Effects of mutant TDP-43 on the Nrf2/ARE pathway and protein expression of MafK and JDP2 in NSC-34 cells.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons and lacks an effective treatment. The disease pathogenesis has not been clarified at present. Pathological transactive response DNA-binding protein 43 (TDP-43) plays an important role in the pathogenesis of ALS. Nuclear translocation of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is found in a mutant TDP-43 transgenic cell model, but its downstream antioxidant enzyme expression is decreased. To elucidate the specific mechanism of Nrf2/ARE (antioxidant responsive element) signaling dysfunction, we constructed an ALS cell model with human mutant TDP-43 using the NSC-34 cell line to evaluate the impact of the TDP-43 mutation on the Nrf2/ARE pathway. We found the nuclear translocation of Nrf2, but the expression of total Nrf2, cytoplasmic Nrf2, and downstream phase II detoxifying enzyme (NQO1) was decreased in NSC-34 cells transfected with the TDP-43-M337V plasmid. Besides, TDP-43-M337V plasmid-transfected NSC-34 cells were rounded with reduced neurites, shortened axons, increased levels of intracellular lipid peroxidation products, and decreased viability, which suggests that the TDP-43-M337V plasmid weakened the antioxidant capacity of NSC-34 cells and increased their susceptibility to oxidative damage. We further showed that expression of the MafK protein and the Jun dimerization protein 2 (JDP2) was reduced in TDP-43-M337V plasmid-transfected NSC-34 cells, which might cause accumulation of Nrf2 in nuclei but a decrease in NQO1 expression. Taken together, our results confirmed that TDP-43-M337V impaired the Nrf2/ARE pathway by reducing the expression of MafK and JDP2 proteins, and provided information for further research on the molecular mechanisms of TDP-43-M337V in ALS.

A simplified schedule to integrate the hepatitis B vaccine into an expanded program of immunization in endemic countries.

OBJECTIVE: To investigate the safety, immunogenicity, and efficacy of a simplified hepatitis B vaccination schedule. METHODS: The second dose of hepatitis B vaccine and the first dose of diphtheria-tetanus-pertussis (DTP) vaccine were given simultaneously at age 6 weeks. The second dose of DTP vaccine was given at age 3.5 months. The third dose of DTP vaccine and the third dose of hepatitis B vaccine were given at age 5.5 months. One hundred three infants (group A) born to mothers without hepatitis B surface antigen (HBsAg) received DTP with whole-cell pertussis vaccine. Fifty-five infants (group B) born to mothers with HBsAg and hepatitis B e antigen received DTP with acellular pertussis vaccine. RESULTS: By age 9 months, none of group A and 4 (7%) group B infants were sero-positive for HBsAg. The protective efficacy against the hepatitis B carrier state in these infants at high risk was 92%. Antibody to hepatitis B surface antigen was 10 mlU/ml or greater in 99 (96%) of group A infants and in 50 (91%) of group B infants. Both the acellular and whole-cell DTP vaccines were immunogenic, and the incidences of adverse reactions were within an expected and acceptable range. CONCLUSIONS: The simplified vaccination schedule to integrate the hepatitis B vaccine into the Expanded Programme of Immunization was safe, Immunogenic, and effective. This schedule may improve vaccine compliance and be applied to DTP and hepatitis B combination vaccines now under investigation.

Long-term efficacy of recombinant hepatitis B vaccine and risk of natural infection in infants born to mothers with hepatitis B e antigen.

To evaluate the long-term protection afforded by the vaccine, recombinant hepatitis B (HB) vaccine was given to 171 infants born to hepatitis B e antigen-positive carrier mothers. Group A (53 infants) and group B (57 infants) received four doses of HB vaccine at birth and at 1, 2, and 12 months of age, with a dose of 20 micrograms in group A and 10 micrograms in group B. Group C (61 infants) received three 20 micrograms doses of HB vaccine at birth and at 1 and 6 months of age. These children were followed up annually up to 5 years of age. Six children (4%) became HB carriers before 1 year of age, and the carrier state persisted to the end of follow-up. The overall seropositive rate of HB surface antibody (anti-HBs) dropped from 99% at 1 year of age to 83% at 5 years of age. Among 548 serum pairs taken at 1-year intervals from children negative for HB surface antigen (HBsAg), a fourfold rise of anti-HBs titer was noted in 58 (11%) and a 10-fold rise of anti-HBs was noted in 17 (3%). Maternal HB core antibody disappeared in most children (151/152, 99%) before 2 years of age. Natural infections, as judged by persistence or reappearance of HB core antibody, occurred in 19 of 163 (12%) HBsAg-negative children. None of these episodes was associated with HBsAg positivity. We conclude that the long-term protection afforded by recombinant HB vaccine is satisfactory and that a further booster dose before 5 years of age is not necessary.