TCRs are randomly distributed on the plasma membrane of resting antigen-experienced T cells.

The main function of T cells is to identify harmful antigens as quickly and precisely as possible. Super-resolution microscopy data have indicated that global clustering of T cell antigen receptors (TCRs) occurs before T cell activation. Such pre-activation clustering has been interpreted as representing a potential regulatory mechanism that fine tunes the T cell response. We found here that apparent TCR nanoclustering could be attributed to overcounting artifacts inherent to single-molecule-localization microscopy. Using complementary super-resolution approaches and statistical image analysis, we found no indication of global nanoclustering of TCRs on antigen-experienced CD4+ T cells under non-activating conditions. We also used extensive simulations of super-resolution images to provide quantitative limits for the degree of randomness of the TCR distribution. Together our results suggest that the distribution of TCRs on the plasma membrane is optimized for fast recognition of antigen in the first phase of T cell activation.

Phosphorylation of MSI-1 is implicated in the regulation of associative memory in Caenorhabditis elegans.

The Musashi family of RNA-binding proteins controls several biological processes including stem cell maintenance, cell division and neural function. Previously, we demonstrated that the C. elegans Musashi ortholog, msi-1, regulates forgetting via translational repression of the Arp2/3 actin-branching complex. However, the mechanisms controlling MSI-1 activity during the regulation of forgetting are currently unknown. Here we investigated the effects of protein phosphorylation on MSI-1 activity. We showed that MSI-1 function is likely controlled by alterations of its activity rather than its expression levels. Furthermore, we found that MSI-1 is phosphorylated and using mass spectrometry we identified MSI-1 phosphorylation at three residues (T18, S19 and S34). CRISPR-based manipulations of MSI-1 phosphorylation sites revealed that phosphorylation is necessary for MSI-1 function in both short- and long-term aversive olfactory associative memory. Thus, our study provides insight into the mechanisms regulating memory-related MSI-1 activity and may facilitate the development of novel therapeutic approaches.

Microcirculation disorders of the skin.

Changes in the microcirculation of the skin are a frequently observed accompanying phenomenon of many diseases, far beyond the spectrum of dermatological diseases. Not all of these changes are pathological, many are transient and have no serious consequences. This is true for many inflammatory diseases such as psoriasis vulgaris or atopic eczema. However, there are also diseases in which functionally and morphologically recognizable microangiopathies lead to severe disease consequences. One of the most important diseases in this context is systemic sclerosis, an autoimmune systemic disease with multiple organ manifestations. Investigations of the cutaneous microcirculation are of great importance for the initial diagnosis as well as for prognosis and assessment of disease progression. In peripheral hemodynamic disorders such as peripheral arterial disease (PAD) and chronic venous insufficiency (CVI), understanding microcirculatory disturbances also plays an important role in therapy and in monitoring the success of therapeutic interventions.

Polysomnographic characteristics of sleep in adults with and without physician-diagnosed atopic dermatitis: results from the Study of Health in Pomerania.

PURPOSE: To analyze sleep characteristics as measured with polysomnography (PSG) in adults from the general population with and without physician-diagnosed atopic dermatitis (AD). METHODS: We analyzed data from participants from the German population-based Study of Health in Pomerania (SHIP) TREND-0. AD was diagnosed in a standardized skin examination. The following polysomnographic parameters were measured: total sleep duration (min), sleep latency (min), wake after sleep onset (WASO; min), rapid eye movement (REM) latency (min), sleep efficiency (%), total number of wakefulness and movement episodes, stages of sleep (%), and apnea-hypopnea index (AHI). Additionally, the subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). We compared sleep characteristics of participants with and without AD. RESULTS: Among 1187 participants, 47 (4.0%) had AD. We found no differences between participants with and without AD in any of the analyzed PSG parameters except for the total number of wakefulness and movement episodes and the percentage of REM sleep. Participants with AD had a higher number of wakefulness and movement episodes, and a lower proportion of REM sleep compared to those without AD. Regarding subjective sleep parameters, no significant differences were found between participants with and without AD. CONCLUSION: Our data do not provide evidence for poor sleep quality in individuals with AD. Major limitations of the study include the unavailability of data on AD severity and the small number of participants with AD. Larger-scaled longitudinal studies considering disease severity and specific AD symptoms with an effect on sleep are required.

Comparison between incus short process and long process coupling of the vibrant soundbridge in human temporal bones.

OBJECTIVE: The Vibrant Soundbridge (VSB) is one of the most widely used implantable hearing devices. It consists of a vibrating floating mass transducer (FMT) that is connected to a middle ear structure. The standard coupling devices for sensorineural hearing loss are short process (SP) or long process (LP) couplers. DESIGN AND STUDY SAMPLE: This study directly compared the electro-mechanical performance of the SP- and LP-coupled FMT of the VSB in the same temporal bone specimen (n = 10). We measured velocity magnitudes and total harmonic distortions (THD) of the stapes (ST) and the round window (RW) using laser Doppler Vibrometry (LDV). RESULTS: Comparison shows a maximally 10 dB higher magnitude for the LP coupler at ST and RW for frequencies below 600 Hz, whereas the SP coupler shows a maximally 20 dB higher magnitude at the ST and RW for frequencies above 600 Hz. THD show similar behaviour with less distortion at 500 Hz for the LP coupler and less distortions for the SP coupler in higher frequencies. CONCLUSIONS: Our experiments showed that the SP coupling may be mechanically favourable, in terms of magnitude and distortion, for the transmission of FMT vibrations at higher frequencies.

Contact force guided radiofrequency current application at developing myocardium.

INTRODUCTION: Catheter contact is a key determinant for lesion size in radiofrequency catheter ablation (RFA). Monitoring of contact force (CF) during RFA has been shown to improve efficacy of RFA in experimental settings as well as in adult patients. Coronary artery narrowing after RFA has been described in experimental settings as well as in children and adults and may be dependent from catheter contact. The value of CF monitoring concerning these issues has not been systematically studied yet. Value of high versus low CF during RFA in piglets was studied to assess lesion size and potential coronary artery involvement mimicking RFA in small children. METHODS: RFA with continuous CF monitoring was performed in 24 piglets (median weight 18.5 kg) using a 7 F TactiCath Quartz radiofrequency (RF) ablation catheter (Abbott). A total of 7 lesions were induced in each animal applying low (10-20 g) or high (40-60 g) CF. RF energy was delivered with a target temperature of 65°C at 30 W for 30 s. Coronary angiography was performed prior and immediately after RF application. Animals were assigned to repeat coronary angiography followed by heart removal after 48 h (n = 12) or 6 months (n = 12). Lesions with surrounding myocardium were excised, fixated, and stained. Lesion volumes were measured by microscopic planimetry. RESULTS: A total of 148 RF lesions were identified in the explanted hearts. Only in the subset of lesions at the AV annulus 6 month after ablation, lesion size and number of lesions exhibiting transmural extension were higher in the high CF group compared to low CF. In all other locations CF had no impact on lesion size and mural extension after 48 h as well as after 6 months. Additional parameters such as lesion size index and force time integral were also not related to lesion size. Coronary artery damage was present in two animals after 48 h and in one after 6 months and was not related to CF. CONCLUSION: In our experimental setting, lesion size in piglets was not related to catheter CF. Transmural extension of the RF lesions involving the layers of the coronary arteries was frequently noted irrespective of CF. Coronary artery narrowing was present in 3/24 animals and was not related to CF. In infants and toddlers, low CF (10-20 g) may be of adequate effect. Impact of CF monitoring during conventional RF ablation in children requires further investigation.

Validation of the psychometric properties of a "Modified Version of the Hornheider Screening Instrument" (HSI-MV) using a sample of outpatient and inpatient skin tumor patients.

BACKGROUND: The basis for adequate psycho-oncological care is the identification of patients with psychosocial support needs. The German Working Group for Psychooncology also recommends the Hornheider Screening Instrument (HSI) for this purpose. The question, "Is anyone in your family particularly burdened by the hospital stay?" is intended to capture disease-related family stress. But is this item equally suitable for outpatients and inpatients? The study objective was to examine how replacing the original item affects the test performance of this modified version of the HSI and the frequency of psychosocial stress. PATIENTS AND METHODS: 92 outpatients and 98 inpatients with skin tumors assessed their psychosocial situation using different questionnaires. RESULTS: Compared to inpatients, less than half as many outpatients answered the item in the affirmative. If the question was replaced by: "Is someone in your family particularly burdened by your disease or the course of the disease?" this setting-related difference did not arise. The "Alternative item" and the "Modified version of the HIS" (HSI-MV) proved to be superior to the original item and the original HSI with regard to all examined criteria. CONCLUSIONS: The HSI-MV can be used as a reliable and valid instrument for the systematic assessment of psychosocial care needs in outpatient and inpatient settings. Depending on care capacity, a threshold of ≥ 5 or ≥ 4 is appropriate. In addition to screening, the desire for support should be enquired.

Skin Cancer Development in Solid Organ Transplant Recipients in Switzerland (Swiss Transplant Cohort Study).

IMPORTANCE: Skin cancer, in particular squamous cell carcinoma, is the most frequent malignancy among solid organ transplant recipients with a higher incidence compared to the general population. OBJECTIVE: To determine the skin cancer incidence in organ transplant recipients in Switzerland and to assess the impact of immunosuppressants and other risk factors. DESIGN: Prospective cohort study of solid organ transplant recipients in Switzerland enrolled in the Swiss Transplant Cohort Study from 2008 to 2013. PARTICIPANTS: 2,192 solid organ transplant recipients. MATERIALS AND METHODS: Occurrence of first and subsequent squamous cell carcinoma, basal cell carcinoma, melanoma and other skin cancers after transplantation extracted from the Swiss Transplant Cohort Study database and validated by medical record review. Incidence rates were calculated for skin cancer overall and subgroups. The effect of risk factors on the occurrence of first skin cancer and recurrent skin cancer was calculated by the Cox proportional hazard model. RESULTS: In 2,192 organ transplant recipients, 136 (6.2%) developed 335 cases of skin cancer during a median follow-up of 32.4 months, with squamous cell carcinoma as the most frequent one. 79.4% of skin cancer patients were male. Risk factors for first and recurrent skin cancer were age at transplantation, male sex, skin cancer before transplantation and previous transplantation. For a first skin cancer, the number of immunosuppressive drugs was a risk factor as well. CONCLUSIONS AND RELEVANCE: Skin cancer following solid organ transplantation in Switzerland is greatly increased with risk factors: age at transplantation, male sex, skin cancer before transplantation, previous transplantation and number of immunosuppressive drugs.

Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression.

BACKGROUND: Fifteen percent of atopic dermatitis (AD) liability-scale heritability could be attributed to 31 susceptibility loci identified by using genome-wide association studies, with only 3 of them (IL13, IL-6 receptor [IL6R], and filaggrin [FLG]) resolved to protein-coding variants. OBJECTIVE: We examined whether a significant portion of unexplained AD heritability is further explained by low-frequency and rare variants in the gene-coding sequence. METHODS: We evaluated common, low-frequency, and rare protein-coding variants using exome chip and replication genotype data of 15,574 patients and 377,839 control subjects combined with whole-transcriptome data on lesional, nonlesional, and healthy skin samples of 27 patients and 38 control subjects. RESULTS: An additional 12.56% (SE, 0.74%) of AD heritability is explained by rare protein-coding variation. We identified docking protein 2 (DOK2) and CD200 receptor 1 (CD200R1) as novel genome-wide significant susceptibility genes. Rare coding variants associated with AD are further enriched in 5 genes (IL-4 receptor [IL4R], IL13, Janus kinase 1 [JAK1], JAK2, and tyrosine kinase 2 [TYK2]) of the IL13 pathway, all of which are targets for novel systemic AD therapeutics. Multiomics-based network and RNA sequencing analysis revealed DOK2 as a central hub interacting with, among others, CD200R1, IL6R, and signal transducer and activator of transcription 3 (STAT3). Multitissue gene expression profile analysis for 53 tissue types from the Genotype-Tissue Expression project showed that disease-associated protein-coding variants exert their greatest effect in skin tissues. CONCLUSION: Our discoveries highlight a major role of rare coding variants in AD acting independently of common variants. Further extensive functional studies are required to detect all potential causal variants and to specify the contribution of the novel susceptibility genes DOK2 and CD200R1 to overall disease susceptibility.

Psychosocial stress of dermatology inpatients and their relatives - Comparison of patients with and without cancer.

BACKGROUND: In the clinical treatment pathways of certified oncological centers, psychotherapeutic services are mandatory. Although patients with somatic, non-oncological illnesses show an equally high prevalence of psychosocial stress, these guidelines do not exist for the general hospital sector. Are these patients really less burdened and is psychological support only needed in individual cases? The example of dermatological patients will be used to show whether the need for psychosocial care and the desire for support vary between individuals with and without malignant disease. PATIENTS AND METHODS: Using the Hornheider screening instrument and distress thermometer, 216 dermatological inpatients assessed their psychosocial stress and that of a close relative. In addition, they were asked about their desire for support and preferred support provider. RESULTS: i) Patients without skin cancer were more frequently and more severely distressed than cancer patients. ii) Patients of both groups assessed their relatives to be approximately equally distressed. Compared with their own distress, cancer patients assessed their relatives as more frequently and on average more severely distressed. More than 50 % of all patients regarded their own disease as the cause of their relatives' distress. iii) The desire for support in both groups was about 18 %. iv) Doctors and psychologists were usually named as potential contact persons. CONCLUSIONS: The expansion of psychosocial support services for non-tumor patients and their relatives seems necessary. The establishment of appropriate screening methods should be considered. Further studies in other clinical areas are required.

Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.

Varying label density allows artifact-free analysis of membrane-protein nanoclusters.

We present a method to robustly discriminate clustered from randomly distributed molecules detected with techniques based on single-molecule localization microscopy, such as PALM and STORM. The approach is based on deliberate variation of labeling density, such as titration of fluorescent antibody, combined with quantitative cluster analysis, and it thereby circumvents the problem of cluster artifacts generated by overcounting of blinking fluorophores. The method was used to analyze nanocluster formation in resting and activated immune cells.

Dislocation rates of postoperative airway exchange catheters - a prospective case series of 200 patients.

BACKGROUND: The dislocation rate of oral versus nasal airway exchange catheters (AEC) in the postoperative care unit (PACU) are unknown. Our aim was to establish dislocation rates and to assess the usefulness of waveform capnography to detect dislocation. METHODS: In this non-randomized, prospective observational trial at the University Hospital Bern, Switzerland, we included 200 patients admitted to PACU after extubation via AEC, having provided written informed consent. The study was approved by the local ethical committee. AEC position was assessed by nasal fiberoptic endoscopy at beginning of PACU stay and before removal of the AEC. Capnography was continuously recorded via the AEC. Additional measurements included retching and coughing of the patient, and re-intubation, if necessary. RESULTS: Data from 182 patients could be evaluated regarding dislocation. Overall dislocation rate was not different between oral and nasal catheters (7.2% vs. 2.7%, p = 0.16). Retching was more often noted in oral catheters (26% vs. 8%, p < 0.01). Waveform capnography was unreliable in predicting dislocation (negative predictive value 17%). Re-intubation was successful in all five of the nine re-intubations where an AEC was still in situ. In four patients, the AEC was already removed when re-intubation became necessary, and re-intubation failed once, with a front of neck access as a rescue maneuver. CONCLUSIONS: We found no difference in dislocation rate between nasal and oral position of an airway exchange catheter. However, nasal catheters seemed to be tolerated better. In the future, catheters like the staged extubation catheter may further increase tolerance. TRIAL REGISTRATION: The study was registered in a clinical study registry ( ISRCTN 96726807 ) on 10/06/2010.

[An erythematous macule is not always a fungal infection]. / Der dermatologische Rundherd, nicht immer Tinea corporis.

An erythematous macule is not always a fungal infection Abstract. In this article we show ten cases of erythematic macules and plaques which we think are most important in the differential diagnosis to a fungal infection of the skin. The macules are mostly solitary. A few of them can be also exanthematous. It is important to know about the differential diagnosis because clinic is often doubtful and can be challenging, especially if the evolution is not clear.

NXS, Morpholine, and HFIP: The Ideal Combination for Biomimetic Haliranium-Induced Polyene Cyclizations.

In contrast to Nature that accomplishes polyene cyclizations seemingly with ease, such transformations are difficult to conduct in the lab. In our program dealing with the development of selective halogenations of alkenes, we now asserted that standard X+ reagents are perfectly suited for the biomimetic cation-π cyclization of both electron rich and poor linear polyenes in the presence of the Lewis base morpholine and the Lewis acid HFIP. The method stands out due to its broad substrate scope and practicability together with high chemical yields and excellent selectivities, even for highly challenging chloriranium-induced polyene cyclizations.

Tunable DNA Hybridization Enables Spatially and Temporally Controlled Surface-Anchoring of Biomolecular Cargo.

The controlled immobilization of biomolecules onto surfaces is relevant in biosensing and cell biological research. Spatial control is achieved by surface-tethering molecules in micro- or nanoscale patterns. Yet, there is an increasing demand for temporal control over how long biomolecular cargo stays immobilized until released into the medium. Here, we present a DNA hybridization-based approach to reversibly anchor biomolecular cargo onto micropatterned surfaces. Cargo is linked to a DNA oligonucleotide that hybridizes to a sequence-complementary, surface-tethered strand. The cargo is released from the substrate by the addition of an oligonucleotide that disrupts the duplex interaction via toehold-mediated strand displacement. The unbound tether strand can be reloaded. The generic strategy is implemented with small-molecule or protein cargo, varying DNA sequences, and multiple surface patterning routes. The approach may be used as a tool in biological research to switch membrane proteins from a locally fixed to a free state, or in biosensing to shed biomolecular receptors to regenerate the sensor surface.

Recurrent parotid gland carcinoma: how effective is salvage surgery?

OBJECTIVE: Recurrent parotid gland carcinomas (PGCs) are poorly characterized and studies focusing on this topic are rare due to their low incidence. The goal of this study is to analyze the therapeutic strategies, prognostic factors, and oncological outcomes of a series of patients with recurrent PGCs. PATIENTS AND METHODS: Retrospective chart review (1997-2012) of patients with recurrent PGCs was initially treated with curative intent. RESULTS: We identified 20 patients with recurrent PGCs. Eleven patients presented isolated local, regional, or distant metastases, while the rest had recurrences in multiple sites. Recurrent tumors tended to present more advanced T-stage (p = 0.01) and overall stage (p < 0.001), but not N-stage (p = 0.74) when compared to the initial tumors. Half the patients (50%) had distant metastases at the moment of recurrence diagnosis, and another three developed them after attempted salvage surgery. Only 8/20 patients with isolated local or regional recurrences were surgically salvaged with extended revision parotidectomy and neck dissection, respectively. The remaining 12 patients were managed on palliative basis. Overall survival (31.70 months vs. 20.73 months) and progression-free survival (28.70 months vs. 13.61 months) were not significantly different in patients managed surgically vs. palliatively. CONCLUSION: Recurrent PGCs are aggressive neoplasms with a high rate of distant metastases. Surgical salvage can be considered in patients with limited local and/or regional recurrences. The alternative to surgical salvage is palliative management with different chemotherapeutic regimens. Survival does not differ between the two strategies in the present series.

Psychosocial distress and desire for support among skin cancer patients - impact of treatment setting.

BACKGROUND: Diagnosis and treatment of malignancies are frequently associated with a variety of problems for affected individuals and their relatives. In order to ensure adequate psycho-oncological and social care, it is recommended to routinely assess patients' psychosocial distress. While psychosocial services for inpatients have been expanded in recent years, the outpatient care structure in terms of psycho-oncological support is far from satisfactory, especially in Mecklenburg-Western Pomerania. We therefore set out to investigate the following questions: Does the need for psychosocial care vary in relation to (a) the treatment setting (inpatients vs. outpatients) and (b) the diagnosis? (c) Do patients experiencing psychological distress desire support? PATIENTS AND METHODS: We asked both inpatients and outpatients to rate their psychosocial situation using the Hornheide Questionnaire. Patients were also asked about their desire for psychological support and the preferred contact person. RESULTS: (a) The treatment setting had no impact on the need for psychosocial care and the desire for support. (b) Depending on the type of skin cancer, there were significant differences in the need for such care among the 251 patients surveyed. (c) Despite a certain discrepancy, there was a significant correlation between psychosocial distress (39.0 %; n = 98/251) and desire for support (14.3 %; n = 35/245). (d) Patients experiencing distress primarily chose physicians (n = 21) and psychologists (n = 20) as potential contact persons. CONCLUSIONS: (1) In addition to the level of distress, the desire for support should be inquired. (2) Recommendations by physicians represent an important means of access to psycho-oncological services. (3) Services for outpatient support should be expanded.

Evaluation of the National Swiss Skin Cancer Screening Campaign 2013: Do We Do the Right Thing.

BACKGROUND: Skin cancer prevention and screening programs are performed in many countries. Their benefit is discussed controversially. OBJECTIVE: Our aim is to evaluate the Skin Cancer Screening Program 2013 in Switzerland by following up screenees upon interventions. METHODS: Quality was assessed by personal follow-up via phone/e-mail of every patient that had been screened during this campaign and histological follow-up of all participants with suspicious skin lesions. RESULTS: Of the 1,087 screenees requiring interventions, 263 agreed to participate in the follow-up. We were able to obtain 66 histology reports. During this campaign 33 malignant lesions (8 melanomas) were removed. CONCLUSION: The overall melanoma detection rate in our free Skin Cancer Screening Program is comparable to those in European public activities. The costs of free screening programs compare favorably with the prevented potential therapeutic costs of late-stage melanoma. The low response rate of screenees agreeing to be followed up limits conclusions of this study.