Blazar spectral variability as explained by a twisted inhomogeneous jet.

Blazars are active galactic nuclei, which are powerful sources of radiation whose central engine is located in the core of the host galaxy. Blazar emission is dominated by non-thermal radiation from a jet that moves relativistically towards us, and therefore undergoes Doppler beaming. This beaming causes flux enhancement and contraction of the variability timescales, so that most blazars appear as luminous sources characterized by noticeable and fast changes in brightness at all frequencies. The mechanism that produces this unpredictable variability is under debate, but proposed mechanisms include injection, acceleration and cooling of particles, with possible intervention of shock waves or turbulence. Changes in the viewing angle of the observed emitting knots or jet regions have also been suggested as an explanation of flaring events and can also explain specific properties of blazar emission, such as intra-day variability, quasi-periodicity and the delay of radio flux variations relative to optical changes. Such a geometric interpretation, however, is not universally accepted because alternative explanations based on changes in physical conditions-such as the size and speed of the emitting zone, the magnetic field, the number of emitting particles and their energy distribution-can explain snapshots of the spectral behaviour of blazars in many cases. Here we report the results of optical-to-radio-wavelength monitoring of the blazar CTA 102 and show that the observed long-term trends of the flux and spectral variability are best explained by an inhomogeneous, curved jet that undergoes changes in orientation over time. We propose that magnetohydrodynamic instabilities or rotation of the twisted jet cause different jet regions to change their orientation and hence their relative Doppler factors. In particular, the extreme optical outburst of 2016-2017 (brightness increase of six magnitudes) occurred when the corresponding emitting region had a small viewing angle. The agreement between observations and theoretical predictions can be seen as further validation of the relativistic beaming theory.

Histopathology of the skin in rheumatic diseases.

Rheumatological systemic autoimmune diseases, such as connective tissue diseases, rheumatoid arthritis or spondyloarthritis, are characterized by the presence of joint involvement associated with extra-articular manifestations. Among them, cutaneous diseases are often the most relevant and representative clinical manifestation, as in psoriatic arthritis, scleroderma or systemic lupus erythematosus. In this context, it is useful for rheumatologists to understand better skin diseases and their histopathological features. Evaluation of skin biopsy specimens can be helpful not only to confirm the diagnosis in both classic and clinically atypical variants, but also to improve further our knowledge of the pathogenetic mechanisms and the close link between skin and articular diseases. In this review, we discuss the clinical features, diagnostic evaluation and the histopathological features of skin manifestation of the most relevant rheumatological autoimmune diseases.

Dose adjustment of biologic therapies for psoriasis in dermatological practice: a retrospective study.

INTRODUCTION: Despite the large routine use of biologic drugs in psoriasis treatment, the majority of studies do not take into consideration dose-adjustment practice in 'real-life' dermatological setting. In routine clinical practice, the disease management may include a large number of conditions requiring non-standard dosage regimens, including dose escalation, dose reduction and/or off-label treatment interruption. OBJECTIVE: The ONDA (Outcome of non-standard dosing regimen in Psoriasis and Psoriatic Arthritis) study aim was to retrospectively analyse dose-adjustment strategies among biologic therapies for psoriasis in dermatological practice during a 3-year period. RESULTS: This retrospective, observational, multicentre study was carried out in 350 patients (68% male, 32% female) affected by plaque-type psoriasis (Pso) with a coexistence of psoriatic arthritis in 164 patients (46.9%). At baseline mean PASI score was 14.9 (SD 7.2). Dose adjustment was demonstrated to be a common practice with 70/350 patients (20%) who needed a dose variation during the treatment time, in particular a dose increase in 20/70 patients (28.6%) and a dose reduction in 50/70 patients (71.4%). Dose increase was due to inefficacy on Pso parameters in 60% of cases and to inefficacy of PsA parameters in 40% of cases, while dose reduction (or temporary off-label treatment interruption) was due to prolonged remission in 54% of cases, other reason in 18% of cases, patient choice or request in 14% of cases, occurrence of concomitant event in 12% of cases. CONCLUSION: Dose adjustment is a common clinical practice, consisting of frequent dose reduction when a disease prolonged remission is obtained or dose increase to improve efficacy on Pso and PsA disease parameters.

Survival rate of antitumour necrosis factor-α treatments for psoriasis in routine dermatological practice: a multicentre observational study.

BACKGROUND: Adherence is an overall marker of treatment success, and it depends on multiple factors including efficacy and safety. Despite the wide use of tumour necrosis factor (TNF)-α blockers in the treatment of plaque-type psoriasis, few data regarding treatment adherence in routine clinical practice are available. OBJECTIVES: To estimate the long-term survival rate of anti-TNF-α therapy in a cohort of patients with psoriasis in routine clinical practice; to evaluate the reasons for and predictors of treatment discontinuation. METHODS: The Outcome and Survival rate Concerning Anti-TNF Routine treatment (OSCAR) study was based on a retrospective analysis to estimate the long-term survival rate of the first anti-TNF-α treatment in patients with psoriasis, from three Italian academic referral centres. Adult patients (n = 650) with plaque psoriasis treated with a first course of adalimumab, etanercept or infliximab for ≥ 3 months were included. RESULTS: Global adherence to anti-TNF-α treatments after 28·9 ± 15·4 months (867 ± 462 days) of observation was 72·6%. Etanercept showed a longer survival (mean 51·4 months, 1565 days; P < 0·001) compared with infliximab (36·8 months, 1120 days) and adalimumab (34·7 months, 1056 days). Treatment discontinuation due to primary and secondary inefficacy was observed in 5·2% and 14·5% of patients, respectively, whereas discontinuation due to adverse events was reported in 29 subjects (4·5%). Independent predictors of treatment withdrawal were female gender [hazards ratio (HR) 1·3], treatment with adalimumab or infliximab compared with etanercept (HR 2·7 and 1·7, respectively), and the concomitant use of traditional systemic treatment, as a rescue therapy, compared with monotherapy (HR 1·9). CONCLUSIONS: Overall survival of anti-TNF-α agents in psoriasis is elevated, with drug discontinuation mostly due to inefficacy. Etanercept showed a longer adherence compared with adalimumab and infliximab.

Remission of psoriatic arthritis after etanercept discontinuation: analysis of patients' clinical characteristics leading to disease relapse.

Psoriatic arthritis is a chronic, inflammatory, disabling arthritis affecting up to 30 percent of psoriatic patients. Recently, it has been demonstrated that tumor necrosis factor alpha (TNF-alpha) plays a pivotal role in inducing and maintaining joint damage and that molecules that block this cytokine are effective in the treatment of psoriatic arthritis. Etanercept is a recombinant fusion protein acting as a competitive inhibitor of TNF-alpha, and numerous clinical trials have demonstrated its efficacy in determining psoriatic arthritis remission. However, specific criteria defining psoriatic arthritis remission have not been delineated and few data describing the length of the remission after etanercept discontinuation are available. The aim of this observational, retrospective study was to assess post-remission efficacy maintenance and relapse characteristics after etanercept interruption in patients with moderate-to-severe peripheral psoriatic arthritis (PsA) and cutaneous involvement.

Real-life experience with ixekizumab in plaque psoriasis: a multi-center, retrospective, 3-year study.

BACKGROUND: Confirmatory data on the long-term effectiveness and safety of ixekizumab in psoriatic patients from real-world studies are needed. OBJECTIVES: The primary aim was to evaluate the 3-year drug survival of ixekizumab in the treatment of patients with moderate-to-severe plaque psoriasis, in a multicenter real-world setting. The secondary aim was to assess the influence of predictive factors on the drug survival of ixekizumab. METHODS: A retrospective analysis was performed on a cohort of patients with chronic plaque psoriasis, who received at least one dose of ixekizumab before December 2018. The drug survival analysis was performed and descriptively analyzed using Kaplan-Meier survival curves. Multivariable Cox regression analyses were carried out including variables considered to be of clinical importance. RESULTS: A total of 306 patients were enrolled. The overall drug survival at 12, 24, and 36 months of treatment with ixekizumab was 92.11%, 83.85%, and 80.19%, respectively. A higher probability (HR 2.34) of drug withdrawal was found among patients who had already received an anti-IL-17 agent compared with bio-naive patients (p 0.017). CONCLUSIONS: We found that ixekizumab is a biological agent characterized by long-term effectiveness, not influenced by several clinical factors and associated with a good safety profile.

A single-centre, observational, retrospective, real-life study evaluating adalimumab biosimilar ABP 501 in the treatment of plaque-type psoriasis and psoriatic arthritis in originator-naïve patients and in patients undergoing non-medical switch from originator.

BACKGROUND: ABP 501 is a biosimilar to the anti-tumor necrosis factor-alfa monoclonal antibody adalimumab and despite its effectiveness and safety in the treatment of psoriasis was demonstrated in randomized clinical trials, no real-life data are available, in particular in patients undergoing non-medical switch from originator to biosimilar. METHODS: We retrospectively searched our clinical records for all patients receiving ABP 501 between March 10, 2019 and September 7, 2019 at our Department. Therefore, we identified 94 patients, 46 patients underwent non-medical switch from adalimumab reference product to ABP 501. RESULTS: In originator-naïve patients, mean PASI significantly improved from baseline to week 24 (p < .0001) in both Pso and PsA cohorts. In these patients, mean DAS-28 ESR improved with no significant differences from baseline. In patients undergoing non-medical switch from adalimumab reference product to ABP 501, no significant difference in PASI or DAS-28 ESR were observed from week 16 before switch to week 24 after switch. CONCLUSIONS: AB- 501 is an effective treatment for plaque-type psoriasis and psoriatic arthritis regardless if patients are originator-naïve or if they were switched from the reference product.

Continuous treatment of plaque-type psoriasis with etanercept: an observational long-term experience.

To assess the long-term efficacy and safety profile and the patient-reported outcomes (PRO) in patients with moderate-to-severe plaque-type psoriasis receiving continuous etanercept treatment. An open-label study was conducted to evaluate etanercept as long-term treatment for moderate-to-severe plaque psoriasis. Continuous therapy was administered at a dose of 50 mg subcutaneously twice weekly for 12 weeks followed by a continuous treatment with 50 mg subcutaneously once weekly or 25 mg twice weekly throughout a 96-week study. The primary measure of efficacy was the proportion of patients with PASI 75 at week 24, 48 and 96. Patient-reported outcomes (PRO) were also assessed during the study, at week 24, 48 and 96, including the Dermatology Life Quality Index (DLQI) and the Psoriasis Disability Index (PDI). At baseline, mean PASI score, DLQI and PDI for patients eligible to initiate treatment with etanercept showed significant disease severity, quality-of-life impairment and psoriasis-related disability. At week 96, patients showed statistically significant and meaningful improvements. The continuous etanercept regimen provided a consistent improvement in both clinical disease parameters and PRO measures.

The impact of methodological approaches for presenting long-term clinical data on estimates of efficacy in psoriasis illustrated by three-year treatment data on infliximab.

BACKGROUND: Psoriasis affects about 2-3% of the Caucasian population. Biologics such as infliximab, etanercept, adalimumab and ustekinumab are efficacious treatments of plaque-type psoriasis. Critical to monitoring drug efficacy and safety is availability of long-term data. Despite the chronic nature of psoriasis, to date limited long-term clinical data have been available, as challenges are inherent in conducting a long-term analysis. With increasing time, it is more likely that the number of patients discontinuing treatment will also increase, due to loss of efficacy, adverse events or loss to follow-up. Interpretation of these data becomes confounded when one must consider missing data. Several approaches to analysing long-term data exist, and each accounts for missing data differently. OBJECTIVE: To demonstrate that the choice of a particular analysis method to account for missing data has great impact on the assessed response rate. METHODS: We used data from an open-label study over 3 years of continuous treatment with infliximab in patients with plaque-type psoriasis. These data were analysed by three methods--last observation carried forward, observed values and non-responder imputation--to account for missing data. RESULTS: The 3-year PASI 75 responses varied from 41 to 75%, depending on the method of analysis; this shows that the response rate can almost double when a more liberal analytical approach is used. CONCLUSIONS: While it is clear that the need for long-term data on biologics in psoriasis is great, considering the analysis undertaken is important when designing long-term studies and interpreting the resulting data. When analysis methods such as observed values only or last observation carried forward are used, the results of the more conservative non-responder imputation should also be presented to give a fair overview of the long-term efficacy of a treatment for plaque-type psoriasis.

European S3-guidelines on the systemic treatment of psoriasis vulgaris.

Of the 131 studies on monotherapy or combination therapy assessed, 56 studies on the different forms of phototherapy fulfilled the criteria for inclusion in the guidelines. Approximately three-quarters of all patients treated with phototherapy attained at least a PASI 75 response after 4 to 6 weeks, and clearance was frequently achieved (levels of evidence 2 and 3). Phototherapy represents a safe and very effective treatment option for moderate to severe forms of psoriasis vulgaris. The onset of clinical effects occurs within 2 weeks. Of the unwanted side effects, UV erythema from overexposure is by far the most common and is observed frequently. With repeated or long-term use, the consequences of high, cumulative UV doses (such as premature aging of the skin) must be taken into consideration. In addition, carcinogenic risk is associated with oral PUVA and is probable for local PUVA and UVB. The practicability of the therapy is limited by spatial, financial, human, and time constraints on the part of the physician, as well as by the amount of time required by the patient. From the perspective of the cost-bearing institution, phototherapy has a good cost-benefit ratio. However, the potentially significant costs for, and time required of, the patient must be considered.

Volatile and Within-Needle Terpene Changes to Douglas-fir Trees Associated With Douglas-fir Beetle (Coleoptera: Curculionidae) Attack.

Mass attack by tree-killing bark beetles (Curculionidae: Scolytinae) brings about large chemical changes in host trees that can have important ecological consequences. For example, mountain pine beetle (Dendroctonus ponderosae Hopkins) attack increases emission of terpenes by lodgepole pine (Pinus contorta Dougl. ex Loud.), affecting foliage flammability with consequences for wildfires. In this study, we measured chemical changes to Douglas-fir (Pseudotsuga menziesii var. glauca (Mirb.) Franco) foliage in response to attack by Douglas-fir beetles (Dendroctonus pseudotsugae Hopkins) as trees die and crowns transitioned from green/healthy, to green-infested (year of attack), to yellow (year after attack), and red (2 yr after attack). We found large differences in volatile and within-needle terpene concentrations among crown classes and variation across a growing season. In general, emissions and concentrations of total and individual terpenes were greater for yellow and red needles than green needles. Douglas-fir beetle attack increased emissions and concentrations of terpene compounds linked to increased tree flammability in other conifer species and compounds known to attract beetles (e.g., [Formula: see text]-pinene, camphene, and D-limonene). There was little relationship between air temperature or within-needle concentrations of terpenes and emission of terpenes, suggesting that passive emission of terpenes (e.g., from dead foliage) does not fully explain changes in volatile emissions. The potential physiological causes and ecological consequences of these bark beetle-associated chemical changes are discussed.

Sinonasal and rhinopharyngeal solitary fibrous tumour: a case report and review of the literature.

Solitary fibrous tumours are rare neoplasms that arise mostly from the pleura. Much more rarely they can also be found in extrapleural sites, including the head and neck. We report a rare case of a sinonasal and rhinopharyngeal solitary fibrous tumour. The tumour, measuring 67 x 28 x 55 mm, was first embolised and then successfully removed through endonasal endoscopic surgery. Histopathologic analysis confirmed the nature of the lesion, which was positive for CD34 and vimentin. A post-operative CT scan and endoscopic follow-up demonstrated total resection and absence of recurrence after 13 months.

Body composition and dietary intakes in adult celiac disease patients consuming a strict gluten-free diet.

BACKGROUND: Celiac disease responds to dietary gluten withdrawal, but data on the long-term effects of gluten-free diets are discordant. OBJECTIVE: Our aim was to evaluate the nutritional status and body composition of adult celiac disease patients consuming a gluten-free diet who were in clinical, biochemical, and histologic remission. DESIGN: We studied 71 patients (51 women and 20 men; mean age: 27 y; range: 17-58 y) and 142 healthy control subjects matched by sex and age. The subjects' height, weight, body mass index, fat and lean mass, and bone mineral content (evaluated by dual-energy X-ray absorptiometry) were measured; a 3-d dietary questionnaire was administered; and total daily energy, fat, carbohydrate, and protein intakes were calculated. RESULTS: The weight, height, and body mass index of male celiac disease patients and the weight and body mass index of female celiac disease patients were significantly lower than the corresponding measurements in control subjects. The fat and lean mass of both male and female patients was significantly different from that of control subjects; however, bone mineral content was significantly lower only in females in whom celiac disease was diagnosed in adulthood. Total energy intake was lower in the patients than in the control subjects (9686 +/- 1569 and 11297 +/- 1318 kJ/d in males and 6736 +/- 1318 and 7740 +/- 1715 kJ/d in females), and the diet of the patients was unbalanced, with a higher percentage of energy as fat and a lower percentage of energy as carbohydrates. CONCLUSIONS: Although strictly compliant with their gluten-free diet and in complete remission, patients with celiac disease showed differences in body composition and dietary intakes compared with control subjects. Strict follow-up and dietary advice in terms of the choice and composition of foods seem necessary to prevent malnutrition.

Echocardiographic analysis of ventricular septal dynamics in hypertrophic cardiomyopathy and other diseases.

It has been suggested that the adynamic or hypokinetic appearance of the ventricular septum is a unique echocardiographic feature of hypertrophic cardiomyopathy (HC). To determine how characteristic of HC the adynamic septum is, 70 patients with this disease, and 31 with other cardiac diseases that produce left ventricular (LV) hypertrophy and pressure overload (aortic valvular stenosis or systemic hypertension), and 25 subjects with normal hearts were studied by echocardiography. On M-mode echocardiography, 53 of 70 patients (75%) with HC had an abnormally low value for percent systolic thickening of the septum associated with either reduced or normal septal excursion; however, 17 patients (25%) showed normal septal dynamics. Twenty of 31 patients (64%) with other cardiac diseases that produce pressure overload showed normal septal thickening and excursion, while 11 (36%) had reduced systolic thickening associated with either diminished or normal excursion. Greatly reduced values for percent systolic thickening of the septum were present both in patients with HC (13 +/- 1%) and in patients with other cardiac diseases (21 +/- 2%). However, differences in systolic septal thickening between the 2 groups were largely a manifestation of the greater absolute diastolic septal thickness in patients with HC. When values for percent systolic thickening were normalized for diastolic septal thickness, or when systolic thickening was compared in only patients with similar diastolic septal thicknesses, differences in septal thickening between patients with HC and those patients with other cardiac diseases were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of flecainide and propafenone on systolic performance in subjects with normal cardiac function.

Flecainide and propafenone are effective in suppressing both ventricular and supraventricular tachyarrhythmias, but their efficacy is often limited by dose-related side effects. This study was performed to evaluate noninvasively the effects of intravenous flecainide and propafenone on left ventricular systolic function indices in a selected population of 40 subjects (28 men and 12 women; mean age, 25 years) with normal cardiac structure and performance. Echocardiographic indexes of global systolic pump function (ejection fraction [EF] and percentage of fractional shortening [percent FS]) as well as monodimensional parameters of the intraventricular septum (IVS) and left ventricular posterior wall (PW) contractility (percent systolic thickening [percent th] and systolic excursion [ex]) were assessed in all subjects at baseline, immediately after, and in the early recovery (15 min) after randomized injection of either flecainide or propafenone. Heart rate and blood pressure did not significantly change after both drugs. A significant increase (p < 0.001) in left ventricular systolic internal diameter was observed after both flecainide and propafenone; simultaneously a significant decrease of percent FS (p < 0.001), EF (p < 0.001), PW percent thickening (th) (p < 0.001), and PWex (p < 0.001 after flecainide and p < 0.01 after propafenone) was recorded. These changes were comparable and promptly reversible. In analyzing individual data, a marked systolic dysfunction was observed in two patients after intravenous flecainide (percent FS from 37 percent to 17 percent and from 42 percent to 13 percent; EF from 55 percent to 40 percent and from 65 percent to 35 percent, respectively) and in one patient after intravenous propafenone (percent FS from 30 percent to 15 percent; EF from 58 percent to 35 percent). We conclude that both intravenous flecainide and propafenone exhibit mild negative inotropic effects leading to a moderate and reversible reduction of left ventricular systolic performance; however, in some cases, a dramatic impairment of systolic pump function may occur, suggesting careful use of both drugs as first-line agents also in normal subjects; finally, the true incidence of this deleterious effect is still unknown.

Ceftazidime monotherapy vs. combined therapy in Pseudomonas pulmonary infections in cystic fibrosis.

To evaluate whether the addition of an aminoglycoside might enhance the clinical efficacy of ceftazidime in cystic fibrosis patients with acute exacerbations of chronic Pseudomonas lung infections we carried out a prospective, comparative, randomized blind study with three schedules: ceftazidime vs. ceftazidime plus sisomicin (C/S) vs. piperacillin plus sisomicin, for a total of 60 courses of 14 days of treatment. Each treatment led to clinical and radiologic improvement with marked reduction of signs of acute infection. Statistically there was no significant difference in clinical responses among the schedules. No side effect appeared during treatments with ceftazidime or C/S. Hyperpyrexia was seen in 35% of patients receiving piperacillin. Decrease in Pseudomonas aeruginosa count to less than 10(5) colony-forming units/ml of sputum was achieved in 60% of patients treated with C/S and in 30% of patients who received ceftazidime or piperacillin plus sisomicin (statistically not significant). A transient increase in mean geometric minimal inhibitory concentrations for ceftazidime and piperacillin was observed at the end of the combined therapies. A larger percentage of persistent resistant strains of P. aeruginosa was seen after the combined therapies. We conclude that ceftazidime as monotherapy may be an effective alternative in Pseudomonas lung infections in cystic fibrosis patients. Its clinical efficacy seems not to be enhanced by the addition of an aminoglycoside, although reduction of Pseudomonas in the sputum was better achieved by the combination of C/S.

Electrophoretical patterns of seminal plasma proteins in patients with cystic fibrosis.

Seminal plasma (n = 12) from cystic fibrosis (CF) patients were analyzed by gel-electrophoresis using seminal plasma and expressed prostatic secretion from fertile men as controls. Heavy precipitation at the entering position of the gel and streaking in the gel matrix was observed, demonstrating a reduced solubility of seminal proteins in CF. Comparison of the protein patterns evidenced that CF-seminal plasma (CF-SP) mainly consisted of prostatic components. Although lactoferrin was undetectable in all samples, trace amounts of low molecular weight proteins were observed in two patients. This latter finding could imply that CF-SP may contain proteolytic fragments of prostatic and/or vesicular proteins or de novo synthesized components.