Since the introduction of the combined antiretroviral therapy, HIV‐1 infection has become a manageable chronic disease in which patients display a life expectancy almost identical to the general ...population. Nevertheless, various age‐related pathologies such as neurocognitive disorders have emerged as serious complications. A “shock and kill” strategy using latency‐reversing agents (LRA) to reactivate HIV‐1 has been proposed to eliminate the viral reservoir in such chronically infected patients. However, the impact of LRA on the central nervous system remains elusive. Given that an increased amyloid beta (Aβ) deposition is a feature of HIV‐1‐infected brains, we investigated the consequences of HIV‐1 infection and treatment with two LRA (bryostatin‐1 and JQ1) on the capacity of human astrocytes to engulf and clear Aβ. We show here that HIV‐1‐infected astrocytes accumulate a very high amount of Aβ compared to uninfected cells, but the engulfed peptide in degraded very slowly. The LRA bryostatin‐1 induces a reduction in Aβ endocytosis, whereas JQ1 treatment results in a very slow degradation of the ingested material associated with a reduced expression of the endopeptidase neprilysin. An exposure to JQ1 also induces a sustained release of Aβ‐loaded microvesicles. Thus, both HIV‐1 infection and treatment with some LRA could contribute to the reported Aβ accumulation in the brain of HIV‐1‐infected persons.
Main Points
Infection by HIV‐1 and treatment by latency reversing agents Bryostatin‐1 and JQ1 modify beta‐amyloid uptake and degradation by astrocytes.
JQ1 induced the release of amyloid loaded microvesicles.
Les hémangiomes du nourrisson représentent les plus communes des tumeurs bénignes du nourrisson. Le pronostic fonctionnel, ou exceptionnellement vital, est en jeu dans 10 à 20 % des cas et justifie ...l’instauration d’un traitement systémique.
Une enfant de 8 mois, présente depuis sa naissance un volumineux hémangiome de l’avant-bras gauche de 12cm×10cm de diamètre et de 4cm d’épaisseur, compliqué récemment en son centre d’une ulcération de 5cm de diamètre, douloureuse et résistante aux antalgiques de palier 1. Adressée initialement pour des séances de laser à colorant pulsé, un traitement complémentaire par voie générale s’avère indispensable et une thérapeutique par bêtabloquants est proposée aux parents. En l’absence de contre-indication, le propanolol, bêta 1 et 2 bloqueur non cardiosélectif est instauré à la posologie de 2mg/kg/24h (Avlocardyl®, présentation injectable en ampoule de 5mg/5ml administrée par voie orale). Une surveillance stricte électrocardiographique et tensionnelle est réalisée, d’abord hebdomadaire pendant 15 j puis espacée tous les 15j les 2 mois suivants. L’efficacité remarquable de cette thérapeutique tant sur la qualité de cicatrisation que sur la rapidité de l’affaissement de l’hémangiome permet un arrêt progressif de cette molécule sur 1 mois ½.
Si la corticothérapie générale est le traitement de référence dans la prise en charge des hémangiomes à problème en phase proliférative chez le nourrisson, la fréquence de ses complications et le recours fréquent à la chirurgie ou l’embolisation impose le choix d’autres alternatives thérapeutiques. La classe des bêtabloquants semble incontournable dans cette indication. Les modalités d’administration et de suivi ambulatoire sont discutées.
Hemangioma is the most common tumor of infancy. Ulceration and functional prognosis justify systemic treatment.
We report the case of an 8-month-old girl with a voluminous ulcerated hemangioma of the left forearm with a large, painful, central ulceration. Conventional treatment with topical and/or systemic antibiotics was unsuccessful. Flashlamp-pumped pulsed-dye laser (FPDL) could not be used because of the thickness of the lesions. We decided to use beta-blocker therapy (propanolol) for 4 months with a noteworthy efficacy.
Systemic corticosteroids and FPDL are currently the reference treatment of the superficial hemangioma during infancy, but the head and neck location or complications such as ulceration or the need for surgical embolization require the use of alternative treatments such as the beta-blocker. We discuss this option.
The interaction of the osmolytes trimethylamine N-oxide (TMAO) and urea in aqueous solutions at 40 °C was investigated by isotopic substitution neutron scattering at a TMAO mole fraction of 0.05 and ...TMAO/urea concentration ratios of 1 : 2 and 1 : 4. The partial pair distribution functions obtained by the empirical potential structure refinement method are consistent with those obtained previously for similar pure TMAO and 1 : 1 TMAO-urea solutions and indicate that urea progressively replaces the water molecules in the first coordination shell of the TMAO oxygen atom. The apparent association constant for the TMAO : urea complex (K(1)) was calculated to be 0.14 M(-1), which is of the same order as the experimental urea-protein binding constants per site reported in the literature. This confirms that the two osmolytes act independently at least in the physiological range.
Purpose
Increased blood glucose level (BGL) has been reported to cause alterations of FDG uptake in the brain that mimic Alzheimer’s disease (AD), even within the "acceptable" range ≤ 160 mg/dl. The ...aim of this study was (i) to confirm this in a large sample of well-characterized normal control (NC) subjects, and (ii) to analyze its impact on the prediction of AD dementia (ADD) in mild cognitive impairment (MCI).
Methods
The study included NCs from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) that were cognitively stable for ≥36 months after PET (
n
= 87, 74.2 ± 5.3 y), and ADNI MCIs with ≥36 months follow-up if not progressed to ADD earlier (
n
= 323, 71.1 ± 7.1 y). Seventy-three of the MCIs had progressed to ADD within 36 months. In the NCs, parenchyma-scaled FDG uptake was tested for clusters of correlation with BGL on the family-wise, error-corrected 5% level. In the MCIs, ROC analysis was used to assess the power of FDG uptake in a predefined AD-typical region for prediction of ADD. ROC analysis was repeated after correcting mean FDG uptake in the AD-typical region for BGL based on linear regression in the NCs.
Results
In the NCs, BGL (59–149 mg/dl) was negatively correlated with FDG uptake in a cluster comprising the occipital cortex and precuneus but sparing the posterior cingulate, independent of amyloid-β and ApoE4 status. In the MCIs, FDG uptake in the AD-typical region provided an area of 0.804 under the ROC curve for prediction of ADD. Correcting FDG uptake in the AD-typical region for BGL (55–189 mg/dl) did not change predictive performance (area = 0.808,
p
= 0.311).
Conclusions
Increasing BGL is associated with relative reduction of FDG uptake in the posterior cortex even in the "acceptable" range ≤ 160 mg/dl. The BGL-associated pattern is similar to the typical AD pattern, but not identical. BGL-associated variability of regional FDG uptake has no relevant impact on the power of FDG PET for prediction of MCI-to-ADD progression.
Lung cancer (LC) patients experience high symptom burden and significant decline of physical fitness and quality of life following lung resection. Good quality of survivorship care post-surgery is ...essential to optimize recovery and prevent unscheduled healthcare use. The use of Information and Communication Technology (ICT) can improve post-surgery care, as it enables frequent monitoring of health status in daily life, provides timely and personalized feedback to patients and professionals, and improves accessibility to rehabilitation programs. Despite its promises, implementation of telehealthcare applications is challenging, often hampered by non-acceptance of the developed service by its end-users. A promising approach is to involve the end-users early and continuously during the developmental process through a so-called user-centred design approach. The aim of this article is to report on this process of co-creation and evaluation of a multimodal ICT-supported cancer rehabilitation program with and for lung cancer patients treated with lung resection and their healthcare professionals (HCPs).
A user-centered design approach was used. Through semi-structured interviews (n = 10 LC patients and 6 HCPs), focus groups (n = 5 HCPs), and scenarios (n = 5 HCPs), user needs and requirements were elicited. Semi-structured interviews and the System Usability Scale (SUS) were used to evaluate usability of the telehealthcare application with 7 LC patients and 10 HCPs.
The developed application consists of: 1) self-monitoring of symptoms and physical activity using on-body sensors and a smartphone, and 2) a web based physical exercise program. 71 % of LC patients and 78 % of HCPs were willing to use the application as part of lung cancer treatment. Accessibility of data via electronic patient records was essential for HCPs. LC patients regarded a positive attitude of the HCP towards the application essential. Overall, the usability (SUS median score = 70, range 35-95) was rated acceptable.
A telehealthcare application that facilitates symptom monitoring and physical fitness training is considered a useful tool to further improve recovery following surgery of resected lung cancer (LC) patients. Involvement of end users in the design process appears to be necessary to optimize chances of adoption, compliance and implementation of telemedicine.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An increased incidence of skin inflammatory diseases is frequently observed in organtransplanted patients being treated with calcineurin inhibitor-based immunosuppressive agents. The mechanism of ...increased skin inflammation in this context has however not yet been clarified. Here we report an increased inflammation following inhibition of calcineurin signaling seen in both chemically induced mouse skin tumors and in tumors grafted from H-rasV12 expressing primary human keratinocytes (HKCs). Following UVB or TPA treatment, we specifically found that deletion of the calcineurin gene in mouse keratinocytes (MKCs) resulted in increased inflammation, and this was accompanied by the enhanced production of pro-inflammatory cytokines, such as TNFα, IL-8 and CXCL1. Furthermore, expression of the RNA-binding protein, tristetraprolin (TTP) was down-regulated in response to calcineurin inhibition, wherein TTP was shown to negatively regulate the production of pro-inflammatory cytokines in keratinocytes. The induction of TTP following TPA or UVB treatment was attenuated by calcineurin inhibition in keratinocytes, and correspondingly, disruption of calcineurin signaling down-regulated the amounts of TTP in both clinical and H-rasV12-transformed keratinocyte tumor models. Our results further demonstrated that calcineurin positively controls the stabilization of TTP in keratinocytes through a proteasome-dependent mechanism. Reducing the expression of TTP functionally promoted tumor growth of H-rasV12 expressing HKCs, while stabilizing TTP expression counteracted the tumor-promoting effects of calcineurin inhibition. Collectively these results suggest that calcineurin signaling, acting through TTP protein level stabilization, suppresses keratinocyte tumors by downregulating skin inflammation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Inborn errors of immunity are mostly monogenic. However, disease phenotype and outcome may be modified by the coexistence of a second gene defect.
We sought to identify the genetic basis of the ...disease in a patient who experienced bleeding episodes, pancytopenia, hepatosplenomegaly, and recurrent pneumonia that resulted in death.
Genetic analysis was done using next-generation sequencing. Protein expression and phosphorylation were determined by immunoblotting. T-cell proliferation and F-actin levels were studied by flow cytometry.
The patient harbored 2 homozygous deletions in STX11 (c.369_370del, c.374_376del; p.V124fs60∗) previously associated with familial hemophagocytic lymphohistiocytosis and a novel homozygous missense variant in SLP76 (c.767C>T; p.T256I) that resulted in an approximately 85% decrease in SLP76 levels and absent T-cell proliferation. The patient's heterozygous family members showed an approximately 50% decrease in SLP76 levels but normal immune function. SLP76-deficient J14 Jurkat cells did not express SLP76 and had decreased extracellular signal-regulated kinase signaling, basal F-actin levels, and polymerization following T-cell receptor stimulation. Reconstitution of J14 cells with T256I mutant SLP76 resulted in low protein expression and abnormal extracellular signal-regulated kinase phosphorylation and F-actin polymerization after T-cell receptor activation compared with normal expression and J14 function when wild-type SLP76 was introduced.
The hypomorphic mutation in SLP76 tones down the hyperinflammation due to STX11 deletion, resulting in a combined immunodeficiency that overshadows the hemophagocytic lymphohistiocytosis phenotype. To our knowledge, this study represents the first report of the opposing effects of 2 gene defects on the disease in a patient with an inborn error of immunity.
The search for practical solutions to alleviate the destructive impact of petroleum hydrocarbons in marine environments is contributing to the implementation of prospecting strategies for indigenous ...microorganisms with biodegradative and bioremediation potential. The levels of petroleum contamination entering the marine environment each year have been estimated at around 1.3 million tonnes, a figure that is expected to increase by 1.9% annually over the next decade. The recent interest in decarbonizing our energy system and accelerating the clean energy transition has created a demand for greener technologies and strategies to find innovative, sustainable, and cost-effective treatments for the marine environment. Diatoms (Bacillariophyta) are one of the most diverse and successful taxa in coastal–marine environments and are a relatively untapped pool of biodiversity for biotechnological applications. Recent reports have revealed the significant presence of diatoms associated with oil spills and petroleum hydrocarbon degradation. Most diatoms can secrete substantial amounts of exopolysaccharides (EPSs) into their environment, which can act as biosurfactants that, in addition to oxygen and other enzymes produced by diatoms, create suitable conditions to enhance hydrocarbon solubility and degradation into less toxic compounds in seawater. Recent reports on the biodegradation of aliphatic and aromatic hydrocarbons by diatoms are indicative of the potential of these taxa to achieve success in the bioremediation of hydrocarbons in marine environments. This review highlights the main attributes and roles that diatoms could play in integrated strategies for biodegradation and bioremediation of petroleum hydrocarbon pollutants and as such represent a green, eco-friendly, and sustainable contribution to mitigate damage to biodiversity and value chains of marine ecosystems.
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