ICU-acquired muscle atrophy occurs commonly and worsens outcomes in adults. The incidence and severity of muscle atrophy in critically ill children are poorly characterized.
To determine incidence, ...severity and risk factors for muscle atrophy in critically ill children.
A single-center, prospective cohort study of 34 children receiving invasive mechanical ventilation for ≥48 hours. Patients 1 week- 18 years old with respiratory failure and without preexisting neuromuscular disease or skeletal trauma were recruited from a tertiary Pediatric Intensive Care Unit (PICU) between June 2015 and May 2016. We used serial bedside ultrasound to assess thickness of the diaphragm, biceps brachii/brachialis, quadriceps femoris and tibialis anterior. Serial electrical impedance myography (EIM) was assessed in children >1 year old. Medical records were abstracted from an electronic database.
Respiratory failure requiring endotracheal intubation for ≥48 hours.
The primary outcome was percent change in muscle thickness. Secondary outcomes were changes in EIM-derived fat percentage and "quality".
Of 34 enrolled patients, 30 completed ≥2 ultrasound assessments with a median interval of 6 (IQR 6-7) days. Mean age was 5.42 years, with 12 infants <1 year (40%) and 18 children >1 year old (60%). In the entire cohort, diaphragm thickness decreased 11.1% (95%CI, -19.7% to -2.52%) between the first two assessments or 2.2%/day. Quadriceps thickness decreased 8.62% (95%CI, -15.7% to -1.54%) or 1.5%/day. Biceps (-1.71%; 95%CI, -8.15% to 4.73%) and tibialis (0.52%; 95%CI, -5.81% to 3.40%) thicknesses did not change. Among the entire cohort, 47% (14/30) experienced diaphragm atrophy (defined a priori as ≥10% decrease in thickness). Eighty three percent of patients (25/30) experienced atrophy in ≥1 muscle group, and 47% (14/30)-in ≥2 muscle groups. On multivariate linear regression, increasing age and traumatic brain injury (TBI) were associated with greater muscle loss. EIM revealed increased fat percentage and decreased muscle "quality".
In children receiving invasive mechanical ventilation, diaphragm and other skeletal muscle atrophy is common and rapid. Increasing age and TBI may increase severity of limb muscle atrophy. Prospective studies are required to link muscle atrophy to functional outcomes in critically ill children.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal ...hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic transplantation. Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including TP53 and PPM1D. Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased. Following autologous transplantation, most clones persist with stable chimerism. However, DNMT3A mutant clones often expand, while PPM1D mutant clones often decrease in size. To assess the leukemic potential of these expanded clones, we genotyped 134 t-AML/t-MDS samples. Mutations in non-TP53 DNA damage response genes are infrequent in t-AML/t-MDS despite several being commonly identified after cytotoxic therapy. These data suggest that different hematopoietic stressors promote the expansion of distinct long-lived clones, carrying specific mutations, whose leukemic potential depends partially on the mutations they harbor.
In patients who had a relapse of acute myeloid leukemia after allogeneic hematopoietic stem-cell transplantation, no characteristic genetic lesions were detected, but alterations in expression of ...genes related to immune function were noted, particularly down-regulation of major histocompatibility complex class II genes.
Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), ...normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is “captured” as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse.
Display omitted
► Normal HSPCs contain random background mutations that increase with aging ► AML genomes contain hundreds of mutations, but very few are recurrent ► Comparison of M1 and M3 AML genomes identifies initiating versus cooperating mutations ► Most AML mutations are probably background events in HSPCs, “captured” by cloning
Comparison of the genomes of two groups of patients, each with a different form of AML, allows the resolution of potential driver and cooperating mutations in each disease and reveals that the genetic history of all AML cases is marked by random, benign mutations acquired by normal HSPCs as a function of age.
Summary
Background
Epidermolysis bullosa simplex generalized severe (EBS‐gen sev) is a genetic disorder caused by mutation in the KRT5 or KRT14 genes. Although it is usually considered a mechanical ...disease, recent data argue for additional inflammatory mechanisms.
Objectives
To assess the inflammation in the skin of patients with EBS‐gen sev.
Methods
A first immunohistochemical retrospective study was performed on frozen skin samples from 17 patients with EBS‐gen sev. A second multicentre prospective study was conducted on 10 patients with severe EBS‐gen sev. Blister fluid and epidermis were processed for immunochemical analysis and quantitative real‐time polymerase chain reaction. Cytokine expression was analysed in blister fluid and compared with that in controls.
Results
Histological analysis showed a constant dermal perivascular CD4+ lymphocyte infiltrate in skin biopsies of both blister (n = 17) and rubbed skin (n = 5), an epidermal infiltration of neutrophils and eosinophils in 70% of cases, and increased immunostaining for CXCL9 and CXCL10 in blistering skin. High levels of T helper 17 cytokines were detected in lesional skin. Three adult patients with EBS‐gen sev were treated with apremilast, with a dramatic improvement of skin blistering and good tolerance.
Conclusions
Our study demonstrates the importance of inflammation in patients with EBS‐gen sev and underlines the key role for T helper 17 cells in its pathogenesis. In addition, this study provides promising new therapeutic approaches for this disabling disorder.
What's already known about this topic?
Epidermolysis bullosa simplex generalized severe (EBS‐gen sev) is a rare disabling skin disorder related to skin fragility.
What does this study add?
We showed the presence of an immune infiltrate characterized by a T helper (Th)17 phenotype in the skin of patients with EBS‐gen sev.
There was a marked improvement of the skin condition in patients with EBS after treatment with apremilast, an anti‐Th17 molecule.
What is the translational message?
Our results demonstrate the importance of inflammation in EBS‐gen sev and underline the key role of Th17 activation.
Anti‐Th17 molecules such as apremilast provide a promising new therapeutic approach for this disabling disorder.
Linked Comment: Mellerio. Br J Dermatol 2019; 180:258–260.
Plain language summary available online
Respond to this article
Vehicular traffic is an ubiquitous source of air pollution in developed nations, yet relatively few epidemiology studies have considered its long-term health effects. This paper uses an areal measure ...of traffic density as a surrogate index of exposure to vehicular traffic. We present associations between county-level traffic density (annual vehicle-km traveled
km
−2), ambient air quality, and mortality in a cohort of about 70,000 male US veterans (the Washington University-EPRI Veterans Cohort) who were enrolled in 1976 and followed through 2001. Traffic density is seen to be a significant and robust predictor of survival in this cohort, more so than ambient air quality, with the possible exception of ozone. Stronger effects of traffic density are seen in the counties that have ambient air quality monitoring data, which also tend to have higher levels of traffic density. These proportional-hazard modeling results indicate only modest changes in traffic-related mortality risks over time, from 1976–2001, despite the decline in regulated tailpipe emissions per vehicle since the mid-1970s. This suggests that other environmental effects may be involved, such as particles from brake, tire, and road wear, traffic noise, psychological stress, and spatial gradients in socioeconomic status.
Depuis 1975, date à laquelle Kohler et Milstein publiaient une méthode permettant de créer efficacement des anticorps monoclonaux, ces molécules ont suscité de gros espoirs pour des utilisations en ...imagerie ou en thérapie, telles les balles magiques dont avait rêvé Paul Ehrlich au début du XX
e siècle. Il a cependant fallu de nombreuses années et de nombreux échecs avant que les anticorps monoclonaux deviennent une réalité pour une utilisation thérapeutique. Le développement des technologies et les premiers succès commerciaux ont cependant changé les choses et l'on peut raisonnablement s'attendre à une croissance explosive du nombre d'anticorps monoclonaux mis sur le marché. Cette revue fait le point sur les technologies clés du domaine et sur les anticorps médicaments disponibles à ce jour.
Since 1975, when Kohler and Milstein developed a procedure to efficiently produce monoclonal antibodies, these molecules gave rise to huge hopes as reagents for imaging or therapy, just like the magic bullets imagined by Paul Ehrlich in the beginning of the twentieth century. However it took numerous years and lots of failures before the concept monoclonal antibodies became a reality in terms of treatment. The development of recombinant antibody technologies and the first commercial successes have changed the way we think about antibodies as medicines, and one can reasonably expects an explosive growth of antibodies approved for medical use. This review gives an update on the key technologies and on antibodies available at this time.
Therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy. There are several ...features that distinguish t-AML from de novo AML, including a higher incidence of TP53 mutations, abnormalities of chromosomes 5 or 7, complex cytogenetics and a reduced response to chemotherapy. However, it is not clear how prior exposure to cytotoxic therapy influences leukaemogenesis. In particular, the mechanism by which TP53 mutations are selectively enriched in t-AML/t-MDS is unknown. Here, by sequencing the genomes of 22 patients with t-AML, we show that the total number of somatic single-nucleotide variants and the percentage of chemotherapy-related transversions are similar in t-AML and de novo AML, indicating that previous chemotherapy does not induce genome-wide DNA damage. We identified four cases of t-AML/t-MDS in which the exact TP53 mutation found at diagnosis was also present at low frequencies (0.003-0.7%) in mobilized blood leukocytes or bone marrow 3-6 years before the development of t-AML/t-MDS, including two cases in which the relevant TP53 mutation was detected before any chemotherapy. Moreover, functional TP53 mutations were identified in small populations of peripheral blood cells of healthy chemotherapy-naive elderly individuals. Finally, in mouse bone marrow chimaeras containing both wild-type and Tp53(+/-) haematopoietic stem/progenitor cells (HSPCs), the Tp53(+/-) HSPCs preferentially expanded after exposure to chemotherapy. These data suggest that cytotoxic therapy does not directly induce TP53 mutations. Rather, they support a model in which rare HSPCs carrying age-related TP53 mutations are resistant to chemotherapy and expand preferentially after treatment. The early acquisition of TP53 mutations in the founding HSPC clone probably contributes to the frequent cytogenetic abnormalities and poor responses to chemotherapy that are typical of patients with t-AML/t-MDS.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
EBS generalized severe is an inflammatory disease Castela, E.; Tulic, M.K.; Rozières, A. ...
British journal of dermatology (1951),
February 2019, 2019-02-00, 20190201, Letnik:
180, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Summary
Epidermolysis bullosa (EB) is a group of genetic disorders in which the skin is abnormally fragile. In EB simplex, the skin cells tend to fall apart because their internal scaffolding of ...keratin fibres is defective, due to mutations in the genes encoding keratins type 5 or 14 (KRT5 and KRT14). But people with the generalised, severe type of EB simplex (EBS‐GS) are sometimes more ill than would be expected just from a mechanical problem with the skin; some even die in infancy, usually from infection. This group from France and Scotland explored the possibility that EBS‐GS patients also have a faulty immune system. They re‐examined skin specimens taken previously for diagnostic purposes from 17 patients with EBS‐GS and also tested fresh skin biopsies and blister fluid from a further 10 patients. They consistently found more inflammatory cells and higher levels of chemicals which promote inflammation (cytokines) than normal. The findings were the same regardless of whether the sample was from blistered or normal‐looking skin and whether the fault was in KRT5 or KRT14. Markers for the cytokine Th17 were particularly high, encouraging them to treat three EBS‐GS patients with the anti‐Th17 drug Apremilast as used in psoriasis. All three reported a dramatic reduction in blisters within the first month, which lasted throughout treatment for up to 10 months, with minimal side‐effects. One patient stopped the Apremilast after 7 months because of nausea and the blistering came back 2 days later. This appears to be a promising new approach to treating EBS‐GS.
Linked Article: Castela et al. Br J Dermatol 2019; 180:357–364
PDF
