Staphylococcus aureus nasal colonization increases the risk of cedar pollinosis.

Background: One-third of the people in Japan are colonized with Staphylococcus aureus (S. aureus) and suffer from virulence factor-mediated subclinical inflammation of the nares. We investigated whether subclinical inflammation contributed to cedar pollinosis affecting 20 million people annually. Methods: The study participants were 814 inhabitants of the A or B prefectures. We compared the colonization rate and population structure of S. aureus, in association with the prevalence of cedar pollinosis, between participants in these two areas. Results: A prefecture had twice the annual amount of airborne cedar pollen compared with B. The prevalence of cedar pollinosis was significantly higher in A (23.5%) than in B (13.1%) (p = 0.0004). Moreover, the prevalence of cedar pollinosis was higher in female participants (23.3%) than in male participants (14.7%) (p = 0.003). In addition, the prevalence of cedar pollinosis was higher in S. aureus carriers (24.2%) than in S. aureus noncarriers (17.9%) (p = 0.03). The isolation rate of clonal complex (CC) 508 was higher in the A group (21%) than in the B group (7%) (p = 0.015). Conclusion: Nasal colonization of S. aureus is a major risk factor for cedar pollinosis. However, the direct mechanism of this risk is currently unknown.

Validation of the "My Headache Checker" that includes osmophobia in the diagnosis of migraine.

BACKGROUND: Migraine is a common headache disorder, with a 1 year prevalence rate of 6.0 %. However, less than 10% of patients with migraine receive medication in hospital. "My Headache Checker," a brief and self-administered migraine screening tool, which includes osmophobia in addition to the ID-Migraine™ three-item subset, was developed. The objective of this study was to analyze the applicability of "My Headache Checker" in Japanese patients. METHODS: A total of 238 patients visiting the outpatient department were enrolled in the study. The patients' chief complaint was not headache. "My Headache Checker" was administered to the patients. Subsequently, they were evaluated by a generalist for the diagnosis of headache. The clinical diagnosis of headache was determined based on the International Classification of Headache Disorders Ⅲ. RESULTS: Twenty (8.4%) patients satisfied the criteria for the diagnosis of migraine. Sensitivity, specificity, positive predictive value, and negative predictive value of "My Headache Checker" were 0.90, 0.83, 0.69, and 0.95, respectively. Sensitivity, specificity, positive predictive value, and negative predictive value of the ID-Migraine™ were 0.90, 0.85, 0.72, and 0.95, respectively. CONCLUSION: The majority of migraine patients are missed in busy outpatient departments. Our results suggest that "My Headache Checker" is a useful tool in diagnosing unrecognized migraine patients. However, the addition of osmophobia did not contribute to improve the screening power of the ID-Migraine™.

End-of-season outbreaks of nosocomial influenza caused by waning vaccine immunity.

The waning of vaccine protection may be responsible for outbreaks toward the end of the influenza season. Three of five outbreaks occurred at the beginning of April following an interval of >100 days from the date of vaccination; the reported index case was a nurse or office worker, and >50% of those affected were healthcare workers. The results are consistent with intra-seasonal waning of vaccine immunity that resulted in outbreaks at the end of season.

Impact of repeated yearly vaccination on immune responses to influenza vaccine in an elderly population.

BACKGROUND: The effectiveness of repeated vaccination for seasonal influenza remains controversial. Here, we measured antibody responses to the influenza virus (A/H1N1, A/H3N2 and B) in a closed cohort of older participants vaccinated against influenza virus in each of 5 consecutive years. METHODS: One hundred and 11 volunteers aged >61 years were vaccinated subcutaneously with 1 dose (0.5 ml) of inactivated influenza vaccine as recommended by the World Health Organization from the 2005-2006 season through the 2009-2010 season. Hemagglutination inhibition (HI) antibody titers were determined. RESULTS: HI antibody titers against all 3 virus strains were significantly higher at 4 weeks after vaccination than at a time point prior to vaccination in each of the 5 seasons (P < .01); HI antibody titers were detected at the original prevaccination levels just prior to re-vaccination the following year. Sero-protection and HI antibody titers at 4 weeks after vaccination were similar against all influenza strains and during most of the 5 seasons evaluated. Vaccine strain changes were associated with specific immune responses in 9 of 12 (75%) intervals. CONCLUSIONS: Taken together, our results suggest that annual vaccination is necessary to maintain humoral immunity for the elderly population. Furthermore, our findings revealed that annual seasonal vaccination was not associated with reduced vaccine effectiveness, and that the reformation of the vaccine resulted in amplified immune responses among those undergoing yearly vaccination in the elderly population.

Consecutive hypoglycemia attacks induced by co-trimoxazole followed by pentamidine in a patient with acquired immunodeficiency syndrome.

Both co-trimoxazole and pentamidine are used for the treatment of pneumocystis pneumonia (PCP) and are known to cause hypoglycemia as an adverse drug reaction. Here, we describe a rare case of a late-diagnosed female patient with acquired immunodeficiency syndrome (AIDS) who developed the first hypoglycemic attack as an adverse effect of co-trimoxazole, followed by a second hypoglycemic attack as an adverse effect of pentamidine. Physicians caring for patients with AIDS and PCP should be aware of possible hypoglycemia in patients with many risk factors.

Prevalence and characteristics of methicillin-resistant Staphylococcus aureus colonization among healthcare professionals in a university hospital in Japan.

BACKGROUND: Asymptomatic carriers of methicillin-resistant Staphylococcus aureus (MRSA) are important sources of nosocomial transmission. MRSA may be transmitted from hospitalized patients to healthcare professionals and vice versa. METHODS: The prevalence of MRSA colonization among forty-five healthcare professionals in a Japanese hospital was determined by performing surveillance cultures to identify unrecognized carriers of MRSA. All MRSA isolates were evaluated using multilocus sequence typing (MLST) to identify the transmission routes. RESULTS: The proportion of MRSA colonization was significantly higher in healthcare professionals (11.1%) than in community residents (0.72%; P < 0.0001) or admission case (2.5%; P = 0.018). MLST analysis revealed that both the ST8 and ST764 strains were identified in residents, patients, and healthcare professionals. MRSA colonization was more frequently observed among physicians (4/13; 31%) than nurses (1/32; 3%) (P = 0.020). CONCLUSION: Multilocus sequence typing results suggest that ST8 and ST764 are involved in the occurrence of nosocomial MRSA infections. These findings emphasize the necessity for the effective education of physicians to prevent MRSA transmissions.

Large abscess formed in the abdominal wall by Mycobacterium avium complex: A case of unmasking immune reconstitution inflammatory syndrome.

Immune reconstitution inflammatory syndrome (IRIS) is a clinical entity with a broad presentation that is complicated in patients with acquired immunodeficiency syndrome after initiating antiretroviral therapy. A 51-year-old Japanese man was diagnosed with disseminated Mycobacterium avium complex (MAC) infection presenting as unmasking IRIS, which formed a large abscess in the patient's abdominal wall. MAC-IRIS commonly involves the lymph nodes, bone marrow, and gastrointestinal tract. To our knowledge, this is the first case report of an abdominal wall abscess caused by MAC-IRIS.

Transmission of methicillin-resistant Staphylococcus aureus in an acute care hospital in Japan.

BACKGROUND: Asymptomatic carriers of methicillin-resistant Staphylococcus aureus (MRSA) are important sources of nosocomial transmission. However, the route of transmission of MRSA is not completely understood. The purpose of this study was to calculate MRSA transmission rates in a hospital with a high MRSA infection/colonization density and inadequate hand hygiene compliance. METHODS: The prevalence of MRSA colonization among 157 patients at the time of admission to and discharge from a medical school hospital in Japan was determined by performing surveillance cultures. All MRSA isolates were evaluated using multilocus sequence typing (MLST) to identify the transmission routes. RESULTS: Methicillin-resistant S. aureus was prevalent in 1.9% of our study population. MRSA was acquired during hospitalization at a rate of 4.0/1000 patient-days. At discharge, 5.1% of the patients exhibited MRSA colonization; this was significantly higher than the prevalence noted upon admission (P < 0.001). MLST documented three possible nosocomial transmission events. MRSA colonization was detected using surveillance cultures prior to being identified by conventional, clinically oriented examinations. CONCLUSIONS: Multilocus sequence typing results suggested that patients who were colonized with MRSA acquired it during hospitalization. These results reinforce the importance of infection control for preventing nosocomial MRSA transmission in hospitalized patients.

MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells.

This study explored the effect of MS-275, a novel histone deacetylase inhibitor (HDACI), against a variety of human leukemia cells with defined genetic alterations. MS-275 profoundly induced growth arrest of acute myelogenous leukemia (AML) MOLM13 and biphenotypic leukemia MV4-11 cells, which possess internal tandem duplication mutation in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD), with IC50s less than 1 microM, as measured by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay on day two of culture. Exposure of these cells to MS-275 decreased levels of total, as well as, phosphorylated forms of FLT3, resulting in inactivation of its downstream signal pathways, including Akt, ERK, and STAT5. Further studies found that MS-275 induced acetylation of heat shock protein 90 (HSP90) in conjunction with ubiquitination of FLT3, leading to degradation of FLT3 proteins in these cells. This was blunted by treatment with the proteasome inhibitor bortezomib, confirming that FLT was degraded via ubiquitin/proteasome pathway. Moreover, we found that further inhibition of MEK/ERK signaling potentiated the action of MS-275 in leukemia cells. Taken together, MS-275 may be useful for treatment of individuals with leukemia possessing activating mutation of FLT3 gene.

Sequential occurrence of Graves' disease and immune thrombocytopenic purpura as manifestations of immune reconstitution inflammatory syndrome in an HIV-infected patient.

Immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients after initiating antiretroviral therapy usually involves worsening manifestations of overt infectious disease. Here, we describe a sporadic case of a late-diagnosed HIV-positive man who developed Graves' disease as the first noninfectious IRIS followed by immune thrombocytopenic purpura as the second noninfectious IRIS.

Booster influenza vaccination confers additional immune responses in an elderly, rural community-dwelling population.

This study aimed to examine the effects of a booster vaccination in elderly people using 2 doses of trivalent inactivated influenza vaccine during the 2012-2013 influenza epidemic. Seroprotection rates against the A(H1N1)pdm09 strain in younger elderly people (aged 61-75 years) and the A(H3N2) and B strains in both younger elderly people (aged 61-75 years) as well as very elderly people (aged 76-102 years) did not decrease at 22 weeks after vaccination. This approach confers long-lasting antibody responses and may be useful in clinical practice.

Prevalence and characteristics of methicillin-resistant Staphylococcus aureus in community residents of Japan.

BACKGROUND: To implement effective precautions to avoid methicillin-resistant Staphylococcus aureus (MRSA) nosocomial infections, it is important to clarify when, how, and from whom MRSA was transmitted to the patients. However, MRSA strains obtained from outpatient population were not analyzed, and the transmission routes of MRSA in the community are not completely understood. The purpose of this study was to clarify whether MRSA is spreading in community settings or whether MRSA transmission still occurs only in healthcare institutions. METHODS: Surveillance cultures of 1274 residents living in a community were performed in two different areas, Kochi and Osaka prefectures of Japan. All isolated MRSA strains were evaluated using multilocus sequence typing (MLST) to clarify the transmission routes of MRSA. The results were compared with those of inpatients. Moreover, written questionnaires and medical records were analyzed. RESULTS: Analysis of surveillance cultures from residents living in the community in Japan revealed an MRSA colonization rate of 0.94%. The proportion of MRSA to S. aureus colonization was 2.6% in the 310 residents, which was significantly lower than in the 393 hospitalized patients (63.1%; P < .0001). MRSA strains in residents are different from the endemic strains in the hospitalized patients. Previous hospital admission is a risk factor for MRSA infection of the endemic strain in hospital. CONCLUSIONS: Methicillin-resistant Staphylococcus aureus colonization in community setting is rare in Japan. MLST results suggest that some MRSA strains are moving to the community through previous hospital admissions; however, MRSA is not spreading in community settings.

HIV-1 protease inhibitor ritonavir potentiates the effect of 1,25-dihydroxyvitamin D3 to induce growth arrest and differentiation of human myeloid leukemia cells via down-regulation of CYP24.

HIV-1 protease inhibitor, ritonavir (RTV) is a potent inhibitor of cytochrome p450 (CYPs) enzymes. This study explored the effects of RTV on CYP24 which converts 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] to its inactive form 1,24,25,(OH)(3). Real-time RT-PCR showed that exposure of HL-60 cells to 1,25(OH)(2)D(3) induced expression of CYP24, and pre-incubation of these cells with RTV decreased this transcripts, resulting in increased intracellular levels of 1,25(OH)(2)D(3) and potentiation of the ability of 1,25(OH)(2)D(3) to induce growth arrest and differentiation of these cells. Taken together, inhibition of CYP24 might open a new paradigm for therapy using Vitamin D compounds.

Aberrant methylation in promoter-associated CpG islands of multiple genes in acute lymphoblastic leukemia.

Methylation profile was analyzed in 10 childhood acute lymphoblastic leukemia (ALL) and nine adult ALL cases. Four genes (p15, p16, RARbeta, FHIT) had methylation in both diseases, four genes (p14, Rb, MLH1, DAPK) showed no methylation in both diseases, and the two genes (APC, RIZ) demonstrated methylation only in adult ALL. Methylation of the RARbeta was more frequent in adult ALL than that in childhood ALL (p=0.01). The number of patients with methylation of multiple genes was higher in adult ALL than that in childhood ALL (p=0.006). Moreover, overall frequency of methylation was higher in adult ALL than that in childhood ALL (p=0.01).

SAHA, a HDAC inhibitor, has profound anti-growth activity against non-small cell lung cancer cells.

Current chemotherapy of advanced non-small cell lung cancer (NSCLC) produces only a modest increase in survival time. New approaches are needed for this disease. The development of lung cancer is associated with silencing tumor suppressor genes that can occur not only by deletion or mutation, but also by epigenetic changes including histone deacetylation of key lysines. Histone deacetylase inhibitor (HDACI) increases histone acetylation, resulting in DNA with a more open chromatin that favors transcription. We found that the HDACI, suberoylanilide hydroxamic acid (SAHA), suppressed cell growth of five non-small cell lung cancer cell lines in a dose-dependent manner (50% growth inhibition approximately 2 microM). Cell cycle assay by fluorescence-activated cell sorting (FACS) demonstrated that SAHA induced a significant G0-G1 growth arrest of NSCLC cells. Protein assay by Western blot analysis showed that SAHA induced expression of p21WAF1. These results demonstrated that administration of SAHA may be a novel approach to the treatment of non-small cell lung cancer.

Continued direct observation and feedback of hand hygiene adherence can result in long-term improvement.

BACKGROUND: Hospital-wide multifaceted approaches can improve hand hygiene compliance in health care workers. However, the true effects of monitoring and feedback interventions are not clear. METHODS: Hand hygiene compliance was evaluated by applying direct observation techniques over 5 years (2005-2009) in a tertiary care general hospital in Japan. The observed results were periodically reported as feedback to the health care workers. RESULTS: The overall hand hygiene compliance rate increased from 50.8% in 2005 to 61.0% in 2006 (P = .004) and was sustained at approximately 60% through the completion of the study. The compliance rate for the indication before entering the room increased from 2005 to 2009 (P = .005). The compliance rates for 4 before patient contact indications increased from 2005 to 2009 (P = .002). The combined compliance rate for the 6 indications with the lowest compliance rates in 2005 increased from 2005 to 2009 (P = .001). CONCLUSIONS: Direct observation and feedback methods are effective strategies that resulted in a long-lasting improvement in hand hygiene compliance that was sustained over 5 years through the completion of the study. Focusing on the procedures with high baseline noncompliance rates can be an effective way to improve the overall compliance.

Allelotype analysis in relapsed childhood acute lymphoblastic leukemia.

We performed for the first time the allelotype of relapsed childhood acute lymphoblastic leukemia (ALL). A total of 38 cases were screened for loss of heterozygosity (LOH) using 71 markers. In all, 26 (68%) patients showed LOH on at least one chromosomal arm, indicating that LOH is a frequent event at relapse. The most frequent loss was found on chromosomal arm 9p at the p16/INK4a locus (39%). LOH at the TEL gene locus on chromosomal arm 12p also occurred often (25%). Frequent loss was observed on chromosome arms 4q (20%), 6q (21%), and 17q (20%). Sequential analysis (i.e. samples obtained from both initial diagnosis and relapse) shows that some patients (63%) have the identical LOH status at both phases, suggesting the presence of the same clone. Other samples (37%) showed distinct LOH alterations, indicating clonal evolution at relapse. Despite the heterogeneous and complex changes, some shared LOH loci occurred in these matched samples, suggesting that many of the same tumor-suppressor genes are aberrant at both phases. In summary, novel tumor-suppressor genes on chromosome arms 4q, 6q, and 17q, as well as the p16 and TEL genes, have an important role in the relapse of childhood ALL.

Methylation analysis of the adenomatous polyposis coli (APC) gene in adult T-cell leukemia/lymphoma.

We investigated methylation status of the adenomatous polyposis coli (APC) gene in adult T-cell leukemia/lymphoma (ATL). APC methylation was found in 15 of 31 (48%) primary samples, and 2 of 4 (50%) ATL cell lines. Methylation of the APC gene occurred more frequently in acute ATL (12/21) (57%) than chronic ATL (1/8) (13%) (P = 0.03). APC was not expressed in the APC-methylated ATL cell line ST1. Demethylation with 5-azacytidine treatment restored APC expression in the ST1 cell line. Our data show that hypermethylation of the APC gene is involved in the pathogenesis of ATL.

Methylation of the MLH1 gene in hematological malignancies.

Hypermethylation of the MLH1 gene has been described in many kinds of human cancers with microsatellite instability (MSI). However, it is not clear whether the same mechanism occurs in hematological malignancies. Genomic DNA was extracted from 31 patients with adult T-cell leukemia/lymphoma (ATL), 9 patients with acute lymphoblastic leukemia (ALL) who had MSI, and 12 leukemia and lymphoma cell lines with MSI. Aberrant methylation of the MLH1 gene was found in 2/31 (6%) ATL patients, and in 1/12 (8%) cell lines with MSI. MLH1 promoter was not methylated in either of the twelve peripheral blood samples from normal individuals or ALL samples. The MLH1 gene was expressed in the normal peripheral blood samples, but not in the MLH1-methylated cell line KCL22. Demethylation with 5-Azacytidine treatment restored MLH1 expression in the KCL22 cell line. Methylation of the MSH2 gene was not found in any of the samples. Our data show that hypermethylation of the MLH1 gene is occasionally involved in the pathogenesis of hematological malignancies, but is not always associated with MSI.

Loss of genomic imprinting of insulin-like growth factor 2 is strongly associated with cellular proliferation in normal hematopoietic cells.

OBJECTIVE: The human insulin-like growth factor 2 (IGF2) gene was thought to be imprinted and expressed only from the paternal allele in normal tissue. MATERIALS AND METHODS: Initially, we analyzed the imprinting status of IGF2 in bone marrow cells from 49 patients with myelodysplastic syndromes (MDS) utilizing the Apa I polymorphism of IGF2. Thirteen bone marrow and 14 peripheral blood samples from normal individuals served as controls. We utilized normal peripheral blood T lymphocytes to examine the relationship between genomic imprinting and cell proliferation. Expression of IGF2 was quantified by real-time PCR and proliferation of T cells was measured by 3H-thymidine incorporation. Furthermore, methylation status of the imprinting controlling region (ICR) was analyzed by subcloning and sequencing of genomic DNA after sodium bisulfite modification. RESULTS: Among 24 patients who were heterozygous for IGF2, loss of imprinting (LOI) occurred in 22 cases (92%). Surprisingly, LOI of IGF2 occurred in the normal bone marrow cells, but the normal peripheral blood cells showed retention of imprinting (ROI). Unstimulated normal T cells showed ROI. After 24 hours of exposure to PHA, these cells changed their IGF2 imprinting status from ROI to LOI. Concomitantly, their IGF2 RNA levels increased up to sixfold and their proliferation increased 10- to 20-fold. In contrast, normal T cells not stimulated with PHA did not develop LOI of IGF2, had negligible levels of IGF2 RNA, and did not increase their proliferation. In unstimulated T cells, the CpG islands of the ICR were completely methylated on one allele and nearly completely unmethylated on the other allele. After PHA stimulation, the CpG islands at the ICR became completely methylated on both alleles. CONCLUSION: LOI of IGF2 is strongly associated with cell proliferation and is not limited to cancer cells.