Surface Phenotype Changes and Increased Response to Oxidative Stress in CD4+CD25high T Cells.

Conversion of CD4+CD25+FOXP3+ T regulatory cells (Tregs) from the immature (CD45RA+) to mature (CD45RO+) phenotype has been shown during development and allergic reactions. The relative frequencies of these Treg phenotypes and their responses to oxidative stress during development and allergic inflammation were analysed in samples from paediatric and adult subjects. The FOXP3lowCD45RA+ population was dominant in early childhood, while the percentage of FOXP3highCD45RO+ cells began increasing in the first year of life. These phenotypic changes were observed in subjects with and without asthma. Further, there was a significant increase in phosphorylated ERK1/2 (pERK1/2) protein in hydrogen peroxide (H2O2)-treated CD4+CD25high cells in adults with asthma compared with those without asthma. Increased pERK1/2 levels corresponded with increased Ca2+ response to T cell receptor stimulation. mRNA expression of peroxiredoxins declined in Tregs from adults with asthma. Finally, CD4+CD25high cells from paediatric subjects were more sensitive to oxidative stress than those from adults in vitro. The differential Treg sensitivity to oxidative stress observed in children and adults was likely dependent on phenotypic CD45 isoform switching. Increased sensitivity of Treg cells from adults with asthma to H2O2 resulted from a reduction of peroxiredoxin-2, -3, -4 and increased pERK1/2 via impaired Ca2+ response in these cells.

Survey of the Time-Onset Profiles of Nedaplatin-Induced Adverse Events in Head and Neck Cancer Therapy.

OBJECTIVE: Cisplatin(CDDP)is a key drug for head and neck cancer therapy, but frequently induces severe adverse events including renal dysfunction. Nedaplatin(CDGP)was developed and is used in Japan; it has certain benefits over CDDP. Unlike CDDP, CDGP treatment does not require hydration. However, CDGP is not used globally and thus safety information is lacking. Therefore, we surveyed safety profiles for CDGP-based chemotherapy. METHODS: A survey was conducted at Showa University Hospital. Thirty-eight patients treated for head and neck cancer combined with radiotherapy(RTx)and tegafur- gimeracil-oteracil(S-1)between April 2012 and March 2015 were included. Laboratory-based adverse events(WBC, Hb, platelet[Plt], SCr, Alb)and oral mucositis were assessed according to CTCAE v5.0. Time-onset profiles for adverse events were evaluated after starting chemoradiotherapy. RESULTS: In 38 patients, Plt nadir was observed following 40(30-70)Gy and sustained for 14(7-35)days. WBC patterns followed similar profiles, but for Hb, nadir was observed following 60(40- 70)Gy and was less frequently sustained throughout the RTx. Alb and SCr levels were not correlated with therapy. Oral mucositis was observed following 50(10-70)Gy. CONCLUSION: In conclusion, at approximately 40 Gy, we observed decreases in WBC and Plt, with an increase in oral mucositis. Based on these results, medical staffs must closely monitor patients, especially at doses within range of 40 Gy.

[Effect of the active adult learning/patient oriented clerkship on affective reaction of students ∼ from the results of student survey].

We have previously reported the efficacy of the Patient Oriented Clerkship (POC) in the clinical clerkship in Showa University Hospitals, by a trial with old four-year pharmacy program students. In the unique clerkship, each student has a patient in charge, and follows his/her clinical conditions throughout the rotation. The aim of the POC is that having the students learn spontaneously (Active Learning) and actively (Adult Learning) promoted by student's commitment and responsibility by communicating with patients and health professionals in a team. As the POC requires students both Active Learning and Adult Learning, we define the POC as Active Adult Learning (AAL). Having a patient in charge for each student gives them many opportunities to participate in the medical team and foster their problem solving skills. Our previous study eventually showed positive results of the POC in the one-month short clerkship in the four-year program. On the other hand, the effect of the unique hospital clerkship in the new six-year program is not known. We conducted a student survey to clarify the learning effect in the new six-year education system which was revised and 2.5 month clinical clerkship was scheduled according to the model core clerkship curriculum. This report is the first report to show a challenge of the AAL/POC clerkship in the new six-year pharmacy education program.

Impaired Ca²âº regulation of CD4⁺CD25⁺ regulatory T cells from pediatric asthma.

BACKGROUND: CD4(+)CD25(+) regulatory T (T(reg)) cells can control the allergic response to allergen, airway eosinophilia and airway hypersensitivity. We speculated that chronic inflammation persisting in asthma airways is dependent on abnormalities of these T(reg) cells. There are differences in the pathology of asthma in adults and children, and the airways of pediatric asthma are considered to be more naive than those of adults. Therefore, we analyzed the functionality of T(reg) cells in pediatric asthma and the relationship between T(reg) function and asthma symptoms. METHODS: The anergic state, which is one of the defining properties of T(reg), was analyzed by measuring intracellular Ca(2+) influx following T cell receptor (TCR) stimulation. FOXP3-positive cells and FOXP3 mRNA expression were measured by flow analysis and real-time PCR with the SYBR method, respectively. RESULTS: CD45RO(+) cells make up approximately 99% of CD4(+)CD25(high) T cells and 89% of CD4(+)CD25(low) T cells in human adult blood. The proportion of CD45RO(+) cells in CD4(+)CD25(+) (high + low) T cells from pediatric asthma was much smaller (about 56%). Interestingly, our data indicated that CD45RO(+) T(reg) cells from pediatric asthma aberrantly increased intracellular Ca(2+) concentrations following TCR activation compared with pediatric nonasthma controls. CONCLUSION: These impaired CD45RO(+) T(reg) cell functions were correlated with asthma symptoms. The correlation was observed in the group with a highly expressed atopic phenotype and longer duration of asthma. We suggest that chronic inflammation in pediatric asthma airways may be the result of impaired regulatory functions of CD45RO(+) T(reg) cells.