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Close observation of the local transmission of influenza A(H1N1) viruses enabled an estimate of the length of time the virus was transmitted without a mutation. Of 4,448 isolates from 11 consecutive years, 237 isolates could be categorized into 57 strain groups with identical hemagglutinin genes, which were monitored for the entire duration of an epidemic season. In addition, 35 isolates with identical sequences were identified at the study site and in other countries within 147 days. Consequently, it can be postulated that once an influenza virus enters a temperate region, the strain rarely mutates before the end of the season.

The correlation of viral growth capability (n = 156) with the viral load in nasopharyngeal swabs (n = 76) was assessed. Epidemic influenza A/H1N1, A/H3N2, and B viruses showed a wide range of growth capability (104–1011 copies/mL) in Madin-Darby canine kidney cells. The growth was correlated with the nasopharyngeal viral load (r = 0.53). Six selected strains showed growth-dependent cell death (r = 0.96) in a growth kinetics assay. Epidemic influenza viruses exhibit a wide range of growth capability. Growth capability should be considered one of the key factors in disease prognosis.

To investigate the prevalence and background of children with medical complexity (CMC) and its secular trend in Japan.CMC were defined as patients under the age of 20 years requiring medical care and devices. The patients were enrolled using the national health insurance claims data of three hospitals and two rehabilitation centers in Tottori Prefecture. The study period was divided into three periods: Period 1, 2007-2010; Period 2, 2011-2014; and Period 3, 2015-2018.A total of 378 CMC were enrolled. The prevalence of CMC was 1.88 per 1000 population among subjects aged20 years in 2018, and it increased by approximately 1.9 times during the study period. The number of CMC who presented with severe motor and intellectual disabilities did not change from Period 1 to Period 3. Meanwhile, the number of CMC who had relatively preserved motor and intellectual abilities increased from 58 to 98. The proportion of CMC who required respiratory management and oxygen therapy increased by 1.3 and 1.8 times, respectively. By contrast, the proportion of CMC who need tube feeding decreased significantly between periods 1 and 3 (P 0.05).The prevalence of CMC increased almost twice during the 12-year study period; however, the increase in the number of patients with relatively preserved motor and intellectual abilities was pronounced. This study showed that the need for medical care and devices differed based on the underlying disorders and severity of CMC; therefore, individualized medical, welfare, and administrative services and education about the various types of CMC must be provided.

Background: Early predictors of status epilepticus (SE)-associated mortality and morbidity have not been systematically studied in children, considerably impeding the identification of patients at risk. Objectives: To determine reliable early predictors of SE-associated mortality and morbidity and identify the etiology of SE-associated sequelae in Japanese children. Methods: We conducted a prospective multicenter study of clinical findings and initial laboratory data acquired at SE onset, and assessed outcomes at the last follow-up examination. In-hospital death during the acute period and neurological sequelae were classified as poor outcomes. Results: Of the 201 children who experienced their first SE episode, 16 exhibited poor outcome that was most commonly associated with acute encephalopathy. Univariate analysis revealed that the following were associated with poor outcomes: young age (⩽24months); seizure duration >90min; seizure intractability (failure of the second anticonvulsive drug); biphasic seizures; abnormal blood glucose levels ( 250mg/dL); serum aspartate aminotransferase (AST) ⩾56U/L; and C-reactive protein (CRP) levels >2.00mg/dL. Multivariate analysis revealed that young age, seizure intractability, abnormal blood glucose levels, and elevated AST and CRP levels were statistically significant. Conclusions: Young age and seizure intractability were highly predictive of poor outcomes in pediatric SE. Moreover, abnormal blood glucose levels and elevated AST and CRP levels were predictors that might be closely associated with the etiology, especially acute encephalopathy and severe bacterial infection (sepsis and meningitis) in Japanese children.

Chorioamnionitis has been shown to be one of the most important factors in inducing preterm delivery. The present study was undertaken to examine the effects of chorioamnionitis on placental endocrine functions. Preterm placentas with histologic chorioamnionitis produced smaller amounts of human chorionic gonadotropin (hCG) and human placental lactogen (hPL) than those without chorioamnionitis (P < 0.001). To examine the mechanism involved in the suppression of placental endocrine functions induced by chorioamnionitis, we initially confirmed the expression of lipopolysaccharide (LPS) receptor, i.e. the CD14 molecule, on trophoblasts by Northern blot analysis and immunohistochemistry. We then stimulated purified trophoblasts with LPS, which is the major agent which induces inflammatory responses in the host via the LPS receptor. The trophoblasts stimulated with LPS produced reduced amounts of hCG, hPL, and progesterone in a time- and dose-dependent fashion in spite of the induced manganese-superoxide dismutase (SOD) synthesis. Stimulation of trophoblasts with hypoxanthine and xanthine oxidase resulted in suppressed hCG production, while the simultaneous addition of SOD into the culture medium reversed the suppression of hCG production. LPS in the placenta with chorioamnionitis might directly stimulate trophoblasts through the LPS receptor (CD14), thus reducing placental endocrine functions. Superoxide anions which exogenously act on trophoblasts might be generated by simultaneous stimulation of neutrophils and monocytes at the feto-maternal interface by LPS, and additively reduce placental endocrine functions.

An 84-year-old woman with pulmonary hypertension (PH) secondary to chronic pulmonary thromboembolism suffered from continuous warfarin dependent bleeding from sigmoid colon cancer. Sigmoidectomy was scheduled to control continuous bleeding. Six hours after discontinuation of anticoagulant therapy for elective sigmoidectomy, the patient showed hypoxia, pulmonary thromboembolism and pulmonary hypertension with right ventricular systolic pressure (RVSP) of 81 mmHg. The operation was postponed and heparin was infused. Since two-day heparinization therapy did not improve PH, oral administration of sildenafil citrate 60 mg daily was initiated. Seven days after initiation of sildenafil administration, RVSP decreased to 49 mmHg without improvement of hypoxia. Sigmoidectomy was performed under general anesthesia. The patient showed severe hypotension managed with noradrenaline and dopamine infusion during and after surgery, resulting from interaction between sildenafil and vasodilators. The patient was discharged 36 days after the operation without complications.

A novel swine-origin influenza A(H1N1)pdm09 virus has been circulating in humans since March-April, 2009. The 2009-2010 epidemic involved predominantly a single subtype of A(H1N1)pdm09 (at 96%, 46/48) in the sentinel sites of this study. However, A(H1N1)pdm09 started to circulate together with other type/subtype (49%, 33/68) at the first peak in the next epidemic season in 2010-2011: A(H1N1)pdm09/A(H3N2) (9%, 6/68), A(H1N1)pdm09/B (35%, 24/68), and A(H1N1)pdm09/A(H3N2)/B (4%, 3/68). Single infection of A(H1N1)pdm09 became a rare event (8%, 5/65) at the second peak of the same season in 2010-2011 compared with that at the first peak (50%, 34/68). Concurrently with this decline, single infections of others, A(H3N2) or B, became evident (6%, 4/65; 14%, 9/65, respectively). Triple infections were more common (29%, 19/65) at the second peak than at the first peak (4%). The A(H1N1)pdm09 detected in 2010-2011 produced less virus upon 72 hr of incubation in vitro after the inoculations at 10(4) and 3,300 copies/ml (2.3 × 10(9) and 2.3 × 10(9) copies/ml on average) than that in 2009-2010 (3.7 × 10(9) and 1.3 × 10(10) copies/ml on average; P0.05 by ANOVA test), respectively. As described above, the replication capacity of A(H1N1)pdm09 seems to have deteriorated in the 2010-2011 season presumably due to substantial herd immunity and allowed the existence of other type/subtype. These results suggest that assessment of replication capacity is indispensable for analysis of influenza epidemics.

We investigated the role of leukemia inhibitory factor (LIF) at the implantation site of human embryos. The first trimester decidual tissue produced higher levels of LIF than chorionic tissue, but the decidua produced much smaller amounts of interleukin-6 (IL-6) than the chorion in vitro, as determined by enzyme-linked immunosorbent assay. The reverse transcription-polymerase chain reaction and immunohistochemical analysis revealed the expression and localization, on the trophoblasts, of glycoprotein 130 (gp130), an IL-6 signal transducer receptor component shared by the cytokines such as LIF and IL-6. Trophoblasts stimulated by recombinant LIF (rLIF) produced CG titer at the amount similar to that induced by rIL-6. Recombinant LIF-induced CG production was significantly blocked by anti-gp130 antibody but not by anti-IL-6 receptor antibody, whereas rIL-6-induced CG was completely blocked by both antibodies. Recombinant LIF- and rIL-6-induced CG productions were both significantly blocked by genistein, a tyrosine kinase inhibitor, suggesting an involvement of tyrosine kinase in gp130-mediated CG production. Since CG is capable of stimulating trophoblast growth and differentiation as well as placental metabolism, LIF produced at the fetomaternal interface are considered to stimulate the trophoblasts to produce CG, which may contribute to the maintenance of the placental functions and embryonal growth.

Objective: Because interleukin-6 is an important mediator in the host defense mechanism against infection and tissue damage, we studied the capacity of placentas with or without either labor or chorioamnionitis in the third trimester to produce interleukin-6. Study Design: The placental blocks were cultured, and their interleukin-6 titers were measured by a bioassay. Results: Placentas with labor produced a similar amount of interleukin-6 to placentas without labor. In contrast, placentas with chorioamnionitis produced much more interleukin-6 than the placentas with or without labor (p Conclusion: Placental interleukin-6 is thus surmised to participate in potentiation of the placental and fetomatemal defense mechanisms together with placental interleukin-1 during chorioamnionitis.

IL-8 is a chemotactic and activating cytokine for neutrophils which eliminate invading bacteria by releasing bactericidal metabolites. Cord blood mononuclear cells (CBMCs) obtained from neonates born to mothers with chorioamnionitis actively produced a significantly higher amount of IL-8 than those of neonates without chorioamnionitis, suggesting that the mononuclear cells of fetuses with chorioamnionitis had been activated in utero. As lipopolysaccharide (LPS) can often be detected in the uteroplacental space in chorioamnionitis, the LPS-mediated activation mechanism of neonatal mononuclear cells was analyzed in vitro to produce IL-8. Neonatal mononuclear cells stimulated with LPS increased IL-8 production in a time- and dose-dependent manner. The ability of term or preterm neonatal mononuclear cells to produce IL-8 was comparable with that of adult (maternal) mononuclear cells, suggesting functional maturity of the neonatal or fetal mononuclear cells to produce IL-8. However, IL-8 production by neonatal CBMCs was down-regulated by dexamethasone, a glucocorticoid which is clinically administered to mothers to promote fetal lung maturity in preterm delivery. Our present study revealed a regulatory mechanism of fetal IL-8 production, suggesting that functionally mature fetal mononuclear cells produce IL-8 in response to LPS in chorioamnionitis and activate the fetal defense mechanism against infection.

Prospective studies of an infant of a mother infected with hepatitis C virus indicated that an HCV infection developed in the infant in early life. Perinatal transmission appeared to be the most likely explanation.

PROBLEM: To demonstrate whether monocyte chemotactic and activating factor (MCAF) and interleukin-6 (IL-6) are present in the seminal plasma, and whether these presence is modulated by leukospermia. METHODS: Semen samples from 53 men were obtained by masturbation and examined for the presence of MCAF and IL-6 by enzyme immunoassay (EIA). Semen samples were obtained from 28 infertile men without leukospermia, 16 infertile men with leukospermia, and nine proven-fertile men. The correlation between the amount of MCAF in the seminal plasma with some spermiogram parameters and other cytokines such as IL-6 and IL-8 was statistically evaluated. RESULTS: Immunoreactive MCAF was detected in the seminal plasmas of all 53 subjects. The MCAF titer in the seminal plasma of patients with leukospermia (11.19 +/- 2.75 micrograms/l) was significantly higher than that in the seminal plasma of the patients without leukospermia (3.24 +/- 0.53 micrograms/l) and the fertile men (2.78 +/- 0.35 micrograms/l) (P < 0.001). The IL-6 titer in the seminal plasma of the patients with leukospermia (21.05 +/- 4.49 ng/l) was also significantly higher than that in the seminal plasma of the patients without leukospermia (8.77 +/- 1.92 ng/l) and the fertile men (6.94 +/- 1.27 ng/l) (P < 0.01). There was a high degree of correlation among the levels of MCAF, IL-6 and IL-8 in the seminal plasma. CONCLUSIONS: These findings demonstrated the presence of MCAF and IL-6 in the seminal plasma, and that the levels of these cytokines were elevated in the seminal plasma of the infertile patients with leukospermia.

To study the role of soluble interleukin-6 receptor (sIL-6R) during pregnancy, sIL-6R levels in the sera of pregnant women in the first, second, and third trimesters were determined and found to remain unchanged during pregnancy, but were significantly higher than those in nonpregnant women in the follicular, ovulatory, and luteal phases of the menstrual cycle (P < 0.001). IL-6 levels, however, in the sera of pregnant women at all trimesters showed no difference from those in nonpregnant women at any stage of the menstrual cycle. Recombinant sIL-6R (rsIL-6R) augmented hCG production by rIL-6-stimulated trophoblasts dose dependently, but failed to enhance hCG production by unstimulated trophoblasts. rIL-6- and rsIL-6R-induced hCG production was significantly blocked by anti-IL-6R antibody, PM1; antisignal transducing glycoprotein 130 (gp130) antibody, GPX7; or a tyrosine kinase inhibitor, genistein. Thus, sIL-6R in serum from pregnant women forms a complex with placental and decidual IL-6 in a manner similar to trophoblast membrane-bound IL-6R. These two discrete types of IL-6R and IL-6 complex might act cooperatively by binding to gp130 and subsequently evoking tyrosine kinase activity in the trophoblasts to produce hCG in vivo.

The immunosuppressive activity of a JEG-3 choriocarcinoma-derived factor in human IL-2-dependent T cell responses has been studied, together with its effect on IL-2-independent T cell responses induced by 10 nM TPA. The factor completely suppressed the IL-2-independent proliferative responses of T cells but failed to suppress antigenic expression of activation-associated CD 25 molecules. Further studies examined the effect of the factor on LAK cell generation induced by rIL-2. Recombinant IL-2-induced LAK cell proliferation was observed on Day 4 and Day 5, but not on Day 3. As the factor suppressed the responses of LAK cell proliferation, we tested whether it blocked the generation of Day 3, Day 4 and Day 5 LAK cells. The addition of the factor failed to suppress the generation of Day 3 LAK cells, while it partially suppressed the lytic activity of Day 4 LAK cells and completely suppressed that of Day 5 LAK cells. The data suggest the presence of a heterogeneous pattern for LAK cell generation; one without proliferation, but the other requiring proliferation, to acquire killer activity. Taken together with the evidence that the factor failed to suppress NK activity, the choriocarcinoma-derived factor suppressed only the proliferative events of immunocompetent cells, but inhibited neither their activation nor the differentiation events. This immunosuppressive factor might be involved in the prevention of host-mediated rejection of choriocarcinoma cells or maternal rejection of the fetus.

We examined the functional activity of cord mononuclear cells (MNCs) to produce interleukin (IL)-6 in vitro and in vivo. We stimulated fetal T-cell, B-cell, and macrophage fractions with mitogens. The supernatant of each stimulated cord cell fraction contained a comparable amount of IL-6 to that of each adult cell fraction activated similarly, suggesting functional maturity of cord MNCs' ability to produce IL-6. We then examined fetal cells' activities to produce IL-6 in response to perinatal infections, especially to intraamniotic infections (IAI). Among the cord MNCs from fetuses with IAI, macrophages were major cells producing IL-6. The serum IL-6 level in the fetuses with IAI was elevated, but it decreased to normal levels after antibiotic treatment; this finding indicates that IL-6-mediated host defense mechanisms by cord MNCs are triggered by perinatal infections.

The placenta plays a number of important roles during pregnancy, some of which might be mediated by cytokines with multiple activities such as IL-6. Using an IL-6-dependent cell line, MH6o.BSF2, we showed that the placenta released IL-6 into the culture supernatant. Analysis of single-cell suspensions of placental cells determined the major source of IL-6 to be trophoblast. Using a mouse monoclonal antibody specific for IL-6 (alpha BSF2-I66), immuno-histochemical analysis of placental specimens demonstrated the localization of IL-6 only in the trophoblast layer. Additional immunocytochemical studies with single-cell suspensions of trophoblasts demonstrated the preferential presence of IL-6 molecules in syncytiotrophoblasts rather than cytotrophoblasts. The evidence that a high titer of IL-6 is produced spontaneously by syncytiotrophoblasts indicates that IL-6 may play immunological roles in fetomaternal interactions by means of IL-6-driven multiple immunoregulatory activities.

An immunosuppressive factor released by choriocarcinoma cell lines was analyzed in the present study. It inhibited the proliferative responses of human T cells stimulated by lectins or alloantigens. It also blocked the generation of alloreactive cytotoxic T cells. The suppressive activity of the factor was detected in the responses of the T cells costimulated with 1 nM 12-O-tetradecanoyl phorbol 13-acetate and 1 microM A23187, suggesting the possibility that the factor acted on the intracellular signal transduction in T cells rather than interfering with early events such as T cell receptor signal transduction through cell membranes. Moreover, the factor acted directly on T cell proliferation pathways without activation of suppressor cells but did not act on T cell activation pathways. Taken together, all these findings expanded our previous reports on a factor released by normal trophoblasts, indicating the possible identity of the two factors. The physicochemical properties of the choriocarcinoma-derived factor were examined, and the biological significance of the factor during pregnancy was discussed in this paper.

We examined the nature of cytoplasmic signal transduction pathways in cord blood T cells by stimulating them with tumor promoter (TPA) and calcium ionophore (A23187). Costimulation of T cells with TPA and A23187 induced optimal proliferative responses on Day 2 in cord T cells but on Day 4 in adult T cells. The maximal responses observed in cord T cells were much less than those of adult T cells, whereas the Con A-induced proliferative responses of these cells showed no significant differences. The reduced responses of cord T cells were due to their lower efficiency in activating the cellular events in T cell activation and proliferation phase, because cord T cells have significantly less ability than adult T cells to express IL-2 receptor as well as HLA-DR and produce IL-2 molecules, thereby inducing proliferation. These data show immature characteristics of intracellular signal transduction pathways in cord T cells, which are directly related with the functional immaturity of cord T cells.

We have investigated the functional ability of a choriocarcinoma-cell-derived factor to block human T cell responses and the factor's immunoregulatory site of action on the T cell signal transduction pathway. The factor completely suppressed human T cell responses activated by phorbol ester and calcium ionophore, reagents which strongly stimulate IL-2-mediated T cell responses. It failed to inhibit CD 25 expression and IL-2 production by T cell blasts in the T cell activation phase, but completely blocked recombinant IL-2-induced proliferation of T cell blasts in the T cell proliferation phase. Absorption experiments with the factor and Con A-induced T cell blasts as well as [125I]IL-2 binding experiments with T cell blasts revealed that the factor acted on the physiological events occurring after IL-2-mediated stimulation of IL-2 receptor complexes, demonstrating no interaction of the factor with either IL-2 molecules or IL-2 receptor complexes. Moreover, it suppressed murine IL-2 dependent T cell line proliferation, suggesting the presence of common pathways in human and murine T cell proliferation. The biological and immunological significance of the factor during pregnancy and in the immunosuppressed tumor-bearing hosts are discussed.