Tildrakizumab efficacy and safety in patients with psoriasis and concomitant metabolic syndrome: post hoc analysis of 5-year data from reSURFACE 1 and reSURFACE 2.

BACKGROUND: Limited data are available on long-term efficacy and safety of biologics in patients with psoriasis and metabolic syndrome (MetS), a common comorbidity. OBJECTIVES: This analysis updates tildrakizumab efficacy and safety for up to 5 years in patients with and without MetS. METHODS: This was a post hoc analysis of the double-blind, randomized, placebo-controlled, phase 3 reSURFACE 1 (NCT01722331) and reSURFACE 2 (NCT01729754) trials in adult patients with moderate to severe chronic plaque psoriasis. Analyses included data through Week 244 from patients who continuously received tildrakizumab 100 (TIL100) or 200 mg (TIL200) and entered the extension studies, stratified by baseline MetS status. Efficacy was assessed via Psoriasis Area and Severity Index (PASI) scores. Safety was evaluated from exposure-adjusted incidence rates (EAIRs) of treatment-emergent adverse events (TEAEs). RESULTS: reSURFACE 1 and reSURFACE 2 analyses included 26 and 44 TIL100-treated patients with MetS, 98 and 167 TIL100-treated patients without MetS, 34 and 30 TIL200-treated patients with MetS, and 111 and 130 TIL200-treated patients without MetS, respectively. There were no clinically relevant differences in PASI 75/90/100 response rates at Week 244 between patients with vs without MetS. The proportion of patients with vs without MetS achieving absolute PASI score <3 at Week 244 was 53.8% vs 69.4% and 77.3% vs 80.8% in reSURFACE 1 and 2, respectively, for TIL100-treated patients and 58.8% vs 72.1% and 63.3% vs 72.3%, respectively, for TIL200-treated patients. In both studies, median reduction from baseline PASI score at all time points in patients with vs without MetS was >83% vs >89% for TIL100 and >85% vs >90% for TIL200. Pooled EAIRs of TEAEs, serious TEAEs, and TEAEs of special interest were similar in patients with and without MetS. CONCLUSIONS: Tildrakizumab maintains efficacy and a favorable safety profile over 5 years in patients with psoriasis regardless of MetS status.

Hsa-mir-124-3 CpG island methylation is associated with advanced tumours and disease recurrence of patients with clear cell renal cell carcinoma.

BACKGROUND: Whether methylation of the microRNA (mir)-124-3 CpG island is of relevance for the clinical course of a solid cancer and whether it shows association with clinicopathology or survival of patients with renal cell cancer (RCC) is not known as yet. METHODS: In a cross-sectional study, relative methylation of mir-124-3 was measured in 111 RCC samples and 77 paired normal appearing tissues using quantitative methyl-specific PCR. Results were statistically compared with tumour histology, clinicopathological parameters and disease recurrence. RESULTS: We found tumour-specific hypermethylation of mir-124-3 in samples of RCCs with clear cell histology (ccRCC) compared with paired normal appearing tissues (P<0.0001). Methylation was significantly increased in tumours with state of advanced disease (P<0.0001). Higher relative methylation was associated with worse recurrence-free survival in both univariate (hazard ratio=9.37; P=0.0005) as well as bivariate Cox regression analyses considering age, sex, diameter of tumours and state of advanced disease, metastasis and lymph node metastases as covariates (hazard ratios=5.9-18.2; P-values of 0.0003-0.008). CONCLUSION: We identified mir-124-3 CpG islands (CGI) methylation as a relevant epigenetic mark for ccRCC thus underlining the need for functional studies of potentially affected signalling pathways in kidney tumour models. Methylation of mir-124-3 is suggested as an independent prognosticator for ccRCC.

Effect of dosing frequency on the safety and efficacy of imiquimod 5% cream for treatment of actinic keratosis on the forearms and hands: a phase II, randomized placebo-controlled trial.

BACKGROUND: Clinical studies in cutaneous conditions other than actinic keratosis (AK) have revealed that the safety and efficacy profile of imiquimod is influenced by dosing frequency. OBJECTIVES: To evaluate dosing frequency response of imiquimod 5% for treatment of AK. METHODS: This was a phase II, multicentre, randomized, double-blind, placebo-controlled study. Adults with > or = 10 but < or = 50 clinical AKs, one of which was histologically confirmed, were randomized (4:1) to 2-6 packets of imiquimod or placebo cream applied to the dorsum of the forearms and hands once daily 2, 3, 5 or 7 times per week for 8 weeks. The primary endpoint was complete clearance of AKs in the treatment area at 8 weeks post-treatment. RESULTS: One hundred and forty-nine (94 men and 54 women) white subjects, with a mean +/- SD age of 71 +/- 10.2 years, were enrolled. Twenty-eight subjects (18.8%) discontinued from study: 0%, 3.1%, 6.9%, 30.0% and 33.3% withdrew for local skin reactions or adverse events in the combined placebo, and in the imiquimod 2, 3, 5 or 7 times per week groups, respectively. Seven serious adverse events occurred; none was related to the study drug. Median baseline lesions ranged from 38 to 40 for the treatment groups. Complete clearance was achieved in 0%, 3.2%, 6.9%, 3.3% and 6.7% of subjects, and partial clearance (> or = 75% lesion reduction) in 0%, 22.6%, 24.1%, 20.0% and 36.7% of subjects for the placebo and imiquimod 2, 3, 5 or 7 times per week regimens, respectively. CONCLUSIONS: Imiquimod 5% applied more frequently than 3 times per week to AKs was not well tolerated. Complete clearance rates were low; however, partial clearance rates increased with increased dosing frequency (P = 0.002).

Acute and mid-term outcomes after treatment of multiple, recurrent restenoses of the lower limb arteries.

AIM: Recanalization of long segmental occlusions of femoropopliteal arteries can be achieved by angioplasty and implantation of nitinol stents with high procedural success rates. However, due to recurrent in-stent restenoses (ISR) some patients need repeated interventions and their intermediate success rates are uncertain. METHODS: Patients who were treated in our center from March 2008 through February 2011 due to symptomatic ISR (as determined by Duplex sonography) were retrospectively included in the study. After endovascular treatment of their ISR, they were prospectively evaluated with regard to recurrent ISR of the target lesions. RESULTS: A total of 36 limbs (=lesions) in 32 patients (69% male, mean age 69±9 years) were successfully treated by balloon-angioplasty. Adjunctive cutting balloons and drug eluting balloons were used in 78% and 8%, respectively. Mean follow-up was 326 days. Recurrent ISR occurred in 10 (28%) lesions, while 26 (78%) lesions showed no recurrence of ISR. In a multivariate logistic regression analysis, age, gender, cardiovascular risk factors, renal failure and medication with cilostazol were not significantly associated with recurrent ISR. Moreover, the number of previous interventions of the target lesions was not an independent predictor of recurrent ISR. CONCLUSION: Patients with multiple recurrences of ISR seem to have the same prospects of acute and mid-term success for endovascular treatment as those with first presentation of ISR. However, this observation has to be confirmed by prospective, large scale studies with a longer follow-up period to determine the significance of endovascular intervention within the scope of different revascularization approaches for treatment of recurrent ISR.

Technetium-99m-sestamibi scintimammography for the detection of breast carcinoma: comparison between planar and SPECT imaging.

UNLABELLED: The purpose of our study was to compare the results of planar and SPECT scintimammography for the detection of breast carcinoma. In addition, our goal was to determine whether SPECT reconstructed with filtered backprojection (FBP) or with iterative algorithms (ISA) can improve the sensitivity and specificity of planar scintimammography (SMM). METHODS: One hundred thirteen patients with suspicious physical examinations and/or mammography underwent planar lateral and anterior breast imaging as well as SPECT imaging after injection of 99mTc-sestamibi. We used a blind evaluation, both separately and combined, for planar SMM, ISA-SPECT and FBP-SPECT. Scintigraphic findings were correlated with the final histopathological diagnoses. RESULTS: The sensitivity of planar SMM was 80% with a specificity of 83%. All ISA-SPECT studies were of diagnostic quality, while FBP-SPECT was considered nondiagnostic in 14 that were excluded for statistical calculation. Sensitivity of ISA-SPECT and FBP-SPECT were 71% and 69%, respectively. Specificity was 70% for ISA-SPECT and 66% for FBP-SPECT. Combined planar SMM plus ISA-SPECT sensitivity was 85% (81% for planar SMM plus FBP-SPECT) with a specificity of 72%. Three carcinomas indeterminate on planar SMM were correctly identified by combined planar SMM plus ISA-SPECT. ISA-SPECT and FBP-SPECT provided additional information to planar SMM with respect to localization of sestamibi uptake, tumor extent, improved diagnostic certainty and detection of axillary nodes in 40 and 14 patients, respectively. CONCLUSION: ISA reconstruction is the preferable approach to SPECT data. Combined with planar SMM, ISA-SPECT can improve sensitivity. SPECT is useful in cases of indeterminate and positive planar SMM.

GABAB receptor mediated effects on central respiratory system and their antagonism by phaclofen.

The role of GABAB receptors in control of central respiratory system was evaluated by cycle-triggered averaging of phrenic nerve activity (PNA) of the rabbit. Blockade of GABAB receptors of the caudal brainstem by intracerebroventricular administration of phaclofen augmented PNA, decreased the duration of inspiration and to about the same extent increased the duration of expiration thus unmasking intrinsically active GABA. Analogously, stimulation of brainstem GABAB receptors by exogenous baclofen decreased PNA. Preceding administration of larger doses of phaclofen could block the effects of baclofen. It is proposed that GABAB receptors are involved in tonic and phasic modulation of central respiratory activity.

Efficiency of preparative and process column distribution systems.

An analytical method for computing the residence time distribution of the liquid distribution system in chromatography columns is described. The impact of the distributor design on the separation efficiency is predicted as a function of media properties and packed bed dimensions. The efficiency loss due to the distributor when increasing column diameter during scale-up is quantified. It is shown that this loss can be compensated by modulating the local bed height via a moderate inclination of the bed support. It is concluded that the selection of an appropriate distributor design concept with optimised dimensions enables a scale-up of chromatographic separations without any significant loss of chromatographic efficiency due to the distribution system.

[Management of violent acts within the scope of a pedagogic concept of self and social development--or: talking with school children about violence]. / Bearbeitung von Gewalthandlungen im Rahmen eines pädagogischen Konzeptes von Selbst- und Sozialentwicklung--Oder: Mit Schulkindern über Gewalt reden.

In order to deal with physical aggression in schools it is necessary to develop an educational concept in which the teachers parallel to their observations of the subject orientated learn-track include the relationship- and the self-development-track (three-track-education). In this concept of classifying dialogs which follow the conflict situations have equal importance to other events during school-lessons. The dialogs take place parallel to the lessons. This method requires a flexible organisation of the lessons in which the pupils are used to work on their own. An extension of the teachers competence is necessary. The extension of competence is related to a close observation of social events and to a development of models to explain the problematic behavior of pupils. If it becomes possible for example to interpret part of the pupils' behavior as scenic acting this new point of view may lead to new solutions. The educational concept is orientated on a model of psychoanalytical explanation in which the current situation stands in the foreground. The problem which thus becomes apparent can be now be handled by reconstructing the exterior events (interactions) and by the symbolic presentation of the interior perception (annoyance, anger, rage). Thus the pupils learn to deal with their inner turbulences in the constructive manner. For the acting in the public forms of making amends are practised. Physical aweness and fitness is seen as an important base for self- and social processes. The work of a man within a boys' group and of a woman within a girls' group offers the possibility of sexual identity.

Micro-lightguide spectrophotometry (O2C®) as a predictor of intermediate outcome in patients with critical limb ischemia after percutaneous transluminal angioplasty (PTA).

AIM: Micro-lightguide spectrophotometry (O2C®) provides easily and rapidly measurable parameters of tissue microcirculation. The aim of this study was to assess whether micro-lightguide spectrophotometer (O2C®) based parameters of the tissue microcirculation can serve as predictors of ulcer healing. Furthermore, we tried to identify cut off values to forecast patient outcome and check other diagnostic meanings of individual O2C-parameters. METHODS: Forty individuals, all suffering from critical limb ischemia and arterial or arteriovenous ulcers were retrospectively investigated concerning O2C®- and ankle/toe brachial index-measurements before and up to two times after percutaneous transluminal angioplasty (PTA). At a median follow-up of 7 (range 3 to 14) months after PTA the current peripheral arterial disease (PAD) status, ulcer healing, adverse cardiovascular events including death and endovascular or surgical treatments were noted. RESULTS: We found in patients with healing wounds a significant increase in oxygen saturation (SO2, median 26.35±26.94%) compared to non-healers (-4.27±25.24%, P=0.006) as well as regarding blood flow (median 41.12±51.23AU vs. -9.46±24.01 AU, P=0.005). Additionally, the parameter rHb separated reliably between arterial and arteriovenous ulcers (P=0.024). In Cox regression models, increases after revascularisation of more than 6 % in SO2 (HRR=6.08, 95%CI 1.56-23.65, P=0.009) and flow decreases of less than 12 AU (HRR 4.95, 95%CI 1.42-17.31, P=0.012) were significantly associated with amputation-free survival. CONCLUSION: The O2C®-parameters SO2 and flow provide prognostic information for ulcer healing as well as for amputation-free survival, and rHB adds information about a possible arterial or arteriovenous genesis of an ulcer.

A zero-gravity instrument to study low velocity collisions of fragile particles at low temperatures.

We discuss the design, operation, and performance of a vacuum setup constructed for use in zero (or reduced) gravity conditions to initiate collisions of fragile millimeter-sized particles at low velocity and temperature. Such particles are typically found in many astronomical settings and in regions of planet formation. The instrument has participated in four parabolic flight campaigns to date, operating for a total of 2.4 h in reduced-gravity conditions and successfully recording over 300 separate collisions of loosely packed dust aggregates and ice samples. The imparted particle velocities achieved range from 0.03 to 0.28 m s(-1) and a high-speed, high-resolution camera captures the events at 107 frames/s from two viewing angles separated by either 48.8 degrees or 60.0 degrees. The particles can be stored inside the experiment vacuum chamber at temperatures of 80-300 K for several uninterrupted hours using a built-in thermal accumulation system. The copper structure allows cooling down to cryogenic temperatures before commencement of the experiments. Throughout the parabolic flight campaigns, add-ons and modifications have been made, illustrating the instrument flexibility in the study of small particle collisions.

Tacrolimus ointment does not affect the immediate response to vaccination, the generation of immune memory, or humoral and cell-mediated immunity in children.

BACKGROUND: Concern exists that the prolonged application of immunomodulators to treat atopic dermatitis may cause systemic immunosuppression. AIMS: In a 7-month, multicentre, randomised, controlled trial, we investigated the equivalence of response to vaccination against meningococcal serogroup C disease with a protein-conjugate vaccine in children (2-11 years) with moderate to severe atopic dermatitis, by applying either 0.03% tacrolimus ointment (TAC-O; n = 121[corrected]) or a hydrocortisone ointment regimen (HC-O; n = 111). METHODS: TAC-O was applied twice daily (bid) for 3 weeks, and thereafter daily until clearance. 1% hydrocortisone acetate (HA) for head/neck and 0.1% hydrocortisone butyrate ointment for trunk/limbs was applied bid for 2 weeks; thereafter HA was applied bid to all affected areas. At week 1, patients were vaccinated with protein-conjugate vaccine against meningococcal serogroup C, and challenged at month 6 with low dose meningococcal polysaccharide vaccine. The control group (44 non-atopic dermatitis children) received the primary vaccination and challenge dose. Assessments were made at baseline, weeks 1 and 5, and months 6 and 7. The primary end point was the percentage of patients with a serum bactericidal antibody (SBA) titre > or = 8 at the week 5 visit. RESULTS: The response rate (patients with SBA titre > or = 8) was 97.5% (confidence interval (CI) approximately 97.3 to 100), 99.1% (94.8 to 100) and 97.7% (93.3 to 100) in the TAC-O, HC-O and control groups, respectively. CONCLUSIONS: The immune response to vaccination against meningococcal serogroup C in children with atopic dermatitis applying either 0.03% TAC-O or HC is equivalent. Ointment application does not affect the immediate response to vaccination, generation of immune memory or humoral and cell-mediated immunity.

Photodynamic therapy with topical methyl aminolaevulinate for 'difficult-to-treat' basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) may be difficult to treat by conventional means, particularly if the lesions are large or located in the mid-face (H-zone). Photodynamic therapy (PDT) using topical methyl aminolaevulinate (MAL) may be a good noninvasive option for these patients. OBJECTIVES: To investigate the efficacy and safety of PDT using MAL for BCCs defined as 'difficult to treat', i.e. large lesions, in the H-zone, or in patients at high risk of surgical complications. METHODS: This was a prospective, multicentre, noncomparative study. Patients were assessed 3, 12 and 24 months after the last PDT treatment. One hundred and two patients with 'difficult-to-treat' BCC were treated with MAL PDT, using 160 mg g(-1) cream and 75 J cm(-2) red light (570-670 nm), after lesion preparation and 3 h of cream exposure. Results Ninety-five patients with 148 lesions were included in the per protocol analysis. The histologically confirmed lesion complete response rate at 3 months was 89% (131 of 148). At 12 months, 10 lesions had reappeared, and therefore the cumulative treatment failure rate was 18% (27 of 148). At 24 months, an additional nine lesions had reappeared, resulting in a cumulative treatment failure rate of 24% (36 of 148). The estimated sustained lesion complete response rate (assessed using a time-to-event approach) was 90% at 3 months, 84% at 12 months and 78% at 24 months. Overall cosmetic outcome was judged as excellent or good in 79% and 84% of the patients at 12 and 24 months, respectively. Follow-up is continuing for up to 5 years. CONCLUSIONS: MAL PDT is an attractive option for 'difficult-to-treat' BCC. Because of the excellent cosmetic results, the treatment is particularly well suited for lesions that would otherwise require extensive surgical procedures.

Cutaneous mercury granuloma.

Mercury poisoning arising from cutaneous mercury deposition is highly unusual. The diagnosis is difficult to make when no history of a penetrating injury is given. We report such a case and discuss investigation and management. Other cutaneous manifestations of mercury exposure are outlined.

Sweet's panniculitis.

We report the development of acute, tender, erythematous plaques in a 65 year old female with Myelodysplastic Syndrome transforming to Acute Myeloid Leukaemia. The clinical presentation strongly suggested Sweet's syndrome. Histopathological examination of the plaques showed a normal epidermis, dermal and subcutaneous oedema, and large numbers of polymorphs in the panniculus. The eruption responded quickly to systemic steroids, with recrudescence when steroid dosage was reduced. She remained symptom free when prednisolone dosage was reduced more slowly.

A follow-up study of occupational skin disease in Western Australia.

From a total of 993 previously reported cases of occupational skin disease (OSD), 954 (96%) were contacted and 711 (75%) examined. The review time (i.e., period from original diagnosis of OSD until review) varied from a minimum of 6 months to a maximum of over 8 years. Over 60% of cases were reviewed more than 2 years after the original diagnosis was made. More than 50% were still suffering from OSD or consequences related thereto. Clearance was less likely in those who remained in their original, or similar, occupational environment. However, of those who changed their job due to OSD, many suffered aggravation of the dermatitis from factors in the new work environment. Over 10% of cases had evolved into a persistent postoccupational dermatitis without obvious cause. This condition is responsible for considerable impairment and is of medicolegal importance due to confusion as to its relationship to the original occupational factors.

Occupational skin disease in Western Australia.

993 cases of occupational skin disease (OSD) were diagnosed in a private dermatology practice over an 8-year period. Dermatologists were the major source of referral. The sex ratio was 2.4 males to 1 female. Patch tests were conducted in 79% of cases. Wet work industries predominated in females; in males the causative industries were more varied. Apprentices were affected in a high proportion of hairdressers and food handlers. Atopics accounted for 75% of the apprentice hairdressers. Atopics also were more prevalent in females with OSD than males. 29% of all cases had suffered from OSD for over 2 years before diagnosis. 75% of patients with OSD were less than 40 years of age at onset of OSD. Irritant contact dermatitis predominated over allergic contact dermatitis in all age groups except those over 60 years of age. Nickel was the predominant occupational allergen in females, whereas chromate was the predominant occupational allergen in males. 46% had been in the causative occupation for over 2 years before developing irritant contact dermatitis. Some new occupational allergens have emerged in recent years. OSD in Western Australia does not appear to differ in any major way from that reported from other countries.

Glycine receptor-mediated fast synaptic inhibition in the brainstem respiratory system.

The involvement of glycinergic neurotransmission in the central regulation of respiration was investigated by administration of specific receptor agonists and antagonists into the 4th cerebral ventricle of the rabbit. Central respiratory activity was assessed by cycle-triggered averaging of phrenic nerve activity (PNA). Glycine reduced the peak amplitude of PNA and increased the duration of the respiratory phases. Conversely, strychnine decreased the duration of both phases, being more effective in expiration. Strychnine converted inspiratory ramp activity to a decrescendo type of pattern, with the highest discharge activity present at the onset of the inspiratory phase. Strychnine induced tonic PNA lasting throughout expiration with a decrescendo type of activity. In many cases strychnine induce apneusis with tonic PNA being at a level of about 2/3 of its maximum value during control. We conclude that glycinergic neurotransmission is important for the maintenance of the respiratory rhythm as well as the generation of normal respiratory pattern. Glycine could be involved in phasic as well as tonic inhibitory neurotransmission within the central respiratory system.