin time and thrombin time prolonged to 2-3 times greater than that before PE. However, no bleeding tendency was seen. For children with severe ricinism, the choice of PE to eliminate the toxin from blood, tissues, and organs was safe and effective.

Effects of surfactants on the photolysis of chlorothalonil on pepper (Capsicum annuum var. grossum Sendt).

Chlorothalonil is a widely used fungicide on pepper and other vegetables in China. The present study was aimed to evaluate effects of three different surfactants, sodium dodecyl sulfonate (SDS), Span-20, and cetyltrimethylammonium bromide (CTAB), on the photolysis of chlorothalonil on peppers under irradiation of either high-pressure mercury lamp (HPML) or sunlight inside and outside greenhouse. Results showed that both SDS and Span-20 at a low concentration exhibited a photosensitization effect on the photolysis of chlorothalonil under HPML. Such effect gradually decreased with increasing concentrations of either surfactant prior to photoquenching effects observed. In contrast, CTAB showed a photoquenching effect on chlorothalonil photolysis, which was gradually enhanced with an increasing CTAB concentration. SDS, Span-20, and CTAB had consistent effects on the photolysis of chlorothalonil under sunlight as those observed under HPML irradiation. The use of appropriate surfactants as pesticide additives at optimal concentrations could decrease the residue of pesticide in agricultural food and improve food safety.

Mutation p.S335X in GATA4 reduces its DNA binding affinity and enhances cell apoptosis associated with ventricular septal defect.

Genetic mutations in GATA4, a transcriptional factor, have been found to cause congenital heart diseases. The underlying mechanism, however, remains largely unknown. We previously reported 7 heterozygous variants in patients with ventricular septal defects (VSD). Here we functionally characterized a de novo mutation p.S335X and demonstrated that this mutation led to the pre-termination of its translation, producing a truncated GATA4 lacking a conservative region at C-terminus. Truncated GATA4 did not disturb its subcellular localization; however, it delayed the cardiomyocyte differentiation in P19cl6 model and prohibited Bcl2 expression that led to apoptosis proved by fragmented genomic DNA and positive TUNEL staining in H9C2 cells. By ChIP assay, we showed that GATA4 without C-terminus reduced its DNA binding affinity and suppressed the expressions of its target genes. These findings suggest that C-terminus of GATA4 is critical to maintain DNA binding, and genetic mutations in this region may affect genes important for myocyte apoptosis and differentiation associated with congenital heart defects.

Identification of the dual specificity and the functional domains of the cardiac-specific protein kinase TNNI3K.

Molecular cloning of cardiac troponin I-interacting kinase (TNNI3K), a novel cardiac-specific protein kinase containing seven N-terminal ankyrin (ANK) repeats followed by a protein kinase domain and a C-terminal Ser-rich domain, has previously been reported. In the present study, we show that the C-terminal functional region of TNNI3K negatively regulates the kinase activity, and the N-terminal ANK domain is necessary for autophosphorylation. An in vitro kinase assay shows that TNNI3K exhibits dual-specific kinase activity and forms dimers or oligomers that may be necessary for its activation.

[Killing effect of human pulmonary adenocarcinoma cells with TK + CD/5-Fc + GCV coexpression suicide gene systems].

OBJECTIVE: To investigate the different killing effect to human pulmonary adenocarcinoma cell line cells GLC-82 with coexpressed double suicide genes compared with single gene. METHODS: Recombinant expression vectors containing CD (cytosine deaminase) and/or TK (thymidine kinase) gene under CMV promoter were constructed successfully. The vectors were transfected to GLC-82 tumor cell lines by use of lipofectamine. The clones were picked out after G418 selection. Extraneous gene integration and expression were confirmed by PCR and semi-quantitative RT-PCR. The cytotoxicity to these transgenic cells under treatment with 5-Fc and GCV were measured by MTT assays. RESULTS: Double and single suicide gene transfer were both stably expressed in GLC-82 cells. The cytotoxic effects of co-expressed TK-CD genes were superior than that of the single gene. CONCLUSION: The CD + TK/5-Fc + GCV co-expression system is more effective for killing effect of tumor cells than CD/5-Fc or TK/GCV system alone.

A two-level hybrid evolutionary algorithm for modeling one-dimensional dynamic systems by higher-order ODE models.

This paper presents a new algorithm for modeling one-dimensional (1-D) dynamic systems by higher-order ordinary differential equation (HODE) models instead of the ARMA models as used in traditional time series analysis. A two-level hybrid evolutionary modeling algorithm (THEMA) is used to approach the modeling problem of HODE's for dynamic systems. The main idea of this modeling algorithm is to embed a genetic algorithm (GA) into genetic programming (GP), where GP is employed to optimize the structure of a model (the upper level), while a GA is employed to optimize the parameters of the model (the lower level). In the GA, we use a novel crossover operator based on a nonconvex linear combination of multiple parents which works efficiently and quickly in parameter optimization tasks. Two practical examples of time series are used to demonstrate the THEMA's effectiveness and advantages.

Effect of recombinant human fibronectin polypeptide CH50 on growth and metastasis of melanoma.

AIM: To study the effect of recombinant human fibronectin polypeptide CH50 on murine melanoma growth and metastasis, and its antitumor mechanism. METHODS: Mouse and melanoma B16 cell tests were used to observe antitumor effect and mechanism of CH50. RESULTS: CH50 markedly inhibited melanoma growth and experimental lung metastasis. The melanoma weight was reduced from (2.3 +/- 1.2) g of control group to (0.7 +/- 0.8) g of test group (P < 0.05). CH50 at 0.125, 0.25, 0.5 mg/mouse reduced melanoma lung metastatic colonies from 87 +/- 49 of control group to 34 +/- 6, 14 +/- 12, 4 +/- 2, respectively. CH50 adhered to melanoma B16 cells and inhibited adhesion of B16 cells to laminin. CH50 enhanced the cytotoxicity of macrophages to melanoma B16 cells. CONCLUSION: CH50 inhibited tumor growth and metastasis of murine melanoma. The antitumor effect of CH50 is related to its adhesion ability to melanoma B16 cells and enhancing macrophage cytotoxicity.