Assessment of hydro-saline retention in bullous pemphigoid patients treated with super-potent topical corticosteroids.

INTRODUCTION: Super-potent topical corticosteroids (CS) are the mainstay of treatment for bullous pemphigoid. Since super-potent topical CS have systemic effects due to their transcutaneous absorption, we assessed whether super-potent CS were responsible for hydro-saline retention (HSR) in bullous pemphigoid patients. PATIENTS AND METHODS: From 2015 to 2017, patients with newly-diagnosed bullous pemphigoid treated using clobetasol propionate cream at a starting daily dose of 20 to 40 g were subsequently included in a prospective study. HSR was assessed by longitudinally measuring extracellular water (ECW) volume using bioimpedance analysis (BodyStat QuadScan 4000®) from Day 0 to Day 30 after the initiation of topical CS. Other parameters related to HSR such as weight, blood pressure, natriuresis and proteinuria, were also recorded. RESULTS: Twenty-nine patients (14 men and 15 women) of mean age 81.8 ±â€¯9.3 years were included and analysed. The mean ECW volume decreased from Day 0 to Day 7 (18.1 ±â€¯4.2 vs 16.7 ±â€¯2.7, p = 0.0094) and was maintained from Day 7 to Day 30 (16.8 ±â€¯2.8 vs 17.0 ±â€¯3.4 L; p = 0.8040). Patient weight loss at Day 30 (69.9 ±â€¯13.6 vs 72.5 ±â€¯14.2 kg, p = 0.0085) was closely correlated with the decrease in ECW volume (r = 0.6740, p < 0.0001). No significant changes in natriuresis, 24-hour proteinuria or blood pressure were observed from Day 0 to Day 30. CONCLUSION: We found no evidence of HSR in bullous pemphigoid patients treated with super-potent topical CS. Conversely, ECW volume decreased from Day 0 to Day 30, which was correlated with patient weight loss.

International multicentre observational study to assess the efficacy and safety of a 0·5 mg kg-1 per day starting dose of oral corticosteroids to treat bullous pemphigoid.

BACKGROUND: European guidelines propose a 0·5 mg kg-1 per day dose of oral prednisone as initial treatment for bullous pemphigoid (BP). We assessed the safety and efficacy of this regimen depending on BP extent and general condition of the patients. METHODS: In a prospective international study, we consecutively included all patients diagnosed with BP. Patients received a 0·5 mg kg-1 per day dose of prednisone, which was then gradually tapered 15 days after disease control, with the aim of stopping prednisone or maintaining minimal treatment (0·1 mg kg-1 per day) within 6 months after the start of treatment. The two coprimary endpoints were control of disease activity at day 21 and 1-year overall survival. Disease severity was assessed according to the Bullous Pemphigoid Disease Area Index (BPDAI) score. RESULTS: In total, 198 patients were included between 2015 and 2017. The final analysis comprised 190 patients with a mean age of 80·9 (SD 9·1) years. Control of disease activity was achieved at day 21 in 119 patients [62·6%, 95% confidence interval (CI) 55·3-69.5]; 18 of 24 patients (75%, 95% CI 53·3-90·2), 75 of 110 patients (68·8%, 95% CI 59·2-77·3) and 26 of 56 patients (46.4%, 95% CI 33·0-60·3) had mild, moderate and severe BP, respectively (P = 0·0218). A total of 30 patients died during the study. The overall Kaplan-Meier 1-year survival was 82·6% (95% CI 76·3-87·4) corresponding to 90·9%, 83·0% and 80·0% rates in patients with mild, moderate and severe BP, respectively (P = 0·5). Thresholds of 49 points for BPDAI score and 70 points for Karnofsky score yielded maximal Youden index values with respect to disease control at day 21 and 1-year survival, respectively. CONCLUSIONS: A 0·5 mg kg-1 per day dose of prednisone is a valuable therapeutic option in patients with mild or moderate BP whose general condition allows them to be autonomous.

International validation of the Bullous Pemphigoid Disease Area Index severity score and calculation of cut-off values for defining mild, moderate and severe types of bullous pemphigoid.

BACKGROUND: The Bullous Pemphigoid Disease Area Index (BPDAI) score has been proposed to provide an objective measure of bullous pemphigoid (BP) activity. OBJECTIVES: The objective of this study was to calculate BPDAI cut-off values defining mild, moderate and severe BP. We also aimed to assess the interrater reliability and correlation with the number of daily new blisters, and anti-BP180 and anti-BP230 antibodies. METHODS: Severity scores were recorded by two blinded investigators. Anti-BP180 and anti-BP230 antibodies were measured using an enzyme-linked immunosorbent assay (ELISA). Cut-off values defining mild, moderate and severe subgroups were calculated based on the 25th and 75th percentiles of the BPDAI score. RESULTS: In total, 285 patients with BP were enrolled from 50 dermatology departments in Europe. Median BPDAI activity was 37·5 points (range 0-164). Cut-off values corresponding to the first and third quartiles of the BPDAI score were 20 and 57, respectively; thus, these values were used to define mild (≤ 19), moderate (≥ 20 and ≤ 56) and severe (≥ 57) BP. The median BPDAI score for patients with ≤ 10 daily new blisters was 26 [interquartile range (IQR) 17-45], and for patients with > 10 daily new blisters the median score was 55 (IQR 39-82). The BPDAI intraclass correlation coefficient measured at baseline was 0·97 and remained higher than 0·90 up to month 6. The improvement in the BPDAI score was correlated with the absolute decrease in anti-BP180 ELISA value (Spearman's rank r = 0·34, P < 0·004), but not with anti-BP230 antibodies (r = 0·17, P = 0·15). CONCLUSIONS: This study suggests cut-off values of 20-57 for BPDAI to distinguish mild, moderate and severe BP, and confirms that it is a robust tool to assess BP severity precisely.

Comparison of real costs in the French healthcare system in newly diagnosed patients with pemphigus for first-line treatment with rituximab vs. standard corticosteroid regimen: data from a national multicentre trial.

BACKGROUND: Rituximab has been demonstrated to be highly effective as a first-line treatment for moderate-to-severe pemphigus; however, its high cost can be considered a limitation of this treatment. OBJECTIVES: To compare direct costs of two regimens, rituximab + short-term prednisone vs. prednisone alone, tested in the Ritux3 trial. METHODS: Patients were randomly assigned to receive 2 g of rituximab and two 500-mg maintenance infusions at month 12 and month 18 along with low doses of prednisone for 3-6 months, or high doses of prednisone alone tapered over 12-18 months. We estimated the direct costs related to (i) protocol (treatments, consultations, hospitalizations); (ii) unfavourable disease course (relapse); and (iii) adverse events in both treatment groups during a 3-year follow-up. RESULTS: Annual individual cost discrepancies related to drugs decreased from +€3597 to -€1589 from the first to the third year, which corresponded to an initially higher cost in the rituximab group, counterbalanced during follow-up by costs related to treatment of patients with persistent disease activity/relapses in the standard corticosteroid (CS) group. Individual costs relating to treatment of adverse events were higher in the standard CS group (€4352) than in the rituximab group (€2468). Overall, mean individual total cost over the 3 years of follow-up was €13 997 in the standard CS arm vs. €14 818 in the rituximab arm, corresponding to a difference of €821 more per patient (+6%). CONCLUSIONS: First-line treatment of pemphigus with rituximab results in a slightly greater cost compared with a standard CS regimen. What's already known about this topic Rituximab is the most effective treatment for moderate-to-severe pemphigus. Rituximab cost might be considered as a limitation of this treatment. What does this study add? After 3 years of follow-up, mean individual total cost for a patient with first-line treatment with rituximab was €14 818 vs. €13 997 with standard corticosteroids (CS), resulting in a slightly higher cost of €821 (+6%). The initially greater cost of rituximab was counterbalanced by costs related to management of flares/relapses in patients treated with a standard CS regimen.

Rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid-sparing effect.

BACKGROUND: Corticosteroids (CS) with or without adjuvant immunosuppressant agents are standard treatment for pemphigus vulgaris (PV). The efficacy of adjuvant therapies in minimizing steroid-related adverse events (AEs) is unproven. OBJECTIVES: To utilize data collected in a French investigator-initiated, phase III, open-label, randomized controlled trial to demonstrate the efficacy and safety of rituximab and seek approval for its use in PV. METHODS: This was an independently conducted post hoc analysis of the moderate-to-severe PV subset enrolled in the Ritux 3 study. Patients were randomized to rituximab plus 0·5 or 1·0 mg kg-1 per day prednisone tapered over 3 or 6 months, or 1·0 or 1·5 mg kg-1 per day prednisone alone tapered over 12 or 18 months, respectively (according to disease severity). The primary end point was complete remission at month 24 without CS (CRoff) for ≥ 2 months, and 24-month efficacy and safety results were also reported. RESULTS: At month 24, 34 of 38 patients (90%) on rituximab plus prednisone achieved CRoff ≥ 2 months vs. 10 of 36 patients (28%) on prednisone alone. Median total cumulative prednisone dose was 5800 mg in the rituximab plus prednisone arm vs. 20 520 mg for prednisone alone. Eight of 36 patients (22%) who received prednisone alone withdrew from treatment owing to AEs; one rituximab-plus-prednisone patient withdrew due to pregnancy. Overall, 24 of 36 patients (67%) on prednisone alone experienced a grade 3/4 CS-related AE vs. 13 of 38 patients (34%) on rituximab plus prednisone. CONCLUSIONS: In patients with moderate-to-severe PV, rituximab plus short-term prednisone was more effective than prednisone alone. Patients treated with rituximab had less CS exposure and were less likely to experience severe or life-threatening CS-related AEs. What's already known about this topic? Pemphigus vulgaris (PV) is the most common type of pemphigus. Corticosteroids, a standard first-line treatment for PV, have significant side-effects. Although their effects are unproven, adjuvant corticosteroid-sparing agents are routinely used to minimize steroid exposure and corticosteroid-related side-effects. There is evidence that the anti-CD20 antibody rituximab is effective in the treatment of patients with severe recalcitrant pemphigus and in patients with newly diagnosed pemphigus. What does this study add? This study provides a more detailed analysis of patients with PV enrolled in an investigator-initiated trial. Rituximab plus prednisone had a steroid-sparing effect and more patients achieved complete remission off prednisone. Fewer patients experienced grade 3 or grade 4 steroid-related adverse events than those on prednisone alone. This collaboration between academia and industry, utilizing independent post hoc analyses, led to regulatory authority approvals of rituximab in moderate-to-severe PV.

Chemodiversity of Essential Oils from Nine Species of Celastraceae.

Extracts and compounds obtained from several species of Celastraceae family are reported as potential sources of drugs due to their diverse pharmacological properties. Nevertheless, essential oil composition from these species is still little known. This work aimed at the analysis of essential oils obtained from different Brazilian Celastraceae species. A total of seventeen oils were obtained using hydrodistillation process and analyzed by gas chromatography/mass spectrometry (GC/MS). Principal component analysis (PCA) allowed the identification of a chemical composition pattern among the analyzed essential oils. Some compounds were more frequent among Celastraceae species, such as cis- and trans-linalool oxide (14/17 oil samples), nerylacetone (13/17), linalool (11/17), ß-ionone (10/17), α-ionone (9/17), nerolidol (10/17), decanal (10/17), and dodecanoic acid (10/17). These results contribute to the chemophenetics of Celastraceae species.

Risk factors for treatment failure in scabies: a cohort study.

BACKGROUND: Treatment failure, which occurs in about one-third of cases, is considered as a major factor in the increasing incidence of scabies in developed countries. OBJECTIVES: To identify predictors of treatment failure of scabies in ambulatory populations. METHODS: This multicentre study compared the clinical characteristics and treatment modalities between a group of patients with scabies treated successfully and another group who were not cured 3 months after antiscabies treatment. RESULTS: In total 210 patients with a diagnosis of scabies were included, comprising 98 patients in the treatment success group and 112 in the treatment failure group. The main risk factors for treatment failure were (i) the use of only one type of treatment, topical benzyl benzoate (BB) or oral ivermectin, vs. the combination of both treatments [odds ratio (OR) 2·15, 95% confidence interval (CI) 1·22-3·77]; (ii) the use of a single intake (vs. two) of oral ivermectin (OR 10·2. 95% CI 4·49-23·2); (iii) intake of ivermectin during a meal vs. on an empty stomach (OR 4·31, 95% CI 1·89-9·84); (iv) absence of decontamination of furnishings (OR 8·72, 95% CI 3·50-21·8), in particular sofa and cushions (OR 5·90, 95% CI 2·34-14·9), mattresses (OR 4·16, 95% CI 1·35-12·8) or car seats (OR 6·57, 95% CI 3·27-13·2) and (v) absence of written documents explaining treatment modalities (OR 5·18, 95% CI 2·57-10·4). In multivariate analysis, treatment failure was mainly associated with (i) use of a single intake (vs. two) of ivermectin (OR 6·62, 95% CI 2·71-16·2); (ii) use of BB alone vs. two intakes of ivermectin (OR 3·51, 95% CI 1·55-7·95) and (iii) absence of decontamination of furniture with acaricides (OR 5·81, 95% CI 1·96-16·7). CONCLUSIONS: Use of topical BB alone and a single intake (vs. two) of ivermectin are predictors of treatment failure.

A single typical trichoscopic feature is predictive of tinea capitis: a prospective multicentre study.

BACKGROUND: Specific trichoscopic signs of tinea capitis (TC) were first described in 2008. The accuracy of this diagnostic tool has not been evaluated. OBJECTIVES: To assess the diagnostic accuracy of trichoscopy. METHODS: A prospective, multicentre study was done between March 2015 and March 2017 at the dermatology departments of four French university medical centres. Patients with a presumed diagnosis of TC were included. Trichoscopy was considered to be positive if at least one specific trichoscopic sign was observed. Trichoscopy results were compared with the gold standard for diagnosis of TC (mycological culture). RESULTS: One hundred patients were included. Culture was positive for 53 patients and negative for 47. The sensitivity of trichoscopy was 94% [95% confidence interval (CI) 88-100], specificity was 83% (95% CI 72-94), positive predictive value was 92% and negative predictive value was 86%. Comma hairs, corkscrew hairs, zigzag hairs, Morse-code-like hairs and whitish sheath were significantly more frequent in patients with a positive mycological culture (P < 0·001). Comma hairs were more frequent in patients with Trichophyton TC (P = 0·026), and zigzag hairs were more frequent in patients with Microsporum TC (P < 0·001). Morse-code-like hair was not observed in any patients with Trichophyton TC and therefore appears to be highly specific for Microsporum TC. CONCLUSIONS: The presence of a single trichoscopic finding is predictive of TC. Trichoscopy is a useful, rapid, painless, highly sensitive tool for the diagnosis of TC - even for dermoscopists with little experience of trichoscopy. It enhances physicians' ability to make treatment decisions. What's already known about this topic? Tinea capitis (TC) must be confirmed by a mycological culture that may take up to 6 weeks, delaying treatment. Specific trichoscopic signs of TC were first described in 2008, but the accuracy of trichoscopy for diagnosing TC has not previously been evaluated. What does this study add? The present series is the largest yet on the use of trichoscopy in the diagnosis of TC. Our results demonstrated that the presence of a single feature (comma hair, corkscrew hair, zigzag hair, Morse-code-like hair or whitish sheath) is predictive of TC. Trichoscopy is painless and highly sensitive. Morse-code-like hair appears to be highly specific for Microsporum TC.

Survey and Risk Assessment of Apis mellifera (Hymenoptera: Apidae) Exposure to Neonicotinoid Pesticides in Urban, Rural, and Agricultural Settings.

A comparative assessment of apiaries in urban, rural, and agricultural areas was undertaken in 2013 and 2014 to examine potential honey bee colony exposure to neonicotinoid insecticides from pollen foraging. Apiaries ranged in size from one to hundreds of honey bee colonies, and included those operated by commercial, sideline (semicommercial), and hobbyist beekeepers. Residues in and on wax and beebread (stored pollen in the hive) were evaluated for the nitro-substituted neonicotinoid insecticides imidacloprid and its olefin metabolite and the active ingredients clothianidin, thiamethoxam, and dinotefuran. Beebread and comb wax collected from hives in agricultural landscapes were more likely to have detectable residues of thiamethoxam and clothianidin than that collected from hives in rural or urban areas (∼50% of samples vs. <10%). The maximum neonicotinoid residue detected in either wax or beebread was 3.9 ppb imidacloprid. A probabilistic risk assessment was conducted on the residues recovered from beebread in apiaries located in commercial, urban, and rural landscapes. The calculated risk quotient based on a dietary no observable adverse effect concentration (NOAEC) suggested low potential for negative effects on bee behavior or colony health.

Assessing natural isothiocyanate air emissions after field incorporation of mustard cover crop.

A regional air assessment was performed to characterize volatile natural isothiocyanate (NITC) compounds in air during soil incorporation of mustard cover crops in Washington State. Field air sampling and analytical methods were developed specific to three NITCs known to be present in air at appreciable concentrations during/after field incorporation. The maximum observed concentrations in air for the allyl, benzyl, and phenethyl isothiocyanates were respectively 188, 6.1, and 0.7 µg m(-3) during mustard incorporation. Based on limited inhalation toxicity information, airborne NITC concentrations did not appear to pose an acute human inhalation exposure concern to field operators and bystanders.

A fast and effective approach for the discrimination of garlic origin using wooden-tip electrospray ionization mass spectrometry and multivariate classification.

This paper presents the combination of wooden-tip electrospray ionization mass spectrometry (WTESI-MS) and multivariate pattern recognition methods (principal component analysis, PCA and partial least squares discriminant analysis, PLS-DA) for the rapid and reliable discrimination, via chemical fingerprints, of garlic origin. A total of 312 garlic samples grown in different countries (Brazil, China, Argentina, Spain, and Chile) were studied. The methodology was based on a direct sampling approach, which relies on loading the sample by penetrating the garlic cloves with a pre-wetted wooden tip, followed by direct prompt analysis by WTESI-MS. Thus, no sample preparation is needed, which prevents the degradation of important metabolites and increases the analytical throughput. Parameters that affects the WTESI were optimized and the best performance in terms of signal stability and intensity was achieved using the positive ion mode. Most of the ions in WTESI mass spectra were assigned to amino acids, sugars, organosulfur compounds, and lipids. The discriminative model showed good performance (accuracy rates between 81.9% and 98.6%) and enabled identifying diagnostic ions for garlic samples from different origins. The differentiation and classification of garlic origin is of major importance as this food flavoring product is widely consumed, with worldwide trade representing billions of dollars every year, and is very often the subject of fraud.

Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat.

Light and electron microscope immunocytochemistry with a monoclonal antibody against the N-terminal domain of the human protein was used to determine the cellular and subcellular localization of serotonin 5-HT2A receptors in the central nervous system of adult rat. Following immunoperoxidase or silver-intensified immunogold labeling, neuronal, somatodendritic, and/or axonal immunoreactivity was detected in numerous brain regions, including all those in which ligand binding sites and 5-HT2A mRNA had previously been reported. The distribution of 5-HT2A-immunolabeled soma/dendrites was characterized in cerebral cortex, olfactory system, septum, hippocampal formation, basal ganglia, amygdala, diencephalon, cerebellum, brainstem, and spinal cord. Labeled axons were visible in every myelinated tract known to arise from immunoreactive cell body groups. In immunopositive soma/dendrites as well as axons, the 5-HT2A receptor appeared mainly cytoplasmic rather than membrane bound. Even though the dendritic labeling was generally stronger than the somatic, it did not extend to dendritic spines in such regions as the cerebral and piriform cortex, the neostriatum, or the molecular layer of the cerebellum. Similarly, there were no labeled axon terminals in numerous regions known to be strongly innervated by the immunoreactive somata and their axons (e.g., molecular layer of piriform cortex). It was concluded that the 5-HT2A receptor is mostly intracellular and transported in dendrites and axons, but does not reach into dendritic spines or axon terminals. Because it has previously been shown that this serotonin receptor is transported retrogradely as well as anterogradely, activates intracellular transduction pathways and intervenes in the regulation of the expression of many genes, it is suggested that one of its main functions is to participate in retrograde signaling systems activated by serotonin.

Similar ultrastructural distribution of the 5-HT(2A) serotonin receptor and microtubule-associated protein MAP1A in cortical dendrites of adult rat.

As visualized by light and electron microscopic immunocytochemistry, the distribution of the neuronal serotonin-2A (5-HT(2A)) receptor is mainly intracellular throughout adult rat brain. This localization is particularly striking in the pyramidal cells of cerebral cortex, the dendrites of which are intensely immunoreactive, but without any labeling of their spines. In view of recent yeast two-hybrid and biochemical results suggesting an association of 5-HT(2A) receptors with the cytoskeletal microtubule-associated protein MAP1A, the respective subcellular distributions of the receptors and of MAP1A were compared by quantitative electron microscopic immunocytochemistry in dendrites of adult rat frontoparietal cortex. Counts of silver-intensified immunogold particles revealed a higher density of 5-HT(2A) receptors in smaller rather than larger dendrites, and an apportionment between pre-defined compartments representing the plasma membrane and the cytoplasm that was proportional to the relative surface area of these compartments. MAP1A immunoreactivity also predominated in smaller versus larger dendrites, but with a slightly lower proportion of labeling in the plasma membrane versus cytoplasmic compartment. The co-localization of 5-HT(2A) receptors and MAP1A protein in the same dendrites could be demonstrated in double immunolabeling experiments. These results confirmed the predominantly somato-dendritic, intracellular localization of 5-HT(2A) receptors in cerebral cortex, showed their higher concentration in distal as opposed to proximal dendrites, and suggested their potential association to the cytoskeleton in cortical neurons in vivo. Such a distribution of 5-HT(2A) receptors reinforces our earlier hypothesis that 5-HT(2A) receptors participate in intraneuronal signaling processes involving the cytoskeleton, and raises the possibility that their activation could be dependent upon that of another co-localized, plasma membrane-bound, 5-HT receptor.

Understanding the tropospheric transport and fate of agricultural pesticides.

Many field monitoring studies have indicated the substantial role of the troposphere as both a sink and transport medium for pesticides. At the same time, this is the least studied and understood environmental compartment in regards to pesticide fate. Although the fundamental principles behind volatilization and tropospheric reactivity are well understood, it is becoming increasingly apparent that the ability to quantitatively measure flux and reaction rates in the air will continue to pose problems for researchers. To date, most deterministic models that try to simulate real world conditions generally fail to provide tropospherically relevant flux and reaction rates because it is virtually impossible to scale down all possible interactions occurring in a near-infinite reservoir. Better field methods for determining flux are emerging and more ambient air monitoring studies are being conducted. This growing database of information, together with an understanding of physicochemical properties and use of expert systems, has increased the predictive capability for estimating volatilization flux of pesticides. Unfortunately, there are very limited environmental data on the tropospheric reaction rates of pesticides, and more experimental studies using semivolatile to low-volatility pesticides or their more volatile homologues are required to validate existing structure-activity relationship (SAR) model predictions. The development of new analytical strategies using elevated temperatures for assessing semivolatile to low-volatility pesticide reaction rates and products may provide an alternative approach to the need for controlled environmental temperature data. Recent international workshops organized by the Health Council of The Netherlands for developing uniform approaches for assessing exposure risks to pesticides in air exemplify efforts to synchronize flux with environmental fate information for determining human health and ecological risks. When more detailed pesticide information is desired, especially in high-use agricultural areas, where exposure to humans and nontarget ecological communities is a major concern, field flux measurements and downwind monitoring, together with experimental fate studies, should be considered. The integration of models, empirical testing, and real world monitoring will provide the ultimate safety net needed for assessing exposure risks to airborne pesticides.