To investigate the influence of surgical stress on fibroblast proliferation, serum samples were collected from 12 patients within 1 week after they had undergone gastrointestinal surgery, and the effect of these samples on the growth of fibroblasts from neonatal mice were evaluated by an in vitro assay. In addition, the course of the postoperative plasma levels of the stress-induced hormones, adrenaline, noradrenaline, and cortisol, and the direct effects of these substances on the proliferation of fibroblasts, were also analyzed. The sera collected from patients on the 1st, 3rd, and 7th postoperative day had a significant antiproliferative effect on the growth of fibroblasts. The evaluation of the levels of plasma catecholamines (adrenaline and noradrenaline) and cortisol revealed elevated postoperative concentrations of these substances in three patients, and the peaks were seen on the 1st or 3rd postoperative day. Furthermore, the growth of cultured fibroblasts was inhibited when each of these substances was added to the medium at a concentration comparable to the level found in the postoperative sera. These results suggest that adrenaline, noradrenaline, and cortisol may thus be among the circulating fibroblast growth inhibitors in postoperative patients and that surgical stress affects the formation of granulation in an inhibitory manner through the elevation of these stress-induced substances.

Background and AimNatural Killer (NK) cells are involved in the control of viral infection. However, the role of NK cells in chronic hepatitis B (CHB) remains unclear. This study investigated the frequencies and roles of NK cells in CHB, with a focus on activating receptor NKp46 and inhibitory receptor NKG2A.Patients/MethodPeripheral blood lymphocytes were obtained from 71 CHB patients and 37 healthy subjects (HS). The expressions of NKp46 and NKG2A were analyzed using flow cytometry. The role of NKp46-ligand was assessed using an in vitro co-culture system. Cytotoxicity and IFN-γ production in NK cells were evaluated using RT-PCR and flow cytometry.ResultsCHB patients were classified into treatment-naïve patients with low HBV DNA titer (CHB-L; n = 28), high HBV DNA titer (CHB-H; n = 24) by the cut-off level of serum HBV DNA 4 log copies/ml, and patients receiving nucleos(t)ide analogue (CHB-NA; n = 19). The expressions of NKp46 and NKG2A were higher in CHB-H than in HS/CHB-L/CHB-NA. HepG2.2.15 had higher NKp46-ligand expression than HepG2. When NK cells from HS were co-cultured with HepG2.2.15, inhibition of the NKp46 and NKp46-ligand interaction by anti-NKp46 antibody significantly reduced cytolysis of HepG2.2.15 and IFN-γ production. However, those reductions were not observed in co-culture with HepG2. Additionally, NK cells that highly expressed NKp46 also highly expressed NKG2A (NKp46highNKG2Ahigh subset). The frequencies of NKp46highNKG2Ahigh subset in CHB-H were higher than those in HS/CHB-L/CHB-NA. Among treatment-naïve CHB patients, the frequencies of NKp46highNKG2Ahigh subset were positively correlated with serum ALT (P<0.01, r = 0.45) and HBV DNA (P<0.01, r = 0.59) levels. The expressions of Fas-L, STAT1, TRAIL and CD107a were higher and IFN-γ expression was lower in the NKp46highNKG2Ahigh subset than in the other subsets.ConclusionThe NKp46 and NKp46-ligand interaction contributes to NK cell activation. A novel NK cell subset, the NKp46highNKG2Ahigh subset, may be associated with liver injury and HBV replication.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease with a spectrum of presentations. S100A8 has been suggested to play a pivotal role as an endogenous immune-activator in inflammatory diseases. In this study, we investigated the involvement of S100A8 in the development of NAFLD. We used a diet model of NAFLD, in which mice were fed either a high-fat and high-cholesterol diet (HFHCD) or a normal diet (ND) as a control. We also assessed liver tissues from patients with NAFLD, including patients with nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). HFHCD-fed mice, but not ND-fed mice, developed steatohepatitis. S100A8 expression was significantly elevated in the livers of HFHCD-fed mice compared with the controls. S100A8 was exclusively expressed in CXCR2-expressing CD11b+Gr-1high cells, which significantly increased in the livers of HFHCD-fed mice. These cells were F4/80 negative and did not possess a suppressor function. TNF-α expression was enhanced by S100A8 in primary liver leukocytes or a hepatocyte cell line and significantly elevated in the livers of HFHCD-fed mice. TNF-α was primarily produced from CD11b+F4/80+ cells in liver leukocytes in response to S100A8. TNF-α deficiency attenuated hepatitis in HFHCD-fed mice. S100A8 was significantly more expressed in the liver tissues of patients with NASH than in those of patients with NAFL. In conclusion, these results suggest that S100A8 is primarily produced from CXCR2-expressing CD11b+Gr-1high cells, and it upregulates TNF-α production in CD11b+F4/80+ cells through cellular cross-talk, which is an important mechanism in the development of NAFLD.

In clinically hyperthermia and irradiation therapy for malignant neoplasms are known that they have antiproliferative activity and cell death (including apoptosis) inducing activity. However not only mechanisms of cell death induction but treatment effects of them still have been unclear. In this time we showed that cell cycles from G0/G1 phase to S-G2/M phase were delayed by hyperthermia and G2/M phase accumulation were caused immediately by irradiation. And we also demonstrated that the combination treatments of hyperthermia and irradiation induced synergistic antiproliferative effects and strong effects of cell death to human esophageal carcinoma cell lines. Although treatments of hyperthermia and irradiation were mild individually, combination treatment of hyperthermia and irradiation were useful for esophageal carcinoma treatment.

The genetic and environmental contributions to physical aging (hair graying, balding, presbyopia) and longevity (age at death) were examined by within-pair comparison in monozygotic (MZ) and dizygotic (DZ) twins in later adulthood. Physical aging was investigated on 135 pairs of adult twins aged over 50. Hair graying and hair loss (baldness) showed significantly higher rates of concordance in the MZ twins than in the DZ twins. The intrapair difference of the degree of hair graying was negligible in 79%, slight in 15% and striking in 5% among the MZ pairs; while negligible in 40%, slight in 50% and striking in 10% among the DZ pairs. The intrapair difference of the degree of hair loss was negligible in 92%, slight in 8% (and striking in none) among the MZ pairs; while negligible in 69%, slight in 25% and striking in 6% among the DZ pairs. The age at onset of presbyopia showed a slightly higher rate of concordance in the MZ than in the DZ pairs. Longevity (age at death) was surveyed on 184 pairs of twins who died at over 40 years of age. The intrapair difference of longevity was 6.65 +/- 5.6 years (maximum 18.0; minimum 0.04) in the MZ pairs, and 8.66 +/- 7.2 years (maximum 18.6; minimum 2.9) in the DZ pairs. The MZ pairs showed a slightly smaller within-pair difference of longevity than the DZ pairs.