An explorative single-arm clinical study to assess craving in patients with alcohol use disorder using Virtual Reality exposure (CRAVE)-study protocol.

BACKGROUND: Alcohol use disorder (AUD) belongs to the most burdensome clinical disorders worldwide. Current treatment approaches yield unsatisfactory long-term effects with relapse rates up to 85%. Craving for alcohol is a major predictor for relapse and can be intentionally induced via cue exposure in real life as well as in Virtual Reality (VR). The induction and habituation of craving via conditioned cues as well as extinction learning is used in Cue Exposure Therapy (CET), a long-known but rarely used strategy in Cognitive Behavioral Therapy (CBT) of AUD. VR scenarios with alcohol related cues offer several advantages over real life scenarios and are within the focus of current efforts to develop new treatment options. As a first step, we aim to analyze if the VR scenarios elicit a transient change in craving levels and if this is measurable via subjective and psychophysiological parameters. METHODS: A single-arm clinical study will be conducted including n = 60 patients with AUD. Data on severity of AUD and craving, comorbidities, demographics, side effects and the feeling of presence in VR will be assessed. Patients will use a head-mounted display (HMD) to immerse themselves into three different scenarios (neutral vs. two target situations: a living room and a bar) while heart rate, heart rate variability, pupillometry and electrodermal activity will be measured continuously. Subjective craving levels will be assessed before, during and after the VR session. DISCUSSION: Results of this study will yield insight into the induction of alcohol craving in VR cue exposure paradigms and its measurement via subjective and psychophysiological parameters. This might be an important step in the development of innovative therapeutic approaches in the treatment of patients with AUD. TRIAL REGISTRATION: This study was approved by the Charité-Universitätsmedizin Berlin Institutional Review Board (EA1/190/22, 23.05.2023). It was registered on ClinicalTrials.gov (NCT05861843).

Robust evidence for bisexual orientation among men.

The question whether some men have a bisexual orientation-that is, whether they are substantially sexually aroused and attracted to both sexes-has remained controversial among both scientists and laypersons. Skeptics believe that male sexual orientation can only be homosexual or heterosexual, and that bisexual identification reflects nonsexual concerns, such as a desire to deemphasize homosexuality. Although most bisexual-identified men report that they are attracted to both men and women, self-report data cannot refute these claims. Patterns of physiological (genital) arousal to male and female erotic stimuli can provide compelling evidence for male sexual orientation. (In contrast, most women provide similar physiological responses to male and female stimuli.) We investigated whether men who self-report bisexual feelings tend to produce bisexual arousal patterns. Prior studies of this issue have been small, used potentially invalid statistical tests, and produced inconsistent findings. We combined nearly all previously published data (from eight previous studies in the United States, United Kingdom, and Canada), yielding a sample of 474 to 588 men (depending on analysis). All participants were cisgender males. Highly robust results showed that bisexual-identified men's genital and subjective arousal patterns were more bisexual than were those who identified as exclusively heterosexual or homosexual. These findings support the view that male sexual orientation contains a range, from heterosexuality, to bisexuality, to homosexuality.

Neural Responses to Sexual Stimuli in Heterosexual and Homosexual Men and Women: Men's Responses Are More Specific.

Patterns of genital arousal in response to gendered sexual stimuli (i.e., sexual stimuli presenting members of only one sex at a time) are more predictive of men's than of women's sexual orientations. Additional lines of evidence may shed light on the nature of these differences. We measured neural activation in homosexual and heterosexual men and women using fMRI while they viewed three kinds of gendered sexual stimuli: pictures of nude individuals, pictures of same-sex couples interacting, and videos of individuals self-stimulating. The primary neural region of interest was the ventral striatum (VS), an area of central importance for reward processing. For all three kinds of stimuli and for both VS activation and self-report, men's responses were more closely related to their sexual orientations compared with women's. Furthermore, men showed a much greater tendency to respond more positively to stimuli featuring one sex than to stimuli featuring the other sex, leading to higher correlations among men's responses as well as higher correlations between men's responses and their sexual orientations. Whole-brain analyses identified several other regions showing a similar pattern to the VS, and none showed an opposite pattern. Because fMRI is measured identically in men and women, our results provide the most direct evidence to date that men's sexual arousal patterns are more gender specific than women's.

Assessment of aeration control strategies for biofilm-based partial nitritation/anammox systems.

The objective of this work was to compare the nitrogen removal in mainstream, biofilm-based partial nitritation anammox (PN/A) systems employing (1) constant setpoint dissolved oxygen (DO) control, (2) intermittent aeration, and (3) ammonia-based aeration control (ABAC). A detailed water resource recovery facility (WRRF) model was used to study the dynamic performance of these aeration control strategies with respect to treatment performance and energy consumption. The results show that constant setpoint DO control cannot meet typical regulatory limits for total ammonia nitrogen (NHx-N). Intermittent aeration shows improvement but requires optimisation of the aeration cycle. ABAC shows the best treatment performance with the advantages of continuous operation and over 20% lower average energy consumption as compared to intermittent aeration.

Skin cancer prevention: a review of current topical options complementary to sunscreens.

The incidence of non-melanoma skin cancer (NMSC) is dramatically increasing worldwide, despite the increased use of improved sunscreens. In 2014, the Surgeon General estimated that 2.2-5.0 million people were treated annually for NMSC. As the number of newly diagnosed skin cancers continues to rise, there is a need for additional preventative measures beyond sunscreens. Several newer topical products that focus on boosting DNA repair, modulating DNA transcription, decreasing inflammation and selectively targeting precancerous cells may play an important role in future skin cancer prevention.

Mutations in osteoprotegerin account for the CCAL1 locus in calcium pyrophosphate deposition disease.

OBJECTIVE: Mutations on chromosomes 5p (CCAL2) and 8q (CCAL1) have been linked to familial forms of calcium pyrophosphate deposition disease (CPDD). Mutations in the ANKH gene account for CCAL2, but the identity of CCAL1 has been elusive. Recently, a single Dutch kindred with a mutation in the Tumor Necrosis Factor Receptor Super Family member 11B (TNFRSF11B) gene coding for osteoprotegerin (OPG) was described as a gain-of-function mutation. Affected family members had premature generalized osteoarthritis (PGOA) and CPDD. As the TNFRSF11B gene is on 8q, we sought additional evidence that TNFRSF11B was CCAL1, and investigated potential disease mechanisms. DESIGN: DNA from two novel PGOA/CPDD families was screened for sequence variants in the TNFRSF11B gene. Mutations were verified by genotype analysis of affected and unaffected family members. We also investigated effects of normal and mutant OPG on regulators of CPP crystal formation in porcine cartilage. RESULTS: The identical TNFRSF11B mutation described in the Dutch family was present in two novel PGOA/CPDD families. ANKH was normal in affected patient fibroblasts. Exogenous OPG did not alter ANKH mRNA or protein levels, affect translocation of ANKH to the membrane, nor increase [pyrophosphate (PPi)] or other key regulators of CPDD. CONCLUSION: We have firmly established the identity of CCAL1 as TNFRSF11B (OPG). Our findings suggest that this mutation produces disease in an ANKH-independent manner via novel mechanisms not primarily targeting cartilage. This work rationalizes further investigation of OPG pathway components as potential druggable targets for CPDD.

Comparing the Resistance, Resilience, and Stability of Replicate Moving Bed Biofilm and Suspended Growth Combined Nitritation-Anammox Reactors.

Combined partial nitritation-anammox (PN/A) systems are increasingly being employed for sustainable removal of nitrogen from wastewater, but process instabilities present ongoing challenges for practitioners. The goal of this study was to elucidate differences in process stability between PN/A process variations employing two distinct aggregate types: biofilm [in moving bed biofilm reactors (MBBRs)] and suspended growth biomass. Triplicate reactors for each process variation were studied under baseline conditions and in response to a series of transient perturbations. MBBRs displayed elevated NH4+ removal rates relative to those of suspended growth counterparts over six months of unperturbed baseline operation but also exhibited significantly greater variability in performance. Transient perturbations led to strikingly divergent yet reproducible behavior in biofilm versus suspended growth systems. A temperature perturbation prompted a sharp reduction in NH4+ removal rates with no accumulation of NO2- and rapid recovery in MBBRs, compared to a similar reduction in NH4+ removal rates but a high level of accumulation of NO2- in suspended growth reactors. Pulse additions of a nitrification inhibitor (allylthiourea) prompted only moderate declines in performance in suspended growth reactors compared to sharp decreases in NH4+ removal rates in MBBRs. Quantitative fluorescence in situ hybridization demonstrated a significant enrichment of anammox in MBBRs compared to suspended growth reactors, and conversely a proportionally higher AOB abundance in suspended growth reactors. Overall, MBBRs displayed significantly increased susceptibility to transient perturbations employed in this study compared to that of suspended growth counterparts (stability parameter), including significantly longer recovery times (resilience). No significant difference in the maximal impact of perturbations (resistance) was apparent. Taken together, our results suggest that aggregate architecture (biofilm vs suspended growth) in PN/A processes exerts an unexpectedly strong influence on process stability.

Who Are Gynandromorphophilic Men? An Internet Survey of Men with Sexual Interest in Transgender Women.

Gynandromorphophilia (GAMP) is attraction to gynandromorphs (GAMs), who are natal males with both breasts and a penis, colloquially known as "she-males." Men with GAMP (n = 314) and heterosexual men not attracted to GAMs (n = 211) completed an Internet survey regarding their sexual attraction patterns, relationship history, and potential correlates of GAMP. Men with GAMP reported much higher attraction to natal women than to men, although they also reported slightly higher levels of bisexual feelings compared with controls. Men with GAMP were equally attracted to natal women and GAMs, on average. Thus, GAMP is best considered an unusual form of heterosexuality rather than a separate sexual orientation. Indeed, men with GAMP scored much higher than controls on a measure of autogynephilia, or sexual arousal by the idea or fantasy of being a woman, which is also considered a variant of heterosexual attraction.

Sexual Arousal Patterns of Autogynephilic Male Cross-Dressers.

Men's sexual arousal patterns have been an important window into the nature of their erotic interests. Autogynephilia is a natal male's paraphilic tendency to be sexually aroused by the thought or image of being a woman. Autogynephilic arousal per se is difficult to assess objectively, because it is inwardly focused. However, assessing sexual arousal patterns of autogynephilic males in response to external stimuli is also potentially useful. For example, there is substantial association between autogynephilia and gynandromorphophilia (GAMP), or sexual attraction to gynandromorphs (GAMs), colloquially "she-males." GAMP men's sexual arousal patterns in response to GAM, female, and male stimuli have recently been characterized. In the present study, we extended this understanding by comparing the sexual arousal patterns of autogynephilic male cross-dressers, GAMP men, heterosexual men, and homosexual men. Erotic stimuli included sexually explicit videos of men, women, and GAMs. Autogynephilic men were much more similar in their arousal patterns to heterosexual and GAMP men than to homosexual men. However, similar to GAMP men, autogynephilic men showed increased arousal by GAM stimuli relative to female stimuli compared with heterosexual men.

Bisexual Phenomena Among Gay-Identified Men.

A high proportion of self-identified gay men exhibit aspects of bisexuality during their lives. Some identify as bisexual before later identifying as gay; this has been called transitional bisexuality. Although many gay men report no attraction to women-or even sexual disgust toward them-others report some slight attraction to women. The latter have been studied as mostly homosexual men. We studied men with and without a history of transitional bisexuality, as well as mostly homosexual (i.e., those with Kinsey scores of 5) and completely homosexual (i.e., those with Kinsey scores of 6) men with respect to their sexual history with women, their current self-reported sexual arousal and disgust toward women and men, and their patterns of genital sexual arousal to female and male stimuli. Gay men with a history of transitional bisexuality generally lacked current sexual attraction and sexual arousal to women, compared with other gay men. Thus, transitional bisexuality among future gay men is mostly a matter of transitional bisexual identification. In contrast, mostly homosexual men showed statistically significant increases in genital arousal to female stimuli, compared with completely homosexual men.

[Incontinentia pigmenti : Herpes simplex infection as an important differential diagnosis in the neonatal period]. / Incontinentia pigmenti : Herpes-simplex-Infektion als wichtige Differenzialdiagnose in der Neonatalperiode.

In this article we present the case of a 2-day-old newborn girl in good general condition, with herpetic arranged pustules on the skin of her whole body. The case highlights the importance of a detailed diagnostic workup for newborns with pustular skin disease. Especially to differentiate between the diagnosis of incontinentia pigmenti and a congenital herpes infection.

Who are gynandromorphophilic men? Characterizing men with sexual interest in transgender women.

BACKGROUND: Gynandromorphophilia (GAMP) is sexual interest in gynandromorphs (GAMs; colloquially, shemales). GAMs possess a combination of male and female physical characteristics. Thus, GAMP presents a challenge to conventional understandings of sexual orientation as sexual attraction to the male v. female form. Speculation about GAMP men has included the ideas that they are homosexual, heterosexual, or especially, bisexual. METHOD: We compared genital and subjective sexual arousal patterns of GAMP men with those of heterosexual and homosexual men. We also compared these groups on their self-ratings of sexual orientation and sexual interests. RESULTS: GAMP men had arousal patterns similar to those of heterosexual men and different from those of homosexual men. However, compared to heterosexual men, GAMP men were relatively more aroused by GAM erotic stimuli than by female erotic stimuli. GAMP men also scored higher than both heterosexual and homosexual men on a measure of autogynephilia. CONCLUSIONS: Results provide clear evidence that GAMP men are not homosexual. They also indicate that GAMP men are especially likely to eroticize the idea of being a woman.

The adverse effects of diabetes on osteoarthritis: update on clinical evidence and molecular mechanisms.

Projected increases in the prevalence of both diabetes mellitus (DM) and osteoarthritis (OA) ensure their common co-existence. In an era of increasing attention to personalized medicine, understanding the influence of common comorbidities such as DM should result in improved care of patients with OA. In this narrative review, we summarize the literature addressing the interactions between DM and OA spanning the years from 1962 to 2014. We separated studies depending on whether they investigated clinical populations, animal models, or cells and tissues. The clinical literature addressing the influence of DM on OA and its therapeutic outcomes suggests that DM may augment the development and severity of OA and that DM increases risks associated with joint replacement surgery. The few high quality studies using animal models also support an adverse effect of DM on OA. We review strengths and weaknesses of the common rodent models of DM. The heterogeneous literature derived from studies of articular cells and tissues also supports the existence of biochemical and biomechanical changes in articular tissues in DM, and begins to characterize molecular mechanisms activated in diabetic-like environs which may contribute to OA. Increasing evidence from the clinic and the laboratory supports an adverse effect of DM on the development, severity, and therapeutic outcomes for OA. To understand the mechanisms through which DM contributes to OA, further studies are clearly necessary. Future studies of DM-influenced mechanisms may shed light on general mechanisms of OA pathogenesis and result in more specific and effective therapies for all OA patients.

Lysophosphatidic acid mediates fibrosis in injured joints by regulating collagen type I biosynthesis.

OBJECTIVE: Articular cartilage is a highly specialized tissue which forms the surfaces in synovial joints. Full-thickness cartilage defects caused by trauma or microfracture surgery heal via the formation of fibrotic tissue characterized by a high content of collagen I (COL I) and subsequent poor mechanical properties. The goal of this study is to investigate the molecular mechanisms underlying fibrosis after joint injury. DESIGN: Rat knee joint models were used to mimic cartilage defects after acute injury. Immunohistochemistry was performed to detect proteins related to fibrosis. Human fetal chondrocytes and bone marrow stromal cells (BMSCs) were used to study the influence of the lipid lysophosphatidic acid (LPA) on COL I synthesis. Quantitative PCR, ELISA and immunohistochemistry were performed to evaluate the production of COL I. Chemical inhibitors were used to block LPA signaling both in vitro and in vivo. RESULTS: After full-thickness cartilage injury in rat knee joints, stromal cells migrating to the injury expressed high levels of the LPA-producing enzyme autotaxin (ATX); intact articular cartilage in rat and humans expressed negligible levels of ATX despite expressing the LPA receptors LPAR1 and LPAR2. LPA-induced increases in COL I production by chondrocytes and BMSCs were mediated by the MAP kinase and PI3 Kinase signaling pathways. Inhibition of the ATX/LPA axis significantly reduced COL I-enriched fibrocartilage synthesis in full-thickness cartilage defects in rats in favor of the collagen II-enriched normal state. CONCLUSION: Taken together, these results identify an attractive target for intervention in reducing the progression of post-traumatic fibrosis and osteoarthritis.

The Psychometric Structure of Items Assessing Autogynephilia.

Autogynephilia, or paraphilic sexual arousal in a man to the thought or image of himself as a woman, manifests in a variety of different behaviors and fantasies. We examined the psychometric structure of 22 items assessing five known types of autogynephilia by subjecting them to exploratory factor analysis in a sample of 149 autogynephilic men. Results of oblique factor analyses supported the ability to distinguish five group factors with suitable items. Results of hierarchical factor analyses suggest that the five group factors were strongly underlain by a general factor of autogynephilia. Because the general factor accounted for a much greater amount of the total variance of the 22 items than did the group factors, the types of autogynephilia that a man has seem less important than the degree to which he has autogynephilia. However, the five types of autogynephilia remain conceptually useful because meaningful distinctions were found among them, including differential rates of endorsement and differential ability to predict other relevant variables like gender dysphoria. Factor-derived scales and subscales demonstrated good internal consistency reliabilities, and validity, with large differences found between autogynephilic men and heterosexual male controls. Future research should attempt to replicate our findings, which were mostly exploratory.

Sentinel lymph node biopsy in vulval cancer: systematic review and meta-analysis.

BACKGROUND: The purpose of this study was to determine the accuracy of sentinel lymph node (SLN) biopsy with technetium 99 (99mTc) and/or blue dye-enhanced lymphoscintigraphy in vulval cancer. METHODS: Sensitive searches of databases were performed upto October 2013. Studies with at least 75% of women with FIGO stage IB or II vulval cancer evaluating SLN biopsy with 99mTc, blue dye or both with reference standard of inguinofemoral lymphadenectomy (IFL) or clinical follow-up were included. Meta-analyses were performed using Meta-Disc version 1.4. RESULTS: Of the 2950 references, 29 studies (1779 women) were included; most of them evaluated 99mTc combined with blue dye. Of these, 24 studies reported results for SLN followed by IFL, and 5 reported clinical follow-up only for SLN negatives. Pooling of all studies was inappropriate because of heterogeneity. Mean SLN detection rates were 94.0% for 99mTc, 68.7% for blue dye and 97.7% for both. SLN biopsy had pooled sensitivity of 95% (95% CI 92-98%) with negative predictive value (NPV) of 97.9% in studies using 99mTc/blue dye, ultrastaging and immunohistochemistry with IFL as reference. Pooled sensitivity for SLN with clinical follow-up for SLN-negatives was 91% (85-95%) with NPV 95.6%. Patients undergoing SLN biopsy experienced less morbidity than those undergoing IFL. CONCLUSIONS: Sentinel lymph node biopsy using 99mTC, blue dye and ultrastaging with immunohistochemistry is highly accurate when restricted to carefully selected patients, within a rigorous protocol, with close follow-up and where sufficient numbers for learning curve optimisation exist. Patients must make an informed choice between the slightly higher groin recurrence rates of SLN biopsy vs the greater morbidity of IFL.

Clodronate exerts an anabolic effect on articular chondrocytes mediated through the purinergic receptor pathway.

OBJECTIVE: Bisphosphonates are commonly used anti-osteoporotic drugs which have controversial effects on joint diseases including osteoarthritis. Certain bisphosphonates have been shown to have anabolic effects on cartilage which could have important ramifications for their proposed effects in vivo; however, the underlying mechanisms are poorly understood. Thus, the purpose of this study was to characterize the effects of clodronate on primary articular chondrocyte metabolism and to determine the underlying signaling pathways responsible. DESIGN: The effects of clodronate and pamidronate on extracellular matrix (ECM) biosynthesis, accumulation and MMP-13 activity were observed in high density, 3D cultures of bovine articular chondrocytes for up to 4 weeks were evaluated. Mechanisms were delineated by measuring intracellular Ca(2+) signaling and the effects of pharmacologic inhibition of the purinergic receptor pathway. RESULTS: Clodronate (100 µM) induced an anabolic effect (increased biosynthesis by 13-14%) which resulted in an 89-90% increase in ECM accumulation after 4 weeks of culture and without an associated effect on matrix turn-over. Stimulation by clodronate resulted in a 3.3-fold increase in Ca(2+) signaling and pharmacological inhibitor experiments suggested that the anabolic effects exerted by clodronate are transduced through the purinergic receptor pathway. CONCLUSIONS: These findings support the previous notion that certain bisphosphonates may be useful as adjunctive therapies to potentially ameliorate progression of cartilage degeneration and improve arthritis management.

Modulation of neurotrophin signaling by monoclonal antibodies.

The neurotrophin family is comprised of the structurally related secreted proteins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophine-4 (NT-4). They bind and activate the tyrosine kinase receptors Trk A, B, and C in a ligand-specific manner and additionally bind a shared p75NTR receptor. The neurotrophins were originally defined by their ability to support the survival and maturation of embryonic neurons. However, they also control important physiological functions of the adult nervous system including learning and memory, sensation, and energy homeostasis. For example, NGF/trkA signaling is critical for normal and pathological sensation of pain. Likewise, the BDNF/trkB pathway controls feeding and metabolism, and its dysfunction leads to severe obesity. Antibodies can modulate neurotrophin signaling. Thus, NGF blocking agents can attenuate pain in several animal models, and a recombinant humanized NGF blocking antibody (Tanezumab) has shown promising results in human clinical trials for osteoarthritic pain. On the other hand trkB agonist antibodies can modulate food intake and body weight in rodents and nonhuman primates. The power of monoclonal antibodies to modulate neurotrophin signaling promises to turn the rich biological insights into novel human medicines.