Over 100 million women use progesterone therapies worldwide. Despite having immunomodulatory and repair properties, their effects on the outcome of viral diseases outside of the reproductive tract have not been evaluated. Administration of exogenous progesterone (at concentrations that mimic the luteal phase) to progesterone-depleted adult female mice conferred protection from both lethal and sublethal influenza A virus (IAV) infection. Progesterone treatment altered the inflammatory environment of the lungs, but had no effects on viral load. Progesterone treatment promoted faster recovery by increasing TGF-β, IL-6, IL-22, numbers of regulatory Th17 cells expressing CD39, and cellular proliferation, reducing protein leakage into the airway, improving pulmonary function, and upregulating the epidermal growth factor amphiregulin (AREG) in the lungs. Administration of rAREG to progesterone-depleted females promoted pulmonary repair and improved the outcome of IAV infection. Progesterone-treatment of AREG-deficient females could not restore protection, indicating that progesterone-mediated induction of AREG caused repair in the lungs and accelerated recovery from IAV infection. Repair and production of AREG by damaged respiratory epithelial cell cultures in vitro was increased by progesterone. Our results illustrate that progesterone is a critical host factor mediating production of AREG by epithelial cells and pulmonary tissue repair following infection, which has important implications for women’s health.
Sepsis, severe sepsis, and septic shock represent increasingly severe systemic inflammatory responses to infection. Sepsis is common in the aging population, and it disproportionately affects patients with cancer and underlying immunosuppression. In its most severe form, sepsis causes multiple organ dysfunction that can produce a state of chronic critical illness characterized by severe immune dysfunction and catabolism. Much has been learnt about the pathogenesis of sepsis at the molecular, cell, and intact organ level. Despite uncertainties in hemodynamic management and several treatments that have failed in clinical trials, investigational therapies increasingly target sepsis induced organ and immune dysfunction. Outcomes in sepsis have greatly improved overall, probably because of an enhanced focus on early diagnosis and fluid resuscitation, the rapid delivery of effective antibiotics, and other improvements in supportive care for critically ill patients. These improvements include lung protective ventilation, more judicious use of blood products, and strategies to reduce nosocomial infections.
Risk of pneumonia associated with incident benzodiazepine use among community-dwelling adults with Alzheimer disease
- CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne
- Published over 1 year ago
Knowledge regarding whether benzodiazepines and similarly acting non-benzodiazepines (Z-drugs) are associated with an increased risk of pneumonia among older adults is lacking. We sought to investigate this association among community-dwelling adults with Alzheimer disease, a condition in which both sedative/hypnotic use and pneumonia are common.
Klebsiella pneumoniae is a Gram-negative pathogen responsible for a wide range of infections, including pneumonia and bacteremia, and is rapidly acquiring antibiotic resistance. K. pneumoniae requires secretion of siderophores, low-molecular-weight, high-affinity iron chelators, for bacterial replication and full virulence. The specific combination of siderophores secreted by K. pneumoniae during infection can impact tissue localization, systemic dissemination, and host survival. However, the effect of these potent iron chelators on the host during infection is unknown. In vitro, siderophores deplete epithelial cell iron, induce cytokine secretion, and activate the master transcription factor hypoxia inducible factor-1α (HIF-1α) protein that controls vascular permeability and inflammatory gene expression. Therefore, we hypothesized that siderophore secretion by K. pneumoniae directly contributes to inflammation and bacterial dissemination during pneumonia. To examine the effects of siderophore secretion independently of bacterial growth, we performed infections with tonB mutants that persist in vivo but are deficient in siderophore import. Using a murine model of pneumonia, we found that siderophore secretion by K. pneumoniae induces the secretion of interleukin-6 (IL-6), CXCL1, and CXCL2, as well as bacterial dissemination to the spleen, compared to siderophore-negative mutants at an equivalent bacterial number. Furthermore, we determined that siderophore-secreting K. pneumoniae stabilized HIF-1α in vivo and that bacterial dissemination to the spleen required alveolar epithelial HIF-1α. Our results indicate that siderophores act directly on the host to induce inflammatory cytokines and bacterial dissemination and that HIF-1α is a susceptibility factor for bacterial invasion during pneumonia.
- European respiratory review : an official journal of the European Respiratory Society
- Published about 6 years ago
The presence of acute or chronic respiratory failure is often seen as a terminal phase of chronic obstructive pulmonary disease. A great variability in end-of-life practice is observed in these patients mainly because physicians are not always able to correctly predict survival. There is a need for a clear discussion about decision making earlier than when acute respiratory failure ensues. Indeed, a perceived poor quality of life does not necessarily correlate with a clear willingness to refuse invasive or noninvasive mechanical ventilation. It has been suggested to start palliative care earlier, together with curative and restorative care, when there is an increased intensity of symptoms. The patients eligible for palliative care are those complaining of breathlessness, pain, fatigue and depression, which in some studies accounted for a prevalence much higher than 50%. Among comfort measures for palliation, oxygen is frequently prescribed even when the criteria for long-term home oxygen therapy are not met; however, when compared with air, no benefits on dyspnoea have been found. The only drug with a proven effect on dyspnoea is morphine, but not when it is delivered with a nebuliser. Finally, noninvasive ventilation may be used only as a comfort measure for palliation to maximise comfort by minimising adverse effects.
We have identified a natural clay mixture that exhibits in vitro antibacterial activity against a broad spectrum of bacterial pathogens. We collected four samples from the same source and demonstrated through antibacterial susceptibility testing that these clay mixtures have markedly different antibacterial activity against Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA). Here, we used X-ray diffraction (XRD) and inductively coupled plasma - optical emission spectroscopy (ICP-OES) and - mass spectrometry (ICP-MS) to characterize the mineralogical and chemical features of the four clay mixture samples. XRD analyses of the clay mixtures revealed minor mineralogical differences between the four samples. However, ICP analyses demonstrated that the concentrations of many elements, Fe, Co, Cu, Ni, and Zn, in particular, vary greatly across the four clay mixture leachates. Supplementation of a non-antibacterial leachate containing lower concentrations of Fe, Co, Ni, Cu, and Zn to final ion concentrations and a pH equivalent to that of the antibacterial leachate generated antibacterial activity against E. coli and MRSA, confirming the role of these ions in the antibacterial clay mixture leachates. Speciation modeling revealed increased concentrations of soluble Cu(2+) and Fe(2+) in the antibacterial leachates, compared to the non-antibacterial leachates, suggesting these ionic species specifically are modulating the antibacterial activity of the leachates. Finally, linear regression analyses comparing the log10 reduction in bacterial viability to the concentration of individual ion species revealed positive correlations with Zn(2+) and Cu(2+) and antibacterial activity, a negative correlation with Fe(3+), and no correlation with pH. Together, these analyses further indicate that the ion concentration of specific species (Fe(2+), Cu(2+), and Zn(2+)) are responsible for antibacterial activity and that killing activity is not solely attributed to pH.
Adoption and maintenance of healthy behaviours is pivotal to chronic disease self-management as this influences disease progression and impact. This qualitative study investigated health behaviour changes adopted by participants with moderate or severe chronic obstructive pulmonary disease (COPD) recruited to a randomised controlled study of telephone-delivered health-mentoring.
Multilocus sequence typing (MLST) is a widely used system for typing microorganisms by sequence analysis of housekeeping genes. The main advantage of MLST in comparison to other typing techniques is the unambiguity and transferability of sequence data. However, a main disadvantage is the high cost of DNA sequencing. Here we introduce a high-throughput MLST (HiMLST) method that employs next-generation sequencing (NGS) technology (Roche 454), to generate large quantities of high-quality MLST data at low costs. The HiMLST protocol consists of two steps. In the first step MLST target genes are amplified by PCR in multi-well plates. During this PCR the amplicons of each bacterial isolate are provided with a unique DNA barcode, the multiplex identifier (MID). In the second step all amplicons are pooled and sequenced in a single NGS-run. The MLST profile of each individual isolate can be retrieved easily using its unique MID. With HiMLST we have profiled 575 isolates of Legionella pneumophila, Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pneumoniae in mixed species HiMLST experiments. In conclusion, the introduction of HiMLST paves the way for a broad employment of the MLST as a high-quality and cost-effective method for typing microbial species.
Sustained high coverage with recommended vaccinations among children has kept many vaccine-preventable diseases at low levels in the United States (1). To assess coverage with vaccinations recommended for children by age 2 years in the United States (2), CDC analyzed data collected by the 2015 National Immunization Survey (NIS) for children aged 19-35 months (born January 2012-May 2014). Overall, coverage did not change during 2014-2015. Coverage in 2015 was highest for ≥3 doses of poliovirus vaccine (93.7%), ≥3 doses of hepatitis B vaccine (HepB) (92.6%), ≥1 dose of measles, mumps, and rubella vaccine (MMR) (91.9%), and ≥1 dose of varicella vaccine (91.8%). The data were also examined for potential vaccination coverage differences by race/ethnicity, poverty status, and urbanicity. Although disparities were noted for each of these factors, the most striking differences were seen for poverty status. Children living below the federal poverty level* had lower coverage with most of the vaccinations assessed compared with children living at or above the poverty level; the largest disparities were for rotavirus vaccine (66.8% versus 76.8%), ≥4 doses of pneumococcal conjugate vaccine (PCV) (78.9% versus 87.2%), the full series of Haemophilus influenzae type b vaccine (Hib) (78.1% versus 85.5%), and ≥4 doses of diphtheria, tetanus, and acellular pertussis vaccine (DTaP) (80.2% versus 87.1%). Although coverage was high in some groups, opportunities exist to continue to address disparities. Implementation of evidence-based interventions, including strategies to enhance access to vaccination services and systems strategies that can reduce missed opportunities, has the potential to increase vaccination coverage for children living below the poverty level and in rural areas (3).
Non-inferiority of mammalian cell-derived quadrivalent subunit influenza virus vaccines compared to trivalent subunit influenza virus in healthy children: a phase III randomized, multicenter, double-blind, clinical trial
- International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases
- Published about 3 years ago
We evaluated the safety and immunogenicity of mammalian cell-derived quadrivalent influenza vaccine (QIVc) as compared with trivalent influenza vaccines (TIV1c/TIV2c) in children aged ≥4 to <18 years.