Current epigenetic aspects the clinical kidney researcher should embrace

Chronic kidney disease (CKD), affecting 10-12% of the world's adult population, is associated with a considerably elevated risk of serious comorbidities, in particular, premature vascular disease and death. Although a wide spectrum of causative factors has been identified and/or suggested, there is still a large gap of knowledge regarding the underlying mechanisms and the complexity of the CKD phenotype. Epigenetic factors, which calibrate the genetic code, are emerging as important players in the CKD-associated pathophysiology. In this article, we review some of the current knowledge on epigenetic modifications and aspects on their role in the perturbed uraemic milieu, as well as the prospect of applying epigenotype-based diagnostics and preventive and therapeutic tools of clinical relevance to CKD patients. The practical realization of such a paradigm will require that researchers apply a holistic approach, including the full spectrum of the epigenetic landscape as well as the variability between and within tissues in the uraemic milieu

Arrival-angle anomalies across the USArray Transportable Array

We construct composite maps of surface-wave arrival-angle anomalies using clustered earthquakes and an array method for measuring wave-front geometry. This results in observations of arrival angles covering the entire footprint of the USArray Transportable Array during 2006–2010. Bands of arrival-angle deviations in the propagation direction indicate the presence of heterogeneous velocity structure both inside and outside of the array. We compare the observed patterns to arrival angles predicted using two global tomographic models, the mantle model S362ANI and the surface-wave-dispersion model GDM52. We use both ray-theory-based prediction methods and measurements on synthetic data calculated using a spectral-element method. Both models and all prediction methods produce similar mean arrival angles and long-wavelength patterns of anomalies which are similar to the observations. Predicted short-wavelength features generally do not agree with the observations. The spectral-element method produces some complexity that is not obtained using the ray-theory-based methods; this predicted complexity is similar in character to the observed patterns, but does not match them

Gene Expression Profiling of Peri-Implant Healing of PLGA-Li+ Implants Suggests an Activated Wnt Signaling Pathway In Vivo

Bone development and regeneration is associated with the Wnt signaling pathway that, according to literature, can be modulated by lithium ions (Li+). The aim of this study was to evaluate the gene expression profile during peri-implant healing of poly(lactic-co-glycolic acid) (PLGA) implants with incorporated Li+, while PLGA without Li+ was used as control, and a special attention was then paid to the Wnt signaling pathway. The implants were inserted in rat tibia for 7 or 28 days and the gene expression profile was investigated using a genome-wide microarray analysis. The results were verified by qPCR and immunohistochemistry. Histomorphometry was used to evaluate the possible effect of Li+ on bone regeneration. The microarray analysis revealed a large number of significantly differentially regulated genes over time within the two implant groups. The Wnt signaling pathway was significantly affected by Li+, with approximately 34% of all Wnt-related markers regulated over time, compared to 22% for non-Li+ containing (control; Ctrl) implants. Functional cluster analysis indicated skeletal system morphogenesis, cartilage development and condensation as related to Li+. The downstream Wnt target gene, FOSL1, and the extracellular protein-encoding gene, ASPN, were significantly upregulated by Li+ compared with Ctrl. The presence of beta-catenin, FOSL1 and ASPN positive cells was confirmed around implants of both groups. Interestingly, a significantly reduced bone area was observed over time around both implant groups. The presence of periostin and calcitonin receptor-positive cells was observed at both time points. This study is to the best of the authors' knowledge the first report evaluating the effect of a local release of Li+ from PLGA at the fracture site. The present study shows that during the current time frame and with the present dose of Li+ in PLGA implants, Li+ is not an enhancer of early bone growth, although it affects the Wnt signaling pathway

Samarbetsprojekt för effektivare brobyggande

Den svenska anläggningsbranschen har i ett flertal utredningar fått skarp kritik på grund av dålig produktivitet. Forskning visar på samma tendenser i övriga Europa och USA. Vissa mätningar tyder på att byggandet i den svenska anläggningsbranschen har en kostnadsökning som är dubbelt så hög jämfört med övriga branscher under de senaste 20 åren. Låg produktivitet och låg innovationsförmåga i byggbranschen leder till högre kostnader som inte garanterat ger en högre kvalitet. Trenden behöver vändas så att avkastningen på investeringar i vår infrastruktur ökar! Det första steget är att integrera konstruktions- och produktionsprocesserna, vilket ger kortare ledtider för både planering och uppförande av byggnadsverk. Onödigt långa byggtider orsakar störningar för andra aktörer i samhället. I ett pågående doktorandprojekt, som är ett samarbete mellan Trafikverket, WSP och Chalmers, söks möjligheten till att öka produktiviteten inom den svenska anläggningsbranschen. Huvudspåret är att utveckla och industrialisera brobyggandet. En effektivare byggindustri skapar möjligheter till att generera ett mervärde för samhället där mervärdet exempelvis kan motsvaras av att konstruktioner byggs med högre kvalitet till samma kostnad som idag alternativt samma eller högre kvalitet till en lägre kostnad än idag. Bortsett från rena kostnader bör naturligtvis en effektivare byggindustri också se till att lösningar väljs utifrån ett hållbart samhälle men med bibehållen fokus på produktivitet och innovation. En sådan lösning kan variera från själva processen till konstruktionsdetaljer

Comparing recalled versus experienced symptoms of breathlessness ratings: An ecological assessment study using mobile phone technology

Background and objective: Recall of breathlessness is important for clinical care but might differ from the experienced (momentary) symptoms. This study aimed to characterize the relationship between momentary breathlessness ratings and the recall of the experience. It is hypothesized that recall is influenced by the peak (worst) and end (most recent) ratings of momentary breathlessness (peak-end rule). Methods: This study used mobile ecological momentary assessment (mEMA) for assessing breathlessness in daily life through an application installed on participants' mobile phones. Breathlessness ratings (0–10 numerical rating scale) were recorded throughout the day and recalled each night and at the end of the week. Analyses were performed using regular and mixed linear regression. Results: Eighty-four people participated. Their mean age was 64.4 years, 60% were female and 98% had modified Medical Research Council (mMRC) ≥ 1. The mean number of momentary ratings of breathlessness provided was 7.7 ratings/participant/day. Recalled breathlessness was associated with the mean, peak and end values of the day. The mean was most closely associated with the daily recall. Associations were strong for weekly values: peak breathlessness (beta=0.95, r2= 0.57); mean (beta=0.91, r2= 0.53); and end (beta=0.67, r2= 0.48); p< 0.001 for all. Multivariate analysis showed that peak breathlessness had the strongest influence on the breathlessness recalled at the end of the week. Conclusion: Over 1 week, recalled breathlessness is most strongly influenced by the peak breathlessness; over 1 day, it is mean breathlessness that participants most readily recalled

The battle for COVID-19 vaccines highlights the need for a new global governance mechanism

To the Editor—Although the rapid development of several vaccines against COVID-19 is an unparalleled scientific accomplishment, one made possible through the collaboration of researchers, industry and funding bodies, the absence of a system that secures equitable access to vaccines has uncovered deep fissures in the global governance systems for health, as noted in a recent Nature Medicine Editorial. For example, advance purchase agreements for vaccines against COVID-19 have favored affluent countries, allowing them to secure 150–500% of their predicted needs, while many citizens of low-and middle-income countries (LMICs) will remain unvaccinated until 2024. Additionally, the power of patent-holders and pharmaceutical companies to place conditions on the use of vaccines prices out access for LMICs, and bilateral purchasing deals are rarely disclosed. By affording priority on the basis of economic or political power, today’s discourse clearly deviates from previous ethical and public-health principles of maximizing lives or life-years saved, and the sentiment that “people’s entitlement to lifesaving resources should not depend on nationality”. The COVID-19 pandemic has tested wealthy nations’ commitments to Agenda 2030 and to ‘leaving no one behind’ at the same time that it has revealed democratic deficits, institutional rigidity, weak accountability systems, and inadequate policy space that protects health-governance systems from economic goals. Thus, the as-yet-limited support for the vaccine-sharing and allocation principles of the COVAX initiative may be a sign not only of a moral catastrophe, to quote the director-general of the World Health Organization (WHO), but also of inadequate global accountability mechanisms that exposes the consequences of commercial determinants of health

Relating Experienced To Recalled breathlessness Observational (RETRO) study: a prospective study using a mobile phone application

Background: Breathlessness, the subjective sensation of breathing discomfort, is common and appears in the daily life of people with cardiorespiratory diseases. Physicians often rely on patient's history based on symptom recall. The relation between recalled and experienced breathlessness is still poorly understood. This paper presents the protocol for a study primarily aimed at evaluating the relationship between experienced breathlessness and (1) recalled breathlessness and (2) predicted future breathlessness. Methods: A mobile phone application will be used to collect data during daily life. Medically stable participants, >= 18 years of age with mean daily breathlessness of Numerical Rating Scale (NRS) 3/10 and able to use a mobile phone with internet will rate their breathlessness intensity on a 0-10 NRS prompted the user several times daily for 1 week. Participants will recall their breathlessness each day and week. Multivariable random effects regression models will be used for statistical analyses. Results: Results of the study will be submitted for publication in peer-reviewed journals and presented at relevant conferences. Discussion: This protocol describes a study aimed at investigating previously unknown areas of the experience and recall of breathlessness using a new method of data collection.Scientific Committee of Blekinge County Council; Swedish Society of Medicine; Swedish Respiratory Society; Swedish Heart-Lung Foundation; Wera and Emil Cornell Foundation; Swedish Society for Medical ResearchOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Immunomodulatory effects exerted by extracellular vesicles from <i>Staphylococcus epidermidis</i> and <i>Staphylococcus aureus</i> isolated from bone-anchored prostheses

Staphylococcus aureus and Staphylococcus epidermidis are the bacteria that most frequently cause osteomyelitis. This study aimed to determine whether staphylococci isolated from osteomyelitis associated with septic loosening of orthopedic prostheses release extracellular vesicles (EVs) and, if so, to determine tentative immunomodulatory effects on the human monocytic cell line THP-1. EVs were isolated from bacterial cultures using filtration and ultracentrifugation and characterized by scanning electron microscopy, nanoparticle tracking analysis and Western Blot. The cytotoxic effect of EVs was analyzed by NucleoCounter and lactate dehydrogenase (LDH) analyses. Confocal laser scanning microscopy was employed to visualize the uptake of EVs by THP-1 cells. Activation of the transcription factor nuclear factor-κB (NF-κB) was determined in THP1-Blue™ NF-κB cells, and the gene expression and secretion of cytokines were determined by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. All investigated strains, irrespective of their biofilm formation ability, were able to secrete EVs in vitro. The S. aureus strains produced significantly more EVs than the S. epidermidis strains. Both S. aureus-derived EVs and S. epidermidis-derived EVs were internalized by THP-1 cells, upregulated Toll-like receptor 3 (TLR3) gene expression, activated NF-κB, and promoted the gene expression and secretion of interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1, matrix metallopeptidase (MMP)-9 and IL-10. Whereas EVs from both staphylococcal species upregulated the proapoptotic DNA damage-inducible transcript 4 (DDIT4) gene and downregulated the antiapoptotic B-cell lymphoma 2 (Bcl-2) gene, cytolysis was preferentially induced in S. aureus EV-stimulated cells, possibly related to the expression of cytolytic proteins predominantly in S. aureus EVs. In conclusion, staphylococcal EVs possess potent cytolytic and immunomodulatory properties

Electrostimulation of the lingual nerve by an intraoral device may lead to salivary gland regeneration : a case series study

Salivary gland function is controlled by the salivary reflex, whose efferent arm is composed by the parasympathetic and the sympathetic divisions of the autonomic nervous system. Parenchymal injury is the main salivary gland involvement of Sjögren?s syndrome and head and neck radiotherapy, but neural damage has been reported as well. Recently an intraoral device for electrostimulation of the lingual nerve in vicinity to the lower third molar has been introduced. At this point this nerve carries efferent fibers for the innervation of the submandibular, sublingual and several minor salivary glands and afferent fibers of the salivary reflex. Therefore, excitation of these fibers potentially leads to increased secretion of all salivary glands. Thus, the study objective was to assess whether comprehensive neural activation by electrostimulation of the lingual nerve carries the potential to induce the regeneration of damaged salivary glands. The device was tested on three patients with no collectable resting and stimulated secretion of saliva during a double blind, sham controlled period of two months and nine open-label months. All three subjects developed the capacity to spit saliva, not only in direct response to the electrostimulation but also after free intervals without electrostimulation. In addition, their symptoms of dry mouth severity and frequency improved. This recovery is probably due to the combined effect of increase in secretory functional gland mass and regain of nervous control of the secretory elements and blood vessels. Both are phenomena that would contribute to gland regeneration

The Visually Related Posterior Pretectal Nucleus in the Non-Percomorph Teleost Osteoglossum bicirrhosum Projects to the Hypothalamus

This study was done to elucidate the ancestral (plesiomorphic) condition for visual pathways to the hypothalamus in teleost fishes. Three patterns of pretectal organization can be discerned morphologically and histochemically in teleosts. Their taxonomic distribution suggests that the intermediately complex pattern (seen in most teleost groups) is ancestral to both the elaborate pattern (seen in percomorphs) and the simple pattern (seen in cyprinids). The pretectal nuclei involved can be demonstrated with acetylcholinesterase histochemistry selectively and reliably in different species of teleosts, suggesting that the same-named nuclei are homologous in representatives of the three different patterns. Whereas there are visual pathways to the hypothalamus in both the elaborate (percomorph) and the simple (cyprinid) patterns, different pretectal and hypothalamic nuclei are involved. Thus visual hypothalamic pathways in these two patterns would not appear to be homologous. In this study, circuitry within the third, i.e., the intermediately complex, pattern is investigated. It is demonstrated that visual pathways project via the pretectum to the hypothalamus in Osteoglossum bicirrhosum and that they are very similar to the visual pathways in the elaborate pattern. This suggests that the circuitry in the intermediately complex pattern, as represented by Osteoglossum, is plesiomorphic (evolutionarily primitive) and the circuitry in both the simple pattern (seen in cyprinids) and the elaborate pattern (seen in percomorphs) is apomorphic (evolutionarily derived) for teleosts