Alterations in specific signal transduction pathways may explain the increased expression of proinflammatory cytokines seen in inflammatory diseases such as psoriasis. We reveal increased TNF-alpha ...protein expression, but similar TNF-alpha mRNA levels, in lesional compared with nonlesional psoriatic skin, demonstrating for the first time that TNF-alpha expression in lesional psoriatic skin is regulated posttranscriptionally. Increased levels of activated MAPK-activated protein kinase 2 (MK2) together with increased MK2 kinase activity were found in lesional compared with nonlesional psoriatic skin. Immunohistochemical analysis showed that activated MK2 was located in the basal layers of the psoriatic epidermis, whereas no positive staining was seen in nonlesional psoriatic skin. In vitro experiments demonstrated that both anisomycin and IL-1beta caused a significant activation of p38 MAPK and MK2 in cultured normal human keratinocytes. In addition, TNF-alpha protein levels were significantly up-regulated in keratinocytes stimulated with anisomycin or IL-1beta. This increase in TNF-alpha protein expression was completely blocked by the p38 inhibitor, SB202190. Transfection of cultured keratinocytes with MK2-specific small interfering RNA led to a significant decrease in MK2 expression and a subsequent significant reduction in the protein expression of the proinflammatory cytokines TNF-alpha, IL-6, and IL-8, whereas no change in the expression of the anti-inflammatory cytokine IL-10 was seen. This is the first time that MK2 expression and activity have been investigated in an inflammatory disease such as psoriasis. The results strongly suggest that increased activation of MK2 is responsible for the elevated and posttranscriptionally regulated TNF-alpha protein expression in psoriatic skin, making MK2 a potential target in the treatment of psoriasis.
Abstract
Primary ciliary dyskinesia (PCD) is an inherited ciliopathy leading to chronic suppurative lung disease, chronic rhinosinusitis, middle ear disease, sub-fertility and
situs
abnormalities. As ...PCD is rare, it is important that scientists and clinicians foster international collaborations to share expertise in order to provide the best possible diagnostic and management strategies. ‘Better Experimental Approaches to Treat Primary Ciliary Dyskinesia’ (BEAT-PCD) is a multidisciplinary network funded by EU COST Action (BM1407) to coordinate innovative basic science and clinical research from across the world to drive advances in the field. The fourth and final BEAT-PCD Conference and fifth PCD Training School were held jointly in March 2019 in Poznan, Poland. The varied program of plenaries, workshops, break-out sessions, oral and poster presentations were aimed to enhance the knowledge and skills of delegates, whilst also providing a collaborative platform to exchange ideas. In this final BEAT-PCD conference we were able to build upon programmes developed throughout the lifetime of the COST Action. These proceedings report on the conference, highlighting some of the successes of the BEAT-PCD programme.
The hallmark of serpins is the ability to undergo the so-called “stressed-to-relaxed” switch during which the surface-exposed reactive center loop (RCL) becomes incorporated as strand 4 in central ...β-sheet A. RCL insertion drives not only the inhibitory reaction of serpins with their target serine proteases but also the conversion to the inactive latent state. RCL insertion is coupled to conformational changes in the flexible joint region flanking β-sheet A. One interesting serpin is plasminogen activator inhibitor-1 (PAI-1), a fast and specific inhibitor of the serine proteases tissue-type and urokinase-type plasminogen activator. Via its flexible joints' region, native PAI-1 binds vitronectin and relaxed, protease-complexed PAI-1 certain endocytosis receptors. From a library of 35-nucleotides long 2′-fluoropyrimidine-containing RNA oligonucleotides, we have isolated two aptamers binding PAI-1 by the flexible joint region with low nanomolar K D values. One of the aptamers exhibited measurable binding to native PAI-1 only, while the other also bound relaxed PAI-1. While none of the aptamers inhibited the antiproteolytic effect of PAI-1, both aptamers inhibited vitronectin binding and the relaxed PAI-1-binding aptamer also endocytosis receptor binding. The aptamer binding exclusively to native PAI-1 increased the half-life for the latency transition to more than 6 h, manyfold more than vitronectin. Contact with Lys124 in the flexible joint region was critical for strong inhibition of the latency transition and the lack of binding to relaxed PAI-1. We conclude that aptamers yield important information about the serpin conformational switch and, because they can compete with high-affinity protein−protein interactions, may provide leads for pharmacological intervention.
Maintaining competence in airway management Bessmann, Ebbe L.; Rasmussen, Lars S.; Konge, Lars ...
Acta anaesthesiologica Scandinavica,
July 2020, Letnik:
64, Številka:
6
Journal Article
Recenzirano
Background
Airway management is a defining skill for anaesthesiologists. Anaesthesiologists must maintain and update these crucial skills throughout their career, but how this is best achieved ...remains unclear. This study aimed to clarify anaesthesiologists’ procedural volume, confidence in airway management and their current and preferred future educational strategies.
Methods
A questionnaire was developed consisting of 28 items exploring essential skills in airway management. All anaesthesiologists in the Capital Region of Denmark were invited to participate.
Results
The response rate was 84% (240/285). Most anaesthesiologists felt competent to a high or very high degree in basic airway management. Anaesthesiologists from anaesthesia felt confident to a significantly higher degree than those working in the intensive care unit (ICU) regarding the practical aspects of airway management in both the anticipated difficult airway (93% vs 73%, P < .001) and the unanticipated difficult airway (81% vs 61%, P = .002). Both groups performed most of the key advanced techniques ≤4 times yearly, whereas anaesthesiologists from the ICU had a lower and less diverse procedural volume than those working in anaesthesia. The anaesthesiologists preferred training through their daily clinical work, hands‐on workshops, and scenario‐based simulation training. However, a large discrepancy was identified between the current and the desired level of training.
Conclusion
The anaesthesiologists felt competent to a high or very high degree in basic airway management but the current procedural volume in advanced airway management causes concern for skill maintenance. Furthermore, we found a gap between the current and the desired level of supplemental training.
Purpose
Despite the benefits of physical activity for breast cancer survivors, the majority remain insufficiently active. Mobile health (mHealth) physical activity interventions may be a more ...scalable strategy to increase activity among survivors. However, little is known about their preferences for mHealth intervention features. This study explored survivors’ preferences for these features.
Methods
Survivors (
N
= 96;
M
age
= 55.8 (SD = 10.2)) self-reported demographic and disease characteristics, physical activity. A subset (
n
= 28) completed a semi-structured phone interview. Transcribed interviews were evaluated using a thematic content analysis approach and consensus review. Following interviews, the full sample self-reported interests and preferences for intervention features via online questionnaires. Quantitative data were analyzed using descriptive statistics.
Results
Five themes emerged from interview data: (1) importance of relevance to breast cancer survivors; (2) easy to use; (3) integration with wearable activity trackers; (4) provide sense of accomplishment; and (5) variability in desired level of structure and personalization. The highest ranked intervention features were: daily and weekly progress feedback (87.5%), newsfeed (86.6%), activity challenges (81.3%), and scheduling tool (79.2%). Survivors were interested in receiving progress feedback (80.2%) and motivational (78.1%) and reminder (75.0%) messages.
Conclusions
Breast cancer survivors are interested in mHealth physical activity promotion interventions, but preferences varied around themes of relevance, ease of use, and enhancing personal motivation.
Implications for cancer survivors
Engaging survivors in developing and implementing remotely delivered mHealth activity promotion interventions may enhance their effectiveness.
Abstract
Background
Streptococcus pyogenes (GAS) is a common cause of non-invasive mucosal infections in childhood as well as life-threatening invasive infections. Since 1997, emm1 has been the most ...common emm type associated with invasive GAS (iGAS) in the US. Apparent increases in iGAS have been reported in several countries during the winter of 2022-23. We sought to characterize changing clinical and molecular epidemiology of iGAS disease in Utah children before and after the emergence of COVID-19.
Methods
We retrospectively identified children 0-18 years with iGAS treated at Primary Children’s Hospital (Salt Lake City, Utah) from 2018- 2023. Cases were identified through the laboratory database. Electronic health record review confirmed that cases met the CDC definition of iGAS and streptococcal toxic shock syndrome (STSS). We abstracted demographics, disease classification and outcomes (Table). Comparisons were made across years. GAS isolates underwent whole genome sequencing for emm type determination.
Results
From 1/2018 to 3/2023, we identified 141 cases of iGAS. Case numbers ranged from 6/yr (2021) to 39 (2019). The highest number of cases by quarter was seen in Q1 2023 (Figure). We observed a marked decrease in iGAS from Q1 2020 through Q3 2022 followed by a steep increase, coinciding with surges in RSV and influenza. Demographics were similar across the study period. 60% of iGAS cases were in males. Complicated pneumonia and head/neck infections predominated. iGAS associated with STSS appeared higher post-pandemic (4/73 5% cases in 2018-19 vs. 8/51 16% in 2022-23 OR = 3.2; 95% CI 0.8-15). The majority of STSS (7/12; 57%) was associated with complicated pneumonia. Clinical outcomes were comparable pre- and post-pandemic. emm types were available for 49/51 (96%) of isolates in 2022-23. emm1 and emm12 were associated with 67% of iGAS disease (emm1 n = 16 33%; emm12 n = 17 35%).
Conclusion
After a marked drop in iGAS infections in children during the COVID-19 pandemic in Utah there was a resurgence of iGAS starting in late 2022 and early 2023, modestly exceeding pre-pandemic levels. emm1 and emm12 predominated in the surge. Further analysis of disease severity and molecular epidemiology are in progress.
Disclosures
Kwabena Krow Ampofo, MD, Merck: Advisor/Consultant|Merck: Grant/Research Support Andrew T. Pavia, MD, GlaxoSmith Kline: Advisor/Consultant|Sanofi: Advisor/Consultant Anne J. Blaschke, MD, PhD, BioFire Diagnostics: Grant/Research Support|BioFire Diagnostics: I have IP owned by the U. of Utah licensed to BioFire and receive royalties. I have been a consultant and received grant support as well.|Merck and Company, Inc.: Advisor/Consultant
To identify disclosure, stigma and predictors of non-disclosure among women living with HIV in Denmark.
A questionnaire study of women living with HIV in Denmark was performed. The enrolment period ...was from February 2013 to March 2014. Logistic regression was used to estimate predictors of non-disclosure.
A total of 234 participants were included. The majority (94%) had disclosed their HIV status to at least one person outside their healthcare environment, although 29% had disclosed to fewer than three people. Confidantes were mostly partners (96%), siblings (63%), friends (63%) and children (41%). The primary reason for non-disclosure was a feeling that it did not concern others (55%), although reactions upon disclosure were mainly positive in 53%. Predictors of non-disclosure were being of black or Asian ethnicity. Following their HIV diagnosis, 40% no longer dared to have sex, 40% felt isolated and 23% felt that others were afraid and kept a physical distance. In contrast, after disclosure 75% felt better at taking decisions about life and 50% were in closer contact with family and friends.
Almost one-third of participants disclosed their HIV diagnosis to fewer than three people and black or Asian ethnicity predicted non-disclosure. HIV-related stigma regarding sex and contact with others is still highly prevalent; however, reactions to disclosure were mainly positive and associated with secondary positive gains. We strongly urge healthcare professionals to initiate a dialogue regarding stigma and disclosure with women living with HIV with a view to increasing disclosure and minimising stigmatisation in this vulnerable population.
Sepsis caused by Staphylococcus aureus constitutes an important cause of morbidity and mortality in humans, and the incidence of this disease-entity is increasing. In this paper we describe the ...initial microbial dynamics and lesions in pigs experimentally infected with S. aureus, with the aim of mimicking human sepsis and pyemia.
The study was conducted in anaesthetized and intravenously inoculated pigs, and was based on bacteriological examination of blood and testing of blood for IL-6 and C-reactive protein. Following killing of the animals and necropsy bacteriological and histological examinations of different organs were performed 4, 5 or 6 h after inoculation.
Clearance of bacteria from the blood was completed within the first 2 h in some of the pigs and the highest bacterial load was recorded in the lungs as compared to the spleen, liver and bones. This probably was a consequence of both the intravenous route of inoculation and the presence of pulmonary intravascular macrophages. Inoculation of bacteria induced formation of acute microabscesses in the lungs, spleen and liver, but not in the kidneys or bones. No generalized inflammatory response was recorded, i.e. IL-6 was not detected in the blood and C-reactive protein did not increase, probably because of the short time course of the study.
This study demonstrates the successful induction of acute pyemia (microabscesses), and forms a basis for future experiments that should include inoculation with strains of S. aureus isolated from man and an extension of the timeframe aiming at inducing sepsis, severe sepsis and septic shock.
Women with urge urinary incontinence are commonly treated with antimuscarinic medications, but many discontinue therapy.
To determine whether combining antimuscarinic drug therapy with supervised ...behavioral training, compared with drug therapy alone, improves the ability of women with urge incontinence to achieve clinically important reductions in incontinence episodes and to sustain these improvements after discontinuing drug therapy.
2-stage, multicenter, randomized clinical trial conducted from July 2004 to January 2006.
9 university-affiliated outpatient clinics.
307 women with urge-predominant incontinence.
10 weeks of open-label, extended-release tolterodine alone (n = 153) or combined with behavioral training (n = 154), followed by discontinuation of therapy and follow-up at 8 months.
The primary outcome, measured at 8 months, was no receipt of drugs or other therapy for urge incontinence and a 70% or greater reduction in frequency of incontinence episodes. Secondary outcomes were reduction in incontinence, self-reported satisfaction and improvement, and scores on validated questionnaires measuring symptom distress and bother and health-related quality of life. Study staff who performed outcome evaluations, but not participants and interventionists, were blinded to group assignment.
237 participants completed the trial. According to life-table estimates, the rate of successful discontinuation of therapy at 8 months was the same in the combination therapy and drug therapy alone groups (41% in both groups; difference, 0 percentage points 95% CI, -12 to 12 percentage points). A higher proportion of participants who received combination therapy than drug therapy alone achieved a 70% or greater reduction in incontinence at 10 weeks (69% vs. 58%; difference, 11 percentage points CI, -0.3 to 22.1 percentage points). Combination therapy yielded better outcomes over time on the Urogenital Distress Inventory and the Overactive Bladder Questionnaire (both P <0.001) at both time points for patient satisfaction and perceived improvement but not health-related quality of life. Adverse events were uncommon (12 events in 6 participants 3 in each group).
Behavioral therapy components (daily bladder diary and recommendations for fluid management) in the group receiving drug therapy alone may have attenuated between-group differences. Assigned treatment was completed by 68% of participants, whereas 8-month outcome status was assessed on 77%.
The addition of behavioral training to drug therapy may reduce incontinence frequency during active treatment but does not improve the ability to discontinue drug therapy and maintain improvement in urinary incontinence. Combination therapy has a beneficial effect on patient satisfaction, perceived improvement, and reduction of other bladder symptoms.
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