Thymic Alterations in GM2 Gangliosidoses Model Mice

BACKGROUND: Sandhoff disease is a lysosomal storage disorder characterized by the absence of β-hexosaminidase and storage of GM2 ganglioside and related glycolipids. We have previously found that the progressive neurologic disease induced in Hexb(-/-) mice, an animal model for Sandhoff disease, is associated with the production of pathogenic anti-glycolipid autoantibodies. METHODOLOGY/PRINCIPAL FINDINGS: In our current study, we report on the alterations in the thymus during the development of mild to severe progressive neurologic disease. The thymus from Hexb(-/-) mice of greater than 15 weeks of age showed a marked decrease in the percentage of immature CD4(+)/CD8(+) T cells and a significantly increased number of CD4(+)/CD8(-) T cells. During involution, the levels of both apoptotic thymic cells and IgG deposits to T cells were found to have increased, whilst swollen macrophages were prominently observed, particularly in the cortex. We employed cDNA microarray analysis to monitor gene expression during the involution process and found that genes associated with the immune responses were upregulated, particularly those expressed in macrophages. CXCL13 was one of these upregulated genes and is expressed specifically in the thymus. B1 cells were also found to have increased in the thy mus. It is significant that these alterations in the thymus were reduced in FcRγ additionally disrupted Hexb(-/-) mice. CONCLUSIONS/SIGNIFICANCE: These results suggest that the FcRγ chain may render the usually poorly immunogenic thymus into an organ prone to autoimmune responses, including the chemotaxis of B1 cells toward CXCL13

Bloodstream infections in the elderly Japanese population : current reality and countermeasures

Abstract: We reviewed bloodstream infections in the elderly in Japan, referring to data recently reported from the National Center for Global Health and Medicine in Tokyo. We divided the locations of bloodstream infections into Hospital-onset (HO), healthcare-associated (HCA), and CA (community-acquired), as the elderly reside in different places. The study focused on the fact that the general condition and underlying diseases of the elderly differ by age group. And thus, we divided them into three groups: Pre-old (65-74 years), Old (75-89 years), and Super-old (>= 90 years), and compared their characteristics of bloodstream infections. HO bacteremia was most common in the preold group. On the other hand, HCA bloodstream infections tended to increase as the population aged, and it was most prevalent in super-old group. According to the study results, early intervention through infectious diseases (ID) consultation may improve the prognosis of bloodstream infections even in the elderly. Since the rate of ID consultation is lower in the super-old group than in other groups, this group may be a significant target. In conclusion, a study of a cohort of elderly patients with bloodstream infections in Japan indicates that bloodstream infections in patients over 65 years is not uniform

Clinical determinants of the severity of Middle East respiratory syndrome (MERS): a systematic review and meta-analysis

Abstract Background While the risk of severe complications of Middle East respiratory syndrome (MERS) and its determinants have been explored in previous studies, a systematic analysis of published articles with different designs and populations has yet to be conducted. The present study aimed to systematically review the risk of death associated with MERS as well as risk factors for associated complications. Methods PubMed and Web of Science databases were searched for clinical and epidemiological studies on confirmed cases of MERS. Eligible articles reported clinical outcomes, especially severe complications or death associated with MERS. Risks of admission to intensive care unit (ICU), mechanical ventilation and death were estimated. Subsequently, potential associations between MERS-associated death and age, sex, underlying medical conditions and study design were explored. Results A total of 25 eligible articles were identified. The case fatality risk ranged from 14.5 to 100%, with the pooled estimate at 39.1%. The risks of ICU admission and mechanical ventilation ranged from 44.4 to 100% and from 25.0 to 100%, with pooled estimates at 78.2 and 73.0%, respectively. These risks showed a substantial heterogeneity among the identified studies, and appeared to be the highest in case studies focusing on ICU cases. We identified older age, male sex and underlying medical conditions, including diabetes mellitus, renal disease, respiratory disease, heart disease and hypertension, as clinical predictors of death associated with MERS. In ICU case studies, the expected odds ratios (OR) of death among patients with underlying heart disease or renal disease to patients without such comorbidities were 0.6 (95% Confidence Interval (CI): 0.1, 4.3) and 0.6 (95% CI: 0.0, 2.1), respectively, while the ORs were 3.8 (95% CI: 3.4, 4.2) and 2.4 (95% CI: 2.0, 2.9), respectively, in studies with other types of designs. Conclusions The heterogeneity for the risk of death and severe manifestations was substantially high among the studies, and varying study designs was one of the underlying reasons for this heterogeneity. A statistical estimation of the risk of MERS death and identification of risk factors must be conducted, particularly considering the study design and potential biases associated with case detection and diagnosis

The impact of infectious disease consultation in candidemia in a tertiary care hospital in Japan over 12 years.

BackgroundCandidemia is one of the major causes of morbidity and mortality as a hospital acquired infection. Infectious diseases consultation (IDC) might be beneficial to improve candidemia outcomes; however, only limited data from short periods of time are available thus far.MethodsAn observational study of all candidemia patients at a large tertiary care hospital between 2002 and 2013 was conducted. A candidemia episode was defined as ≥ 1 positive result for Candida spp. in blood culture. Patients who died or transferred to another hospital within two days after their first positive blood culture were excluded. Independent risk factors for 30-day mortality were determined.ResultsAmong 275 patients with 283 episodes of candidemia, 194 (68.6%) were male, and the mean age was 70.0 ± 15.8 years. Central line-associated bloodstream infections, peripheral line-associated bloodstream infections, intra-abdominal infection, and unknown source comprised 220 (77.7%), 35 (12.4%), 13 (4.7%), and 15 (5.3%) episodes, respectively. A total of 126 patients (44.5%) received IDC. Factors independently associated with 30-day mortality in patients with candidemia were urinary catheters use (adjusted hazard ratio [HR] = 2.94; 95% confidence interval [CI] = 1.48-5.87; P = 0.002) and severe sepsis/septic shock (adjusted HR = 2.10; 95% CI = 1.20-3.65; P = 0.009). IDC was associated with a 46% reduction in 30-day mortality (adjusted HR = 0.54; 95% CI = 0.32-0.90; P = 0.017).ConclusionIDC was independently associated with a reduction in 30-day mortality. Only 44.5% of patients with candidemia in this cohort received IDC. Routine IDC should be actively considered for patients with candidemia

Epidemiology of Blood Stream Infection due to Candida Species in a Tertiary Care Hospital in Japan over 12 Years: Importance of Peripheral Line-Associated Candidemia.

Candidemia is an important cause of mortality in healthcare settings. Peripheral lines are a source of candidemia, yet few studies have reported on the clinico-epidemiological features of candidemia due to peripheral-line associated blood stream infection (PLABSI).We conducted a single-centre retrospective cohort study of all patients with candidemia between 2002 and 2013. PLABSI was defined as the presence of at least one of the following: the presence of phlebitis or the resolution of clinical symptoms after peripheral-line withdrawal, with careful exclusion of an alternative explanation for bacteraemia. We described the epidemiology of candidemia and assessed predictive factors of PLABSI due to Candida spp., peripheral line-associated candidemia (PLAC), compared with non-PLAC.A total of 301 episodes of candidemia, including 37 of PLAC, were diagnosed during the study period. Central-line associated blood stream infection, intra-abdominal infection, and infection of unknown source accounted for the remaining 233, 14, and 17 cases, respectively. The overall incidence rate of candidemia was 0.11/1000 patient-days. In multivariate analysis, cephalosporin exposure (odds ratio [OR] = 2.22, 95% CI 1.04-4.77), polymicrobial bacteraemia/fungaemia (OR = 2.87, 95% CI 1.02-8.10), and ID specialist consultation (OR = 2.40, 95% CI 1.13-5.13) were identified as independent predictors of PLAC. Although non-PLAC had a higher mortality, the length of hospital stay after candidemia was similar between the two groups and candidemia duration was longer in the PLAC group.PLACs are an important cause of candidemia in hospitalized patients. Appropriate identification and management of PLAC are crucial