The Gut Microbiome of Adults with Allergic Rhinitis Is Characterised by Reduced Diversity and an Altered Abundance of Key Microbial Taxa Compared to Controls.

INTRODUCTION: Unique gut microbial colonisation patterns are associated with the onset of allergic disease in infants; however, there is insufficient evidence to determine if aberrant microbial composition patterns persist in adult allergic rhinitis (AR) sufferers. OBJECTIVE: To compare the gut microbiome composition between adult AR sufferers and controls. METHODS: Gut microbial composition in stool samples was compared between 57 adult AR sufferers (39.06 ± 13.29 years) and 23 controls (CG; 36.55 ± 10.51 years) via next-generation sequencing of the V3-V4 hypervariable regions of the 16S rRNA gene. Taxonomic classification and identity assignment was performed using a reference-based approach with the NCBI database of 16S rRNA gene sequences. RESULTS: Species richness determined via the Shannon index was significantly reduced in the AR cohort compared to the CG (4.35 ± 0.59 in AR vs. 4.65 ± 0.55 in CG, p = 0.037); trends for reductions in operational taxonomic unit (OTU) counts, inverse Simpson, and CHAO1 diversity indices were also noted. Bacteroidetes (p = 0.014) was significantly more abundant in the AR group than in the CG. In contrast, the Firmicutes phylum was significantly less abundant in the AR group than in the CG (p = 0.006). An increased abundance of Parabacteroides (p = 0.008) and a reduced abundance of Oxalobacter (p = 0.001) and Clostridiales (p = 0.005) were also observed in the AR cohort compared to the CG. CONCLUSION: Adult AR sufferers have a distinct gut microbiome profile, marked by a reduced microbial diversity and altered abundance of certain microbes compared to controls. The results of this study provide evidence that unique gut microbial patterns occur in AR sufferers in adulthood and warrant further examination in the form of mechanistic studies.

Key viral immune genes and pathways identify elite athletes with URS.

PURPOSE: Habitual intense exercise may increase the incidence of upper respiratory symptoms (URS) in elite athletes. This study investigated whether immune gene expression could identify gene markers that discriminate athletes with a higher prevalence of URS. METHODS: This cross-sectional analysis of elite Australian athletes from various sports investigated whether athletes retrospectively reporting URS for two days or more in a month (n=38), had an altered immune gene expression profile compared with asymptomatic athletes (n=33). Peripheral blood samples were collected during Olympic selection events with corresponding URS data collected for the one-month period before sampling. Digital immune gene expression analysis was undertaken using the NanoString PanCancer Immune Profiling panel. RESULTS: Fifty immune genes were differentially expressed between the groups (p<0.05) and approximately 78% of these genes were more highly expressed in athletes reporting URS. Many of these genes were interferon-stimulated genes or genes involved in the Jak/Stat signalling pathway. Only interferon alpha inducible protein 27 (IFI27), an interferon stimulated gene involved in viral response, remained significantly higher in athletes reporting URS (log2 fold-difference=2.49, odds ratio 1.02 per unit increase; p<0.01) post-adjustment and discriminated athletes reporting URS from asymptomatic athletes with 78% accuracy. CONCLUSIONS: Expression of IFI27 could differentiate athletes reporting URS from asymptomatic athletes, a gene that is upregulated in the immune response to viral infection. Upregulation of viral signalling pathways provides novel information on the potential aetiology of URS in elite Olympic athletes.

Fucoidan Supplementation Restores Fecal Lysozyme Concentrations in High-Performance Athletes: A Pilot Study.

Nutritional strategies to help promote immune competence are of particular interest for a range of population groups. This study aimed to assess the potential impacts of fucoidan, a seaweed-derived bioactive polysaccharide, on gut markers of immunity and inflammation. A group of professional team-sport athletes were selected for inclusion in the study given the recognized potential for intense physical activity to induce alterations in immune function. A retrospective analysis was performed on stored fecal samples which had been collected from professional team-sport athletes (n = 22) and healthy adults (n = 11) before and after seven days of supplementation with fucoidan (Fucus vesiculosus/Undaria pinnatifida extract, 1 g/d). Fecal concentrations of calprotectin, secretory immunoglobulin A (sIgA) and lysozyme were determined using enzyme-linked immunosorbent assays. The supplement was well tolerated by participants with no adverse events reported. At baseline, fecal lysozyme concentrations were ~73% higher in the healthy adults compared to the professional athletes (p = 0.001). For the professional athletes, a significant (~45%) increase in fecal lysozyme was observed following the supplementation period (p = 0.001). These data suggest that fucoidan supplementation may have the potential to promote the secretion of antimicrobial peptides in specific population groups and contribute to the regulation of mucosal immune health.

A correlation-based network for biomarker discovery in obesity with metabolic syndrome.

BACKGROUND: Obesity is associated with chronic activation of the immune system and an altered gut microbiome, leading to increased risk of chronic disease development. As yet, no biomarker profile has been found to distinguish individuals at greater risk of obesity-related disease. The aim of this study was to explore a correlation-based network approach to identify existing patterns of immune-microbiome interactions in obesity. RESULTS: The current study performed correlation-based network analysis on five different datasets obtained from 11 obese with metabolic syndrome (MetS) and 12 healthy weight men. These datasets included: anthropometric measures, metabolic measures, immune cell abundance, serum cytokine concentration, and gut microbial composition. The obese with MetS group had a denser network (total number of edges, n = 369) compared to the healthy network (n = 299). Within the obese with MetS network, biomarkers from the immune cell abundance group was found to be correlated to biomarkers from all four other datasets. Conversely in the healthy network, immune cell abundance was only correlated with serum cytokine concentration and gut microbial composition. These observations suggest high involvement of immune cells in obese with MetS individuals. There were also three key hubs found among immune cells in the obese with MetS networks involving regulatory T cells, neutrophil and cytotoxic cell abundance. No hubs were present in the healthy network. CONCLUSION: These results suggest a more complex interaction of inflammatory markers in obesity, with high connectivity of immune cells in the obese with MetS network compared to the healthy network. Three key hubs were identified in the obese with MetS network, involving Treg, neutrophils and cytotoxic cell abundance. Compared to a t-test, the network approach offered more meaningful results when comparing obese with MetS and healthy weight individuals, demonstrating its superiority in exploratory analysis.

Selection of microbial biomarkers with genetic algorithm and principal component analysis.

BACKGROUND: Principal components analysis (PCA) is often used to find characteristic patterns associated with certain diseases by reducing variable numbers before a predictive model is built, particularly when some variables are correlated. Usually, the first two or three components from PCA are used to determine whether individuals can be clustered into two classification groups based on pre-determined criteria: control and disease group. However, a combination of other components may exist which better distinguish diseased individuals from healthy controls. Genetic algorithms (GAs) can be useful and efficient for searching the best combination of variables to build a prediction model. This study aimed to develop a prediction model that combines PCA and a genetic algorithm (GA) for identifying sets of bacterial species associated with obesity and metabolic syndrome (Mets). RESULTS: The prediction models built using the combination of principal components (PCs) selected by GA were compared to the models built using the top PCs that explained the most variance in the sample and to models built with selected original variables. The advantages of combining PCA with GA were demonstrated. CONCLUSIONS: The proposed algorithm overcomes the limitation of PCA for data analysis. It offers a new way to build prediction models that may improve the prediction accuracy. The variables included in the PCs that were selected by GA can be combined with flexibility for potential clinical applications. The algorithm can be useful for many biological studies where high dimensional data are collected with highly correlated variables.

Paediatric and adult bronchiectasis: Vaccination in prevention and management.

Bronchiectasis has received increased attention recently, including an emphasis on preventing infective exacerbations that are associated with disease progression and lung function decline. While there are several bacteria and viruses associated with bronchiectasis, licensed vaccines are only currently available for Streptococcus pneumoniae, Haemophilus influenzae (H. influenzae protein D as a conjugate in a pneumococcal vaccine), Mycobacterium tuberculosis, Bordetella pertussis and influenza virus. The evidence for the efficacy and effectiveness of these vaccines in both preventing and managing bronchiectasis in children and adults is limited with the focus of most research being on other chronic lung disorders, such as chronic obstructive pulmonary diseases, asthma and cystic fibrosis. We review the existing evidence for these vaccines in bronchiectasis and highlight the existing gaps in knowledge. High-quality experimental and non-experimental studies using current state-of-the-art microbiological methods and validated, standardised case definitions are needed across the depth and breadth of the vaccine development pathway.

Recovery of Lactobacillus casei strain Shirota (LcS) from faeces with 14 days of fermented milk supplementation in healthy Australian adults.

BACKGROUND AND OBJECTIVES: A key measure for classifying bacteria as a probiotic is the ability to survive gastric transport and be recoverable in faeces. The aim of this study was to determine whether Lactobacillus casei strain Shirota (LcS) could be recovered in the faeces of healthy young Australian adults following ingestion of a fermented milk drink. METHODS AND STUDY DESIGN: A cohort of 25 healthy individuals (male/female: 14/11; age: 29.3±6.6 years; BMI: 25.3±2.7 kg/m2, mean±SD) ingested one 65 ml bottle of fermented milk containing 6.5×109 LcS live cells daily for 14 days. Participants provided a faecal sample at day 0, day 7 (mid-supplementation), day 14 (end of supplementation) and 14 days after cessation of the supplement (day 28) for assessment of the number of viable LcS via microbial culture on selective media with confirmation using a colony-direct polymerase chain reaction and species-specific primers. RESULTS: The supplement was well tolerated by participants. No LcS colonies were recovered from participants prior to ingestion of the fermented milk drink. All participants had recoverable LcS colonies at day 7 and day 14, with a mean recovery of 6.5±1.1 and 6.4±1.1 log10 CFU/g of faeces (mean±SD) at each time point respectively. LcS was detectable in only one sample at 14 days following the cessation of supplementation. CONCLUSIONS: Live LcS is recoverable in faeces from healthy Australian adults following daily ingestion of a fermented milk drink.

Nontypeable Haemophilus influenzae and chronic obstructive pulmonary disease: a review for clinicians.

Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of morbidity and mortality worldwide. In the lower airways of COPD patients, bacterial infection is a common phenomenon and Haemophilus influenzae is the most commonly identified bacteria. Haemophilus influenzae is divided into typeable and nontypeable (NTHi) strains based on the presence or absence of a polysaccharide capsule. While NTHi is a common commensal in the human nasopharynx, it is associated with considerable inflammation when it is present in the lower airways of COPD patients, resulting in morbidity due to worsening symptoms and increased frequency of COPD exacerbations. Treatment of lower airway NTHi infection with antibiotics, though successful in the short term, does not offer long-term protection against reinfection, nor does it change the course of the disease. Hence, there has been much interest in the development of an effective NTHi vaccine. This review will summarize the current literature concerning the role of NTHi infections in COPD patients and the consequences of using prophylactic antibiotics in patients with COPD. There is particular focus on the rationale, findings of clinical studies and possible future directions of NTHi vaccines in patients with COPD.

Distinct Gene Expression Patterns between Nasal Mucosal Cells and Blood Collected from Allergic Rhinitis Sufferers.

BACKGROUND: Investigations of gene expression in allergic rhinitis (AR) typically rely on invasive nasal biopsies (site of inflammation) or blood samples (systemic immunity) to obtain sufficient genetic material for analysis. New methodologies to circumvent the need for invasive sample collection offer promise to further the understanding of local immune mechanisms relevant in AR. METHODS: A within-subject design was employed to compare immune gene expression profiles obtained from nasal washing/brushing and whole blood samples collected during peak pollen season. Twelve adults (age: 46.3 ± 12.3 years) with more than a 2-year history of AR and a confirmed grass pollen allergy participated in the study. Gene expression analysis was performed using a panel of 760 immune genes with the NanoString nCounter platform on nasal lavage/brushing cell lysates and compared to RNA extracted from blood. RESULTS: A total of 355 genes were significantly differentially expressed between sample types (9.87 to -9.71 log2 fold change). The top 3 genes significantly upregulated in nasal lysate samples were Mucin 1 (MUC1), Tight Junction Protein 1 (TJP1), and Lipocalin-2 (LCN2). The top 3 genes significantly upregulated in blood samples were cluster of differentiation 3e (CD3E), FYN Proto-Oncogene Src Family Tyrosine Kinase (FYN) and cluster of differentiation 3d (CD3D). CONCLUSIONS: Overall, the blood and nasal lavage samples showed vastly distinct gene expression profiles and functional gene pathways which reflect their anatomical and functional origins. Evaluating immune gene expression of the nasal mucosa in addition to blood samples may be beneficial in understanding AR pathophysiology and response to allergen challenge.

Enteroendocrine and adipokine associations with type 2 diabetes: Phenotypic risk scoring approaches.

BACKGROUND AND AIM: The contribution of gut-derived factors to the mechanisms linking obesity and metabolic disease remains under-investigated. The aim of the current study was to examine the associations between glucagon and enteroendocrine signaling and type 2 diabetes (T2D) using a derived risk score approach. To compare the relative importance of the enteroendocrine system, associations between adipokine measures and T2D were also investigated. METHODS: A total of 130 individuals with T2D and 161 individuals without T2D were included in the study. Circulating concentrations of enteroendocrine (glucagon, ghrelin, glucagon-like peptide-1, and gastric inhibitory peptide) and adipokine mediators (adiponectin, leptin, resistin, visfatin, and adipsin) were measured. Standard scores (Z-scores) were determined for each measure and enteroendocrine risk scores (ERS) and adipokine risk scores (ARS) calculated based on summation of the component measures. Associations between both the ERS and ARS and T2D status were assessed using logistic regression models. RESULTS: The ERS was significantly associated with T2D status in an adjusted model (odds ratio: 1.36; 95% confidence interval [CI]: 1.08-1.72; P = 0.009). Associations between the ARS and T2D status were not independent of age, sex, and body mass index (odds ratio: 1.21; 95%CI: 0.99-1.47; P = 0.06). Quantification of risk across ERS tertiles revealed that individuals with an ERS in the upper tertile were 10 times more likely (CI: 3.23-32.73; P < 0.001) to have T2D. CONCLUSIONS: These data support an association between enteroendocrine signaling and T2D. Use of the ERS as a potential tool for classifying individuals with metabolic syndrome as high or low risk for T2D development is being considered.

Effect of the Streptococcus agalactiae Virulence Regulator CovR on the Pathogenesis of Urinary Tract Infection.

Background: Streptococcus agalactiae can cause urinary tract infection (UTI). The role of the S. agalactiae global virulence regulator, CovR, in UTI pathogenesis is unknown. Methods: We used murine and human bladder uroepithelial cell models of UTI and S. agalactiae mutants in covR and related factors, including ß-hemolysin/cytolysin (ß-h/c), surface-anchored adhesin HvgA, and capsule to study the role of CovR in UTI. Results: We found that covR-deficient serotype III S. agalactiae 874391 was significantly attenuated for colonization in mice and adhesion to uroepithelial cells. Mice infected with covR-deficient S. agalactiae produced less proinflammatory cytokines than those infected with wild-type 874391. Acute cytotoxicity in uroepithelial cells triggered by covR-deficient but not wild-type 874391 was associated with significant caspase 3 activation. Mechanistically, covR mutation significantly altered the expression of several genes in S. agalactiae 874391 that encode key virulence factors, including ß-h/c and HvgA, but not capsule. Subsequent mutational analyses revealed that HvgA and capsule, but not the ß-h/c, exerted significant effects on colonization of the murine urinary tract in vivo. Conclusions: S. agalactiae CovR promotes bladder infection and inflammation, as well as adhesion to and viability of uroepithelial cells. The pathogenesis of S. agalactiae UTI is complex, multifactorial, and influenced by virulence effects of CovR, HvgA, and capsule.

A role for whey-derived lactoferrin and immunoglobulins in the attenuation of obesity-related inflammation and disease.

Obesity is a strong predictive factor in the development of chronic disease and has now superseded undernutrition as a major public health issue. Chronic inflammation is one mechanism thought to link excess body weight with disease. Increasingly, the gut and its extensive population of commensal microflora are recognized as playing an important role in the development of obesity-related chronic inflammation. Obesity and a high fat diet are associated with altered commensal microbial communities and increased intestinal permeability which contributes to systemic inflammation as a result of the translocation of lipopolysaccharide into the circulation and metabolic endotoxemia. Various milk proteins are showing promise in the prevention and treatment of obesity and chronic low-grade inflammation via reductions in visceral fat, neutralization of bacteria at the mucosa and reduced intestinal permeability. In this review, we focus on evidence supporting the potential antiobesogenic and anti-inflammatory effects of bovine whey-derived lactoferrin and immunoglobulins.

Haemophilus influenzae oral vaccination for preventing acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease.

BACKGROUND: Chronic bronchitis and chronic obstructive pulmonary disease (COPD) are serious conditions in which patients are predisposed to viral and bacterial infections resulting in potentially fatal acute exacerbations. Chronic obstructive pulmonary disease is defined as a lung disease characterised by obstruction to lung airflow that interferes with normal breathing. Antibiotic therapy has not been particularly useful in eradicating bacteria such as non-typeable Haemophilus influenzae (NTHi) because they are naturally occurring flora of the upper respiratory tract in many people. However, they can cause opportunistic infection. An oral NTHi vaccine has been developed to protect against recurrent infective acute exacerbations in chronic bronchitis. OBJECTIVES: To assess the effectiveness of an oral, whole-cell NTHi vaccine in protecting against recurrent episodes of acute exacerbations of chronic bronchitis and COPD in adults. To assess the effectiveness of NTHi vaccine in reducing NTHi colonising the respiratory tract during recurrent episodes of acute exacerbations of COPD. SEARCH METHODS: We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 1), MEDLINE (1946 to January 2017), Embase (1974 to January 2017), CINAHL (1981 to January 2017), LILACS (1985 to January 2017), and Web of Science (1955 to January 2017). We also searched trials registries and contacted authors of trials requesting unpublished data. SELECTION CRITERIA: We included randomised controlled trials comparing the effects of an oral monobacterial NTHi vaccine in adults with recurrent acute exacerbations of chronic bronchitis or COPD when there was overt matching of the vaccine and placebo groups on clinical grounds. The selection criteria considered populations aged less than 65 years and those older than 65 years. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data from original records and publications for incidence and severity of bronchitis episodes and carriage rate of NTHi measured in the upper respiratory tract, as well as data relevant to other primary and secondary outcomes. MAIN RESULTS: We identified six placebo-controlled randomised controlled trials with a total of 557 participants. These trials investigated the efficacy of enteric-coated, killed preparations of H influenzae in populations prone to recurrent acute exacerbations of chronic bronchitis or COPD. The vaccine preparation and immunisation regimen in all trials consisted of at least three courses of formalin-killed H influenzae in enteric-coated tablets taken at intervals (e.g. days 0, 28, and 56). Each course generally consisted of two tablets taken after breakfast over three consecutive days. In all cases the placebo groups took enteric-coated tablets containing glucose. Risk of bias was moderate across the studies, namely due to the lack of information provided about methods and inadequate presentation of results.Meta-analysis of the oral NTHi vaccine showed a small, non-statistically significant reduction in the incidence of acute exacerbations of chronic bronchitis or COPD (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.57 to 1.10; P = 0.16). There was no significant difference in mortality rate between the vaccine and placebo groups (odds ratio (OR) 1.62, 95% CI 0.63 to 4.12; P = 0.31).We were unable to meta-analyse the carriage levels of NTHi in participants as each trial reported this result using different units and tools of measurement. Four trials showed no significant difference in carriage levels, while two trials showed a significant decrease in carriage levels in the vaccinated group compared with the placebo group.Four trials assessed severity of exacerbations measured by requirement for antibiotics. Three of these trials were comparable and when meta-analysed showed a statistically significant 80% increase in antibiotic courses per person in the placebo group (RR 1.81, 95% CI 1.35 to 2.44; P < 0.001). There was no significant difference between the groups with regard to hospital admission rates (OR 0.96, 95% CI 0.13 to 7.04; P = 0.97). Adverse events were reported in five trials but were not necessarily related to the vaccine; a point estimate is suggestive that they occurred more frequently in the vaccine group, however this result was not statistically significant (RR 1.43, 95% CI 0.70 to 2.92; P = 0.87). Quality of life was not meta-analysed but was reported in two trials, with results at six months showing an improvement in quality of life in the vaccinated group (scoring at least two points better than placebo). AUTHORS' CONCLUSIONS: Analyses demonstrate that NTHi oral vaccination of people with recurrent exacerbations of chronic bronchitis or COPD does not yield a significant reduction in the number and severity of exacerbations. Evidence was mixed, and the individual trials that showed a significant benefit of the vaccine are too small to advocate widespread oral vaccination of people with COPD.

Effects of short-term supplementation with bovine lactoferrin and/or immunoglobulins on body mass and metabolic measures: a randomised controlled trial.

Given the role of the intestinal microbiota in obesity and related disease, strategies to modulate the composition of the intestinal microbiota may augment traditional weight-management approaches. Here, we examined the safety and tolerability of 28 days of supplementation with bovine whey-derived lactoferrin and immunoglobulin supplements in a cross-sectional cohort of free-living adults. Participants (n = 20 each group) received enteric-coated whey-derived bovine lactoferrin (200 mg), immunoglobulin (200 mg or 800 mg), combination lactoferrin/immunoglobuiln supplements (200 mg/200 mg, 200 mg/800 mg) or placebo in a double-blind design. Supplement use was generally well tolerated and routine haematology, and clinical chemistry measures were largely unchanged following supplementation. Measures of body composition remained stable and indices of glycaemic control and blood lipids revealed fluctuations of <5% but were not significantly different between groups. Overall, short-term lactoferrin/immunoglobulin supplementation was well tolerated in this cohort; use of these types of supplements to enhance other weight management strategies should be investigated over extended periods.

Discovery and Characterization of Human-Urine Utilization by Asymptomatic-Bacteriuria-Causing Streptococcus agalactiae.

Streptococcus agalactiae causes both symptomatic cystitis and asymptomatic bacteriuria (ABU); however, growth characteristics of S. agalactiae in human urine have not previously been reported. Here, we describe a phenotype of robust growth in human urine observed in ABU-causing S. agalactiae (ABSA) that was not seen among uropathogenic S. agalactiae (UPSA) strains isolated from patients with acute cystitis. In direct competition assays using pooled human urine inoculated with equal numbers of a prototype ABSA strain, designated ABSA 1014, and any one of several UPSA strains, measurement of the percentage of each strain recovered over time showed a markedly superior fitness of ABSA 1014 for urine growth. Comparative phenotype profiling of ABSA 1014 and UPSA strain 807, isolated from a patient with acute cystitis, using metabolic arrays of >2,500 substrates and conditions revealed unique and specific l-malic acid catabolism in ABSA 1014 that was absent in UPSA 807. Whole-genome sequencing also revealed divergence in malic enzyme-encoding genes between the strains predicted to impact the activity of the malate metabolic pathway. Comparative growth assays in urine comparing wild-type ABSA and gene-deficient mutants that were functionally inactivated for the malic enzyme metabolic pathway by targeted disruption of the maeE or maeK gene in ABSA demonstrated attenuated growth of the mutants in normal human urine as well as synthetic human urine containing malic acid. We conclude that some S. agalactiae strains can grow in human urine, and this relates in part to malic acid metabolism, which may affect the persistence or progression of S. agalactiae ABU.

Urinary tract infection of mice to model human disease: Practicalities, implications and limitations.

Urinary tract infections (UTIs) are among the most common bacterial infections in humans. Murine models of human UTI are vital experimental tools that have helped to elucidate UTI pathogenesis and advance knowledge of potential treatment and infection prevention strategies. Fundamentally, several variables are inherent in different murine models, and understanding the limitations of these variables provides an opportunity to understand how models may be best applied to research aimed at mimicking human disease. In this review, we discuss variables inherent in murine UTI model studies and how these affect model usage, data analysis and data interpretation. We examine recent studies that have elucidated UTI host-pathogen interactions from the perspective of gene expression, and review new studies of biofilm and UTI preventative approaches. We also consider potential standards for variables inherent in murine UTI models and discuss how these might expand the utility of models for mimicking human disease and uncovering new aspects of pathogenesis.

Effect of acupuncture on house dust mite specific IgE, substance P, and symptoms in persistent allergic rhinitis.

BACKGROUND: Clinical evidence suggests that acupuncture improves symptoms in persistent allergic rhinitis, but the physiologic basis of these improvements is not well understood. OBJECTIVE: A randomized, sham-controlled trial of acupuncture for persistent allergic rhinitis in adults investigated possible modulation of mucosal immune responses. METHODS: A total of 151 individuals were randomized into real and sham acupuncture groups (who received twice-weekly treatments for 8 weeks) and a no acupuncture group. Various cytokines, neurotrophins, proinflammatory neuropeptides, and immunoglobulins were measured in saliva or plasma from baseline to 4-week follow-up. RESULTS: Statistically significant reduction in allergen specific IgE for house dust mite was seen only in the real acupuncture group, from 18.87 kU/L (95% CI, 10.16-27.58 kU/L) to 17.82 kU/L (95% CI, 9.81-25.83 kU/L) (P = .04). A mean (SE) statistically significant down-regulation was also seen in proinflammatory neuropeptide substance P (SP) 18 to 24 hours after the first treatment from 408.74 (299.12) pg/mL to 90.77 (22.54) pg/mL (P = .04). No significant changes were seen in the other neuropeptides, neurotrophins, or cytokines tested. Nasal obstruction, nasal itch, sneezing, runny nose, eye itch, and unrefreshed sleep improved significantly in the real acupuncture group (postnasal drip and sinus pain did not) and continued to improve up to 4-week follow-up. CONCLUSION: Acupuncture modulated mucosal immune response in the upper airway in adults with persistent allergic rhinitis. This modulation appears to be associated with down-regulation of allergen specific IgE for house dust mite, which this study is the first to report. Improvements in nasal itch, eye itch, and sneezing after acupuncture are suggestive of down-regulation of transient receptor potential vanilloid 1. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Identifier: ACTRN 12610001052022.

Post-exposure passive immunisation for preventing rubella and congenital rubella syndrome.

BACKGROUND: Control of rubella is desired because infection in early pregnancy can result in miscarriage, foetal death or congenital abnormality. Primary studies examining the effectiveness of immunoglobulins for post-exposure prophylaxis of rubella have small sample sizes and varying results. National public health recommendations suggest a degree of effectiveness. OBJECTIVES: To assess the effectiveness of intramuscular injection or intravenous infusion of polyclonal immunoglobulins of human sera or plasma origin for preventing rubella and congenital rubella syndrome when administered to exposed susceptible people before the onset of disease. SEARCH METHODS: We searched CENTRAL (2014, Issue 7), MEDLINE (1946 to August week 2, 2014), EMBASE (1974 to August 2014), CINAHL (1981 to August 2014), LILACS (1982 to August 2014) and Web of Science (1955 to August 2014). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry on 16 October 2014. We searched the reference lists of relevant retrieved reviews and studies and identified national public health guidelines. SELECTION CRITERIA: For the outcome 'preventing cases of rubella', we included randomised controlled trials (RCTs) and quasi-RCTs. We found several studies addressing this outcome where the design was a controlled clinical trial (CCT) (with exposure to rubella virus controlled by the investigators) but the method of allocation of participants to groups was not reported. We found an alternative report of one of these studies that indicated participants were assigned to groups randomly. We therefore included such studies as meeting criteria for RCTs or quasi-RCTs and undertook sensitivity analyses. For the outcomes, 'congenital rubella infection' and 'congenital rubella syndrome', we included RCTs, quasi-RCTs and prospective controlled (cohort) studies. Participants were necessarily susceptible and exposed to rubella. Polyclonal immunoglobulins derived from human sera or plasma must have been administered intramuscularly or intravenously as the only intervention in at least one group. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included 12 studies (430 participants) in the review: seven RCTs and five CCTs where it was not clear whether participants were randomly allocated to groups. We did not include any unpublished studies. Participants included children and adults of both sexes. Only one study included pregnant women. All studies were conducted in high-income countries.The quality of the 11 studies in the initial meta-analysis was moderate, although we classified no study as having a low risk of bias on all criteria.We included 11 studies in the initial meta-analysis of gamma-globulin (concentrated polyclonal immunoglobulins) versus control (saline or no treatment) for rubella cases. The result favoured the intervention group (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.45 to 0.83) but was heterogenous (Chi² test = 36.59, df = 10 (P value < 0.0001); I² statistic = 73%). Heterogeneity was explained by subgrouping studies according to the estimated volume of gamma-globulin administered per pound of bodyweight and then removing those studies where the intervention was administered more than five days after participant exposure to rubella (post hoc analysis). The test of subgroup differences demonstrated heterogeneity between subgroups according to our protocol definition (P value < 0.1; I² statistic > 60%) and there appeared to be greater effectiveness of the intervention when a greater volume of gamma-globulin was administered ('0.027 to 0.037 ml/lb' RR 1.60 (95% CI 0.57 to 4.52); '0.1 to 0.15 ml/lb' RR 0.53 (95% CI 0.29 to 0.99); '0.2 to 0.5 ml/lb' RR 0.20 (95% CI 0.04 to 1.00)).None of the studies reported the outcome 'congenital rubella infection'. One included study reported on congenital rubella syndrome, with no cases among participants who were fewer than nine weeks pregnant at enrolment and who were randomised to one of two gamma-globulin groups ('high' or 'low' rubella titre). However, the study did not report how congenital rubella syndrome was measured and did not report the length of follow-up according to intervention group. This study did not include a non-treatment group.No included study measured adverse events. AUTHORS' CONCLUSIONS: Compared to no treatment, polyclonal immunoglobulins seem to be of benefit for preventing rubella. The available evidence suggests that this intervention may be of benefit up to five days after exposure, and that effectiveness is dependent on dose. Considering the attack rate for rubella cases in the control group of the highest volume gamma-globulin subgroup (333 per 1000), the absolute risk reduction (calculated from the RR) for this volume of gamma-globulin was 266 (95% CI 0 to 320) and the number needed to treat to benefit is four (95% CI 3 to incalculable).The included studies did not measure rubella-specific antibodies in the immunoglobulin products used in a standard way and thus estimation of the dose of rubella-specific antibodies in international units administered was not possible. As the concentration of rubella-specific antibodies in today's polyclonal immunoglobulin products may vary from those products used in the studies in the review, the volume required per pound of bodyweight to produce similar results may also vary.There is insufficient evidence to make direct conclusions about the effectiveness of polyclonal immunoglobulins for preventing congenital rubella syndrome. This is an area requiring further research.

Innate transcriptional networks activated in bladder in response to uropathogenic Escherichia coli drive diverse biological pathways and rapid synthesis of IL-10 for defense against bacterial urinary tract infection.

Early transcriptional activation events that occur in bladder immediately following bacterial urinary tract infection (UTI) are not well defined. In this study, we describe the whole bladder transcriptome of uropathogenic Escherichia coli (UPEC) cystitis in mice using genome-wide expression profiling to define the transcriptome of innate immune activation stemming from UPEC colonization of the bladder. Bladder RNA from female C57BL/6 mice, analyzed using 1.0 ST-Affymetrix microarrays, revealed extensive activation of diverse sets of innate immune response genes, including those that encode multiple IL-family members, receptors, metabolic regulators, MAPK activators, and lymphocyte signaling molecules. These were among 1564 genes differentially regulated at 2 h postinfection, highlighting a rapid and broad innate immune response to bladder colonization. Integrative systems-level analyses using InnateDB (http://www.innatedb.com) bioinformatics and ingenuity pathway analysis identified multiple distinct biological pathways in the bladder transcriptome with extensive involvement of lymphocyte signaling, cell cycle alterations, cytoskeletal, and metabolic changes. A key regulator of IL activity identified in the transcriptome was IL-10, which was analyzed functionally to reveal marked exacerbation of cystitis in IL-10-deficient mice. Studies of clinical UTI revealed significantly elevated urinary IL-10 in patients with UPEC cystitis, indicating a role for IL-10 in the innate response to human UTI. The whole bladder transcriptome presented in this work provides new insight into the diversity of innate factors that determine UTI on a genome-wide scale and will be valuable for further data mining. Identification of protective roles for other elements in the transcriptome will provide critical new insight into the complex cascade of events that underpin UTI.

Post-exposure passive immunisation for preventing measles.

BACKGROUND: Measles outbreaks continue to occur in countries with high vaccination coverage. Passive immunisation is generally considered to prevent measles in someone who is not immune and has been exposed to infection. Estimates of effectiveness have varied and no minimum effective dose has been determined. OBJECTIVES: To assess the effectiveness and safety of intramuscular injection or intravenous infusion of immunoglobulins (passive immunisation) for preventing measles when administered to exposed susceptible people before the onset of symptoms. SEARCH METHODS: We searched CENTRAL (2013, Issue 7), MEDLINE (1946 to July week 5, 2013), CINAHL (1981 to August 2013) and EMBASE (1974 to August 2013). SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-RCTs and prospective, controlled (cohort) studies if: participants were susceptible and exposed to measles, polyclonal immunoglobulins derived from human sera or plasma were administered intramuscularly or intravenously as the only intervention in at least one group and the number of subsequent measles cases was measured. We excluded studies of other sources of immunoglobulins. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and critically appraised the included studies. We attempted to contact study authors for missing information. We described the results of studies not included in meta-analyses. MAIN RESULTS: We included one RCT, two quasi-RCTs and 10 cohort studies (3925 participants). No studies were rated as low risk of bias for all criteria. Critical appraisal was constrained by a lack of information in most studies. The overall quality of the evidence was moderate.Seven studies (1432 participants) assessed cases of measles after immunoglobulin versus no treatment. Heterogeneity was explained by subgrouping according to the blood product used as an approximation of dose of immunoglobulin. When given within seven days of exposure, immunoglobulins were effective at preventing measles: gamma globulin (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.08 to 0.36), convalescent serum (RR 0.21, 95% CI 0.15 to 0.29 to RR 0.49, 95% CI 0.44 to 0.54) and adult serum (RR 0.52, 95% CI 0.45 to 0.59). The differences in the effectiveness of different blood products were supported by studies not included in the meta-analysis and by two studies (702 participants) that found gamma globulin more effective than serum (RR 0.56, 95% CI 0.46 to 0.69).Based on three studies (893 participants) immunoglobulin was effective at preventing death due to measles compared to no treatment (RR 0.24, 95% CI 0.13 to 0.44).Two studies included measles vaccine alone among the intervention groups. Meta-analysis could not be undertaken. Both studies suggested the vaccine was more effective than gamma globulin.No serious adverse events were observed in any of the included studies, although reporting of adverse events was poor overall. Non-serious adverse events included transient fever, rash, muscle stiffness, local redness and induration. AUTHORS' CONCLUSIONS: Passive immunisation within seven days of exposure is effective at preventing measles, with the risk for non-immune people up to 83% less than if no treatment is given. Given an attack rate of 45 per 1000 (per the control group of the most recent included study), gamma globulin compared to no treatment has an absolute risk reduction (ARR) of 37 per 1000 and a number needed to treat to benefit (NNTB) of 27. Given an attack rate of 759 per 1000 (per the attack rate of the other included study assessing gamma globulin), the ARR of gamma globulin compared to no treatment is 629 and the NNTB is two.It seems the dose of immunoglobulin administered impacts on effectiveness. A minimum effective dose of measles-specific antibodies could not be identified.Passive immunisation is effective at preventing deaths from measles, reducing the risk by 76% compared to no treatment. Whether the benefits of passive immunisation vary among subgroups of non-immune exposed people could not be determined.Due to a paucity of evidence comparing vaccine to passive immunisation, no firm conclusions can be drawn regarding relative effectiveness.The included studies were not specifically designed to detect adverse events.Future research should consider the effectiveness of passive immunisation for preventing measles in high-risk populations such as pregnant women, immunocompromised people and infants. Further efforts should be made to determine the minimum effective dose of measles-specific antibodies for post-exposure prophylaxis and the relative effectiveness of vaccine compared to immunoglobulin.