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Effects of lactoferrin on infectious diseases in Japanese summer: A randomized, double-blinded, placebo-controlled trial.
Oda, H, Wakabayashi, H, Tanaka, M, Yamauchi, K, Sugita, C, Yoshida, H, Abe, F, Sonoda, T, Kurokawa, M
Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi. 2021;(4):566-574
Abstract
PURPOSE To investigate the effects of lactoferrin (LF) on infectious diseases in Japanese summer. METHODS An intake of placebo, 200 mg, or 600 mg of LF were administered to healthy adults in Kyushu University of Health and Welfare for 12 weeks in a randomized, double-blinded, placebo-controlled parallel-group comparative trial. The primary endpoints were the prevalence and duration of infectious diseases and changes in immune parameters. RESULTS Three hundred and ten subjects were randomized (placebo, n = 104; 200 mg, n = 103; 600 mg, n = 103). Twenty subjects were lost to the follow-up, leaving 290 for a full analysis set (n = 99; n = 95; n = 96). The duration (day) of total infectious diseases was shorter in the 200 mg group (2.0, p = 0.045) and 600 mg group (2.0, p = 0.010) than in the placebo group (3.0). The duration of summer colds was shorter in the 600 mg group (2.0, p = 0.036) than in the placebo group (3.0). No significant differences were observed in the prevalence of infectious diseases or changes in immune parameters. In exploratory investigations, changes in the neutrophil phagocytic capacity, cortisol concentrations, and T score of "Vigor/Activity" in the Profile of Mood States 2 were greater in the 600 mg group than in the placebo group, when analysis was done on the lower half groups at the baseline. Adverse events were similar in each group and none had a causal relationship with the intake of the test foods. CONCLUSIONS In summer, the intake of LF attenuates infectious diseases, including summer colds.
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Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial.
Anstrom, KJ, Noth, I, Flaherty, KR, Edwards, RH, Albright, J, Baucom, A, Brooks, M, Clark, AB, Clausen, ES, Durheim, MT, et al
Respiratory research. 2020;(1):68
Abstract
Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02759120.
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Prophylactic lactoferrin for preventing late-onset sepsis and necrotizing enterocolitis in preterm infants: A PRISMA-compliant systematic review and meta-analysis.
He, Y, Cao, L, Yu, J
Medicine. 2018;(35):e11976
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Abstract
BACKGROUND Currently, prophylactic use of drugs to promote a healthy gut microbiota and immune system in preterm infants is hot debated, among which lactoferrin is a promising supplementation. However, the effect and safety of lactoferrin to prevent late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants remains controversial. METHODS Databases including Medline, Ovid-Embase, The Cochrane Library, CBM, CNKI, and VIP database of Chinese Journal were searched to collect randomized controlled trials (RCTs) about lactoferrin for preventing LOS and NEC in preterm infants. Languages of included RCTs were restricted to English and Chinese. Meta-analysis was conducted by Rev Man 5.3 software. The Mantel-Haenszel method with random-effects model was used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs). RESULTS A total of 9 RCTs, involving 1834 patients, were included. Pooled analysis showed that prophylactic lactoferrin could significantly reduce the incidence all culture-proven LOS (41/629 [6.5%] vs 96/659 [15.3%]; RR 0.47; 95% CI 0.33-0.67; P < .01) and NEC (stage II or more) (9/448 [2.0%] vs 26/462 [5.6%]; RR 0.40; 95% CI 0.18-0.86; P < .01). Lactoferrin was also associated with a significantly decreased hospital-acquired infection (16/139 [11.5%] vs 35/140 [25%]; RR 0.47; 95% CI 0.27-0.80; P < .01); and infection-related mortality (4/474 [0.8%] vs 25/505 [4.9%]; RR 0.24; 95% CI 0.04-1.32; P < .01, I = 53%). Lactoferrin could shorten time to reach full enteral feeding (weighted mean difference [WMD] = -2.11, 95% CI -3.12 to -1.10; P < .01) and showed a decreasing trend of duration of hospitalization (WMD = -1.69, 95% CI -6.87 to 3.50; P < .01; I = 95%). Lactoferrin did not have a significant effect on all-cause mortality (22/625 [3.5%] vs 35/647 [5.4%]; RR 0.70; 95% CI 0.38-1.30; P = .16; I = 13%). None of the included trials reported any confirmed adverse effects caused by the supplemented lactoferrin or probiotics. CONCLUSION Current evidence indicates that lactoferrin could significantly reduce the incidence of NEC and LOS, and decrease the risk of hospital-acquired infection and infection-related mortality in premature infants without obvious adverse effects.
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Multidrug resistant (or antimicrobial-resistant) pathogens - alternatives to new antibiotics?
Brunel, AS, Guery, B
Swiss medical weekly. 2017;:w14553
Abstract
For the last few decades, multidrug resistance has become an increasing concern for both Gram-positive and Gram-negative bacteria. The number of new molecules has dramatically decreased and antibiotic resistance is now a priority in the international community. Facing this new threat, a large number of new as well as "old" solutions are now being discussed in the medical community to propose an alternative to antibiotic treatments. A first option is to potentiate the effect of existing molecules through combinations to circumvent the individual molecule resistance. The second option is to neutralise either the infectious agent itself or its by-products using specific antibodies. A third option is to use the pathogen signaling mechanism and inhibit the production of virulence factor through quorum sensing inhibition. A fourth pathway would be to interact with the patient's microbiota using either probiotics or faecal transplantation to modulate the innate immune response and improve response to the infectious challenge, but also to act directly against colonisation by resistant bacteria by replacing the flora with susceptible strains. The last option is to target the bacteria using phage therapy. Phages are natural viruses that specifically infect target bacteria independently of any antibiotic-susceptibility profile. In this review, we will discuss each of these options and provide the scientific rationale and the available clinical data. In the majority of cases, these treatments represent an interesting approach but not the ultimate solution to multiresistance. Well-performed clinical trials are still missing and the major priority remains to promote good use and appropriate stewardship of antibiotics to decrease resistance.
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Using CRISPR-Cas systems as antimicrobials.
Bikard, D, Barrangou, R
Current opinion in microbiology. 2017;:155-160
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Abstract
Although CRISPR-Cas systems naturally evolved to provide adaptive immunity in bacteria and archaea, Cas nucleases can be co-opted to target chromosomal sequences rather than invasive genetic elements. Although genome editing is the primary outcome of self-targeting using CRISPR-based technologies in eukaryotes, self-targeting by CRISPR is typically lethal in bacteria. Here, we discuss how DNA damage introduced by Cas nucleases in bacteria can efficiently and specifically lead to plasmid curing or drive cell death. Specifically, we discuss how various CRISPR-Cas systems can be engineered and delivered using phages or phagemids as vectors. These principles establish CRISPR-Cas systems as potent and programmable antimicrobials, and open new avenues for the development of CRISPR-based tools for selective removal of bacterial pathogens and precise microbiome composition alteration.
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Food Fight: Role of Itaconate and Other Metabolites in Antimicrobial Defense.
Luan, HH, Medzhitov, R
Cell metabolism. 2016;(3):379-387
Abstract
Itaconate is a newly discovered mammalian metabolite bearing significant implications for our understanding of cellular immunometabolism and antimicrobial defense. Here, we explore recent findings regarding the role of itaconate in the innate immune response and highlight the emerging principle that metabolites can have distinct immunological functions independent of bioenergetics.
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An Evaluation of Blood Compatibility of Silver Nanoparticles.
Huang, H, Lai, W, Cui, M, Liang, L, Lin, Y, Fang, Q, Liu, Y, Xie, L
Scientific reports. 2016;:25518
Abstract
Silver nanoparticles (AgNPs) have tremendous potentials in medical devices due to their excellent antimicrobial properties. Blood compatibility should be investigated for AgNPs due to the potential blood contact. However, so far, most studies are not systematic and have not provided insights into the mechanisms for blood compatibility of AgNPs. In this study, we have investigated the blood biological effects, including hemolysis, lymphocyte proliferation, platelet aggregation, coagulation and complement activation, of 20 nm AgNPs with two different surface coatings (polyvinyl pyrrolidone and citrate). Our results have revealed AgNPs could elicit hemolysis and severely impact the proliferation and viability of lymphocytes at all investigated concentrations (10, 20, 40 μg/mL). Nevertheless, AgNPs didn't show any effect on platelet aggregation, coagulation process, or complement activation at up to ~40 μg/mL. Proteomic analysis on AgNPs plasma proteins corona has revealed that acidic and small molecular weight blood plasma proteins were preferentially adsorbed onto AgNPs, and these include some important proteins relevant to hemostasis, coagulation, platelet, complement activation and immune responses. The predicted biological effects of AgNPs by proteomic analysis are mostly consistent with our experimental data since there were few C3 components on AgNPs and more negative than positive factors involving platelet aggregation and thrombosis.
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A comparative phase 1 clinical trial to identify anti-infective mechanisms of vitamin D in people with HIV infection.
Lachmann, R, Bevan, MA, Kim, S, Patel, N, Hawrylowicz, C, Vyakarnam, A, Peters, BS
AIDS (London, England). 2015;(10):1127-35
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Abstract
OBJECTIVES To determine if there is a biological mechanism that explains the association between HIV disease progression and increased mortality with low circulating vitamin D levels; specifically, to determine if restoring vitamin D levels induced T-cell functional changes important for antiviral immunity. DESIGN This was a pilot, open-label, three-arm prospective phase 1 study. METHODS We recruited 28 patients with low plasma vitamin D (<50 nmol/l 25-hydroxyvitamin D3), comprising 17 HIV+ patients (11 on HAART, six treatment-naive) and 11 healthy controls, who received a single dose of 200 000 IU oral cholecalciferol. Advanced T-cell flow cytometry methods measured CD4 T-cell function associated with viral control in blood samples at baseline and 1-month after vitamin D supplementation. RESULTS One month of vitamin D supplementation restored plasma levels to sufficiency (>75 nmol/l) in 27 of 28 patients, with no safety issues. The most striking change was in HIV+ HAART+ patients, where increased frequencies of antigen-specific T cells expressing macrophage inflammatory protein (MIP)-1β - an important anti-HIV blocking chemokine - were observed, with a concomitant increase in plasma MIP-1β, both of which correlated significantly with vitamin D levels. In addition, plasma cathelicidin - a vitamin D response gene with broad antimicrobial activity - was enhanced. CONCLUSION Vitamin D supplementation modulates disease-relevant T-cell functions in HIV-infected patients, and may represent a useful adjunct to HAART therapy.
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Novel approaches to improve the intrinsic microbiological safety of powdered infant milk formula.
Kent, RM, Fitzgerald, GF, Hill, C, Stanton, C, Ross, RP
Nutrients. 2015;(2):1217-44
Abstract
Human milk is recognised as the best form of nutrition for infants. However; in instances where breast-feeding is not possible, unsuitable or inadequate, infant milk formulae are used as breast milk substitutes. These formulae are designed to provide infants with optimum nutrition for normal growth and development and are available in either powdered or liquid forms. Powdered infant formula is widely used for convenience and economic reasons. However; current manufacturing processes are not capable of producing a sterile powdered infant formula. Due to their immature immune systems and permeable gastro-intestinal tracts, infants can be more susceptible to infection via foodborne pathogenic bacteria than other age-groups. Consumption of powdered infant formula contaminated by pathogenic microbes can be a cause of serious illness. In this review paper, we discuss the current manufacturing practices present in the infant formula industry, the pathogens of greatest concern, Cronobacter and Salmonella and methods of improving the intrinsic safety of powdered infant formula via the addition of antimicrobials such as: bioactive peptides; organic acids; probiotics and prebiotics.
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Lactoferrin for prevention of common viral infections.
Wakabayashi, H, Oda, H, Yamauchi, K, Abe, F
Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 2014;(11):666-71
Abstract
Although lactoferrin has many biological functions, the host-protective effects against pathogenic microorganisms including bacteria, fungi, and viruses are regarded as one of the most important. Here, we review research on the protective role of lactoferrin administration against common viral infections. Many studies have shown the in vitro antiviral activity of lactoferrin against viral pathogens that cause common infections such as the common cold, influenza, gastroenteritis, summer cold, and herpes, where lactoferrin inhibits mainly viral attachment to the target cells. Recently, studies indicating the in vivo protective effects of lactoferrin by oral administration against common viral infections have been increasing. For instance, norovirus is an extremely important emerging human pathogen that causes a majority of gastroenteritis outbreaks worldwide that may be a target candidate for lactoferrin. Lactoferrin consumption reduced the incidence of noroviral gastroenteritis in children and a similar effect was observed in a wide range of ages in a preliminary survey. A recent in vitro study reported that lactoferrin inhibits both cellular attachment of the murine norovirus, a virus closely-related to the human norovirus, and viral replication in the cells by inducing antiviral cytokines interferon (IFN)-α/β. Lactoferrin administration also enhances NK cell activity and Th1 cytokine responses, which lead to protection against viral infections. In conclusion, lactoferrin consumption may protect the host from viral infections through inhibiting the attachment of a virus to the cells, replication of the virus in the cells, and enhancement of systemic immune functions.