Background

This study aimed to compare the cytokine-mediated immune response in children submitted to primary vaccination with the YF-17D-213/77 or YF-17DD yellow fever (YF) substrains.

Methods

A non-probabilistic sample of eighty healthy primary vaccinated (PV) children was selected on the basis of their previously known humoral immune response to the YF vaccines. The selected children were categorized according to their YF-neutralizing antibody titers (PRNT) and referred to as seroconverters (PV-PRNT+) or nonseroconverters (PV-PRNT−). Following revaccination with the YF-17DD, the PV-PRNT− children (YF-17D-213/77 and YF-17DD groups) seroconverted and were referred as RV-PRNT+. The cytokine-mediated immune response was investigated after short-term in vitro cultures of whole blood samples. The results are expressed as frequency of high cytokine producers, taking the global median of the cytokine index (YF-Ag/control) as the cut-off.

Results

The YF-17D-213/77 and the YF-17DD substrains triggered a balanced overall inflammatory/regulatory cytokine pattern in PV-PRNT+, with a slight predominance of IL-12 in YF-17DD vaccinees and a modest prevalence of IL-10 in YF-17D-213/77. Prominent frequency of neutrophil-derived TNF-α and neutrophils and monocyte-producing IL-12 were the major features of PV-PRNT+ in the YF-17DD, whereas relevant inflammatory response, mediated by IL-12+CD8+ T cells, was the hallmark of the YF-17D-213/77 vaccinees. Both substrains were able to elicit particular but relevant inflammatory events, regardless of the anti-YF PRNT antibody levels. PV-PRNT− children belonging to the YF-17DD arm presented gaps in the inflammatory cytokine signature, especially in terms of the innate immunity, whereas in the YF-17D-213/77 arm the most relevant gap was the deficiency of IL-12-producing CD8+T cells. Revaccination with YF-17DD prompted a balanced cytokine profile in YF-17DD nonresponders and a robust inflammatory profile in YF-17D-213/77 nonresponders.

Conclusion

Our findings demonstrated that, just like the YF-17DD reference vaccine, the YF-17D-213/77 seed lot induced a mixed pattern of inflammatory and regulatory cytokines, supporting its universal use for immunization.

Background/Aims

CIBIC plus-J is the Japanese language version equivalent to CIBIC plus. Variability of CIBIC plus-J arises among raters in accordance with their experience and their memories of patients’ conditions at baseline. Therefore, in a multicenter trial of Alzheimer's disease, CIBIC plus-J interviews with Alzheimer's disease patients were videotaped, and the tapes were assessed by central raters as a means to improve the reliability of CIBIC plus-J assessment.

Methods

Two of eight central raters were randomly selected and independently assessed the CIBIC plus-J of each patient.

Results

CIBIC plus-J of 41 patients was assessed. The agreement rate between the two raters was 46.3% (19/41), when two raters assessed the CIBIC plus-J of the same patient. However, when considering disagreement between adjacent points as ‘agree’, the agreement rate was 97.6% (40/41). Although the kappa coefficients contained coincidence, simple and quadratic weighted kappa coefficients [95% confidential interval (CI)] were 0.226 (0.066–0.386) and 0.633 (0.507–0.759), respectively, and when considering disagreement between adjacent points as ‘agree’, the agreement kappa was 0.896 (0.752–1.041). The interclass coefficient from the two-way layout model was 0.639.

Conclusion

The reliability of the CIBIC plus-J assessment with the videotaped method was acceptable.

Background

As of 2010, the rivastigmine patch was licensed for the treatment of Alzheimer's disease (AD) in 64 countries.

Methods

This 24-week, multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy, safety and tolerability of the 5-cm2 (9-mg loading dose; 4.6 mg/24 h delivery rate) and 10-cm2 (18-mg loading dose; 9.5 mg/24 h delivery rate) rivastigmine patch in Japanese patients with AD.

Results

In the primary analysis population (intent-to-treat last observation carried forward) at week 24, delayed deterioration was seen with the 10-cm2 patch versus placebo on the Japanese version of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-J cog; p = 0.005) and the Japanese version of the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC plus-J; p = 0.067). Participants receiving the rivastigmine patch showed numerically less decline versus placebo at week 24 on the CIBIC plus-J, although this did not reach statistical significance. Statistical significance for the CIBIC plus-J was met following adjustment for body weight and baseline Mini-Mental State Examination score as dynamic allocation factors (p = 0.042) and on the Disability Assessment for Dementia (DAD; p = 0.024) and Mental Function Impairment (MENFIS; p = 0.016) subscales. Serious adverse events were rare and were consistent with the known safety profile of the rivastigmine patch. Conclusion: The rivastigmine patch has a favorable efficacy and tolerability profile in Japanese patients with AD.

Background

The rate of use of nursing-care services has been increasing dramatically in recent years with the upgrading of the public long-term care insurance system in Japan. We addressed how the increased use of the nursing-care services might affect the information on the patients provided by their caregivers.

Methods

A questionnaire survey of 531 family caregivers caring for dementia patients at home was carried out to investigate how the use of these services might affect the information about the patients provided by the caregivers. The survey revealed that the use of the nursing-care services reduced the burden (quality, quantity, time of nursing care, and feeling) on the caregivers.

Results

According to the observation provided by the caregivers, the patients’ behaviors and activities at home tended to decrease. These results indicated that the use of the nursing-care services resulted in a reduction in the opportunity for and the time spent on observation of the patients by the caregivers, making it more difficult for the caregiver to provide an appropriate assessment of the patient's condition.

Conclusions

We discussed the impact of the use of the nursing-care services on the Clinician's Interview-Based Impression of Change plus (CIBIC-plus) rating. Due to the reduction in the time spent on nursing care and in the opportunity for observation of the patient's activities of daily living by the caregiver resulting from the use of the nursing-care services, it is difficult to obtain an accurate picture of the patient's clinical condition using the CIBIC-plus, probably leading to an inappropriate CIBIC-plus rating.

Yellow fever (YF) vaccines (17D-204 and 17DD) are well tolerated and cause very low rates of severe adverse events (YEL-SAE), such as serious allergic reactions, neurotropic adverse diseases (YEL-AND), and viscerotropic diseases (YEL-AVD). Viral and host factors have been postulated to explain the basis of YEL-SAE. However, the mechanisms underlying the occurrence of YEL-SAE remain unknown. The present report provides a detailed immunological analysis of a 23-year-old female patient. The patient developed a suspected case of severe YEL-AVD with encephalitis, as well as with pancreatitis and myositis, following receipt of a 17D-204 YF vaccination. The patient exhibited a decreased level of expression of Fc-γR in monocytes (CD16, CD32, and CD64), along with increased levels of NK T cells (an increased CD3+ CD16+/− CD56+/−/CD3+ ratio), activated T cells (CD4+ and CD8+ cells), and B lymphocytes. Enhanced levels of plasmatic cytokines (interleukin-6 [IL-6], IL-17, IL-4, IL-5, and IL-10) as well as an exacerbated ex vivo intracytoplasmic cytokine pattern, mainly observed within NK cells (gamma interferon positive [IFN-γ+], tumor necrosis factor alpha positive [TNF-α+], and IL-4 positive [IL-4+]), CD8+ T cells (IL-4+ and IL-5+), and B lymphocytes (TNF-α+, IL-4+, and IL-10+). The analysis of CD4+ T cells revealed a complex profile that consisted of an increased frequency of IL-12+ and IFN-γ+ cells and a decreased percentage of TNF-α+, IL-4+, and IL-5+ cells. Depressed cytokine synthesis was observed in monocytes (TNF-α+) following the provision of antigenic stimuli in vitro. These results support the hypothesis that a strong adaptive response and abnormalities in the innate immune system may be involved in the establishment of YEL-AND and YEL-AVD.

Subunit vaccines are a potential intervention strategy against leptospirosis, which is a major public health problem in developing countries and a veterinary disease in livestock and companion animals worldwide. Leptospiral immunoglobulin-like (Lig) proteins are a family of surface-exposed determinants that have Ig-like repeat domains found in virulence factors such as intimin and invasin. We expressed fragments of the repeat domain regions of LigA and LigB from Leptospira interrogans serovar Copenhageni. Immunization of Golden Syrian hamsters with Lig fragments in Freund’s adjuvant induced robust antibody responses against recombinant protein and native protein, as detected by ELISA and immunoblot, respectively. A single fragment, LigANI, which corresponds to the six carboxy-terminal Ig-like repeat domains of the LigA molecule, conferred immunoprotection against mortality (67-100%, P <0.05) in hamsters which received a lethal inoculum of L. interrogans serovar Copenhageni. However, immunization with this fragment did not confer sterilizing immunity. These findings indicate that the carboxy-terminal portion of LigA is an immunoprotective domain and may serve as a vaccine candidate for human and veterinary leptospirosis.

There is an urgent need for improved diagnosis of leptospirosis, an emerging infectious disease which imparts a large disease burden in developing countries. We evaluated the use of Leptospira immunoglobulin (Ig)-like (Lig) proteins as a serodiagnostic marker for leptospirosis. Lig proteins have bacterial immunoglobulin-like (Big) tandem repeat domains, a moiety found in virulence factors in other pathogens. Sera from patients identified during urban outbreaks in Brazil reacted strongly with immunoblots of a recombinant fragment comprised of the second to sixth Big domains of LigB from L. interrogans serovar Copenhageni, the principal agent for transmission in this setting. Furthermore, the sera recognized an analogous LigB fragment derived from L. kirschneri serovar Grippotyphosa, a pathogenic serovar which is not endemic to the study area. The immunoblot assay detected anti-LigB IgM antibodies in sera from 92% (95% confidence interval, 85 to 96%) of patients during acute-phase leptospirosis. The assay had a sensitivity of 81% for sera from patients with less than 7 days of illness. Anti-LigB antibodies were found in sera from 57% of the patients who did not have detectable anti-whole-Leptospira responses as detected by IgM enzyme-linked immunosorbent assay and microagglutination test. The specificities of the assay were 93 to 100% and 90 to 97% among sera from healthy individuals and patients with diseases that have clinical presentations that overlap with those of leptospirosis, respectively. These findings indicate that the antibody response to this putative virulence determinant is a sensitive and specific marker for acute infection. The use of this marker may aid the prompt and timely diagnosis required to reduce the high mortality associated with severe forms of the disease.

A method for rapid concentration and purification of influenza virus by adsorption on and elution from an insoluble polyelectrolyte is described. To accomplish this task, influenza virus had to be rendered stable at pH 4 to 5, since viruses adsorb to the polyelectrolyte more efficiently at this pH range. A precipitate which forms in influenza harvests under acid conditions in the cold can be removed by ammonium sulfate at a concentration which traps the precipitate but not the virus. Thus, ammonium sulfate-treated influenza virus in allantoic fluid could be readily concentrated on the polyelectrolyte. Elution yielded a virus concentrate essentially free of nonviral proteins.