Quantification of the impact of port activities on PM10 levels at the port-city boundary of a mediterranean city.

The main objective of this work was to quantify the impact of handling of bulk materials on PM10 levels measured at the port-city border of Alicante (Spain), located on the western Mediterranean coast. To achieve that goal, 355 PM10 samples were collected at the perimeter of the harbor of Alicante from March 2017 to February 2018. A 181 sample subgroup was chemically characterized in order to perform a source apportionment study with the EPA PMF 5.0 model. Eight factors were identified, two of them directly related to the handling of bulk materials (Limestone + gypsum and Clinker), accounting jointly for 35% of the average PM10 concentration. A Road traffic factor was the second highest contributor to PM10 levels (17%) while the Shipping emissions factor accounted for only 6% of the average PM10 mass. Other factors such as Biomass burning+ secondary nitrate and Aged sea salt represented a joint contribution of 25% of the PM10 mass. Results indicate that emission abatement strategies should primarily focus on the reduction of fugitive emissions caused by the handling of bulk materials at the docks. Moreover, scenarios including reductions of more than 50% in bulk handling sources and 10% in other anthropogenic sources would help to reduce anthropogenic exceedances of the daily PM10 limit (50 µg·m-3) and to approach to WHO daily PM10 standard (20 µg m-3).

Therapeutic management of adults with atopic dermatitis: comparison with psoriasis and chronic urticaria.

BACKGROUND: The therapeutic options in atopic dermatitis rely on consensus-based guidelines, also established for psoriasis and chronic urticaria. However, the therapeutic approach in atopic dermatitis, especially in the moderate-to-severe forms of the disease, seems less aggressive than in psoriasis and in chronic urticaria with a less frequent use of systemic agents. OBJECTIVES: To compare in real-life conditions the therapeutic management of adults with atopic dermatitis with those with psoriasis and chronic urticaria. METHODS: A transversal analysis was performed in May 2017, using retrospective data from a monocentric database. Data on epidemiology, severity, therapeutic educational intervention and systemic treatments were analysed from 401 patients with atopic dermatitis, compared with data from 230 patients with chronic urticaria and 535 patients with psoriasis. RESULTS: A high proportion (73%) of atopic dermatitis patients presented with a moderate-to-severe form of the disease compared to only 39% of chronic urticaria and 17% of psoriasis patients. Most of atopic dermatitis patients (78%) had completed a therapeutic educational programme, while the adherence was lower in chronic urticaria (35%) and in psoriasis (3%) patients. A systemic treatment, including biologicals, was recorded in 8% of atopic dermatitis patients, while it concerned 26% and 47% of chronic urticaria and psoriasis patients, respectively. CONCLUSIONS: We confirmed that atopic dermatitis treatment mostly relies on topical treatments. Only a minority of moderate-to-severe atopic dermatitis patients who are eligible for a systemic treatment receive such therapy. This may suggest promoting a more frequent use of systemic agents in moderate-to-severe atopic dermatitis.

Physiopathologie de la dermatite atopique et des autres maladies atopiques : une approche globale est-elle possible ?: Pathophysiology of atopic dermatitis and other atopic diseases: is a global approach possible?

Atopy is defined by the propensity to develop an exaggerated type-2 inflammatory response to environmental molecules. Clinically, atopy is diagnosed when atopic disease occurs: atopic dermatitis, food allergy, atopic asthma and allergic rhinitis and conjunctivitis. Whereas the classical "atopic march" is increasingly challenged through epidemiological studies, type-2 cellular inflammation is a characteristic shared by the atopic diseases. This inflammation can be innate (non-specific: eosinophils, mast cells, dendritic cells, innate lymphoid cells [ILC]), or adaptive (antigen-specific, involving T cells). Interleukins (IL-)4, 5 and 13 are major actors of type-2 inflammation and are mainly produced by ILC and T cells. The efficacy of treatments targeting these type-2 cytokines highlight the importance of type-2 inflammation in atopic diseases. However, several patients do not respond to type-2 targeting treatments, highlighting the presence of other actors in pathophysiology of atopic diseases: alteration of epithelial barrier, IgE-mediated allergic responses, type-17 inflammation. Thus, the term "endotype" can illustrate this diversity in pathophysiology. Finally, a global approach of atopic diseases, as type-2 inflammatory diseases, is fundamental, but not sufficient. An approach by endotype is advisable, in a personalized medicine perspective. © 2020 Elsevier Masson SAS. All rights reserved.

Automatic depletion with Spectra Optia allows a safe 16% reduction of red blood cell pack consumption in exchanged sickle cell anemia patients.

BACKGROUND: Chronic red blood cell exchanges (RBCXs) are frequently used to prevent complications in patients with sickle cell anemia, but the scarcity of matched red blood cell packs (RBCPs) is a serious concern. The main goal of this study was to compare the number of RBCPs used during RBCXs between the Spectra Optia (SO) device (with the automatic depletion step) and the former Cobe Spectra (CSP) device. STUDY DESIGN AND METHODS: The performances and safety of 300 SO sessions using the automatic depletion step (SO/DE) in 50 patients with sickle cell anemia under a chronic transfusion program over a 1-year period were prospectively analyzed. The numbers of RBCPs saved using this protocol compared to the SO device without depletion and to the CSP device were determined. RESULTS: The SO/DE protocol appeared to be safe, as only 5% and 17% of the sessions were characterized by a significant decrease in blood pressure and increase in heart rate (grade 2 adverse events), respectively. Postapheresis hematocrit and fraction of cells remaining reached expected values. The SO/DE protocol required 16% fewer RBCPs compared to SO without depletion, allowing a mean saving of 12 RBCPs per patient and per year and 13% fewer compared to CSP device. Interestingly, the saving was more important for patients with high total blood volume and/or high preapheresis hematocrit. CONCLUSION: The SO/DE protocol is an efficient, safe and cost-effective procedure for patients with sickle cell anemia under a chronic transfusion program.

Epidermolysis bullosa simplex generalized severe induces a T helper 17 response and is improved by apremilast treatment.

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.

Topical ivermectin improves allergic skin inflammation.

BACKGROUND: Ivermectin (IVM) is widely used in both human and veterinary medicine to treat parasitic infections. Recent reports have suggested that IVM could also have anti-inflammatory properties. METHODS: Here, we investigated the activity of IVM in a murine model of atopic dermatitis (AD) induced by repeated exposure to the allergen Dermatophagoides farinae, and in standard cellular immunological assays. RESULTS: Our results show that topical IVM improved allergic skin inflammation by reducing the priming and activation of allergen-specific T cells, as well as the production of inflammatory cytokines. While IVM had no major impact on the functions of dendritic cells in vivo and in vitro, IVM impaired T-cell activation, proliferation, and cytokine production following polyclonal and antigen-specific stimulation. CONCLUSION: Altogether, our results show that IVM is endowed with topical anti-inflammatory properties that could have important applications for the treatment of T-cell-mediated skin inflammatory diseases.

Comparative histological analysis of drug-induced maculopapular exanthema and DRESS.

BACKGROUND: Cutaneous adverse drug reactions frequently present as a benign maculopapular exanthema (MPE) with a rapid healing. Sometimes systemic signs are present, which could represent a more severe or systemic MPE (sMPE) or even be the initial phase of a drug reaction with eosinophilia and systemic symptoms (DRESS). Histopathology associated with MPE, sMPE and DRESS has not been well characterized. OBJECTIVES: To study the cutaneous histopathological changes associated with MPE, sMPE and DRESS. METHODS: A retrospective clinicopathological analysis of 13 cases of MPE, 13 of sMPE and 45 of DRESS, collected in one centre from 2005 to 2013. RESULTS: The number of histopathological changes per section increased gradually from MPE to sMPE and DRESS. Prevalence of spongiosis, dermal lymphocytes, eosinophils and neutrophils did not differ between MPE, sMPE and DRESS. Keratinocyte damage, rare in MPE, was regularly found in sMPE and frequent in DRESS. The density of the inflammatory infiltrate increased progressively from MPE to sMPE and DRESS. Atypical lymphocytes were absent in MPE, present in sMPE and more frequent in DRESS. Deep dermal involvement and leukocytoclastic vasculitis were only observed in DRESS. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Numerous histopathological changes per section in drug-induced exanthema should alert for a more severe form of cutaneous adverse drug reactions, i.e. DRESS.

Chronic urticaria and hormones: Is there a link?

BACKGROUND: While the role of oestrogens in bradykinin angioedema (AE) has been clearly demonstrated, scarce data are available about the role of sex hormones in chronic urticaria (CU). OBJECTIVES: To gather information from a population of women with various forms of CU [chronic spontaneous urticaria (CSU), including a subtype of isolated histaminic AE and a classic subtype of association of wheals and AE, and exclusive inducible urticaria (IU)] about the impact of sex hormones and reproductive factors on their symptoms. METHODS: This was a cross-sectional study comprising interviews of 200 women consulting for CU at nine centres throughout France between May and July 2013. The dermatologists filled in an online questionnaire on the impact of reproductive factors (puberty, contraception and pregnancy) and hormonal treatments on the course of CU, including CSU and IU, in the presence of the women. RESULTS: Most of the women did not experience CU before puberty and if so, puberty did not influence the course of CU. Only 16 women had experienced a pregnancy during CU which caused a worsening of symptoms in four. Hormonal contraception was associated with aggravation in a minority of women, mostly women with CSU (10%). Women with isolated histaminic AE did not exhibit any female sex hormone dependency. CONCLUSIONS: It would appear that sex hormones act as a trigger in only a small subset of women with CU. Nevertheless, this should be taken into account to improve patient management.

[Fixed drug eruption to clarithromycin: The importance of challenge tests in diagnosis]. / Érythème pigmenté fixe à la clarithromycine : importance des tests de provocation pour le diagnostic.

BACKGROUND: Determining the substance responsible for recurrent fixed drug eruption (FDE) may be difficult in the case of patients on multiple medication. Allergy testing may prove invaluable in such situations, as we demonstrate herein with an original case. PATIENTS AND METHODS: A 49-year-old man presented a rash on the seventh day of treatment with esomeprazole, clarithromycin and amoxicillin prescribed for gastritis involving Helicobacter pylori. The condition regressed spontaneously within a few days, but left three areas of hyperpigmentation. The patient subsequently reported four further episodes consisting of stereotypical reactivation in the areas of the three initial lesions and occurring 24hours after use of clarithromycin (2 episodes) and amoxicillin (2 episodes). The patient resumed proton pump inhibitor therapy (esomeprazole) without incident. Based on history taking, an initial diagnosis was made of multiple fixed drug eruption involving amoxicillin and clarithromycin. The initial skin allergy investigations were negative (patch-tests for amoxicillin and clarithromycin on healthy skin on the patient's back and on the affected area). After discussion, we decided to reintroduce the suspected drugs in succession. Beginning with clarithromycin, 12h after a single dose of 250mg, we noted an erythematous reaction on the pigmented areas, together with a burning sensation. In an identical challenge test with amoxicillin (500mg), the latter drug was perfectly well tolerated, ruling out the diagnosis of FDE to amoxicillin and thus the diagnosis of multiple FDE suggested by the patient history. DISCUSSION: FDEs to macrolides are rare, and herein we report a new case. Our observation confirms the diagnostic value of challenge tests in FDE. These tests should only be performed in the event of non-severe FDE, in other words not in bullous or systemic reactions, and they often constitute the only diagnostic approach possible, since skin tests are rarely positive during investigation for FDE.

Drug reaction with eosinophilia and systemic symptoms (DRESS): clinicopathological study of 45 cases.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and severe adverse drug reaction. Large detailed studies of histopathological features of DRESS are sparse and suggest an association between keratinocyte damage and the severity of visceral involvement. OBJECTIVES: To describe the dermatopathological features in a large series of DRESS and their possible association with clinical features and the severity of the disease. METHODS: A retrospective analysis of the clinicobiological and dermatopathological features in a monocentric cohort of patients with DRESS. RESULTS: From January 2005 to January 2013, 45 patients were validated as probable or definite cases of DRESS. The median age was 64 years (range 3-87). The most frequent clinical and biological features included: fever ≥38.5°C (95%), facial oedema (72%), enlarged lymph nodes (51%), visceral involvement (75%), blood eosinophilia (97%) and atypical lymphocytes (82%). Severe DRESS occurred in 24% and a fatal outcome in 6% of patients. Histopathological analysis showed that no specific histopathological pattern was characteristic for DRESS. However, several changes in different cutaneous compartments were observed in 2 of 3 of cases. Spongiosis (55%) and keratinocyte damage (53%) were the most common epidermal changes. Spongiosis was associated with non-severe DRESS (P = 0.041) whereas confluent keratinocyte necrosis correlated with severe DRESS (P = 0.011). Vascular changes were frequent (88%). A moderate dermal perivascular lymphocytic infiltrate was invariably present, containing eosinophils, neutrophils and/or atypical lymphocytes in 57% of cases. CONCLUSIONS: Epidermal changes are indicative for the severity of DRESS.

[Diversity of cutaneous bacteria decreases inflammation]. / Plus il y a de bactéries différentes, moins il y a d'inflammation : la révolution microbiotique.

Human microbiota includes all microorganisms, saprophytes and pathogens that colonize our bodies. Recent advances in metagenomic analysis techniques have expanded our knowledge of the microbiota and fundamentally changed our view of its relationships with the immune system. The commensal flora appears to be essential to the development of the immune system, and the diversity of the microbiota is correlated with good health status of individuals. These findings open up new conceptual and therapeutic approaches in chronic inflammatory diseases.

One-year safety and efficacy of ustekinumab and results of dose adjustment after switching from inadequate methotrexate treatment: the TRANSIT randomized trial in moderate-to-severe plaque psoriasis.

BACKGROUND: There are limited long-term, 'real-world' data on ustekinumab, or the effect of dose adjustment in suboptimal responders. OBJECTIVES: We describe 52-week data from TRANSIT, which initiated ustekinumab by licensed regimen and investigated exploratory dose adjustment. METHODS: Patients with moderate-to-severe psoriasis and inadequate methotrexate response received ustekinumab, with immediate or gradual methotrexate withdrawal. Outcomes were similar between treatment arms at week 12 (primary endpoint), so week 52 data were pooled. Patients weighing ≤ 100 kg or > 100 kg were administered ustekinumab 45 or 90 mg, respectively. Patients weighing ≤ 100 kg without 75% improvement in Psoriasis Area and Severity Index (PASI 75) response at weeks 28 or 40 received a dose adjustment to 90 mg. The primary analysis used observed data. RESULTS: Overall, 391 and 98 patients received ustekinumab 45 and 90 mg, respectively. Forty-four patients (9%) discontinued before week 52 (0·4% due to adverse events). At week 52 (in the overall population), 369 patients (83%) achieved a PASI score ≤ 5, and 341 patients (77%) achieved PASI 75; the median PASI score decreased from 15 at baseline to 1·8. At weeks 28 and 40, 84 and 31 patients, respectively, did not achieve PASI 75 and received a dose adjustment; by week 52, 35/82 (43%) and 15/31 (48%) of these patients, respectively, achieved PASI 75 (two discontinued between weeks 28 and 40). CONCLUSIONS: Ustekinumab showed sustained 1-year efficacy and was well tolerated when initially administered according to label. Adjusting the ustekinumab dose to 90 mg may result in clinically meaningful improvement in response in patients weighing ≤ 100 kg with suboptimal initial response.

Transition to ustekinumab in patients with moderate-to-severe psoriasis and inadequate response to methotrexate: a randomized clinical trial (TRANSIT).

BACKGROUND: Limited data exist on transitioning patients with psoriasis from conventional systemic agents to biologics. OBJECTIVES: The TRANSIT study aimed to assess the efficacy and safety of two methotrexate-to-ustekinumab transition strategies. METHODS: Patients with moderate-to-severe psoriasis and inadequate methotrexate response were randomized 1 : 1 to receive ustekinumab with immediate (arm 1) or 4-week gradual (arm 2) methotrexate withdrawal. Patients weighing ≤ 100 kg or > 100 kg received ustekinumab 45 mg or 90 mg, respectively. The primary endpoint was the frequency of adverse events (AEs) at week 12. Secondary endpoints included additional safety, efficacy and patient-reported outcomes. We report the 12-week efficacy and safety results. RESULTS: Overall, 244 patients in arm 1 and 245 in arm 2 were randomized and received ustekinumab. Four patients per arm discontinued the trial by week 12. At week 12 in arms 1 and 2, respectively, 61% and 65% of patients experienced an AE, 2·9% and 2·4% had a serious AE, and 1·2% and 0·4% had an AE leading to ustekinumab discontinuation. In arms 1 and 2, respectively, median Psoriasis Area and Severity Index (PASI) score decreased from 15·2 and 15·4 at baseline to 2·9 and 2·8 at week 12; 58% and 62% of patients achieved a 75% reduction from baseline in PASI score (PASI 75) at week 12; median baseline Dermatology Life Quality Index fell from 8 and 9 at baseline to 1 (both arms) at week 16. CONCLUSIONS: Ustekinumab was well tolerated and effective in patients who had an inadequate response to methotrexate. Both transition strategies resulted in similar week 12 safety and efficacy outcomes.

[Pathophysiology of urticaria]. / Physiopathologie de l'urticaire.

Urticaria is a dermal edema resulting from vascular dilatation and leakage of fluid into the skin in response to molecules released from mast cells. The major mediator responsible for urticaria is histamine. However, the clinical spectrum and pattern of lesions indicate that other molecules, including prostaglandins, leukotrienes, cytokines, and chemokines, produced at different times after mast cell activation contribute to the polymorphism of this symptom and the variable evolution of this disease. It is a common practice to distinguish immunological and nonimmunological urticaria. Immunological urticaria is a hypersensitivity reaction mediated by antibodies and/or T-cells that results in mast cell activation. Although immunoglobulin (Ig) E-mediated type I hypersensitivity (HS) was long postulated to be the major immunological pathway associated with mast cell activation, interaction between IgEbound mast cells and allergens is unlikely to be the mechanism by which urticaria develops in most patients. It is now well established that urticaria may result from the binding of IgG auto-antibodies to IgE and/or to the receptor for IgE molecules on mast cells, thus corresponding to a type II HS reaction. These auto-immune urticarias represent up to 50 % of patients with chronic urticaria. Mast cell activation can also result from type III HS through the binding of circulating immune complexes to mast cell-expressing Fc receptors for IgG and IgM. Finally, under certain circumstances, T-cells can induce activation of mast cells, as well as histamine release (type IV HS). Nonimmunological urticarias result from mast cell activation through membrane receptors involved in innate immunity (e.g., complement, Toll-like, cytokine/chemokine, opioid) or by direct toxicity of xenobiotics (haptens, drugs). In conclusion, urticaria may result from different pathophysiological mechanisms that explain the great heterogeneity of clinical symptoms and the variable responses to treatment.

[Recurrent pyoderma gangrenosum-like ulcers induced by oral anticoagulants]. / Ulcérations récidivantes à type de pyoderma grangrenosum induites par les antivitamines K.

BACKGROUND: Other than the classic skin necrosis induced by oral anticoagulants (OAC) in patients with protein C and S deficiencies, other types of OAC induced-skin ulcers are little known. Herein, we describe an original case of recurrent pyoderma gangrenosum (PG)-like ulcers induced by OAC. PATIENTS AND METHODS: A 70-year-old female heart-transplant recipient presented deep, hyperalgesic and quickly-spreading necrotic ulceration of the right leg 6 weeks after starting oral anticoagulant therapy with fluindione. Histological analysis revealed dermal infiltrate containing polynuclear neutrophils, which accords with the histopathological diagnosis of leukocytoclastic vasculitis or PG. Infectious, autoimmune and thrombophilic causes were ruled out. Fluindione was withdrawn and the ulcer healed completely within a month. Six months later, right leg ulceration recurred two weeks after the patient resumed fluindione but healed within 1 month of discontinuation of the drug. An OAC from another chemical family (warfarin) was then introduced, with further recurrence of ulceration after 2 weeks of treatment. DISCUSSION: The chronology of events and the negativity of aetiological explorations allowed a diagnosis to be made of OAC-induced skin ulcer, a rare complication of which the pathophysiology is unclear. This is the first case of PG-like ulcers induced by OAC.

Sensitivity of PM10 oxidative potential to aerosol chemical composition at a Mediterranean urban site: ascorbic acid versus dithiothreitol measurements.

The oxidative potential (OP) of PM10 daily samples collected at a traffic site in southeastern Spain during summer and winter was assessed by two acellular assays: the ascorbic acid (AA) and dithiothreitol (DTT) methods. Although PM10 levels were similar during both periods, OP values (expressed in nmol min-1 m-3) showed a defined seasonal trend. The AA activity was higher in summer than in winter, whereas the DTT reactivity exhibited an opposite seasonal pattern. Both assays were sensitive to different PM10 components, as shown by the results of the linear correlation analysis. Moreover, the relationship between OP values and PM10 chemical species was not the same during summer and winter, indicating that particle toxicity is associated with different sources during the warm and cold seasons. When OP values were expressed on a mass basis (nmol min-1 µg-1), lower correlation coefficients with PM10 chemical species were generally obtained compared to volume-normalized activities. These outcomes suggest that only some specific components have a significant intrinsic oxidative potential. Supplementary Information: The online version contains supplementary material available at 10.1007/s11869-023-01332-1.