Inhibitors of dipeptidyl peptidase IV and aminopeptidase N target major pathogenetic steps in acne initiation

Acne is a chronic disease hallmarked by sebaceous hyperplasia, follicular hyperkeratosis, and inflammation. Parallel targeting of these factors is required to treat acne effectively. Inhibitors of dipeptidyl peptidase IV (DP IV) and aminopeptidase N (APN) show strong anti-inflammatory effects on immune cells and therapeutic efficacy in autoimmune disorders. Our investigation focused on the expression and functional relevance of these ectopeptidases in three cell types which exhibit an altered phenotype in early acne lesions. We showed for the first time expression of DP IV and APN on human sebocytes. In the SZ95 sebocyte cell line, the DP IV inhibitors Lys[Z(NO2)]-thiazolidide and Lys[Z(NO2)]-pyrrolidide and the APN inhibitors actinonin and bestatin suppressed proliferation, enhanced terminal differentiation, and slightly decreased total neutral lipid production. The anti-inflammatory and differentiation-restoring cytokine IL-1 receptor antagonist was significantly upregulated in SZ95 sebocytes and the HaCaT keratinocyte cell line in the presence of inhibitors. Furthermore, the inhibitors suppressed proliferation and IL-2 production of Propionibacterium acnes-stimulated T cells ex vivo and enhanced the expression of the immunosuppressive cytokine transforming growth factor-beta1. Our data provide first evidence for a functional role of DP IV and APN in the sebaceous gland apparatus and for their inhibitors, used alone or in combination, as completely new substances possibly affecting acne pathogenesis in a therapeutic manner.     

Management of atopic dermatitis using photo(chemo)therapy

The conclusions that may be drawn by interpreting the current literature on the efficacy of photo(chemo)therapy in the treatment of atopic dermatitis (AD) are limited by several factors including publication bias, small sample sizes, high variability of parameters used in different studies, and in particular the lack of randomized controlled trials comparing different photo(chemo)therapeutic modalities. The newer ultraviolet (UV) modalities, such as medium-dose UVA1 and narrowband (NB) UVB, with a high output and a narrow emission spectrum may be considered the probably most efficacious regimens for treating acute and chronic AD, respectively, in particular when compared to conventional broadband UV regimens. There are no prospective trials on AD patients comparing NB UVB and UVA1 with more complex regimens such as heliotherapy, balneophototherapy, psoralen plus UVA (PUVA), and extracorporeal photophoresis. Support for the role of the aforementioned regimens in the treatment of AD is generally weaker than for the newer modalities including medium-dose UVA1 and NB UVB. When photo(chemo)therapy is considered for AD patients, its use is very much dedicated by the cost-effectiveness, availability, and the practicality of attending the clinic several times a week.     

Expression of gp130 in Tumors and Inflammatory Disorders of the Skin: Formal Proof of its Identity as CD146 (MUC18, Mel-CAM)

Two antibodies, BT14 and L101, detect a tumor-associated cell surface glycoprotein (gp130) whose properties in normal and diseased skin were assessed, and whose molecular identity was determined in this study. In normal skin, gp130 was constitutively expressed on dermal blood vessels and epidermal appendages, but not in interfollicular epidermis. Marked induction was detected within benign and malignant tumors of various origins including viral warts, basal cell carcinomas, squamous cell carcinomas, metastatic melanomas, and cutaneous T cell lymphomas. In vitro studies confirmed the general upregulation of gp130 expression in malignantly transformed cells. Surprisingly, gp130 was also induced in inflammatory skin diseases including psoriasis and allergic contact dermatitis. Halting proliferation of transformed keratinocytes through cytostatic drugs or increasing the Ca²⁺ concentration in the medium resulted in increased gp130 expression. In addition, overexpression of Bcl-2 led to upregulation of gp130. When the protein was purified and analyzed by peptide mass fingerprinting, we could demonstrate that it is MUC18 (Mel-CAM, CD146). Sequential immunoprecipitations and western blot analyses confirmed the identity of the antigen. Thus, both expression pattern and regulation characteristics of the now-known glycoprotein gp130 extended beyond previously published data regarding MUC18, thus shedding some new light on a supposedly well-known antigen.     

164. Immunantwort des aktiv tetanusimmunisierten Splenektomierten nach Boosterung

Zusammenfassung Bei 31 Tetanusimmuisierten die im Alter von 5 bis 67,5 Jahren wegen einer traumatischen Milzruptur splenektomiert worden waren, wurde die humorale Immunantwort auf die Boosterinjektion untersucht. Am Tag 0 lag der Serumantitoxinspiegel um das 5–2500fache über dem protektiven Schutzwert. Nach der Boosterinjektion kam es bei allen Probanden zu einen starken Anstieg des Tetanusantitoxins im Serum. Die arithmetischen Mittelwerte und die Standardabweichungen betrugen am 7. Tag 13,95 ± 12,28 iU/ml, am 42. Tag 17,11 ± 14,37 iU/ml Serum.     

A Comparison of Voxel-Based Morphometry and Volumetry Methods in the Context of the Neural Basis of Aggression

The assumption that voxel-based morphometry (VBM) offers an automated substitution for manually-traced volumetry was subjected to empirical evaluation. Data available from a previous volumetry study (Gansler et al. Psychiatry Research: Neuroimaging 171:145–154, 2009) provided the basis for the current study, which assessed for convergence between the methods. Optimized modulated VBM was used to preprocess images (N = 40). Gray matter volume and self-reported aggression associations were tested. Results indicate convergence, as both methods revealed significant negative associations of the left orbitofrontal cortex (OFC) and aggression. VBM detected an additional positive left OFC result not revealed with volumetry, suggesting that VBM may allow greater within-region localization than volumetry. However, the methods differentially deal with error rates and power demands and as such are better conceptualized as complementary than interchangeable.     

Observation on the integrity of the blood-brain barrier after microbubble destruction by diagnostic transcranial color-coded sonography.

OBJECTIVE: To investigate alteration of the blood-brain barrier from ultrasonic contrast agent destruction by diagnostic transcranial color-coded sonography using gadolinium-enhanced magnetic resonance imaging. METHODS: Healthy male volunteers received 10 mL (400 mg/dL) of Levovist (SH U 508A; Schering AG, Berlin, Germany; n = 6) or 3 mL of Optison (FS069; Mallinckrodt Inc, St Louis, MO; n = 4) followed by 0.3 mmol/kg magnetic resonance imaging contrast agent (Magnevist; Schering) intravenously. Then transcranial color-coded sonography was performed with a conventional color duplex sonographic system, which insonated the brain in a slightly angulated axial plane with temporal average intensity of less than 700 mW/cm2 or acoustic pressure amplitude of less than 2.69 MPa, attenuated by the temporal bone. Before, immediately after, and 2 hours after insonation, T1-weighted axial magnetic resonance imaging was performed. All magnetic resonance images were individually assessed, and T1 signal intensities were measured in 2 regions of interest in both hemispheres at the 3 time points. RESULTS: No focal contrast enhancement or damage to the brain and no significant difference between T1 signal intensities in the right and left brain regions could be detected during early or late phases when either ultrasonic contrast agent was used. CONCLUSIONS: This bioeffects study gives further evidence of the safety of ultrasonic destruction of Levovist and Optison microbubbles by diagnostic transcranial color-coded sonography. However, more subtle local effects may have been missed by gadolinium-enhanced magnetic resonance imaging. Studies on diagnostic contrast-enhanced transcranial color-coded sonography as well as microbubble-based drug delivery strategies should consider ultrasonic contrast agent microbubble characteristics and concentration as well as ultrasound transmission power levels.     

Genetic and phenotypic variations of a resistant Pseudomonas aeruginosa epidemic clone

From May 1997 to December 2001, a serotype O:6 multidrug-resistant strain of Pseudomonas aeruginosa colonized or infected 201 patients in the University Hospital of Besan?on (France). The susceptibility profile of this epidemic clone to fluoroquinolones and aminoglycosides was relatively stable during the outbreak but showed important isolate-to-isolate variations (up to 64-fold) in the MICs of beta-lactams. Analysis of 18 genotypically related isolates selected on a quarterly basis demonstrated alterations in the two DNA topoisomerases II and IV (Thr83-->Ile in GyrA and Ser87-->Leu in ParC) and production of an ANT(2")-I enzyme. Although constitutively overproduced in these bacteria, the MexXY efflux system did not appear to contribute significantly to aminoglycoside resistance. beta-Lactam resistance was associated with derepression of intrinsic AmpC beta-lactamase (with isolate-to-isolate variations of up to 58-fold) and sporadic deficiency in a 46-kDa protein identified as the carbapenem-selective porin OprD. Of the 18 isolates, 14 were also found to overproduce the efflux system MexAB-OprM as a result of alteration of the repressor protein MexR (His107-->Pro). However, complementation experiments with the cloned mexR gene demonstrated that MexAB-OprM contributed only marginally to beta-lactam and fluoroquinolone resistance. Of the four isolates exhibiting wild-type MexAB-OprM expression despite the MexR alteration, two appeared to harbor secondary mutations in the mexA-mexR intergenic region and one harbored secondary mutations in the putative ribosome binding site located upstream of the mexAB oprM operon. In conclusion, this study shows that many mechanisms were involved in the multiresistance phenotype of this highly epidemic strain of P. aeruginosa. Our results also demonstrate that the clone sporadically underwent substantial genetic and phenotypic variations during the course of the outbreak, perhaps in relation to local or individual selective drug pressures.     

Art participation for psychosocial wellbeing during stroke rehabilitation: a feasibility randomised controlled trial

Purpose: To examine the feasibility of undertaking a pragmatic single-blind randomised controlled trial (RCT) of a visual arts participation programme to evaluate effects on survivor wellbeing within stroke rehabilitation.

Methods: Stroke survivors receiving in-patient rehabilitation were randomised to receive eight art participation sessions (n?=?41) or usual care (n?=?40). Recruitment, retention, preference for art participation and change in selected outcomes were evaluated at end of intervention outcome assessment and three-month follow-up.

Results: Of 315 potentially eligible participants 81 (29%) were recruited. 88% (n?=?71) completed outcome and 77% (n?=?62) follow-up assessments. Of eight intervention group non-completers, six had no preference for art participation. Outcome completion varied between 97% and 77%. Running groups was difficult because of randomisation timing. Effectiveness cannot be determined from this feasibility study but effects sizes suggested art participation may benefit emotional wellbeing, measured on the positive and negative affect schedule, and self-efficacy for Art (d?=?0.24–0.42).

Conclusions: Undertaking a RCT of art participation within stroke rehabilitation was feasible. Art participation may enhance self-efficacy and positively influence emotional wellbeing. These should be outcomes in a future definitive trial. A cluster RCT would ensure art groups could be reliably convened. Fewer measures, and better retention strategies are required.

• Implications for Rehabilitation

• This feasibility randomised controlled trial (RCT) showed that recruiting and retaining stroke survivors in an RCT of a visual arts participation intervention within stroke rehabilitation was feasible.

• Preference to participate in art activities may influence recruitment and drop-out rates, and should be addressed and evaluated fully.

• Art participation as part of rehabilitation may improve some aspects of post-stroke wellbeing, including positive affect and self-efficacy for art.

• A future definitive cluster RCT would facilitate full evaluation of the value art participation can add to rehabilitation.

     

Assessing paedophilia based on the haemodynamic brain response to face images

Objectives: Objective assessment of sexual preferences may be of relevance in the treatment and prognosis of child sexual offenders. Previous research has indicated that this can be achieved by pattern classification of brain responses to sexual child and adult images. Our recent research showed that human face processing is tuned to sexual age preferences. This observation prompted us to test whether paedophilia can be inferred based on the haemodynamic brain responses to adult and child faces. Methods: Twenty-four men sexually attracted to prepubescent boys or girls (paedophiles) and 32 men sexually attracted to men or women (teleiophiles) were exposed to images of child and adult, male and female faces during a functional magnetic resonance imaging (fMRI) session. Results: A cross-validated, automatic pattern classification algorithm of brain responses to facial stimuli yielded four misclassified participants (three false positives), corresponding to a specificity of 91% and a sensitivity of 95%. Conclusions: These results indicate that the functional response to facial stimuli can be reliably used for fMRI-based classification of paedophilia, bypassing the problem of showing child sexual stimuli to paedophiles.