Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome.

Nakajo-Nishimura syndrome (NNS) is a disorder that segregates in an autosomal recessive fashion. Symptoms include periodic fever, skin rash, partial lipomuscular atrophy, and joint contracture. Here, we report a mutation in the human proteasome subunit beta type 8 gene (PSMB8) that encodes the immunoproteasome subunit ß5i in patients with NNS. This G201V mutation disrupts the ß-sheet structure, protrudes from the loop that interfaces with the ß4 subunit, and is in close proximity to the catalytic threonine residue. The ß5i mutant is not efficiently incorporated during immunoproteasome biogenesis, resulting in reduced proteasome activity and accumulation of ubiquitinated and oxidized proteins within cells expressing immunoproteasomes. As a result, the level of interleukin (IL)-6 and IFN-γ inducible protein (IP)-10 in patient sera is markedly increased. Nuclear phosphorylated p38 and the secretion of IL-6 are increased in patient cells both in vitro and in vivo, which may account for the inflammatory response and periodic fever observed in these patients. These results show that a mutation within a proteasome subunit is the direct cause of a human disease and suggest that decreased proteasome activity can cause inflammation.

Changes in cardiovascular risk factors over a 24-year follow-up period: a Japanese pediatric cohort study.

This study examined changes in body mass index (BMI), fasting blood sugar (FBS), total cholesterol (TC) and HDL-cholesterol (HDL-C) levels over a 24-year follow-up period in a pediatric cohort. An appropriate starting age for intervention to prevent cardiovascular diseases is still unclear. The subjects were 655 children, aged 10-12. A follow-up survey was conducted when the subjects reached ages 13-15, 16-18, and 35-45, respectively, and height, weight, and blood tests including FBS, TC and HDL-C were examined. Forty (6%) of these subjects participated. BMI at ages 35-45 were significantly higher than those at ages 10-12 (p < 0.0001), 13-15 (p < 0.001), and 16-18 (p < 0.001). TC levels at ages 35-45 were significantly higher than at ages 10-12 (p < 0.0001), 13-15 (p < 0.0001), and 16-18 (p < 0.0001). BMI at the end of the follow-up (ages 35-45) had a significant correlation with BMI at ages 13-15 (R = 0.38, p = 0.041) and 16-18 (R = 0.41, p = 0.049). TC and HDL-C values at the end of the follow-up had a significant correlation with those at ages 10-12 (R = 0.55, p = 0.0004; R = 0.55, p = 0.016), 13-15 (R = 0.35, p = 0.045; R = 0.42, p = 0.015), and 16-18 (R = 0.47, p = 0.019; R = 0.44, p = 0.028). These results may suggest that intervention for children in Japan with cardiovascular risk factors should be initiated in the early years of life.

A novel 1-bp deletion variant in DAG1 in Japanese familial asymptomatic hyper-CK-emia.

Asymptomatic hyper-CK-emia (ASCK) is characterized by persistent elevation of creatine kinase (CK) in serum without any neurological symptoms. We ascertained a two-generation family of ASCK patients without clear neurological abnormalities except for the high levels of serum CK (810.5 ± 522.4 U/L). We identified a novel 1-bp deletion variant in the DAG1 gene shared by the patients in the family (NM_001177639: exon 3: c.930delC:p.R311Gfs*70). The variant causes premature termination of translation at codon 477, resulting in a protein product completely devoid of the essential DAG1 domain. Since ASCK has been associated with DAG1 in only one case carrying compound heterozygous missense variants, our new finding of a novel 1-bp deletion revealed the previously unknown dominant effect of DAG1 on ASCK.

Influence of pneumococcal conjugate vaccines on acute otitis media in Japan.

OBJECTIVE: This study investigated: (i) changes in the incidence of acute otitis media (AOM) following introduction of public funding for free inoculation with 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13, respectively) and (ii) changes in the rate of myringotomies for AOM (MyfA) in children 1year following the publication of the first edition of the clinical practice guidelines for the diagnosis and management of AOM in children in Japan. METHODS: PCV7 was launched on the Japanese market in 2010 and gained public funding in 2011. PCV7 was replaced with PCV13 in November 2013. Using the Japan Medical Data Center Claims Database, an 11-year study conducted between January 2005 and December 2015 investigated the decline in the incidence of visits to medical institutions (VtMI) due to all-cause AOM in children <15years. The rate of MyfA from January 2007 to December 2015was also investigated and changes before and after introduction of public funding for PCV7 (pfPCV7) and PCV13 (pfPCV13) for children were examined. Statistical data for the age group between 10 years and <15years served as the control. An analysis was conducted to examine changes for each age group, from infants that had received PCVs to children <5years. Statistical analysis was performed using the chi-square test and Ryan's multiple comparison tests. Ryan's multiple comparison tests were applied at a 5% level of significance. Due to significant changes in the guidelines on the indications for myringotomy introduced in 2013, statistical analysis of the rate of MyfA was limited to the pre- and post-PCV7 period. RESULTS: After introduction of pfPCV7 and pfPCV13, no significant suppression of the incidence of VtMI was observed in any age group. There was a gradual decline in the rate of MyfA after 2011. Compared to the control group, significant differences in all age groups from infants to children <5years were observed (p<0.009, chi-square test). Within 2 years after the introduction of PCV7, a significant decline in the rate of MyfA was observed in 1- and 5-year-olds using Ryan's multiple comparison tests at a 5% level of significance. CONCLUSION: The preventative effect of PCVs on AOM was not established in this study. There was, however, a significant decline in the rate of MyfA among 1- and 5-year-olds. Taking into consideration past studies, PCV7 may play a role in preventing the aggravation of AOM in 1-year-olds. When evaluating the effectiveness of PCVs, measures to evaluate severity may be as important as evaluating disease prevention.

Influence of Pneumococcal Conjugate Vaccine on Acute Otitis Media with Severe Middle Ear Inflammation: A Retrospective Multicenter Study.

The Japanese guidelines for acute otitis media in children recommend classifying acute otitis media by age, manifestations and local findings, and also recommend myringotomy for moderate-grade cases with severe local findings, severe-grade cases, and treatment-resistant cases. The heptavalent pneumococcal conjugate vaccine was released in Japan in February 2010. In Hiroshima City, public funding allowing free inoculation with this vaccine was initiated from January 2011, and the number of vaccinated individuals has since increased dramatically. This study investigated changes in the number of myringotomies performed to treat acute otitis media during the 5-year period from January 2008 to December 2012 at two hospitals and five clinics in the Asa Area of Hiroshima City, Japan. A total of 3,165 myringotomies for acute otitis media were performed. The rate of procedures per child-year performed in <5-year-old children decreased by 29.1% in 2011 and by 25.2% in 2012 compared to the mean rate performed in the 3 years prior to the introduction of public funding. A total of 895 myringotomies were performed for 1-year-old infants. The rate of myringotomies per child-year performed for acute otitis media in 1-year-old infants decreased significantly in the 2 years after the introduction of public funding for heptavalent pneumococcal conjugate vaccine compared to all years before introduction (p<0.000001). Our results suggest a benefit of heptavalent pneumococcal conjugate vaccine for acute otitis media in reducing the financial burden of myringotomy. In addition, this vaccine may help prevent acute otitis media with severe middle ear inflammation in 1-year-old infants.

A case report of a patient in whom antibodies against the 2009 pandemic influenza A/H1N1 virus have been present since June 1999.

A 69-y-old man with a history of hepatitis C since May 1985 and his 6 healthy immediate relatives were examined for hemagglutination inhibition antibodies against 2009 pandemic influenza A/H1N1 virus. This patient had a hemagglutination inhibition antibody titer of 640 against 2009 pandemic influenza A/H1N1 virus in a serum sample collected on July 4, 1999, and the antibody titers fluctuated between 40 and 320 in serum samples collected after 1999. The fluctuations in hemagglutination inhibition antibody titers against pandemic 2009 influenza A/H1N1 virus were not consistent with his history of seasonal influenza, and our results suggest a relationship to his vaccination with seasonal trivalent inactivated influenza vaccine. This patient as well as three relatives showed cross-reactive antibody titers of 10 or more against 2009 pandemic A/H1N1 influenza virus in serum samples taken after June 1999. From these results we conclude that the cross-reactivity to pandemic 2009 A/H1N1 influenza virus emerged after June 1999.

A case of periodic-fever-syndrome-like disorder with lipodystrophy, myositis, and autoimmune abnormalities.

A 24-year-old Japanese woman had been suffering from a periodic fever since 10 months of age. She developed deformities in her fingers, with severe atrophy of subcutaneous adipose tissue, myositis, and frostbitten hands. She showed elevated C-reactive protein, creatine kinase, and gamma-globulin. She was also positive for antinuclear, anti-DNA, anti-SS-B, and anti-U1RNP antibodies. Her myositis was similar to amyopathic dermatomyositis rather than juvenile dermatomyositis. Although consanguineous marriage of her parents and early onset of disease suggested her disease as a hereditary disorder with periodic fever, her clinical feature and laboratory tests were unlike any known periodic fever syndromes. Her disease was regarded as a unique type of periodic-fever-syndrome-like disorder with autoimmune abnormalities.

Five patients with localized facial eruptions associated with Gianotti-Crosti syndrome caused by primary Epstein-Barr virus infection.

Five infants exhibited an exclusively facial rash associated with Gianotti-Crosti syndrome(GCS). On all patient cheeks, multiple erythematous papules were seen symmetrically. All patients tested positive for the immunoglobulin (Ig)M antibody against the Epstein-Barr viral capsid antigen, suggesting that a primary Epstein-Barr virus (EBV) infection caused localized facial rash, an alternative clinical picture of GCS.