Short and Extended Provocation Tests Have Similar Negative Predictive Value in Non-Immediate Hypersensitivity to Beta-Lactams in Children

Drug provocation tests (DPTs) are the gold-standard method to diagnose non-immediate hypersensitivity reactions (NIHSR) to beta-lactam antibiotics (BL) in children. Our aim was to compare the negative predictive value (NPV) of one-day (short) DPT versus 3-7 days (extended) DPT for the diagnosis of NIHSR to BL in paediatric age. A secondary aim was to compare confidence on drug re-exposure after short and extended negative DPTs.info:eu-repo/semantics/publishedVersio

Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease.

Mycobacterium ulcerans infection causes a neglected tropical disease known as Buruli ulcer that is now found in poor rural areas of West Africa in numbers that sometimes exceed those reported for another significant mycobacterial disease, leprosy, caused by M. leprae. Unique among mycobacterial diseases, M. ulcerans produces a plasmid-encoded toxin called mycolactone (ML), which is the principal virulence factor and destroys fat cells in subcutaneous tissue. Disease is typically first manifested by the appearance of a nodule that eventually ulcerates and the lesions may continue to spread over limbs or occasionally the trunk. The current standard treatment is 8 weeks of daily rifampin and injections of streptomycin (RS). The treatment kills bacilli and wounds gradually heal. Whether RS treatment actually stops mycolactone production before killing bacilli has been suggested by histopathological analyses of patient lesions. Using a mouse footpad model of M. ulcerans infection where the time of infection and development of lesions can be followed in a controlled manner before and after antibiotic treatment, we have evaluated the progress of infection by assessing bacterial numbers, mycolactone production, the immune response, and lesion histopathology at regular intervals after infection and after antibiotic therapy. We found that RS treatment rapidly reduced gross lesions, bacterial numbers, and ML production as assessed by cytotoxicity assays and mass spectrometric analysis. Histopathological analysis revealed that RS treatment maintained the association of the bacilli with (or within) host cells where they were destroyed whereas lack of treatment resulted in extracellular infection, destruction of host cells, and ultimately lesion ulceration. We propose that RS treatment promotes healing in the host by blocking mycolactone production, which favors the survival of host cells, and by killing M. ulcerans bacilli

Frequent and Persistent PLCG1 Mutations in Sezary Cells Directly Enhance PLC gamma 1 Activity and Stimulate NF kappa B, AP-1, and NFAT Signaling

Phospholipase C Gamma 1 (PLCG1) is frequently mutated in primary cutaneous T-cell lymphoma (CTCL). This study functionally interrogated nine PLCG1 mutations (p.R48W, p.S312L, p.D342N, p.S345F, p.S520F, p.R1158H, p.E1163K, p.D1165H, and the in-frame indel p.VYEEDM1161V) identified in Sézary Syndrome, the leukemic variant of CTCL. The mutations were demonstrated in diagnostic samples and persisted in multiple tumor compartments over time, except in patients who achieved a complete clinical remission. In basal conditions, the majority of the mutations confer PLCγ1 gain-of-function activity through increased inositol phosphate production and the downstream activation of NFκB, AP-1, and NFAT transcriptional activity. Phosphorylation of the p.Y783 residue is essential for the proximal activity of wild-type PLCγ1, but we provide evidence that activating mutations do not require p.Y783 phosphorylation to stimulate downstream NFκB, NFAT, and AP-1 transcriptional activity. Finally, the gain-of-function effects associated with the p.VYEEDM1161V indel suggest that the C2 domain may have a role in regulating PLCγ1 activity. These data provide compelling evidence to support the development of therapeutic strategies targeting mutant PLCγ1

Evaluation of matrix metalloproteinases-2 and-9 in cats under bone demineralization secondary to induced thyrotoxicosis

Significant increase of activity of active forms of matrix metalloproteinases -2 and -9 in cats under induced thyrotoxicosis and bone demineralization was observed. Pro and intermediated forms of matrix metalloproteinases -2 and -9 increased at 14 days of hormonal treatment, followed by decrease tendency. A negative correlation between active forms of matrix metalloproteinases -2 and -9 and bone mineral density of radius distal extremity was also observed. The results suggest an increase of collagen matrix degradation secondary to high levels of thyroid hormones.6051053106

The Impact of Donor Risk Index, Recipients’ and Operative Characteristics on Post Liver Transplant One-Year Graft Failure: A Cohort Analysis

Background and Aims: The donor risk index (DRI) quantifies donor-related characteristics potentially associated with increased risk of early graft failure. We aimed to assess the impact of the DRI, recipient and perioperative factors on post liver transplant (LT) outcomes. Methods: This was a singlecenter retrospective cohort study including all adult (≥18 years) patients who underwent LT from 01/2019 to 12/2019 at Curry Cabral Hospital, Lisbon, Portugal. Primary endpoint was 1-year graft failure post LT. Associations were studied with logistic regression. Results: A total of 131 cadaveric donor LT procedures were performed in 116 recipients. Recipients’ median (IQR) age was 57 (47–64) years and 101/131 (77.1%) were males. Cirrhosis was the underlying etiology in 95/131 (81.2%) transplants. Based on 8 predefined donors’ characteristics, median (IQR) DRI was 1.96 (1.67–2.16). Following adjustment for MELDNa score pre LT and SOFA score (adjusted odds ratio [aOR], 95% confidence interval [CI] = 0.91 [0.56–1.47]) or lactate (aOR [95% CI] = 2.76 [0.71–10.7]) upon intensive care unit (ICU) admission post LT, DRI was not associated with 1-year graft failure. However, higher SOFA score (aOR [95% CI] = 1.20 [1.05–1.37]) or lactate (aOR [95% CI] = 1.27 [1.10–1.46]) upon ICU admission post LT were independently associated with higher odds of 1-year graft failure. Conclusions: In a recent cohort of patients who underwent LT, DRI, despite being high, was not associated with 1-year graft failure, but SOFA score or lactate upon ICU admission post LT were.info:eu-repo/semantics/publishedVersio

Low and moderate, rather than high intensity strength exercise induces benefit regarding plasma lipid profile

<p>Abstract</p> <p>Background</p> <p>The effects of chronic aerobic exercise upon lipid profile has been previously demonstrated, but few studies showed this effect under resistance exercise conditions.</p> <p>Objective</p> <p>The aim of this study was to examine the effects of different resistance exercise loads on blood lipids.</p> <p>Methods</p> <p>Thirty healthy, untrained male volunteers were allocated randomly into four groups based at different percentages of one repetition maximum (1 RM); 50%-1 RM, 75%-1 RM, 90%-1 RM, and 110%-1 RM. The total volume (sets × reps × load) of the exercise was equalized. The lipid profile (Triglycerides [TG], HDL-cholesterol [HDL-c], LDL-cholesterol, and Total cholesterol) was determined at rest and after 1, 24, 48 and 72 h of resistance exercise.</p> <p>Results</p> <p>The 75%-1 RM group demonstrated greater TG reduction when compared to other groups (p < 0.05). Additionally, the 110%-1 RM group presented an increased TG concentration when compared to 50% and 75% groups (p = 0.01, p = 0.01, respectively). HDL-c concentration was significantly greater after resistance exercise in 50%-1 RM and 75%-1 RM when compared to 110%-1 RM group (p = 0.004 and p = 0.03, respectively). Accordingly, the 50%-1 RM group had greater HDL-c concentration than 110%-1 RM group after 48 h (p = 0.05) and 72 h (p = 0.004), respectively. Finally, The 50% group has showed lesser LDL-c concentration than 110% group after 24 h (p = 0.007). No significant difference was found in Total Cholesterol concentrations.</p> <p>Conclusion</p> <p>These results indicate that the acute resistance exercise may induce changes in lipid profile in a specific-intensity manner. Overall, low and moderate exercise intensities appear to be promoting more benefits on lipid profile than high intensity. Long term studies should confirm these findings.</p

Therapeutic Activity of Superoxide Dismutase-Containing Enzymosomes on Rat Liver Ischaemia-Reperfusion Injury Followed by Magnetic Resonance Microscopy

Liver ischaemia-reperfusion injury (IRI) may occur during hepatic surgery and is unavoidable in liver transplantation. Superoxide dismutase enzymosomes (SOD-enzymosomes), liposomes where SOD is at the liposomal surface expressing enzymatic activity in intact form without the need of liposomal disruption, were developed with the aim of having a better insight into its antioxidant therapeutic outcome in IRI. We also aimed at validating magnetic resonance microscopy (MRM) at 7T as a tool to follow IRI. SOD-enzymosomes were characterized and tested in a rat ischaemia-reperfusion model and the therapeutic outcome was compared with conventional long circulating SOD liposomes and free SOD using biochemical liver injury biomarkers, histology and MRM. MRM results correlated with those obtained using classical biochemical biomarkers of liver injury and liver histology. Moreover, MRM images suggested that the therapeutic efficacy of both SOD liposomal formulations used was related to prevention of peripheral biliary ductular damage and disrupted vascular architecture. Therefore, MRM at 7T is a useful technique to follow IRI. SOD-enzymosomes were more effective than conventional liposomes in reducing liver ischaemia-reperfusion injury and this may be due to a short therapeutic window.info:eu-repo/semantics/publishedVersio

IL-17 Produced during Trypanosoma cruzi Infection Plays a Central Role in Regulating Parasite-Induced Myocarditis

Chagas disease is caused by the intracellular parasite Trypanosoma cruzi. This infection has been considered one of the most neglected diseases and affects several million people in the Central and South America. Around 30% of the infected patients develop digestive and cardiac forms of the disease. Most patients are diagnosed during the chronic phase, when the treatment is not effective. Here, we showed by the first time that IL-17 is produced during experimental T. cruzi infection and that it plays a significant role in host defense, modulating parasite-induced myocarditis. Applying this analysis to humans could be of great value in unraveling the elements involved in the pathogenesis of chagasic cardiopathy and could be used in the development of alternative therapies to reduce morbidity during the chronic phase of the disease, as well as clinical markers of disease progression. The understanding of these aspects of disease may be helpful in reducing the disability-adjusted life years (DALYs) and costs to the public health service in developing countries