Structural basis of the Meinwald rearrangement catalysed by styrene oxide isomerase.

Membrane-bound styrene oxide isomerase (SOI) catalyses the Meinwald rearrangement-a Lewis-acid-catalysed isomerization of an epoxide to a carbonyl compound-and has been used in single and cascade reactions. However, the structural information that explains its reaction mechanism has remained elusive. Here we determine cryo-electron microscopy (cryo-EM) structures of SOI bound to a single-domain antibody with and without the competitive inhibitor benzylamine, and elucidate the catalytic mechanism using electron paramagnetic resonance spectroscopy, functional assays, biophysical methods and docking experiments. We find ferric haem b bound at the subunit interface of the trimeric enzyme through H58, where Fe(III) acts as the Lewis acid by binding to the epoxide oxygen. Y103 and N64 and a hydrophobic pocket binding the oxygen of the epoxide and the aryl group, respectively, position substrates in a manner that explains the high regio-selectivity and stereo-specificity of SOI. Our findings can support extending the range of epoxide substrates and be used to potentially repurpose SOI for the catalysis of new-to-nature Fe-based chemical reactions.

Comparing Synchronicity in Body Movement among Jazz Musicians with Their Emotions.

This paper presents novel preliminary research that investigates the relationship between the flow of a group of jazz musicians, quantified through multi-person pose synchronization, and their collective emotions. We have developed a real-time software to calculate the physical synchronicity of team members by tracking the difference in arm, leg, and head movements using Lightweight OpenPose. We employ facial expression recognition to evaluate the musicians' collective emotions. Through correlation and regression analysis, we establish that higher levels of synchronized body and head movements correspond to lower levels of disgust, anger, sadness, and higher levels of joy among the musicians. Furthermore, we utilize 1-D CNNs to predict the collective emotions of the musicians. The model leverages 17 body synchrony keypoint vectors as features, resulting in a training accuracy of 61.47% and a test accuracy of 66.17%.

Best Practice Guideline - DEGUM Recommendations on Breast Ultrasound. / Best Practice Guideline ­ Empfehlungen der DEGUM zur Durchführung und Beurteilung der Mammasonografie ­ TEIL I ­ Untersuchungstechnik, Ultraschall-DEGUM-Kriterien und deren Dokumentation.

For many years, breast ultrasound has been used in addition to mammography as an important method for clarifying breast findings. However, differences in the interpretation of findings continue to be problematic 1 2. These differences decrease the diagnostic accuracy of ultrasound after detection of a finding and complicate interdisciplinary communication and the comparison of scientific studies 3. In 1999, the American College of Radiology (ACR) created a working group (International Expert Working Group) that developed a classification system for ultrasound examinations based on the established BI-RADS classification of mammographic findings under consideration of literature data 4. Due to differences in content, the German Society for Ultrasound in Medicine (DEGUM) published its own BI-RADS-analogue criteria catalog in 2006 3. In addition to the persistence of differences in content, there is also an issue with formal licensing with the current 5th edition of the ACR BI-RADS catalog, even though the content is recognized by the DEGUM as another system for describing and documenting findings. The goal of the Best Practice Guideline of the Breast Ultrasound Working Group of the DEGUM is to provide colleagues specialized in senology with a current catalog of ultrasound criteria and assessment categories as well as best practice recommendations for the various ultrasound modalities.

[Hidradenitis suppurativa/acne inversa in daily practice]. / Hidradenitis suppurativa/Acne inversa in der Praxis.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease, characterized by abscess formation and mutilating scar formation in the body folds. The burden of disease is high for both patient and treating physician. In dermatological daily practice, proper patient education and formation of a trustful physician-patient relationship are of highest importance. HS patients are treated both conservatively and surgically mostly by dermatologists, which requires extensive knowledge of the pathogenesis, trigger factors, comorbidities and treatment options. Interdisciplinary collaboration with other disciplines is still underdeveloped. New physical treatments (laser, radiofrequency, intense pulsed light [IPL]), topical and systemic therapies enable good ambulatory long-term management for all HS stages.

A Giant Mammary Hamartoma in a Young Breast Cancer Patient.

BACKGROUND: Hamartomas of the breast are rare benign tumors. Pre- and also postoperative differentiation from other benign or even malignant tumors is challenging. CASE PRESENTATION: A 36-year-old female presented with a giant tumor of the left breast. The patient had suffered from an early breast cancer of the contralateral right breast the year before, which was treated with breast-conserving therapy, radiation, and endocrine therapy ever since. The hamartoma was classified as BI-RADS 2 in mammography and BI-RADS 4 in ultrasound. On clinical examination, a tumor of nearly 15 cm in size led to an abstruse deformity of the breast and the nipple-areola complex. We found an indolent, grand bulging tumor with an elastic texture directly beneath the skin. A biopsy that had been performed before was compatible with the suspected hamartoma. Because of the remaining diagnostic uncertainties after contralateral breast cancer and the progressive malformation of the left breast, a tumor extirpation utilizing a reduction mammaplasty was performed without complications. Subsequent genetic analyses excluded a loss of PTEN in this patient. CONCLUSION: We presented the rare case of a 36-year-old woman with a history of breast cancer and a 700-g breast hamartoma. The preoperative and even the postoperative specification of a hamartoma remains challenging, and associations with genetic alterations should be considered.

[Treatment of pigmentation disorders in association with systemic diseases]. / Therapie von Pigmentstörungen in Zusammenhang mit systemischen Erkrankungen.

Pigmentation disorders are a frequent skin problem and incorporate a broad spectrum of diseases, caused by an abnormal melanin pigmentation or also non-melanin pigmentation of the skin. Both hypermelanosis and hypomelanosis can be hereditary or acquired. This article summarizes the treatment approaches that are used in the majority of acquired pigmentation disorders of the skin. The following forms of hypermelanosis are addressed: lentiginosis, hyperpigmentation due to endocrine disorders or other systemic diseases, drug-induced hyperpigmentation. Acquired hypomelanoses include postinflammatory hypomelanosis, chemical depigmentation, idiopathic guttate hypomelanosis and punctate leucoderma. With reference to non-melanin pigmentation, the exogenous pigmentation due to chemicals, metals and drug exposure are discussed. The treatment is primarily based on finding the cause of the alterations to the pigment. The affected area, age and ethnic origin are also important factors. The spectrum of therapeutic options is broad: topical agents, chemical peeling, systemic agents, laser and light-based treatment. As some of these treatment procedures can have side effects, the availability of a protocol that contains information on the drug concentration, dose, parameters for laser treatment and the number of sessions is important. For every disorder the specific dermatological treatment is presented even when some pigmentation alterations that occur in association with systemic diseases, are cured by the treatment of the primary disease. Most diseases are exacerbated by exposure to UV light. Therefore, sun protection is recommended and a cosmetic coverage is indicated.

Untreated PKU Patients without Intellectual Disability: What Do They Teach Us?

Phenylketonuria (PKU) management is aimed at preventing neurocognitive and psychosocial dysfunction by keeping plasma phenylalanine concentrations within the recommended target range. It can be questioned, however, whether universal plasma phenylalanine target levels would result in optimal neurocognitive outcomes for all patients, as similar plasma phenylalanine concentrations do not seem to have the same consequences to the brain for each PKU individual. To better understand the inter-individual differences in brain vulnerability to high plasma phenylalanine concentrations, we aimed to identify untreated and/or late-diagnosed PKU patients with near-normal outcome, despite high plasma phenylalanine concentrations, who are still alive. In total, we identified 16 such cases. While intellectual functioning in these patients was relatively unaffected, they often did present other neurological, psychological, and behavioral problems. Thereby, these "unusual" PKU patients show that the classical symptomatology of untreated or late-treated PKU may have to be rewritten. Moreover, these cases show that a lack of intellectual dysfunction despite high plasma phenylalanine concentrations does not necessarily imply that these high phenylalanine concentrations have not been toxic to the brain. Also, these cases may suggest that different mechanisms are involved in PKU pathophysiology, of which the relative importance seems to differ between patients and possibly also with increasing age. Further research should aim to better distinguish PKU patients with respect to their cerebral effects to high plasma phenylalanine concentrations.

Can untreated PKU patients escape from intellectual disability? A systematic review.

BACKGROUND: Phenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients. METHODS: To this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 µmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers. RESULTS: In total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms. CONCLUSIONS: Based on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients.

[The 308 nm Excimer laser : Treatment of vitiligo and hypopigmentation]. / 308 nm-Excimerlaser : Therapie von Vitiligo und Hypopigmentierungen.

Use of the 308 nm Excimer laser to treat hypopigmentation and vitiligo is usually superior to conventional ultraviolet (UV) therapy with regard to results and safety. It is particularly advantageous because specific areas of skin can be targeted without burdening the rest of the skin. Fewer sessions with lower cumulative doses are required. Various combination therapies can improve the outcome; selection criteria such as early initiation of treatment and more frequent sessions with shorter intervals make it easier to decide which patients should be treated and how to achieve the greatest benefit.

[Light-based inflammatory acne treatments]. / Phototherapie der entzündlichen Akne.

Light-based acne treatments may represent a new emerging treatment for acne that does not increase the risk of bacterial resistance and they may be potentially effective with a favorable safety profile. Current data show that photodynamic therapy reduces inflammatory lesions and significantly improves acne. However, there is no consensus on the optimal implementation in the treatment of acne. In addition to topically applied photodynamic therapy, intense pulsed light, pulsed dye lasers, potassium-titanyl-phosphate lasers, infrared diode lasers, broad-spectrum continuous-wave light sources (red light, blue-red light) have been introduced as alternative treatments. Since well-designed studies to evaluate their efficacy versus traditional medical therapies are lacking and standardized regimens have not been agreed upon, procedures including laser, intense pulsed light, and photodynamic therapy should currently not be considered first-line treatment for inflammatory acne.

[The 308 nm Excimer laser for the treatment of psoriasis and inflammatory skin diseases]. / 308 nm-Excimerlaser zur Therapie von Psoriasis und entzündlichen Hauterkrankungen.

Overall, the 308 nm Excimer laser enables not only a more effective and safer UVB therapy than classical UV phototherapy, but also targeted irradiation in higher doses with a lower cumulative load, which results in faster healing of mainly circumscribed skin changes. This also applies to therapy-resistant residual lesions which, despite systemic therapy, did not diminish. Combination therapies usually improve the result and enable the dose of UVB and systemic medication to be reduced. Excimer laser therapy can be used for an increasing number of skin diseases, especially those that respond to phototherapy or photochemotherapy.

[Laser treatment of basal cell carcinoma]. / Lasertherapie des Basalzellkarzinoms.

With a clear increase in the incidence and a continuously earlier onset, the main risk factors for the development of basal cell carcinoma are still exposure to sunlight, fair skin, immunosuppression, carcinogens such as arsenic, chronic irritations and certain genodermatoses. Treatment options for localized resectionable basal cell carcinoma include micrographically controlled surgery, simple excision, curettage, laser ablation, cryosurgery, imiquimod, 5­fluorouracil, photodynamic treatment and radiotherapy. Non-surgical treatment options are more suited for cases in which surgical procedures lead to disfigurement or functional impairments or for patients with a high surgical risk. Laser treatment, ablative and non-ablative as monotherapy or in combination can represent a meaningful treatment option in selected cases. In recent years there has been an increase in knowledge about the indications and effects of laser treatment of basal cell carcinoma; nevertheless, further studies with a high level of evidence are necessary.

Consensus statement on prevention and management of adverse effects following rejuvenation procedures with hyaluronic acid-based fillers.

Facial fillers play an important role in the correction of facial changes associated with ageing. They offer quick treatments in the outpatient setting with minimal subsequent downtime that provide predictable, natural-looking, long-lasting results. Adverse reactions after hyaluronic acid injections tend to be mild or moderate and rather temporary. However, as with all injected or implanted biomaterials, severe adverse events can occur and patients must be fully informed of potential risks prior to undergoing treatment. A panel of experts from Germany (D), Austria (A) and Switzerland (CH) developed recommendations, and this study provides the 'DACH Consensus Recommendations' from this group specifically on the use of hyaluronic acid fillers. The aim is to help clinicians recognize potential risks and to provide guidance on how best to treat adverse events if they arise. Contraindications to hyaluronic acid fillers are also detailed, and ways to prevent adverse events occurring are discussed. Hyaluronic acid-based products are claimed to be very close to an ideal tissue augmentation agent; nevertheless, profound medical, anatomical and product knowledge are of paramount importance to minimize the occurrence of adverse reactions.

Key European guidelines for the diagnosis and management of patients with phenylketonuria.

We developed European guidelines to optimise phenylketonuria (PKU) care. To develop the guidelines, we did a literature search, critical appraisal, and evidence grading according to the Scottish Intercollegiate Guidelines Network method. We used the Delphi method when little or no evidence was available. From the 70 recommendations formulated, in this Review we describe ten that we deem as having the highest priority. Diet is the cornerstone of treatment, although some patients can benefit from tetrahydrobiopterin (BH4). Untreated blood phenylalanine concentrations determine management of people with PKU. No intervention is required if the blood phenylalanine concentration is less than 360 µmol/L. Treatment is recommended up to the age of 12 years if the phenylalanine blood concentration is between 360 µmol/L and 600 µmol/L, and lifelong treatment is recommended if the concentration is more than 600 µmol/L. For women trying to conceive and during pregnancy (maternal PKU), untreated phenylalanine blood concentrations of more than 360 µmol/L need to be reduced. Treatment target concentrations are as follows: 120-360 µmol/L for individuals aged 0-12 years and for maternal PKU, and 120-600 µmol/L for non-pregnant individuals older than 12 years. Minimum requirements for the management and follow-up of patients with PKU are scheduled according to age, adherence to treatment, and clinical status. Nutritional, clinical, and biochemical follow-up is necessary for all patients, regardless of therapy.

Laser therapies for onychomycosis - critical evaluation of methods and effectiveness.

The number of medical devices designed specifically to treat onychomycosis has recently increased, although their mechanism of action is not clear. We evaluated available laser therapies for onychomycosis by reviewing the existing literature. Twenty-two reports, published in peer-reviewed journals and as white papers out of 926 initial search results conveyed enough details to be included in this study. In most cases, the methodology of the trials described in the papers we reviewed was not comprehensive and the reporting of outcomes was not unified. We therefore found it hard to compare different clinical trials to one another. The majority of studies (81.82%) reported using an Nd:YAG laser device to treat onychomycosis. A total of 47.37% of the studies which used a 1064 device (and 47.83% of all studies we reviewed) reported that all treated patients responded positively to laser therapy. A total of 60% of studies reported achieving a complete cure (no clinical symptoms, nor negative mycology) in at least 50% of the treated patients. A low number of adverse events and their mild intensity were consistently reported across all studies, which makes this form of therapy particularly attractive to patients with contraindications for receiving systemic antifungal medication. In order to achieve more unified, comparable studies in the future, we suggest that researchers report a minimum set of outcome measurements: the calculation of the infected nail area pre- and posttreatment, as well as the number of patients achieving mycological, clinical and complete cures.

PEPFAR support of alcohol-HIV prevention activities in Namibia and Botswana: a framework for investigation, implementation and evaluation.

BACKGROUND: The association between harmful use of alcohol and HIV infection is well documented. To address this dual epidemic, the US President's Emergency Plan for AIDS Relief (PEPFAR) developed and implemented a multi-pronged approach primarily in Namibia and Botswana. We present the approach and preliminary results of the public health investigative and programmatic activities designed, initiated and supported by PEPFAR to combat the harmful use of alcohol and its association as a driver of HIV morbidity and mortality from 2008 to 2013. APPROACH: PEPFAR supported comprehensive alcohol programming using a matrix model approach that combined the socio-ecological framework and the Alcohol Misuse Prevention and Intervention Continuum. This structure enabled seven component objectives: (1) to quantify harmful use of alcohol through rapid assessments; (2) to develop and evaluate alcohol-based interventions; (3) to promote screening programs and alcohol abuse resource services; (4) to support stakeholder networks; (5) to support policy interventions and (6) structural interventions; and (7) to institutionalize universal prevention messages. DISCUSSION: Targeted PEPFAR support for alcohol activities resulted in several projects to address harmful alcohol use and HIV. Components are graphically conceptualized within the matrix model, demonstrating the intersections between primary, secondary and tertiary prevention activities and individual, interpersonal, community, and societal factors. Key initiative successes included leveraging alcohol harm prevention activities that enabled projects to be piloted in healthcare settings, schools, communities, and alcohol outlets. Primary challenges included the complexity of multi-sectorial programming, varying degrees of political will, and difficulties monitoring outcomes over the short duration of the program.

[Undesired treatment effects in behavior group therapy: Frequency and spectrum]. / Unerwünschte Therapiewirkungen bei verhaltenstherapeutischer Gruppentherapie : Häufigkeit und Spektrum.

BACKGROUND: Psychotherapy not only has positive but also negative effects, which is especially true for group psychotherapy due to psychodynamic and interactional processes. METHODS: Using the UE-G questionnaire 71 patients who participated in cognitive behavioral group psychotherapy reported on negative experiences in the context of the group therapy. The answers were then validated in a qualitative interview. RESULTS: Of the patients 98.6% reported about at least one negative experience and 43.7% about severe or extremely severe negative experiences. Most prominent was the induction of hopelessness and demoralization by what patients saw and heard from other patients in the group. CONCLUSION: Burdensome and therefore undesired treatment effects are regularly seen in group psychotherapy, because of treatment or patient related factors. In any case they must be taken into account during treatment, in the training of group psychotherapists and in quality control.

Structure and thermodynamics of effector molecule binding to the nitrogen signal transduction PII protein GlnZ from Azospirillum brasilense.

The trimeric PII signal transduction proteins regulate the function of a variety of target proteins predominantly involved in nitrogen metabolism. ATP, ADP and 2-oxoglutarate (2-OG) are key effector molecules influencing PII binding to targets. Studies of PII proteins have established that the 20-residue T-loop plays a central role in effector sensing and target binding. However, the specific effects of effector binding on T-loop conformation have remained poorly documented. We present eight crystal structures of the Azospirillum brasilense PII protein GlnZ, six of which are cocrystallized and liganded with ADP or ATP. We find that interaction with the diphosphate moiety of bound ADP constrains the N-terminal part of the T-loop in a characteristic way that is maintained in ADP-promoted complexes with target proteins. In contrast, the interactions with the triphosphate moiety in ATP complexes are much more variable and no single predominant interaction mode is apparent except for the ternary MgATP/2-OG complex. These conclusions can be extended to most investigated PII proteins of the GlnB/GlnK subfamily. Unlike reported for other PII proteins, microcalorimetry reveals no cooperativity between the three binding sites of GlnZ trimers for any of the three effectors under carefully controlled experimental conditions.