The effect of BI 409306 on heart rate in healthy volunteers: a randomised, double-blind, placebo-controlled, crossover study.

PURPOSE: The potent, selective phosphodiesterase-9A inhibitor BI 409306 may be beneficial for patients with attenuated psychosis syndrome and could prevent relapse in patients with schizophrenia. Transient BI 409306-dependent increases in heart rate (HR) demonstrated previously necessitated cardiac safety characterisation. We evaluated cardiac effects of BI 409306 in healthy volunteers during rest and exercise. METHODS: In this double-blind, three-way crossover study, volunteers received placebo, BI 409306 50 mg or 200 mg in randomised order (same treatment on Days 1 [resting] and 3 [exercise]). Cardiopulmonary exercise testing was performed twice post treatment on Day 3 of each period. BI 409306-mediated effects on placebo-corrected change from baseline in resting HR (ΔΔHR) were evaluated based on exposure-response analysis and a random coefficient model. Adverse events (AEs) were recorded. RESULTS: Overall, 19/20 volunteers completed. Resting ΔΔHR versus BI 409306 concentration yielded a slope of 0.0029 beats/min/nmol/L. At the geometric mean (gMean) maximum plasma concentration (Cmax) for BI 409306 50 and 200 mg, predicted mean (90% CI) ΔΔHRs were 0.80 (- 0.76, 2.36) and 5.46 (2.44, 8.49) beats/min, respectively. Maximum adjusted mean differences from placebo (90% CI) in resting HR for BI 409306 50 and 200 mg were 3.85 (0.73, 6.97) and 4.93 (1.69, 8.16) beats/min. Maximum differences from placebo in resting HR occurred at/near gMean Cmax and returned to baseline after approximately 4 h. The proportion of volunteers with AEs increased with BI 409306 dose. CONCLUSION: Observed hemodynamic effects following BI 409306 administration were of low amplitude, transient, and followed the pharmacokinetic profile of BI 409306.

Dicer Sequencing, Whole Genome Methylation Profiling, mRNA and smallRNA Sequencing Analysis in Basal Cell Carcinoma.

BACKGROUND/AIMS: Perturbations in the expression of microRNAs (miRNAs) and their maturing machinery components such as Dicer have been previously described for basal cell carcinoma (BCC). However, the mutational status of Dicer in BCC is unclear. Further, the sclerodermiform subtype of BCC (sBCC) has not been previously investigated regarding its methylation profile or its smallRNA expression profile via RNA sequencing. We conducted this study to investigate the mutational status of Dicer in BCC. METHODS: Dicer sequencing was performed on the Illumina MiSeq System in a total of 16 BCC samples (8 nodular BCCs, 8 sBCCs) and mapped against the human reference genome (i.e., hg19). Dicer sequencing was performed in all 16 BCC samples. We performed whole genome methylation profiling with Infinium MethylationEPIC BeadChips as well as mRNA and smallRNA sequencing in 5 sBCCs with the Illumina NextSeq500 next-generation sequencing system. RESULTS: Compared to the wildtype Dicer sequence, we found 5 to 7 variants per sBCC sample including insertion, deletion, and multiple nucleotide variants. Global methylation profiles were highly similar between groups. mRNA sequencing revealed S100A9, KRT14, KRT10, S100A8, S100A7, COX1, KRT1, COX3, and smallRNA sequencing analysis miR-21, miR-99a, miR26-a-2, let-7f, let-7g, let-7i, miR-100, and miR-205 were the most strongly expressed in sBCCs. CONCLUSION: We identified a variety of Dicer mutations that could play a role in aberrant miRNA expression in BCC. The noted RNA sequences should be further evaluated in functional studies to explore their potential pathogenetic role in sBCC.

Altered Global 5-Hydroxymethylation Status in Hidradenitis Suppurativa: Support for an Epigenetic Background.

BACKGROUND: The pathogenesis of hidradenitis suppurativa (HS), with its complex inflammatory network, is still elusive. Imbalances in DNA methylation can lead to genome destabilization and have been assumed to play a role in inflammatory diseases. Global DNA methylation and hydroxymethylation have not been studied in HS yet. OBJECTIVE: We conducted this study to investigate the global DNA methylation and hydroxymethylation status in lesional and perilesional HS skin compared to healthy controls. METHODS: Immunohistochemical analysis was performed for 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in 30 lesional and 30 corresponding healthy-appearing perilesional HS tissue samples. We included 30 healthy subjects as an interindividual control group. RESULTS: 5-hmC levels were significantly lower in healthy-appearing perilesional (p < 0.0001) and lesional HS skin (p < 0.0001) when compared to healthy controls. There was no significant difference between lesional HS skin and perilesional HS skin regarding 5-hmC levels (p = 0.6654). In contrast to 5-hmC, 5-mC staining showed no significant changes between the 3 groups. Univariate analysis revealed no significant association between patients' characteristics, disease severity, and the levels of 5-mC and 5-hmC. CONCLUSION: Our findings indicate that imbalances in DNA hydroxymethylation may play a role in the pathogenesis of HS rather than DNA methylation. Further studies are warranted to investigate the significance of DNA hydroxymethylation and the regulating enzymes in HS in order to advance our knowledge of the inflammatory network in this disease.

A phase I, randomized, proof-of-clinical-mechanism study assessing the pharmacokinetics and pharmacodynamics of the oral PDE9A inhibitor BI 409306 in healthy male volunteers.

OBJECTIVE: Cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE) inhibitors are hypothesized to improve cognition in schizophrenia and Alzheimer disease by increasing cGMP levels in certain brain regions. This phase I, randomized, parallel-group, double-blind, placebo-controlled study provides proof-of-mechanism evidence for BI 409306, a novel, oral PDE9A inhibitor. METHODS: In healthy males, exposure of BI 409306 (25-, 50-, 100-, and 200-mg single dose) and placebo was assessed in plasma and cerebrospinal fluid (CSF). Effect of BI 409306 on CSF cGMP levels was evaluated, and adverse events (AEs) were monitored. RESULTS: In all enrolled subjects (N = 20), plasma BI 409306 concentration increased rapidly (median tmax : 0.75-1.25 hr) followed by rapid increases in CSF (median tmax : 1.5-2.0 hr). Maximum CSF cGMP concentrations were achieved within 2 to 5 hr, declining to baseline levels 10 to 14 hr after dosing. Dose-dependent increases in plasma and CSF exposure and CSF cGMP were shown. BI 409306 was safe and well tolerated. Most AEs were mild to moderate in intensity and study procedure-related. CONCLUSIONS: BI 409306 increased rapidly in plasma and was subsequently detected in CSF, resulting in dose-dependent increases in cGMP levels in CSF. Results indicate BI 409306 efficiently crosses the blood-CSF barrier, with an acceptable level of AEs.

Quality of life in caregivers with and without chronic disease: Welsh Health Survey, 2013.

Background: The aim of the present study was to investigate and compare quality of life after regular care provision in people with and without currently treated chronic disease in a country-wide and population-based setting. Methods: Data were retrieved from Welsh Health Survey, 2013. Information on demographics, lifestyle factors, health conditions, regular care provision and quality of life was obtained by household interview. Chi-square test, t-test and survey-weighted multi-nominal regression modelling were performed. Results: Of 15 007 Welsh adults aged 16 and above, 2751 (19.1%) people reported that they have been giving care for any sick, disabled or frail person. They tended to be aged 40-74, being female, education 25, physically active, current smokers and living in second-hand smoking households. In caregivers with current chronic disease (n = 1562), they have experienced physical health limits, bodily pains, emotional problems, less calm and less cheerful. In caregivers without current chronic diseases (n = 1151), they have experienced physical health limits, bodily pains, less cheerful, downhearted and unhappiness. Conclusions: This is the first study to examine quality of life in caregivers both with and without currently treated chronic disease. Longitudinal monitoring and increasing education, training and support to lessen caregiving burden would be suggested.

Long-noncoding RNAs in basal cell carcinoma.

Long noncoding RNAs (lncRNAs) are fundamental regulators of pre- and post-transcriptional gene regulation. Over 35,000 different lncRNAs have been described with some of them being involved in cancer formation. The present study was initiated to describe differentially expressed lncRNAs in basal cell carcinoma (BCC). Patients with BCC (n = 6) were included in this study. Punch biopsies were harvested from the tumor center and nonlesional epidermal skin (NLES, control, n = 6). Microarray-based lncRNA and mRNA expression profiles were identified through screening for 30,586 lncRNAs and 26,109 protein-coding transcripts (mRNAs). The microarray data were validated by RT-PCR in a second set of BCC versus control samples. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of mRNAs were performed to assess biologically relevant pathways. A total of 1851 lncRNAs were identified as being significantly up-regulated, whereas 2165 lncRNAs were identified as being significantly down-regulated compared to nonlesional skin (p < 0.05). Oncogenic and/or epidermis-specific lncRNAs, such as CASC15 or ANRIL, were among the differentially expressed sequences. GO analysis showed that the highest enriched GO targeted by up-regulated transcripts was "extracellular matrix." KEGG pathway analysis showed the highest enrichment scores in "Focal adhesion." BCC showed a significantly altered lncRNA and mRNA expression profile. Dysregulation of previously described lncRNAs may play a role in the molecular pathogenesis of BCC and should be subject of further analysis.

Toward a More Evidence-Based Nosology and Nomenclature for Female Sexual Dysfunctions-Part I.

INTRODUCTION: A nomenclature is defined as a classification system for assigning names or terms in a scientific discipline. A nosology more specifically provides a scientific classification system for diseases or disorders. Historically, the nosologic system informing female sexual dysfunction (FSD) has been the system developed by the American Psychiatric Association in its Diagnostic and Statistical Manual of Mental Disorders (DSM-III through DSM-5). Experts have recognized limitations of its use in clinical practice, including concerns that the DSM-5 system does not adequately reflect the spectrum and presentation of FSD. AIM: To review the central considerations and issues that underlie the development of a new evidence-based nomenclature that reliably and validly defines the categories of FSD and will effectively function in clinical and research settings, serve as a basis for International Classification of Diseases (ICD) codes, and provide regulatory guidance for interventions designed as FSD treatments. METHODS: The International Society for the Study of Women's Sexual Health conducted a 2-day conference on nomenclature for FSD in December 2013. Key opinion leaders representing diverse areas of expertise discussed ideal characteristics, existing DSM definitions, and current and future ICD coding to develop consensus for this new nomenclature. MAIN OUTCOME MEASURE: A comprehensive appreciation of the parameters and characteristics essential to a new FSD nomenclature and terminology that will serve as the principal nosology for the description and diagnosis of FSD. RESULTS: A critical appraisal of the essential elements of a classification system for diagnosing FSD was accomplished. The applicability of DSM-5 FSD definitions was challenged; and the considerations for developing a new nomenclature were discussed, including comorbidities, clinical thresholds, alternative etiologies, and validity. CONCLUSION: The essential elements for developing a valid, reliable, credible, and clinically applicable nosology for FSD were enumerated as a preamble to constructing the actual nosologic system (Part II).

First-in-human study assessing safety, tolerability and pharmacokinetics of BI 409306, a selective phosphodiesterase 9A inhibitor, in healthy males.

AIMS: The aim of the present study was to investigate the safety, tolerability, dose proportionality and relative bioavailability of tablet and oral solution formulations of BI 409306 in healthy male subjects, and to compare the safety and pharmacokinetics in subjects who were extensive metabolizers (EMs) or poor metabolizers (PMs) of cytochrome P450 (CYP)-2C19. METHODS: The present randomized, double-blind, placebo-controlled, single-centre study evaluated single rising doses of BI 409306 (0.5-500 mg) administered as a tablet or oral solution to EMs or PMs. RESULTS: Of 80 enrolled subjects (mean age 36.7 years), 79 (CYP2C19 EMs, 71; CYP2C19 PMs, eight) received treatment and completed the study. Adverse events (AEs) were mild to moderate in intensity. Overall, 17/71 (23.9%) EMs and 6/8 (75.0%) PMs experienced 28 and eight AEs, respectively, of which, 25 and seven AEs, respectively, were considered to be drug related. The most frequently reported AEs were nervous system and eye disorders; all occurred shortly (20-30 min) after administration and mostly resolved within 1-2 h. No serious AEs occurred. BI 409306 systemic absorption and elimination were rapid; peak plasma concentration (Cmax ) was reached <1 h after drug administration, and the half-life ranged from 0.99 h to 2.71 h. Both the tablet and oral solution resulted in similar exposures. In PMs, at dose levels of 10 mg and 100 mg, Cmax was 2.2-2.3-fold higher, and the area under the plasma concentration-time curve over the time interval 0 extrapolated to infinity was 4.1-5.0-fold higher compared with EMs. CONCLUSIONS: In healthy male subjects, BI 409306 was generally safe and well tolerated, with rapid absorption and elimination. Systemic exposure was higher in CYP2C19 PMs than EMs at the same dose level.

Men with Sexual Problems and Their Partners: Findings from the International Survey of Relationships.

Epidemiologic studies of sexual function problems in men have focused on the individual male and related sociodemographic characteristics, individual risk factors and lifestyle concomitants, or medical comorbidities. Insufficient attention has been given to the role of sexual and relationship satisfaction and, more particularly, to the perspective of the couple as causes or correlates of sexual problems in men or women. Previously, we reported results of the first large, multi-national study of sexual satisfaction and relationship happiness in 1,009 midlife and older couples in five countries (Brazil, Germany, Japan, Spain, U.S.). For the present study, we examined, within each problem, the association of four major sexual problems in men (loss of sexual desire, erectile problems, premature ejaculation, delayed/absent orgasm) and multiple problems, with male and female partners' assessments of physical intimacy, sexual satisfaction, and relationship happiness, as well as associations with well-known health and psychosocial correlates of sexual problems in men. Sexual problem rates of men in our survey were generally similar to rates observed in past surveys in the general population, and similar risk factors (age, relationship duration, overall health) were associated with lack of desire, anorgasmia, or erection difficulties in our sample. As in previous surveys, there were few correlates of premature ejaculation. As predicted, men with one or more sexual problems reported decreased relationship happiness as well as decreased sexual satisfaction compared to men without sexual problems. Moreover, female partners of men with sexual problems had reduced relationship happiness and sexual satisfaction, although these latter outcomes were less affected in the women than the men. The association of men's sexual problems with men's and women's satisfaction and relationship happiness were modest, as these couples in long-term, committed relationships were notable for their relatively high levels of physical affection and relationship happiness.

Microbial Profile and Antimicrobial Susceptibility of Bacteria Found in Inflammatory Hidradenitis Suppurativa Lesions.

BACKGROUND: The role of bacterial colonization in hidradenitis suppurativa (HS) lesions is poorly understood. To date, data on the related microbial profile and especially on bacterial resistance rates are scarce. METHODS: The results of bacterial cultures and susceptibility patterns of the isolated microorganisms obtained from deep portions of HS lesions from patients who underwent surgery at our HS Centre between 2010 and 2015 were retrospectively evaluated. RESULTS: Analyses of 113 bacterial samples from 113 HS patients revealed bacterial growth in 95 samples (84.1%). Polymicrobial growth was found in 51 samples (45.1%). Coagulase-negative staphylococci and Staphylococcus aureus were the most commonly isolated bacteria, followed by Proteus mirabilis and Escherichia coli. Data on susceptibility testing were available for 68 samples, which yielded 129 isolates. The isolated strains were primarily resistant to penicillin G, followed by erythromycin, clindamycin and ampicillin. The highest effectiveness against isolates was observed for fosfomycin, imipenem, fluoroquinolones (moxifloxacin, ciprofloxacin, levofloxacin), and cotrimoxazole. CONCLUSIONS: Our findings on bacterial species and their topographical distribution revealed that the microbial flora in HS lesions reflects commensal flora of the skin. Due to the susceptibility rate and immunomodulatory and anti-inflammatory properties, cotrimoxazole may represent an alternative antibiotic agent and should be considered for therapy in HS patients.

Reconstruction of nasal tip support in primary, open approach septorhinoplasty : A retrospective analysis between the tongue-in-groove technique and the columellar strut.

The reconstruction of the nasal tip support is one of the most essential issues in septorhinoplasty. A comparison of the results after using the tongue-in-groove technique and the columellar strut technique was the target of this study. Thirty-three patients who underwent a primary, open approach septorhinoplasty using the above-mentioned techniques were retrospectively analyzed. The gain in tip rotation postoperatively, the sensitivity and the rigidity of the nasal tip and the aesthetic outcome after surgery were examined and evaluated. Both techniques led to an increase in nasal tip rotation postoperatively. The gain in rotation was higher in patients, treated with the tongue-in-groove technique (p = 0.0052). The sensitivity of the tip region in the tongue-in-groove group of patients was significantly lower than that in the columellar strut group of patients (p = 0.0424). Both techniques led to high percentages of tip rigidity after surgery with satisfactory aesthetic results though. The tongue-in-groove technique and the columellar strut technique are both reliable techniques for reconstructing the nasal tip support and correcting a droopy tip. Although the tongue-in-groove technique might result in a more significant increase in tip rotation, it leads to less sensitivity in the tip region.

A pilot study of quality of life in German prehospital emergency care physicians.

BACKGROUND: Quality of life in patients represents an important area of assessment. However, attention to health professionals should be equally important. The literature on the quality of life (QOL) of emergency physicians is scarce. This pilot study investigated QOL in emergency physicians in Germany. MATERIALS AND METHODS: We conducted a cross-sectional study from January to June in 2015. We approached the German Association of Emergency Medicine Physicians and two of the largest recruitment agencies for emergency physicians in Germany and invited their members to participate. We used the WHO Q-BREF to obtain QOL scores in four domains that included physical, mental, social, and environmental health. RESULTS: The 478 German emergency physicians included in the study held board certifications in general medicine (n = 40; 8.4%), anesthesiology (n = 243; 50.8%), surgery (n = 63; 13.2%), internal medicine (n = 81; 17.0%), or others (n = 51; 10.7%). The women surveyed tended to report a better QOL but worse general health than the men. Regarding specific domains, women scored worse in physical health, particularly energy during everyday work (relative risk ratio [RRR]: 1.98 [1.21-3.24]). Both men and women scored worse in psychological health than general health, particularly young women. Women were also more likely to view their safety (RRR: 1.87 [1.07-3.28]) and living place (RRR: 2.51 [1.10-5.73]) as being poor than their male counterparts. CONCLUSION: QOL in German prehospital emergency care physicians is satisfactory for the included participants; however, there were some negative effects in the psychological health domain. This is particularly obvious in young female emergency physicians.

Endorsement of models describing sexual response of men and women with a sexual partner: an online survey in a population sample of Danish adults ages 20-65 years.

INTRODUCTION: Several models have been used to describe men's and women's sexual responses. These models have been conceptualized as linear or circular models. The circular models were proposed to describe women's sexual function best. AIM: This study aims to determine whether men and women thought that current theoretical models of sexual responses accurately reflected their own sexual experience and to what extent this was influenced by sexual dysfunction. METHODS: A cross-sectional study of a large, broadly sampled, nonclinical population, cohort of Danish men and women. The Female Sexual Function Index, Female Sexual Distress Scale, and the International Index of Erectile Function were used to describe sexual function. Also, participants completed questionnaires with written descriptions of different sexual responses to describe their most experienced sexual response. MAIN OUTCOME MEASURE: For women, we measured desire, arousal, lubrication, orgasm, sexual satisfaction, pain during sexual activity, sexual distress, and satisfaction with sexual life. For men, we measured erectile function, orgasm, desire, intercourse satisfaction, overall satisfaction, and satisfaction with sexual life. RESULTS: A total of 499 men and 573 women participated. We only analyzed responses from sexually active participants with a partner (401 men and 429 women). The majority of men endorsed the Masters & Johnson model (48.5%) or the Kaplan model (38.3%); only 5.4% endorsed the Basson model, and 7.3% endorsed none of the models. Among women, 34% endorsed the Kaplan model, 28% the Masters & Johnson model, 25.6% the Basson model, and 12.5% none of the models. Among women, sexual dysfunction and distress were significantly (P = 0.01) related to endorsement of the Basson model or none of the models. Among men, erectile dysfunction and dissatisfaction with sexual life were significantly related to endorsement of the Basson model or none of the models (P = 0.01). CONCLUSIONS: No single model of sexual response could describe men's and women's sexual responses. The majority of men and women with no sexual dysfunction that were satisfied with their sexual life endorsed the linear models.

Correlation of inflammatory serum markers with disease severity in patients with hidradenitis suppurativa (HS).

BACKGROUND: Data regarding the association of routinely obtained serum markers of inflammation, namely C-reactive protein (CRP), white blood cell count, and neutrophil count, with disease severity of hidradenitis suppurativa (HS) according to a scoring system have not been reported to our knowledge. OBJECTIVE: We sought to evaluate these inflammatory serum markers for assessing disease severity of HS. METHODS: Medical files of 275 patients who were referred to the outpatient HS center of the Department of Dermatology, Venereology, and Allergology, Ruhr-University Bochum, in 2013 were evaluated retrospectively. RESULTS: CRP levels and neutrophil count significantly differed among Hurley stages I, II and III (P < .0001, P = .0002, respectively). There were significant positive correlations among CRP levels (r = 0.496, P < .0001) and neutrophil count (r = 0.330, P = .0009) with modified Hidradenitis Suppurativa Score. CRP was a significant independent predictor for Hurley stage III (odds ratio 1.077, 95% confidence interval 1.013-1.145, P = .016). CRP and body mass index were significant independent predictors for severe disease according to modified Hidradenitis Suppurativa Score (odds ratio 1.065, 95% confidence interval 1.015-1.117, P = .009; and odds ratio 1.12, 95% confidence interval 1.009-1.243, P = .032, respectively). LIMITATIONS: Files were analyzed retrospectively. CONCLUSION: These inflammatory markers, especially CRP, are effective for assessing the extent of disease severity and the grade of inflammation in patients with HS.

Individual and Partner Correlates of Sexual Satisfaction and Relationship Happiness in Midlife Couples: Dyadic Analysis of the International Survey of Relationships.

The current research reports a dyadic analysis of sexual satisfaction, relationship happiness, and correlates of these couple outcomes in a large multinational dataset consisting of 1,009 midlife heterosexual couples (2,018 individuals) recruited in Japan, Brazil, Germany, Spain, and the United States (Heiman et al., 2011). Actor-Partner Interdependence Models (Kenny, Kashy, & Cook, 2006) identified correlates of sexual satisfaction that included individuals' reports of good health; frequent kissing, cuddling, and caressing; frequent recent sexual activity; attaching importance to one's own and one's partner's orgasm; better sexual functioning; and greater relationship happiness. Even after controlling for individual-level effects, partners' reports of good health; frequent kissing, cuddling, and caressing; frequent recent sexual activity; attaching importance to one's own and one's partner's orgasm; better sexual functioning; and greater relationship happiness contributed significantly to predicting and understanding individuals' sexual satisfaction. Correlates of relationship happiness included individuals' reports of good health; frequent kissing, cuddling, and caressing; frequent recent sexual activity; attaching importance to one's own and one's partner's orgasm; better sexual functioning; and greater sexual satisfaction, and once again, even after controlling for individual-level effects, partners' reports of each of these correlates contributed significantly to predicting and understanding individuals' relationship happiness. Interactions of individual and partner effects with participant gender are also reported. Current results demonstrate empirically that the partner "matters" to an individual's sexual satisfaction and relationship happiness and indicate that a comprehensive understanding of factors contributing to these couple outcomes requires a couple-level research strategy. Partner effects, even when controlling for individual effects, were consistently observed, and explanation of sexual satisfaction and relationship happiness always depended on identifying and understanding mutual and concurrent individual and partner influences.

Scar hinge flap for inner lining reconstruction of full-thickness defects on the ala of the nose.

BACKGROUND: Reconstruction of inner lining of the nose often requires complex surgical procedures. METHODOLOGY: To evaluate the scar hinge flap as an alternative reconstruction technique, 21 patients with full-thickness defects of the ala who received a scar hinge flap were retrospectively analysed. RESULTS: Twenty-one patients were included. The average defect size was 1.9 cm2. Cartilage grafts were used in 11 patients. For skin reconstruction the scar hinge flap was covered by local flaps, interpolated melolabial flaps, full-thickness skin grafts, or paramedian forehead flaps. The mean follow-up was 10.7 months. No severe complications were observed. CONCLUSIONS: The scar hinge flap is a safe and simple technique for reconstruction of the inner lining of the nose although it is limited being a two-stage procedure.

The keystone flap: expanding the dermatologic surgeon's armamentarium.

First described in 2003, the keystone flap has become an established plastic and reconstructive surgery technique for the closure of soft tissue defects following the excision of skin tumors. Complex reconstruction procedures may thus be avoided [3]. In dermatosurgery, however, the keystone flap remains largely unknown.Compared to subcutaneous pedicle flaps, the keystone flap technique warrants better vascular supply by additional-ly preserving musculocutaneous and fasciocutaneous perforator vessels [4]. Moreover, the flap is hyperemic compared to the surrounding skin [5]. Adequate perfusion and its specific design result in high safety of the flap. According to both published data and the authors' experience, the keystone flap technique is associated with a low complication rate [1, 6].In summary, the keystone flap method yields good aesthetic and functional results by preserving shape and cont-our, avoiding differences in skin coloration and preserving sensitivity (Figure 1b). The flap is particularly well suited for deep defects with exposed bones or tendons, especially on the extremities or the trunk. Alternative closing options such as secondary intention healing, primary closure, or local flaps appear less adequate in these cases. In addition, skin grafting without long-term wound conditioning­for example negative pressure wound therapy­or expensive der-mal replacement products are not very promising. Thus, the keystone flap provides the dermatosurgeon with an effective alternative to reconstruction techniques.

Comparative microarray analysis of microRNA expression profiles in primary cutaneous malignant melanoma, cutaneous malignant melanoma metastases, and benign melanocytic nevi.

Perturbations in microRNA (miRNA) expression profiles have been reported for cutaneous malignant melanoma (CMM) predominantly when examined in cell lines. Despite the rapidly growing number of newly discovered human miRNA sequences, the availability of up-to-date miRNA expression profiles for clinical samples of primary cutaneous malignant melanoma (PCMM), cutaneous malignant melanoma metastases (CMMM), and benign melanocytic nevi (BMN) is limited. Specimens excised from the center of tumors (lesional) from patients with PCMM (n=9), CMMM (n=4), or BMN (n=8) were obtained during surgery. An exploratory microarray analysis was performed by miRNA expression profiling based on Agilent platform screening for 1205 human miRNAs. The results from the microarray analysis were validated by TaqMan quantitative real-time polymerase chain reaction. In addition to several miRNAs previously known to be associated with CMM, 19 unidentified miRNA candidates were found to be dysregulated in CMM patient samples. Among the 19 novel miRNA candidates, the genes hsa-miR-22, hsa-miR-130b, hsa-miR-146b-5p, hsa-miR-223, hsa-miR-301a, hsa-miR-484, hsa-miR-663, hsa-miR-720, hsa-miR-1260, hsa-miR-1274a, hsa-miR-1274b, hsa-miR-3663-3p, hsa-miR-4281, and hsa-miR-4286 were upregulated, and the genes hsa-miR-24-1*, hsa-miR-26a, hsa-miR-4291, hsa-miR-4317, and hsa-miR-4324 were downregulated. The results of this study partially confirm previous CMM miRNA profiling studies identifying miRNAs that are dysregulated in CMM. However, we report several novel miRNA candidates in CMM tumors; these miRNA sequences require further validation and functional analysis to evaluate whether they play a role in the pathogenesis of CMM.

Efficacy of flibanserin in women with hypoactive sexual desire disorder: results from the BEGONIA trial.

INTRODUCTION: Hypoactive Sexual Desire Disorder (HSDD) is characterized by low sexual desire that causes marked distress or interpersonal difficulty. AIM: The aim of this study was to assess the efficacy and safety of the 5-HT1A agonist/5-HT2A antagonist flibanserin in premenopausal women with HSDD. METHODS: This was a randomized, placebo-controlled trial in which premenopausal women with HSDD (mean age: 36.6 years) were treated with flibanserin 100 mg once daily at bedtime (qhs) (n = 542) or placebo (n = 545) for 24 weeks. MAIN OUTCOME MEASURES: Coprimary end points were the change from baseline to study end in Female Sexual Function Index (FSFI) desire domain score and in number of satisfying sexual events (SSE) over 28 days. Secondary end points included the change from baseline in FSFI total score, Female Sexual Distress Scale-Revised (FSDS-R) total score, and FSDS-R Item 13 score. RESULTS: Compared with placebo, flibanserin led to increases in mean (standard deviation) SSE of 2.5 (4.6) vs. 1.5 (4.5), mean (standard error [SE]) FSFI desire domain score of 1.0 (0.1) vs. 0.7 (0.1), and mean (SE) FSFI total score of 5.3 (0.3) vs. 3.5 (0.3); and decreases in mean (SE) FSDS-R Item 13 score of -1.0 (0.1) vs. -0.7 (0.1) and mean (SE) FSDS-R total score of -9.4 (0.6) vs. -6.1 (0.6); all P ≤ 0.0001. The most frequently reported adverse events in the flibanserin group were somnolence, dizziness, and nausea, with adverse events leading to discontinuation in 9.6% of women receiving flibanserin vs. 3.7% on placebo. CONCLUSION: In premenopausal women with HSDD, flibanserin 100 mg qhs resulted in significant improvements in the number of SSE and sexual desire (FSFI desire domain score) vs. placebo. Flibanserin was associated with significant reductions in distress associated with sexual dysfunction (FSDS-R total score) and distress associated with low sexual desire (FSDS-R Item 13) vs. placebo. There were no significant safety concerns associated with the use of flibanserin for 24 weeks.

A new era for schizophrenia drug development - Lessons for the future.

For many patients and their treating clinicians, the pharmacological management of psychotic symptoms centres on trying to find a regime that balances efficacy and quality of life-impairing side effects associated with dopamine antagonism. Recent reports of a positive Phase III study from Karuna Therapeutics indicate that the first primarily non-dopamine-based treatment for schizophrenia may come to market soon with the potential for substantially reduced or differentiated side effects. Against a background of repeated failures, Karuna's success promises a desperately needed new treatment option for patients. It also reflects some hard-won lessons about the methodology for schizophrenia drug development.