Effectiveness and safety of secukinumab in 69 patients with moderate to severe plaque psoriasis: A retrospective multicenter study.

Secukinumab (anti-IL17A) is effective as treatment for moderate to severe plaque psoriasis, but real-life data on effectiveness and safety lack. We aimed to present real-life data of all Danish patients treated with secukinumab (n = 69). At baseline, before initiation of treatment with secukinumab 300 mg (47.8%) or off-label treatment with secukinumab 150 mg (52.2%), the median PASI score was 7.1. A total of 66.7% (34/51) and 52.9% (27/51) of patients still on secukinumab at week 12 achieved a PASI (Psoriasis Area and Severity Index)-50 and PASI-75 of 66.7% and 52.9%, respectively. A total of 83.0% (44/53) and 60.4% (32/53) of the patients had a PASI-score < 5 and PASI-score < 2, respectively, after 12 weeks on treatment with secukinumab. A third of the patients had secukinumab discontinued due to limited clinical improvement or adverse events (n = 23) within a median of 92 days (interquartile range 51-212 days). Notably, the majority of the patients may represent a particularly difficult-to-treat group of patients, as 92.8% had been refractory to other biologic treatment. A total of 26.1% (n = 18) experienced adverse events. Secukinumab appears to be an effective treatment option with a favorable side effect profile in patients with plaque psoriasis who are refractory to or have side effects of traditional biologic drugs.

ESR1 polymorphisms and statin therapy: a sex-specific approach.

Lipid-lowering therapy has shown a high degree of variability in clinical response and there is evidence that the variability in drug response between individuals is due to genetic factors. Thirteen single nucleotide polymorphisms (SNPs) within the ESR1 gene were evaluated with basal lipid and lipoprotein levels, as well as response to lipid-lowering therapy, in 495 hypercholesterolemic individuals of European descent receiving simvastatin or atorvastatin. Significant associations were detected between rs4870061 (P=0.040, corrected P-value (PC)=0.440), rs1801132 (P=0.002, PC=0.022) and the SNP rs3020314 (P=0.013, PC=0.143) with triglyceride (TG) baseline levels. The rs4870061 was also associated with high-density lipoprotein cholesterol (HDL-C) baseline levels (P=0.045, PC=0.495). Regarding statin efficacy, rs2234693 C/C was associated with greater HDL-C increase (P=0.037; PC=0.407) and rs3798577 T allele was associated with greater total cholesterol (TC) reduction (P=0.019; PC=0.209) and greater TG reduction (P=0.026; PC=0.286). These associations suggest that ESR1 polymorphisms are in part responsible for the TC, HDL-C and TG variation levels and this effect may be sex-specific.

Providing Competent and Affirming Services for Transgender and Gender Nonconforming Older Adults.

Despite the growing visibility and acceptance of transgender and gender nonconforming (TGNC) individuals, TGNC older adults experience many barriers in accessing competent and affirming health and social services due to anti-TGNC prejudice, discrimination, and lack of competent healthcare training on the part of healthcare workers. Clinical gerontologists and geriatricians will likely encounter TGNC adults in their practice given population aging and greater numbers of TGNC people who are living in their affirmed gender identities. The American Psychological Association recently published its Guidelines for Psychological Practice with Transgender and Gender Nonconforming People, which document the unique needs of TGNC individuals and outlines approaches for competent and affirming service provision (APA, 2015). We interpret these Guidelines using a gerontological lens to elucidate specific issues faced by the TGNC older adult along with the practice and policy implications for this population.

[Perianal and rectal ulcers due to abuse of paracetamol-codeine suppositories]. / Perianale und rektale Ulzera nach Abusus von Paracetamol-Codein-Suppositorien.

A 61-year-old woman presented with a progressive perianal ulcer which had developed 4 months ago. Upon further examination, another ulcer of the rectum was detected. Anorectal malignancies, viral infections or primary inflammatory bowel disease were not found. It could be demonstrated that the ulcers were induced by paracetamol and codeine suppositories. After discontinuation of these suppositories, the perianal ulcers healed almost completely within 3 weeks. The pathogenesis of paracetamol-induced ulcers is unknown. However, dose-dependent vasoconstriction is a possible explanation.

A role for mitogen kinase kinase 3 in pulmonary inflammation validated from a proteomic approach.

Proteomics is a powerful tool to ascertain which proteins are differentially expressed in the context of disease. We have used this approach on inflammatory cells obtained from patients with asthma to ascertain whether novel drugs targets could be illuminated and to investigate the role of any such target in a range of in vitro and in vivo models of inflammation. A proteomic study was undertaken using peripheral blood mononuclear cells from mild asthmatic subjects compared with healthy subjects. The analysis revealed an increased expression of the intracellular kinase, mitogen activated protein kinase (MKK3), and the function of this protein was investigated further in preclinical models of inflammation using MKK3 knockout mice. We describe a 3.65 fold increase in the expression of MKK3 in CD8(+) T lymphocytes obtained from subjects with asthma compared with healthy subjects using a proteomic approach which we have confirmed in CD8(+), but not in CD4(+) T lymphocytes or human bronchial epithelial cells from asthmatic patients using a Western blot technique. In wild type mice, bacterial lipopolysaccharide (LPS) caused a significant increase in MKK3 expression and significantly reduced airway neutrophilia in MKK3(-/-) mice (median, 25, 75% percentile; wild/LPS; 5.3 (0.7-9.9) × 10(5) cells/mL vs MKK3(-/-)/LPS; 0 (0-1.9) × 10(5) cells/mL, P < 0.05). In contrast, eosinophilia in sensitized wild type mice challenged with allergen (0.5 (0.16-0.65) × 10(5) cells/mL) was significantly increased in MKK3(-/-) mice (2.2 (0.9-3.5) × 10(5) cells/mL, P < 0.05). Our results suggest that asthma is associated with MKK3 over-expression in CD8(+) cells. We have also demonstrated that MKK3 may be critical for airway neutrophilia, but not eosinophilia, suggesting that this may be a target worthy of further consideration in the context of diseases associated with neutrophil activation such as severe asthma and COPD.

Performance of a novel microarray multiplex PCR for the detection of 23 respiratory pathogens (SYMP-ARI study).

Symptoms of acute febrile respiratory tract infection are often unspecific, but the rapid identification of pathogens allows optimised patient management. The objective of this study was to evaluate a novel multiplex polymerase chain reaction (PCR) suspension microarray which detects 19 viral and four atypical bacterial targets. A comprehensive set of sensitive monoplex real-time PCR assays was used for each pathogen as the gold standard. A panel of archived as well as 300 prospectively collected clinical samples was analysed by both methods. At least one target was detected in 165/300 (55 %) samples by monoplex PCR and in 140/300 (46 %) samples by multiplex PCR, respectively. The positivity rate was significantly higher in paediatric patients compared to adults [126/154 (82 %) vs. 39/146 (27 %) by monoplex and 114/154 (74 %) vs. 26/146 (18 %) by multiplex PCR, respectively]. Among all samples, 17/300 (5.6 %) were positive for atypical bacteria by monoplex and 8/300 (2.6 %) by multiplex PCR, respectively. Multiple detections were recorded in 35/300 (11.6 %) samples by monoplex and 26/300 (8.7 %) by multiplex PCR. For the most common pathogens, the sensitivity ranged from 57 to 93 % and the specificity ranged from 95 to 100 %. The overall concordance between both methods was 77 % [95 % confidence interval (CI) 72-81 %]. False-negative results by multiplex PCR were mainly due to the low target concentration. Compared to monoplex PCR, the novel microarray assay proved its principle but displayed overall lower sensitivities, potentially restricting its use to paediatric patients. For some targets, only small numbers of positive samples were available, requiring larger studies to firmly assess the sensitivity and specificity.

Comparison of three commercial systems for the identification of germ-tube negative yeast species isolated from clinical specimens.

Three commercial systems were evaluated for their ability to identify 171 germ-tube negative yeasts isolated from clinical specimens. The Yeast Biochemical Card and Analytical Profile Index 20 AUX identified 97% of 171 strains tested. The Biolog system had poor clinical utility: only 48% of strains were identified. For Yeast Biochemical Card and Analytical Profile Index 20 AUX, 9% and 6%, respectively, required repeat testing and both systems required supplemental tests for 28% of the strains. These observations indicate that considerable expertise and a battery of reagents in addition to the basic systems are required for accurate identification of germ-tube negative yeasts.

Evaluation of E test, disk diffusion and broth microdilution to establish tentative quality control limits and review susceptibility breakpoints for two aerobic actinomycetes.

A single laboratory study was carried out to compare E Test with broth microdilution and disk diffusion to establish tentative quality control ranges for Nocardia asteroides ATCC 19247 and Rhodococcus equi ATCC 6939 against a panel of eight antimicrobial agents. Reproducibility testing was performed on 12 consecutive days to establish tentative quality control ranges. A total of 36 clinical strains of the Nocardia asteroides complex and 5 Rhodococcus strains were used in the study. Both candidate control strains and clinical strains grew well on cation-adjusted Mueller-Hinton agar. Adequate growth occurred at 48 to 72 h for the Nocardia isolates and 24 to 48 h for Rhodococcus. A standardized primary inoculum of 5 x 10(4) CFU/mL was used for performance of E Test and disk diffusion for the Nocardia isolates. Tentative population-based error rates were calculated using current breakpoints for Enterobacteriaceae for E Test compared with disk diffusion for the 36 clinical strains of Nocardia species. Significant very major error rates were observed for imipenem (22%) and minor error rates varied from 2.7% to 50%. These methods require more extensive validation before definitive breakpoint criteria can be established.

Evaluation of CHROMagar Candida for presumptive identification of clinically important Candida species.

CHROMagar Candida is a recently described and differential medium for the isolation and the presumptive identification of clinically important yeasts. We evaluated it with 262 yeast strains from clinical specimens, including 173 Candida albicans, 21 Candida tropicalis, 8 Candida krusei, 49 Candida glabrata, and 12 strains of other yeast species. Strains were presumptively identified on the basis of colony color and texture. These observations were compared with conventional identification results. Candida albicans was identified correctly in 170 (98%) of the 173 strains. A total of 46 of the 205 specimens that were plated on CHROMagar contained mixed cultures of yeast. Thirty-seven (80%) of these mixed cultures were not detected in the original specimens. CHROMagar Candida was useful for the rapid presumptive identification of Candida albicans and facilitated the recognition of mixed cultures. For other yeast species, it may provide additional information to laboratories that do not regularly perform identifications beyond the germ tube test.

Rapid identification of clinical yeast isolates using the colorimetric AUXACOLOR system.

The AUXACOLOR colorimetric system (Sanofi Diagnostics Pasteur, Marnes-la-Coquette, France) for the identification of clinical yeast isolates, was compared in its identification of 100 yeast strains to conventional identification methods. Of the 94 correctly identified isolates, 47% (n = 44) were identified by 24 h, and 100% (n = 94) were identified by 48 h. AUXACOLOR is a simple, rapid and accurate method for the identification of yeast pathogens.

Oxidative stress impairs the haemodynamic activity of cardiovascular agents with antioxidant properties.

Reactive oxygen species (ROS) are known to be involved in the pathogenesis and progression of various cardiovascular diseases. For some therapeutics like carvedilol and captopril used in the treatment of such diseases antioxidant properties have been proposed to play a role in addition to their haemodynamic activities. It was the aim of the present study to assess whether ROS may affect the molecular integrity and the primary pharmacological actions of compounds with additional antioxidant properties. Accordingly, well-known drugs as mentioned were exposed to ROS, generated by electrolysis and analyzed by means of functional and chemical investigations. For this purpose rat thoracic aortic rings were incubated with either the beta1,2/alpha1-adrenoceptor antagonist carvedilol (100 nM), the alpha1-adrenoceptor antagonist prazosin (5 nM), the thiol-containing ACE-inhibitor captopril (3 microM) or lisinopril (300 nM), an ACE-inhibitor without a thiol moiety. Furthermore, isolated rat left atria were incubated with either carvedilol (14 nM) or with the beta1,2-adrenoceptor antagonist timolol (50 nM). After an incubation period of 15 min, electrolysis was applied to the buffer medium in order to generate ROS. After an additional 15 min, concentration-response curves were constructed for angiotensin I and phenylephrine in thoracic aortic rings incubated with the ACE-inhibitors and the alpha1-adrenoceptor antagonists, respectively. In addition, concentration-response curves were constructed for isoprenaline in presence of the beta1,2-adrenoceptor antagonists in isolated left atria. After exposure to oxidative stress the alpha1- and beta-adrenoceptor blocking activity of carvedilol was significantly impaired, when compared to control conditions. In contrast, the pharmacological effects of prazosin and timolol remained unaffected. The ACE-inhibition by captopril was completely abolished after electrolysis, while the pharmacological action of lisinopril was only slightly reduced. In addition, a complete oxidative degradation of captopril and carvedilol could be demonstrated by using UV/Vis spectroscopy and HPLC/fluorospectroscopy, respectively. From these results we conclude that the haemodynamic therapeutics with additional radical scavenging properties may undergo a chemical modification due to ROS-exposure which results in a loss of pharmacological activity.

Reactive oxygen species potentiate the negative inotropic effect of cardiac M2-muscarinic receptor stimulation.

The aim of the present study was to investigate the influence of reactive oxygen species (ROS) on the contractile responses of rat isolated left atria to muscarinic receptor stimulation. ROS were generated by means of electrolysis (30 mA, 75 s) of the organ bath fluid. Twenty minutes after the electrolysis period, the electrically paced atria (3 Hz) were stimulated with the adenylyl cyclase activator forskolin (1 microM). Subsequently, cumulative acetylcholine concentration-response curves were constructed (0.01 nM-10 microM). In addition, phosphoinositide turnover and adenylyl cyclase activity under basal and stimulated conditions were measured. For these biochemical experiments we used the stable acetylcholine analogue carbachol. The atria exposed to reactive oxygen species were influenced more potently (pD2 control: 6.2 vs. 7.1 for electrolysis-treated atria, P<0.05) and more effectively (Emax control: 40% vs. 90% reduction of the initial amplitude, P<0.05) by acetylcholine. In contrast, ROS exposure did not alter the responses to adenosine, whose receptor is also coupled via a Gi-protein to adenylyl cyclase. The basal (40% vs. control, P<0.05) as well as the carbachol-stimulated (-85% vs. control, P<0.05) inositol-phosphate formation was reduced in atria exposed to ROS. The forskolin-stimulated adenylyl cyclase activity was identical in both groups but carbachol stimulation induced a more pronounced reduction in adenylyl cyclase activity in the electrolysis-treated atria. Accordingly we may conclude that ROS enhance the negative inotropic response of isolated rat atria to acetylcholine by both a reduction of the positive (inositide turnover) and increase of the negative (adenylyl cyclase inhibition) inotropic components of cardiac muscarinic receptor stimulation. This phenomenon is most likely M2-receptor specific, since the negative inotropic response to adenosine is unaltered by ROS exposure.

The effects of hypochlorite-induced oxidative stress on presynaptic M2-receptors at sympathetic nerve endings in the rat tail artery.

1 It was shown recently that stimulation of cardiac muscarinic M2-receptors revealed an enhanced negative inotropic response in isolated rat left atria after exposure to hypochlorite-induced oxidative stress. This phenomenon was not observed after stimulation of the cardiac A1-receptor, which like the M2-receptor is coupled to Gi-proteins. Since even the contractile response to M3-receptor stimulation was not amplified in the rat portal vein, we hypothesized a M2-receptor specificity of this hypochlorite-induced enhancement. 2 The present study was performed in order to investigate whether the sympathoinhibitory response to presynaptically located M2-receptor stimulation would also be modified after exposure to hypochlorite in the rat tail artery. We applied electrical field stimulation (EFS) in order to mimic sympathetic neurotransmission. 3 EFS increased the vascular tone frequency-dependently (0.3-4 Hz). EFS-induced vasoconstriction could be attenuated by acetylcholine (30 nM-1 microM) in a concentration-dependent manner. Hypochlorite (10 and 100 microM) did not affect the sympathoinhibitory effect of acetylcholine (100 nM). 4 In conclusion, in contrast to cardiac M2-receptors, hypochlorite did not amplify the sympathoinhibitory effects of presynaptic M2-receptors. The different responsiveness between neuronal and cardiac M2-receptors to hypochlorite may be explained by the different G-protein subunits involved in the activation of the underlying signalling cascade.

A multicentre, randomized, double-blind, controlled study of long-term treatment with 0.1% tacrolimus ointment in adults with moderate to severe atopic dermatitis.

BACKGROUND: Atopic dermatis (AD) is a chronic disease that often requires long-term treatment. Topical corticosteroids are the usual therapy for patients with AD, but prolonged usage can result in skin atrophy and other side-effects. OBJECTIVES: In a randomized, double-blind, comparative study, to compare the efficacy and safety of a 6-month treatment period with 0.1% tacrolimus ointment vs. a corticosteroid ointment regimen in adults with moderate to severe AD. METHODS: Treatment was applied twice daily for a maximum of 6 months. Patients in the tacrolimus treatment group (n = 487) applied 0.1% tacrolimus ointment to all affected areas over the whole body. The patients treated with the corticosteroid regimen (n = 485) applied 0.1% hydrocortisone butyrate ointment to affected areas on the trunk and extremities and 1% hydrocortisone acetate ointment to affected areas on the face and neck. The study primary endpoint was the response rate, i.e. the proportion of patients with at least 60% improvement in the modified Eczema Area and Severity Index (mEASI) between baseline and month 3. RESULTS: By month 3, more patients in the 0.1% tacrolimus group responded to treatment (72.6% vs. 52.3% in the corticosteroid group, P < 0.001). The patients treated with 0.1% tacrolimus also showed greater improvement in mEASI, EASI, affected body surface area and physician and patient assessments of global response. Patients applying 0.1% tacrolimus ointment experienced more skin burning (52.4% vs. 13.8% in the corticosteroid group; P < 0.001). In most patients, skin burning was mild to moderate in severity and decreased rapidly after the first week of treatment. There was no increase in the incidence of infections or malignancies over time in either treatment group. CONCLUSIONS: Long-term treatment with 0.1% tacrolimus ointment is significantly more efficacious than a corticosteroid ointment regimen in adults with moderate to severe AD.

Determinants of variable response to simvastatin treatment: the role of common variants of SCAP, SREBF-1a and SREBF-2 genes.

We investigated the effect of single-nucleotide polymorphisms in sterol regulatory element-binding factors-1a and -2 (SREBF-1a and SREBF-2) and SREBF cleavage-activating protein (SCAP) genes on lipid-lowering response to simvastatin. In all, 146 hypercholesterolemic patients of European descent were prospectively treated with simvastatin 20 mg/day for over 6 months. Of these 99 subjects completed the 6-month follow-up. Plasma lipids and lipoproteins were measured before and throughout the study. The mean percentage decrease in plasma total cholesterol (TC) was greater in subject carriers of SCAP 2386G allele compared with those homozygous for 2386A allele (-29.6+/-13.4 vs -22.1+/-13.8%, P=0.007). About 61% of the 2386G carriers were above-average responders for TC levels (DeltaTC -27.8%), whereas only 29% of 2386A homozygous reached this reduction (P=0.009). Our data suggest that the SCAP 2386A>G gene polymorphism was a significant predictor of TC and triglyceride responses to simvastatin treatment.

Inhibitory effects of terbutaline on human esophageal peristalsis and development of tolerance.

To investigate the inhibitory influence on esophageal motility of prolonged beta-2-adrenergic stimulation, esophageal peristalsis was studied in 10 volunteers. The beta-2 agonist terbutaline was given orally, 5 mg three times daily, for 10 days, and the subjects were studied before medication (basal), on days 3 and 10 during the medication, and 1 week after withdrawal of the drug. At each session esophageal peristaltic pressure, heart rate, and finger tremor were assessed. On the 3rd day of medication the peristaltic pressure was significantly decreased and heart rate and finger tremor significantly increased compared with basal values on day 0. On the 10th day of medication there was still a decrease in peristaltic pressure but less pronounced than on day 3 despite similar blood levels of terbutaline. It is concluded that oral medication with a beta-2 agonist initially inhibits esophageal peristalsis, but during continued medication the inhibitory effect on the esophagus decreases. The results indicate development of esophageal tolerance to beta-2-receptor stimulation in accordance with development of tolerance shown in extraintestinal organs.

Treatment of Bowen's disease of the penis with imiquimod 5% cream.

We present a case of persistent and progressive Bowen's disease (squamous cell carcinoma in situ) of the penis, in an otherwise healthy 56-year-old man. Treatment with imiquimod 5% cream was effective when applied once a day for 3 consecutive days followed by 4 days without treatment, over a period of 5 weeks.