Regulatory considerations for paediatric drug evaluation in China.

The regulatory guidelines for the research and development of paediatric drugs are still evolving in China. The formulation of the guidelines started from learning and borrowing existing experience, and gradually changed to the exploration and improvement of local guidelines, which was not only in line with international standards but also had breakthroughs, innovations and Chinese characteristics. In this paper, the current setting of paediatric drug research and development in China and corresponding technical guidelines have been introduced from regulatory perspectives, and the accessibility of further improvement in regulatory strategies has also been discussed.

Evaluation of effectiveness, safety and cost-benefit of the 23- valent pneumococcal capsular polysaccharide vaccine for HIV-Infected patients.

INTRODUCTION: Due to the lack of understanding of the protective effects and safety of 23-valent pneumococcal polysaccharide vaccine (PPV23) in immune-deficient populations, the vaccination rate of PPV23 among HIV-infected patients is still very low in China. The main objectives of this study were to determine whether the efforts to assess measures for the prevention of pneumococcal pneumonia are still worthwhile, and provide designated vaccination program of HIV-infected persons for government policy based on. METHODS: 60 HIV-infected adults in Lanshan county who had never been vaccinated with any pneumococcal vaccine were enrolled in this study, voluntary vaccination of PPV23 and One-year follow-up after vaccination can be completed. RESULT: 76.67% patients (46/60) had serologic response at 12 months after vaccine, CD4 count(≤500 cells/ul or > 500 cells/ul) and Month from diagnosis to first antiviral therapy (≤1 month or > 1 month) were related to antibody responses (p < 0.05).In this study, PPV23 was well tolerated, no adversereaction was reported.11 Streptococcus pneumoniae pneumonia (9.17%,11/120) occurred in the Unvaccinated group and 1 case(1.67%,1/60)in the vaccination group within one year after vaccination(Fisher's exact probability, P = 0.225). The VE was 81.79%. The per capita benefit was 39.32 dollars, thebenefit-costratio = 1.19. There are significant statistical differences between the vaccinated group and the non-vaccinated group in outpatient costs (p < 0.05, 95 %CI: 9.29-32.11), Medicine costs (p = 0.017, 95 %CI: 2.47-24.44), and disease related indirect costs (p = 0.038, 95 %CI: 0.93-33.63) within one year of vaccination. CONCLUSION: Our study results showed that PPV23 can be safely and effectively administered to HIV-1 infected individuals and effectively preventing Streptococcal pneumonia. Considering the cost-benefit of vaccination among HIV-infected persons, as it has been reported in our study, it is necessary to promote the widespread use of the vaccine among HIV-infected persons in the future.

[Expression of Costimulatory Molecule Tim3 on NK Cells and Its Subsets in Patients with Acute Myeloid Leukemia].

OBJECTIVE: To investigate the expression of costimulatory molecule Tim3 and its subsets on NK cells in patients with acute myeloid leukemia. METHODS: 30 patients with acute myeloid leukemia treated in our hospital from August 2016 to August 2018 were randomly selected as the AML group, and 30 healthy persons in our hospital during the same period were randomly selected as the control group. The expression levels of CD56dim NK cells/CD3-CD56+NK cells and Tim3 on CD56dimNK cells in peripheral blood, CD56bright NK cells/CD3-CD56+NK cells and Tim3 on CD56brightNK cells in peripheral blood of the two groups were estimated. The expression of CD3-CD56+NK cells/lymphocytes and their Tim3, CD56dimNK cells/CD3-CD56+NK cells and their Tim3 expression, Tim3+NK, Tim3-NK IFN-gamma secretion levels before and after chemotherapy in the AML group were analyzed. RESULTS: The expression levels of CD56dim NK cells/CD3-CD56+NK cells and their Tim3 in peripheral blood of the AML group were significantly lower than those of the control group (P<0.05). The expression levels of CD56bright NK cells/CD3-CD56+NK cells and their Tim3 in peripheral blood of the AML group were significantly higher than those of the control group (P<0.05). CD3-CD56+NK cells/lymphocytes and Tim3+/CD3-CD56+NK cells in complete remission patients were significantly higher than at initial diagnosis (P<0.05). CD3-CD56+NK cells/lymphocytes and Tim3+/CD3-CD56+NK cells in patients with course of treatment ≥2 times and remission patients time more than 3 months were significantly higher than those in patients with chemotherapy course 1 time and remission time≤3 months (P<0.05). The expression levels of CD56dim NK cells/CD3-CD56+NK cells and their Tim3 in peripheral blood of patients at complete remission were significantly higher than at initial diagnosis (P<0.05). The expression levels of CD56bright NK cells/CD3-CD56+NK cells and Tim3 in peripheral blood of patients at complete remission were significantly lower than of the patients at initial diagnosis (P<0.05), and the IFN-gamma secretion level of Tim3+ NK cells was significantly lower than that of Tim3-NK cells in these patients (P<0.05). CONCLUSION: The expression of costimulatory molecule Tim3 in NK cells and its subsets of patients with acute myeloid leukemia is down-regulated.

An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis.

Ulcerative colitis (UC) is a chronic relapsing-remitting form of inflammatory bowel disease (IBD) that increases the risk of colorectal cancer, the third most common malignancy in humans. Oxidative stress is a risk factor for the development of UC. The Keap1-Nrf2-ARE pathway is one of the most important defensive mechanisms against oxidative and/or electrophilic stresses. In this study, we identified CPUY192018 as a potent small-molecule inhibitor of the Keap1-Nrf2 PPI, investigated the cyto-protective effects of CPUY192018 on the NCM460 colonic cells and evaluated whether treatment with the inhibitor of the Keap1-Nrf2 PPI exerts protection on an established experimental model of UC induced by dextran sodium sulfate (DSS). Our study clearly demonstrated that CPUY192018 had a cytoprotective effect against DSS in both NCM460 cells and mouse colon via the activation of Nrf2 signaling. These results suggested that activation of Nrf2 by directly inhibiting the Keap1-Nrf2 PPI may be beneficial as a treatment for UC.

A systematic molecular dynamics approach to the study of peptide Keap1-Nrf2 protein-protein interaction inhibitors and its application to p62 peptides.

Protein-protein interactions (PPIs) as drug targets have been gaining growing interest, though developing drug-like small molecule PPI inhibitors remains challenging. Peptide PPI inhibitors, which can provide informative data on the PPI interface, are good starting points to develop small molecule modulators. Computational methods combining molecular dynamics simulations and binding energy calculations could give both the structural and the energetic perspective of peptide PPI inhibitors. Herein, we set up a computational workflow to investigate Keap1-Nrf2 peptide PPI inhibitors and predict the activity of novel sequences. Furthermore, we applied this method to investigate p62 peptides as PPI inhibitors of Keap1-Nrf2 and explored the activity change induced by the phosphorylation of serine. Our results showed that because of the unfavorable solvation effects, the binding affinity of the phosphorylated p62 peptide is lower than the Nrf2 ETGE peptide. Our research results not only provide a useful method to investigate the Keap1-Nrf2 peptide inhibitors, but also give a good example to show how to incorporate computational methods into the study of peptide PPI inhibitors. Besides, applying this method to p62 peptides provides a detailed explanation for the expression of cytoprotective Nrf2 targets induced by p62 phosphorylation, which may benefit the further study of the crosstalk between the Keap1-Nrf2 pathway and p62-mediated selective autophagy.

Human infection with an avian influenza A (H9N2) virus in the middle region of China.

During the epidemic period of the novel H7N9 viruses, an influenza A (H9N2) virus was isolated from a 7-year-old boy with influenza-like illness in Yongzhou city of Hunan province in November 2013. To identify the possible source of infection, environmental specimens collected from local live poultry markets epidemiologically linked to the human case in Yongzhou city were tested for influenza type A and its subtypes H5, H7, and H9 using real-time RT-PCR methods as well as virus isolation, and four other H9N2 viruses were isolated. The real-time RT-PCR results showed that the environment was highly contaminated with avian influenza H9 subtype viruses (18.0%). Sequencing analyses revealed that the virus isolated from the patient, which was highly similar (98.5-99.8%) to one of isolates from environment in complete genome sequences, was of avian origin. Based on phylogenetic and antigenic analyses, it belonged to genotype S and Y280 lineage. In addition, the virus exhibited high homology (95.7-99.5%) of all six internal gene lineages with the novel H7N9 and H10N8 viruses which caused epidemic and endemic in China. Meanwhile, it carried several mammalian adapted molecular residues including Q226L in HA protein, L13P in PB1 protein, K356R, S409N in PA protein, V15I in M1 protein, I28V, L55F in M2 protein, and E227K in NS protein. These findings reinforce the significance of continuous surveillance of H9N2 influenza viruses.

Application of a custom-made inlay structure to a sectional maxillary complete denture for a patient with microstomia: a clinical report.

Prosthodontic treatment for edentulous patients with microstomia is a challenge because of the constricted opening of the oral cavity. This clinical report presents the prosthetic management of an edentulous maxilla in a patient with burn-induced microstomia. A sectional maxillary complete denture was fabricated. With the use of a custom-made inlay structure at the overlapping metal base along the palatal midline, the sectional prosthesis was successfully and easily inserted and provided adequate function in the patient's mouth.

[Application of palatal base combined with shield above floor of mouth for restoration of acquired mandibular defect with glossectomy: report of one case].

PURPOSE: To evaluate the prosthetic results of application of palatal base combined with shield above the floor of mouth for restoration of acquired mandibular defect with glossectomy. METHODS: Palatal base with four wrought clasps was designed for the upper prostheses. Shield just above the floor of the mouth and buccal mucosa was fabricated to support the buccal mucosa and muscle. Then the upper and lower prostheses were linked by using thermal curing acrylic resin on the left and right side. RESULTS: Good retention of the prostheses was obtained. The appearance of the patient was remarkably improved. Depression of the lower lip was improved. Oral function was enhanced. CONCLUSIONS: Better prosthetic results could be obtained by using palatal base combined with shield above the floor of mouth for restoration of acquired mandibular defect with glossectomy.

[Clinical application of custom-made key-key attachment in the restoration of maxillofacial defect].

PURPOSE: To evaluate the usefulness of custom-made key-key attachment in restoration of maxillofacial defect. METHODS: Using key-key attachment, facial prostheses and intraoral prostheses were combined to restore dentition, maxilla and right facial defects in a female patient. RESULTS: Good retention of maxillofacial prostheses and intraoral prostheses were obtained. The appearance of the patient was remarkably improved. The function of mastication was improved. CONCLUSIONS: Good result can be obtained by using custom-made key-key attachment in restoration of complex maxillofacial defect. Supported by Shanghai Leading Academic Discipline Project(Grant No.T0202).

[Application of stud structure to sectional upper complete denture for a patient with microstomia].

PURPOSE: Prosthetic rehabilitation with stud structure to sectional complete denture for a patient with microstomia was done and the treatment result was evaluated. METHODS: A sectional impression tray technique was used. And a custom-made palatal hinge mechanism with stud structure on the left and right side of the upper complete denture along the middle line were also designed and fabricated. Half metal abutment was fabricated on the left and right side of the denture on the position of the upper central incisor, and a PFM was made according to the metal abutment. After the sectional upper complete denture was inserted, the PFM was set to connect the sectional denture as a whole and provide stability. RESULTS: The sectional upper complete denture was successfully and easily inserted and provided adequate function in the patient's mouth. CONCLUSIONS: Application of stud structure to sectional upper complete denture for patient with microstomia is feasible.

[Masticatory efficiency and phonetics effects of double dentition denture for cleft lip and palate patients with different base design].

PURPOSE: To evaluate the masticatory efficiency and phonetics in patients with cleft lip and palate before and after double dentition denture treatment, and determine the results of the treatment. METHODS: 6 patients who had cleft lip and palate with defect smaller than 1 cm x 1 cm or submucous cleft palate were selected to undergo double dentition denture treatment. Two kinds of base design were used. One was with artificial teeth and buccal base only. The other was with artificial teeth and base on both the buccal and palatal sides. Masticatory efficiency and phonetics effect were tested before and immediately after treatment and 1 month after treatment. The data were analyzed using SPSS11.0 software package for paired t test. RESULTS: There was statistically significant difference in masticatory efficiency, before and immediately after treatment and 1 month after treatment (P < 0.01). As for phonetics , there was statistically significant difference on F2 and F3 before and immediately after treatment as well as 1 month after treatment (P < 0.05). While there were no statistically significant difference both on masticatory efficiency and phonetics between the two kinds of design. CONCLUSION: Both the two kinds of treatment can improve the masticatory efficiency and phonetics effectively. It is not necessary to use the palatal base when the defect is smaller than 1 cm x 1 cm or submucous cleft palate present.

[Long-term observation of 920 porcelain fused to metal prostheses].

PURPOSE: To evaluate the long-term clinical results of porcelain fused to metal prostheses. METHODS: Since January 1995, 920 porcelain fused to metal prostheses were fabricated. The long-term outcome were evaluated according to the condition of the prosthese, abutment and the periodontal tissue in the respects of successful rate and causes of failure. RESULTS: 74 patients were found to be during the follow up period, including 36 anterior crowns (46 units), 18 posterior crowns (22 units), 12 percentage of anterior bridges and 8 posterior bridges. The overall failure rate was 8.04%, 4.84% for crown, 8.77% for bridge. The failed prostheses was 5.39%. CONCLUSIONS: Porcelain fused to metal prostheses is an ideal method for restoration. The standard process both for the clinician and the technician must be obeyed to improve the success rate.

[Evaluation of the speech outcomes in patients with unilateral maxillary defect rehabilitated with maxillary obturator prosthesis].

PURPOSE: Evaluation of the outcomes in 15 patients with unilateral maxillary defect before and after maxillofacial obturator prosthesis. METHODS: 15 patients with unilateral maxillary defect were included in this study, who received obturator prosthesis for maxillary rehabilitation. The pronunciation of the examined phonetics such as /a/, /o/, /e/, /i/, /u/ were transferred into CSL4400 before and after treatment. The mean value of the first, second, third formant were measured. Paired t test of SPSS11.0 was used for statistical analysis. RESULTS: There was statistically significant difference on F2 and F3 before and after treatment (P<0.05). After treatment the value of F3 was increased significantly. CONCLUSIONS: The soft palate was reconstructed after obturator treatment. The space between the nasal and oral cavity was sealed,through which a similar normal oral cavity was obtained. Except F1, F2 and F3 of all the vowels changed after treatment. Maxillofacial prosthesis can improve the speech function of patients with unilateral maxillary defect effectively.

[Retention and rehabilitation of complex maxillofacial defects based on bar-clip and stud attachment].

PURPOSE: To evaluate the application of precise attachment in restoration of complicated maxillofacial defect. METHODS: A framework with bar-clip and stud attachment was designed and fabricated. Maxillofacial prosthesis with this framework was applied to treat a patient with defects of nose, entire upper lip and the corresponding maxillofacial areas. The retention force was tested with Universal Testing Device. RESULTS: After treatment, the patient got a better appearance, normal function of mastication and clear pronunciation. The dislodgement test showed the retention force was 40N. CONCLUSION: Application of precise attachment in complicated maxillofacial defects can get satisfactory result.

[The analysis of masticatory efficiency after maxillofacial prosthetic treatment for unilateral maxillary defect].

OBJECTIVE: To evaluate the clinic results of maxillofacial prosthetic treatment for unilateral maxillary defect. METHODS: Masticatory efficiency was tested before and after maxillofacial prosthetic treatment for unilateral maxillary defect. RESULTS: There was significant difference between one week, one month, three months after treatment and before treatment(F = 0.635, P = 0.002). Masticatory efficiency was increased by 59.98% after one month. CONCLUSION: Maxillofacial prosthetic treatment can significantly increase the masticatory efficiency of unilateral maxillary defect. It remains stable one month later.