Mastocytosis presenting with mast cell-mediator release-associated symptoms elicited by cyclo oxygenase inhibitors: prevalence, clinical, and laboratory features

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently avoided in mastocytosis, because of a potential increased risk for drug hypersensitivity reactions (DHRs) due to inhibition of cyclo-oxygenase (COX), subsequent depletion of prostaglandin E2 and release of leukotrienes. Objectives: Here, we aimed at determining the prevalence of mast cell (MC) mediator release symptoms triggered by NSAIDs in mastocytosis patients and the associated clinical and laboratory features of the disease. Methods: Medical records from 418 adults to 223 pediatric mastocytosis patients were retrospectively reviewed. Patients were classified according to tolerance patterns to NSAIDs and other COX inhibitors (COXi) and compared for epidemiological, clinical and laboratory findings. Results: Overall, 87% of adults and 91% of pediatric patients tolerated NSAIDs and other COXi. Among adult and pediatric patients presenting DHRs, 5% and 0% reacted to multiple NSAIDs, 4% and 0.7% were single reactors, and 3% and 8% were single reactors with known tolerance to paracetamol but unknown tolerance to other COXi, respectively. Among adults, hypersensitivity to ≥2 drugs was more frequent among females (p = 0.009), patients with prior history of anaphylaxis to triggers other than NSAIDs or other COXi and Hymenoptera venom (p = 0.009), presence of baseline flushing (p = 0.02), baseline serum tryptase ≥48 ng/ml (p = 0.005) and multilineage KIT mutation (p = 0.02). In contrast, tolerance to NSAIDs and other COXi was more frequent among males (p = 0.02), in patients with anaphylaxis caused by Hymenoptera venom (p = 0.02), among individuals who had skin lesions due to mastocytosis (p = 0.01), and in cases that had no baseline pruritus (p = 0.006). Based on these parameters, a score model was designed to stratify mastocytosis patients who have never received NSAIDs or other COXi apart from paracetamol, according to their risk of DHR. Conclusions: Our results suggest that despite the frequency of MC mediator related symptoms elicited by NSAIDs and other COXi apart from paracetamol is increased among mastocytosis patients versus the general population, it is lower than previously estimated and associated with unique disease features. Patients that tolerated NSAIDs and other COXi following disease onset should keep using them. In turn, adults with unknown tolerance to such drugs and a positive score should be challenged with a preferential/selective COX-2 inhibitor, while the remaining may be challenged with ibuprofen. © 2022 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.Funding text 1: This work was supported by grants from the Carlos III Health Institute co‐financed by the European Regional Development Fund (PI19/01166) and CIBERONC CB16/12/00400, Ministerio de Ciencia e Innovación (Madrid, Spain), Asociación Española de Mastocitosis y Enfermedades Relacionadas (AEDM 2019), Fondos de Investigación para Enfermedades Raras del Ministerio de Sanidad, Servicios Sociales e Igualdad (Madrid, Spain). ; Funding text 2: This work was supported by grants from the Carlos III Health Institute co-financed by the European Regional Development Fund (PI19/01166) and CIBERONC CB16/12/00400, Ministerio de Ciencia e Innovación (Madrid, Spain), Asociación Española de Mastocitosis y Enfermedades Relacionadas (AEDM 2019), Fondos de Investigación para Enfermedades Raras del Ministerio de Sanidad, Servicios Sociales e Igualdad (Madrid, Spain)

Quantitative EEG and Functional Outcome Following Acute Ischemic Stroke

Objective: To identify the most accurate quantitative electroencephalographic (qEEG) predictor(s) of unfavorable post-ischemic stroke outcome, and its discriminative capacity compared to already known demographic, clinical and imaging prognostic markers. Methods: Prospective cohort of 151 consecutive anterior circulation ischemic stroke patients followed for 12 months. EEG was recorded within 72 h and at discharge or 7 days post-stroke. QEEG (global band power, symmetry, affected/unaffected hemisphere and time changes) indices were calculated from mean Fast Fourier Transform and analyzed as predictors of unfavorable outcome (mRS ≥ 3), at discharge and 12 months poststroke, before and after adjustment for age, admission NIHSS and ASPECTS. Results: Higher delta, lower alpha and beta relative powers (RP) predicted outcome. Indices with higher discriminative capacity were delta-theta to alpha-beta ratio (DTABR) and alpha RP. Outcome models including either of these and other clinical/imaging stroke outcome predictors were superior to models without qEEG data. In models with qEEG indices, infarct size was not a significant outcome predictor. Conclusions: DTAABR and alpha RP are the best qEEG indices and superior to ASPECTS in post-stroke outcome prediction. They improve the discriminative capacity of already known clinical and imaging stroke outcome predictors, both at discharge and 12 months after stroke. Significance: qEEG indices are independent predictors of stroke outcome.info:eu-repo/semantics/publishedVersio

Post-Stroke Seizures Are Clinically Underestimated

Cerebrovascular disease is the leading cause of epilepsy in adults, although post-stroke seizures reported frequency is variable and few studies used EEG in their identification. To describe and compare EEG and clinical epileptic manifestations frequency in patients with an anterior circulation ischaemic stroke. Prospective study of acute anterior circulation ischaemic stroke patients, consecutively admitted to a Stroke Unit over 24 months and followed-up for 1 year. All patients underwent standardized clinical and diagnostic assessment. Seizure occurrence was clinically evaluated during hospitalization and by a telephone interview at 6 months and a clinical appointment at 12 months after stroke. Video-EEG was performed in the first 72 h (1st EEG), daily after the 1st EEG for the first 7 days after the stroke, or later if neurological worsening, at discharge, and at 12 months. 151 patients were included (112 men) with a mean age of 67.4 (11.9) years. In the 1st year after stroke, 38 patients (25.2%) had an epileptic seizure. During hospitalization, 27 patients (17.9%) had epileptiform activity (interictal or ictal) in the EEG, 7 (25.9%) of them electrographic seizures. During the first week after stroke, 22 (14.6%) patients had a seizure and 4 (2.6%) non-convulsive status epilepticus criteria. Five (22.7%) acute symptomatic seizures were exclusively electrographic. At least one remote symptomatic seizure occurred in 23 (16%) patients. In the first 7 days after stroke, more than one-fifth of patients with seizures had exclusively electrographic seizures. Without a systematic neurophysiological evaluation the frequency of post-stroke seizures are clinically underestimated.info:eu-repo/semantics/publishedVersio

High levels of T lymphocyte activation in Leishmania-HIV-1 co-infected individuals despite low HIV viral load

<p>Abstract</p> <p>Background</p> <p>Concomitant infections may influence HIV progression by causing chronic activation leading to decline in T-cell function. In the Americas, visceral (AVL) and tegumentary leishmaniasis (ATL) have emerged as important opportunistic infections in HIV-AIDS patients and both of those diseases have been implicated as potentially important co-factors in disease progression. We investigated whether leishmaniasis increases lymphocyte activation in HIV-1 co-infected patients. This might contribute to impaired cellular immune function.</p> <p>Methods</p> <p>To address this issue we analyzed CD4⁺T absolute counts and the proportion of CD8⁺T cells expressing CD38 in <it>Leishmania</it>/HIV co-infected patients that recovered after anti-leishmanial therapy.</p> <p>Results</p> <p>We found that, despite clinical remission of leishmaniasis, AVL co-infected patients presented a more severe immunossupression as suggested by CD4⁺T cell counts under 200 cells/mm³, differing from ATL/HIV-AIDS cases that tends to show higher lymphocytes levels (over 350 cells/mm³). Furthermore, five out of nine, AVL/HIV-AIDS presented low CD4⁺T cell counts in spite of low or undetectable viral load. Expression of CD38 on CD8⁺T lymphocytes was significantly higher in AVL or ATL/HIV-AIDS cases compared to HIV/AIDS patients without leishmaniasis or healthy subjects.</p> <p>Conclusions</p> <p><it>Leishmania </it>infection can increase the degree of immune system activation in individuals concomitantly infected with HIV. In addition, AVL/HIV-AIDS patients can present low CD4⁺T cell counts and higher proportion of activated T lymphocytes even when HIV viral load is suppressed under HAART. This fact can cause a misinterpretation of these laboratorial markers in co-infected patients.</p

Host-guest and guest-guest interactions between xylene isomers confined in the MIL-47(V) pore system

The porous MIL-47 material shows a selective adsorption behavior for para-, ortho-, and meta-isomers of xylenes, making the material a serious candidate for separation applications. The origin of the selectivity lies in the differences in interactions (energetic) and confining (entropic). This paper investigates the xylene-framework interactions and the xylene-xylene interactions with quantum mechanical calculations, using a dispersion-corrected density functional and periodic boundary conditions to describe the crystal. First, the strength and geometrical characteristics of the optimal xylene-xylene interactions are quantified by studying the pure and mixed pairs in gas phase. An extended set of initial structures is created and optimized to sample as many relative orientations and distances as possible. Next, the pairs are brought in the pores of MIL-47. The interaction with the terephthalic linkers and other xylenes increases the stacking energy in gas phase (-31.7 kJ/mol per pair) by roughly a factor four in the fully loaded state (-58.3 kJ/mol per xylene). Our decomposition of the adsorption energy shows various trends in the contributing xylene-xylene interactions. The absence of a significant difference in energetics between the isomers indicates that entropic effects must be mainly responsible for the separation behavior

Synchrony of change in depressive symptoms, health status, and quality of life in persons with clinical depression

BACKGROUND: Little is known about longitudinal associations among measures of depression, mental and physical health, and quality of life (QOL). We followed 982 clinically depressed persons to determine which measures changed and whether the change was synchronous with change in depressive symptoms. METHODS: Data were from the Longitudinal Investigation of Depression Outcomes (LIDO). Depressive symptoms, physical and mental health, and quality of life were measured at baseline, 6 weeks, 3 months, and 9 months. Change in the measures was examined over time and for persons with different levels of change in depressive symptoms. RESULTS: On average, all of the measures improved significantly over time, and most were synchronous with change in depressive symptoms. Measures of mental health changed the most, and physical health the least. The measures of change in QOL were intermediate. The 6-week change in QOL could be explained completely by change in depressive symptoms. The instruments varied in sensitivity to changes in depressive symptoms. CONCLUSION: In clinically depressed persons, measures of physical health, mental health, and quality of life showed consistent longitudinal associations with measures of depressive symptoms

H1N1pdm09 Adjuvanted Vaccination in HIV-Infected Adults: A Randomized Trial of Two Single versus Two Double Doses

Since human immunodeficiency virus (HIV)-infected individuals are at increased risk of severe disease from pandemic influenza A (H1N1pdm09), vaccination was recommended as a prevention strategy. The aim of the present study was to evaluate the safety, immunogenicity and persistence of the immune response after vaccination against pandemic influenza A (H1N1pdm09) with an adjuvanted vaccine in human immunodeficiency virus (HIV)-infected adults using two single and two double doses.Open label, randomized trial to evaluate the immune response following H1N1pdm09 vaccination in HIV-infected participants compared to HIV-negative controls (NCT01155037). HIV-infected participants were randomized to receive 2 single (3.75 µg hemagglutinin) or 2 double (7.5 µg hemagglutinin) doses of the vaccine, 21 days apart. Controls received one dose of the vaccine. The primary endpoint was seroconversion as measured by hemagglutination inhibition assay. Two hundred fifty six HIV-infected participants (129 and 127 randomized to single and double doses, respectively) and 71 HIV-negative controls were enrolled. Among HIV-infected participants, seroconversion increased from 46.7% and 51.7% after the first dose to 77.2% and 83.8% after the second dose of the vaccine using single and double doses, respectively. Participants aged >40 years showed higher seroconversion compared to younger participants. Seroconversion among HIV-infected women and those with nadir CD4<200 cells/mm(3) was significantly higher with double doses. Persistence of protective antibodies six months after vaccination was achieved by 80% and 89.9% of the HIV-infected participants who received single and double doses, respectively.Our results support the recommendation of two double doses of adjuvanted H1N1pdm09 vaccine for HIV-infected individuals, particularly women, and those aged >40 years or with nadir CD4<200 cells/mm(3), to achieve antibody levels that are both higher and more sustained.ClinicalTrials.gov NCT01155037

Parasite fate and involvement of infected cells in the induction of CD4+ and CD8+ T cell responses to Toxoplasma gondii

During infection with the intracellular parasite Toxoplasma gondii, the presentation of parasite-derived antigens to CD4+ and CD8+ T cells is essential for long-term resistance to this pathogen. Fundamental questions remain regarding the roles of phagocytosis and active invasion in the events that lead to the processing and presentation of parasite antigens. To understand the most proximal events in this process, an attenuated non-replicating strain of T. gondii (the cpsII strain) was combined with a cytometry-based approach to distinguish active invasion from phagocytic uptake. In vivo studies revealed that T. gondii disproportionately infected dendritic cells and macrophages, and that infected dendritic cells and macrophages displayed an activated phenotype characterized by enhanced levels of CD86 compared to cells that had phagocytosed the parasite, thus suggesting a role for these cells in priming naïve T cells. Indeed, dendritic cells were required for optimal CD4+ and CD8+ T cell responses, and the phagocytosis of heat-killed or invasion-blocked parasites was not sufficient to induce T cell responses. Rather, the selective transfer of cpsII-infected dendritic cells or macrophages (but not those that had phagocytosed the parasite) to naïve mice potently induced CD4+ and CD8+ T cell responses, and conferred protection against challenge with virulent T. gondii. Collectively, these results point toward a critical role for actively infected host cells in initiating T. gondii-specific CD4+ and CD8+ T cell responses

Differential impact of chronic stress along the hippocampal dorsal–ventral axis

First published online 06 February 2014Stress impacts differently in distinct brain regions. However, so far few studies have focused on the differential responses triggered by stressful stimuli on the intrinsic functional heterogeneity of the hippocampal axis. In this study, we assessed the functional and structural alterations caused by exposure to a chronic unpredictable stress (CUS) paradigm on the dorsal-ventral axis of the hippocampus. The morphological analysis demonstrated that CUS had opposite outcomes in the structure of the dorsal (DH) and ventral hippocampus (VH): whereas in the DH, stress triggered a volumetric reduction as a result of atrophy of CA3 and CA1 apical dendrites, in the VH there was an increase in hippocampal volume concurrent with the increase of CA3 apical dendrites. In parallel, electrophysiological data revealed that stress led to a decrease in VH LTD. In summary, the present work showed that stress impacts differently on the structure and function of the DH and VH which contributes to better understand the overall spectrum of the central effects of stress.Pinto V and Mota C were supported by Fundacao para a Ciencia e Tecnologia (FCT) grants (SFRH/BPD/69132/2010; SFRH/BD/81881/2011, respectively). This work was supported by an FCT grant (PTDC/SAU-NSC/120590/2010). The authors declare no competing financial interests

Evaluation of Cellular Phenotypes Implicated in Immunopathogenesis and Monitoring Immune Reconstitution Inflammatory Syndrome in HIV/Leprosy Cases

BACKGROUND: It is now evident that HAART-associated immunological improvement often leads to a variety of new clinical manifestations, collectively termed immune reconstitution inflammatory syndrome, or IRIS. This phenomenon has already been described in cases of HIV coinfection with Mycobacterium leprae, most of them belonging to the tuberculoid spectrum of leprosy disease, as observed in leprosy reversal reaction (RR). However, the events related to the pathogenesis of this association need to be clarified. This study investigated the immunological profile of HIV/leprosy patients, with special attention to the cellular activation status, to better understand the mechanisms related to IRIS/RR immunopathogenesis, identifying any potential biomarkers for IRIS/RR intercurrence. METHODS/PRINCIPAL FINDINGS: Eighty-five individuals were assessed in this study: HIV/leprosy and HIV-monoinfected patients, grouped according to HIV-viral load levels, leprosy patients without HIV coinfection, and healthy controls. Phenotypes were evaluated by flow cytometry for T cell subsets and immune differentiation/activation markers. As expected, absolute counts of the CD4+ and CD8+ T cells from the HIV-infected individuals changed in relation to those of the leprosy patients and controls. However, there were no significant differences among the groups, whether in the expression of cellular differentiation phenotypes or cellular activation, as reflected by the expression of CD38 and HLA-DR. Six HIV/leprosy patients identified as IRIS/RR were analyzed during IRIS/RR episodes and after prednisone treatment. These patients presented high cellular activation levels regarding the expression of CD38 in CD8+ cells T during IRIS/RR (median: 77,15%), dropping significantly (p<0,05) during post-IRIS/RR moments (median: 29,7%). Furthermore, an increase of cellular activation seems to occur prior to IRIS/RR. CONCLUSION/SIGNIFICANCE: These data suggest CD38 expression in CD8+ T cells interesting tool identifying HIV/leprosy individuals at risk for IRIS/RR. So, a comparative investigation to leprosy patients at RR should be conducted