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The aim of this study was to investigate sonographic findings of low-grade malignant tumors of the parotid gland. The sonographic findings of all patients treated for T1-T2 low-grade carcinomas of the parotid gland between 2003 and 2018 were retrospectively examined and compared with those of patients with pleomorphic adenomas for the following parameters: definition of tumor margins, echotexture, echogenicity, shape and vascularization. Statistical analysis was performed using the χ2 test. A p value of

Traditional surgical philosophy condemns extracapsular dissection for pleomorphic adenoma as a euphemism for the enucleation of this lesion.The aims of the study were to trace the development of surgical treatment by pleomorphic adenomas of the parotid gland over the last 15 years and explore its effects on the histopathology specimen.The medical records of all cases with pleomorphic adenomas of the parotid gland between 2006 and 2020 were examined for information on age, gender, and type of surgery. An experienced head and neck pathologist re-evaluated the histology slides from all the cases.The study included 844 patients. Our analysis showed an increase in the performance of extracapsular dissection from 52.8% (2006) to 63.3% (2020), and an increase in histopathology specimens with tumours completely covered by healthy tissue from 27.7% (2006) to 50% (2020).Our decision-making process reached its peak in the last study years, in terms of reduced surgical invasiveness and quality of the pathology specimen.Extracapsular dissection has gained a firm hold as an indispensable tool for the experienced parotid surgeon. Proper indication is based on careful selection of cases and the correct interpretation of preoperative features on palpation and imaging.

The amygdala and goal-directed actions Almost everything we do in our daily lives is goal directed. The brain can maintain a motivational state to direct actions to achieve desired outcomes. Using deep-brain calcium imaging, electrophysiology, and optogenetics in mice, Courtin et al . observed that at the time of goal-directed action, basolateral amygdala principal neurons integrate and encode pursued outcome identity, pursued outcome value, and action-outcome contingency information. At the time of consumption, basolateral amygdala neuronal firing represents current outcome identity and value. Together, action- and consumption-associated activity integrate behaviorally relevant information at distinct time points along goal-directed action-consumption sequences. —PRS

Cardiovascular disease is an important contributor to morbidity and mortality in people living with HIV . The immature platelet fraction (IPF) is increased in HIV-negative patients with cardiovascular disease and evidence suggests that an enlarged IPF is associated with adverse cardiovascular events. In this multi-center observational study, we aimed to investigate how the IPF in people living with HIV is influenced by antiretroviral therapy and cardiovascular disease. Subjects without cardiovascular disease that received antiretroviral therapy showed a smaller IPF accompanied by lower D-dimer and C-reactive protein (CRP) levels compared to therapy-naïve subjects (mean IPF: 2.9% vs. 3.9%

Recently, we discovered the recurrent genomic rearrangement [t(4;9)(q13;q31)] enabling upregulation of the transcription factor Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) through enhancer hijacking as the oncogenic driver event in acinic cell carcinoma (AciCC) of the salivary glands. In the current study, we evaluated the usefulness of NR4A3 immunostaining and NR4A3 fluorescence in situ hybridization (FISH) in the differential diagnosis of AciCC, comparing a total of 64 AciCCs including 17% cases with high-grade transformation, 29 secretory (mammary analog) carcinomas (MASC), and 70 other salivary gland carcinomas. Nuclear NR4A3 immunostaining was a highly specific (100%) and sensitive (98%) marker for AciCC with only 1 negative case, whereas NR4A3 FISH was less sensitive (84%). None of the MASCs or other salivary gland carcinomas displayed any nuclear NR4A3 immunostaining. The recently described HTN3-MSANTD3 gene fusion was observed in 4 of 49 (8%) evaluable AciCCs, all with nuclear NR4A3 immunostaining. In summary, NR4A3 immunostaining is a highly specific and sensitive marker for AciCC, which may be especially valuable in cases with high-grade transformation and in "zymogen granule"-poor examples within the differential diagnostic spectrum of AciCC and MASC.

Background: The insertion of the stapes piston into the vestibule provides the physical basis for a successful stapedotomy. In routine clinical practice, two different ways to handle prosthesis length are performed: (1) an individualized measurement of the stapes prosthesis length or (2) a standard prosthesis length for all cases. Objective: The objective of this study was to compare both ways of handling prosthesis length and the effect of these methods on insertional prosthesis depth. Material and Method: We retrospectively evaluated 39 patients after performing a stapedotomy for radiologically estimated vestibular stapes prosthesis insertion depth. The individual measured length data were hypothetically changed to a standard length of 4.75, 5, 5.25, and 5.5 mm, and the insertion depths were compared. Results: The individually measured prosthesis lengths led to an insertion depth between 0.2 and 1.6 mm (mean 0.74 mm). The ratio of insertion depth/vestibular depth was between 8 and 59.1% (mean 26.6%). The different assumed standard lengths led to different rates of the vestibulum positions and possible bony contacts at the vestibulum floor. Conclusion: The individual measurement led to a zero rate of the vestibulum positions of stapes prosthesis pistons with a low insertion depth/vestibular depth ratio.

OBJECTIVES/HYPOTHESIS The aim of this study was to identify potential associations between epidemiologic, morphologic, and histopathologic features in pleomorphic adenomas (PAs) of the parotid gland in order to extract information about the natural course and biologic behavior of these lesions on the basis of a single-center series of 845 cases within a period of 15 years. STUDY DESIGN Retrospective study in a tertiary academic center. METHODS For this study, an experienced head and neck pathologist critically re-evaluated the histological slides of the pathological specimens of all patients who underwent a parotidectomy for PA of the parotid gland between 2006 and 2020. RESULTS A total of 845 cases made up our study sample. Our analysis showed a statistically significant association of the histologic subtype with younger age (P = .001) and maximal diameter (P = .044), with the hypocellular type being encountered more often in younger patients and in smaller lesions. The same subtype was significantly associated with an incomplete capsule (P = .001), pseudopodia (P = .006), and satellite nodules (P = .001). An incomplete capsule was associated with the presence of pseudopodia (P = .001) and satellite nodules (P = .001). CONCLUSION It seems that various histologic subtypes have different capsule-producing properties. Apparently, over the course of time, tumor material builds a finger-like projection still inside the capsule, separates itself from the parenchyma with fibrous tissue still remaining enclosed within the capsule (pseudopodium), slowly penetrates the capsule (incomplete capsule), and leaves the main lesion taking a part of the capsule with it (satellite nodules). Laryngoscope, 2021.

OBJECTIVE The aim of this study was to investigate and compare the histopathological findings in pleomorphic adenomas (PA) of the parotid and submandibular gland with emphasis on the histological subtype and capsular characteristics. MATERIALS AND METHODS The histopathological specimens of all patients with PAs of the parotid and submandibular gland between 2000 and 2020 were re-examined by an experienced head and neck pathologist. Patients without representative slides allowing evaluation of the whole periphery of the PA were excluded from our study sample. RESULTS Nine hundred and thirty-four patients formed our study sample (327 men, 607 women, male-to-female ratio: 0.53:1). Eight hundred and forty-four cases had a PA in the parotid gland and the remaining 90 in the submandibular gland. Our comparative analysis showed that submandibular PAs are characterized by the consistent presence of an intact anatomical capsule, infrequent occurrence of pseudopodia and satellite nodules, and a low proportion of the high-risk myxoid subtype. CONCLUSION Our study highlights significant differences between PAs of the parotid and submandibular glands in their histopathological characteristics. Their differences likely underlie the favorable surgical outcome observed in PAs of the submandibular glands and may explain the propensity of PAs of the parotid glands for local recurrences.

The growing number of people with multimorbidity and polypharmacy in Germany has led to increasing complexity in health care and risks to patient safety. A high priority should therefore be placed on identifying and preventing avoidable adverse events. The patient perspective plays an important role in improving patient safety. In this study, we conducted a representative, population-based survey of knowledge, perceptions and experiences of patient safety, especially of subjectively experienced errors in health care. Our aim was, in particular, to assess patient safety from the patients' point of view, and to analyze differences in assessments of risk and preventability between persons that felt well or poorly informed about patient safety topics.In 2019, computer-assisted telephone interviews were conducted nationwide as part of the "TK-Monitor Patient Safety" project. Recruitment was carried out by using multistage selection and forming a stratified random sample. Adults (18 years and older) with sufficient knowledge of German were included. The survey was conducted using a structured guideline containing 21 questions concerning perceptions and experiences of patient safety, and 12 questions on sociodemographic factors. The results were analyzed both descriptively and using inferential statistical methods.Of a total of 1,000 respondents (51% female), approx. half (52%) were gainfully employed, and 57% rated their state of health as "very good" or "good". The patients regarded data protection, medication errors, hospital infections and diagnostic (un)certainty as of major relevance to patient safety. Overall, 55% of the respondents rated their knowledge of patient safety as "very good" or "good". The results showed that subjective knowledge was negatively associated with important outcome parameters such as having experience of medication errors or suspecting errors had been made in a medical examination or treatment. Patients that considered themselves well-informed also reckoned they could contribute towards increasing safety in health care.The respondents considered diagnostic uncertainty to be one of the greatest risks to their person. This shows that they recognized a need for further information and felt this need was inadequately satisfied in the German research landscape. With regard to the correlation between subjective knowledge and outcome parameters, it is also necessary to analyze whether the respondents' subjective knowledge reflects their actual knowledge, as this would be necessary for preventive measures to be effective. This question will be the subject of further studies.The patient perspective is an important addition to the study of the safety of medical care in Germany. Factors influencing subjective knowledge should be investigated. Furthermore, regular surveys would be desirable in order to gain greater insight into the topic.

Objectives The aim of this study was to thoroughly investigate the incidence of satellite nodules (SN) and some of their characteristics (number, distance to main lesion) in a large series of pleomorphic adenomas (PA) and to compare several surgical modalities regarding their efficacy in addressing this critical morphological feature. Materials and methods The records of all patients treated for primary PA of the parotid gland between 2006 and 2020 were studied retrospectively. All the histological slides of all tumours were critically re-evaluated for this study by an experienced head and neck pathologist. Results 845 cases made up our initial study sample. SNs were detected in 68/845 cases (8%). No statistically significant difference could be detected in the incidence of SNs in the surgical specimens between the patient groups managed by extracapsular dissection (46/577, 7.9%) and facial nerve dissecting surgery (22/268, 8.2%, p = 0.502). In the group of cases with SNs, no recurrences were detected (mean follow-up time: 71.4 months). The mean distance from the main lesion to the most distant SN was 1.1 mm (0.08–6.3 mm). The mean size of the SN was 1.9 mm (0.1–9.7 mm). Altogether, the mean distance from the main lesion to the outer periphery of the most distant SN was 3.1 mm (0.4–10.5 mm). Conclusion Our analysis could not award SNs the title of an “extracapsular dissection’s nightmare”. In the majority of cases, their favourable histological patterns offer the ideal circumstances for their surgical inclusion in a tumour specimen.

Nutritional interventions have beneficial effects on certain psychiatric disorder symptomatology and common physical health comorbidities. However, studies evaluating nutritional literacy in mental health professionals (MHP) are scarce. This study aimed to assess the across 52 countries. Surveys were distributed via colleagues and professional societies. Data were collected regarding self-reported general nutrition knowledge, nutrition education, learning opportunities, and the tendency to recommend food supplements or prescribe specific diets in clinical practice. In total, 1056 subjects participated in the study: 354 psychiatrists, 511 psychologists, 44 psychotherapists, and 147 MHPs in-training. All participants believed the diet quality of individuals with mental disorders was poorer compared to the general population (p < 0.001). The majority of the psychiatrists (74.2%) and psychologists (66.3%) reported having no training in nutrition. Nevertheless, many of them used nutrition approaches, with 58.6% recommending supplements and 43.8% recommending specific diet strategies to their patients. Only 0.8% of participants rated their education regarding nutrition as ‘very good.’ Almost all (92.9%) stated they would like to expand their knowledge regarding ‘Nutritional Psychiatry.’ There is an urgent need to integrate nutrition education into MHP training, ideally in collaboration with nutrition experts to achieve best practice care., publishedVersion

Contains fulltext : 237881.pdf (Publisher’s version ) (Open Access) Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6‐months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt‐tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease., Heterozygous mutations in nuclear genes interacting with mt‐tRNAGlu induce the integrated stress response and metabolic rearrangements, reducing penetrance and promoting spontaneous recovery in a rare mitochondrial myopathy.

The work highlights the link between dysfunction of the RNA exosome, ribosome biogenesis, p53-dependent signalling, and apoptosis. Pontocerebellar hypoplasia caused by mutations of the exosome subunits could be classified as a ribosomopathy., The RNA exosome is a ubiquitously expressed complex of nine core proteins (EXOSC1-9) and associated nucleases responsible for RNA processing and degradation. Mutations in EXOSC3, EXOSC8, EXOSC9, and the exosome cofactor RBM7 cause pontocerebellar hypoplasia and motor neuronopathy. We investigated the consequences of exosome mutations on RNA metabolism and cellular survival in zebrafish and human cell models. We observed that levels of mRNAs encoding p53 and ribosome biogenesis factors are increased in zebrafish lines with homozygous mutations of exosc8 or exosc9, respectively. Consistent with higher p53 levels, mutant zebrafish have a reduced head size, smaller brain, and cerebellum caused by an increased number of apoptotic cells during development. Down-regulation of EXOSC8 and EXOSC9 in human cells leads to p53 protein stabilisation and G2/M cell cycle arrest. Increased p53 transcript levels were also observed in muscle samples from patients with EXOSC9 mutations. Our work provides explanation for the pathogenesis of exosome-related disorders and highlights the link between exosome function, ribosome biogenesis, and p53-dependent signalling. We suggest that exosome-related disorders could be classified as ribosomopathies.

Psychiatric neurosurgery has resurfaced over the past two decades for the treatment of severe mental health disorders, with improved precision and safety over older interventions alongside the development of novel ones. Little is known, however, about current public opinions, expectations, hopes, and concerns over this evolution in neurotechnology, particularly given the controversial history of psychosurgery. To fill this knowledge gap, we conducted a study with eight focus groups in Vancouver and Montreal (Canada; n = 14), Berlin (Germany; n = 22), and Madrid (Spain; n = 12). Focus group texts were transcribed and analyzed using qualitative content analysis in the language local to each city, guided by the theoretical framework of pragmatic neuroethics. Findings indicate that participants across all cities hold concerns about the last resort nature of psychiatric neurosurgery and the potential impact on the authentic self of patients who undergo these procedures. The views captured serve to advance discussion on the appropriate timing for psychiatric neurosurgery, promote sound health policy for the allocation of this resource, and foster scientific literacy about advances for mental health internationally.

BackgroundThe underestimation of depression among men may result from atypical depression symptoms and male help-seeking behaviour. However, higher suicide rates among men than among women indicate a need for gender-specific services for men with depression. In order to develop gender-specific services, it is essential to examine professionals’ attitudes towards men’s depressive symptoms and treatment needs as well as barriers to and facilitators of treatment. This study examined gender-specific treatment needs in male patients and treatment approaches to male patients from a professional perspective.MethodsSemi-structured face-to-face interviews were conducted with 33 mental health professionals (MHPs) from five German psychiatric institutions. The study assessed the characteristics and attributes of male patients with depression risk factors for the development of depression among men, their condition at the beginning of treatment, male patients’ depressive symptoms, the needs and expectations of male patients, the importance of social networks in a mental health context, and MHPs’ treatment aims and treatment methods. Transcripts were analysed using qualitative content analysis.ResultsThe professionals’ reference group of male patients were men who were characterised in accordance with traditional masculinity. Attributes reported as in line with this type of men were late initiations of inpatient treatment after crisis, suicidal ideation or attempted suicide, and high expectations towards treatment duration, success rate in recovery and therapeutic sessions. In contrast, male patients who deviate from these patterns were partially described with reference to female stereotypes. Professionals referred to psychosocial models in their explanations of the causes of depression and provided sociological explanations for the development of masculine ideals among men. The consequences of these for treatment were discussed against the background of normative expectations regarding the male gender. From the professionals’ point of view, psychoeducation and the acceptance of depression (as a widespread mental illness) were the most important goals in mental health treatment.ConclusionsIn order to improve mental health among men, gender-specific services should be offered. Awareness of the role of gender and its implications on mental health treatment should be an integral part of MHPs’ education and their daily implementation of mental health treatment practices.

Purpose A traditional male role orientation is considered to increase the risk of depression and preventing men from disclosing symptoms of mental illness and seeking professional help. Less is known about the variance of masculinity orientations in men already treated for depression and their role in the treatment process. In this study, patterns of masculinity norms and work role orientations will be identified among men treated for depression. Associations of these patterns with depressive symptoms, stigma and delay in professional help-seeking will be investigated. Methods In a cross-sectional study, male role orientations (MRNS), work-related attitudes (AVEM), symptoms of mental disorders (PHQ), and attitudes related to stigma of mental illness (DSS) were assessed by standardized methods in a sample of 250 men treated for depression in general medical, psychiatric and psychotherapeutic services. Data were analyzed by means of latent profile analysis (LPA), by multinomial and linear regression models, and by path analysis. Results The results of LPA revealed three latent classes of men treated for depression. Men assigned to class one reported a less traditional male role orientation, low professional ambitions and low coping capacities; men assigned to class two reported a traditional masculinity orientation, high professional ambitions but low coping capacities; men assigned to class three reported less traditional masculinity tended orientations, medium professional ambitions and high coping capacities. Men assigned to classes one and two to have more stigmatizing attitudes, longer periods of untreated illness and more severe symptoms of mental disorders, in comparison to men assigned to class three. Conclusions Overall, this study reveals that traditional masculinity norms and work-role orientations in men treated for depression are associated with a worse mental health status. Our study results also suggest that a slackening of traditional masculinity norms is associated with improved psychological well-being if it does not coincide with a complete distancing from professional ambitions and a lack of ability to cope with professional stress.

Objective: Post-traumatic stress disorder (PTSD) increases type 2 diabetes risk, yet the underlying mechanisms are unclear. We investigated how early-life exposure to chronic stress affects long-term insulin sensitivity. Methods: C57Bl/6J mice were exposed to chronic variable stress for 15 days (Cvs) and then recovered for three months without stress (Cvs3m). Results: Cvs mice showed markedly increased plasma corticosterone and hepatic insulin resistance. Cvs3m mice exhibited improved whole-body insulin sensitivity along with enhanced adipose glucose uptake and skeletal muscle mitochondrial function and fatty acid oxidation. Plasma FGF21 levels were substantially increased and associated with expression of genes involved in fatty acid oxidation and formation of brown-like adipocytes. In humans, serum FGF21 levels were associated with stress coping long time after the exposure. Conclusions: Early-life exposure to chronic stress leads to long term improvements in insulin sensitivity, oxidative metabolism and adipose tissue remodeling. FGF21 contributes to a physiological memory mechanism to maintain metabolic homeostasis. Keywords: PTSD, Chronic variable stress, Diabetes, Insulin sensitivity, FGF21, White adipose tissue

Background Performing tympanoplasty for tympanic perforations in children and adolescents is often considered to be less successful than in adults. Objectives The aim of our study was to evaluate the surgical outcome of tympanoplasty type I in patients under 15 years of age with chronic otitis media and to identify potential factors that influence the success rate. Materials und methods The present study was based on a retrospective analysis of the medical records of all patients under the age of 15 who were treated for chronic otitis media by means of type I tympanoplasty between 2005 and 2020. The minimum follow-up period was 6 months. The data were analyzed with regard to epidemiological parameters, tube-related pathologies in the contralateral ear, the local condition and the extent of the eardrum perforation as well as the extent of the surgical intervention (tympanoplasty type I with or without adenotomy). Results 83 cases were included in our study. The mean age at the time of the surgery was 8.9 years. The mean follow-up time was 46 months (6–182 months). The anatomical closure rate was 88.0%. Children with “dry” tympanic perforations tended to perform better (p = 0.052). The average improvement in the air bone gap was 2.0 dB. Conclusion Detailed preoperative counseling about the advantages and disadvantages as well as the expected success rate of an early myringoplasty in this age group is just as important as an individualized approach for a high level of patient satisfaction.

The aim of our study was to perform a comparative analysis in our cases with titanium partial clip ossiculoplasty in terms of audiometric outcome and extrusion rates as well as to review the literature for relevant information on this surgical issue.The records of all patients who had undergone primary partial ossiculoplasty with the implantation of a CliP® Partial Prosthesis Dresden Type (CPPDT, group A) or a CliP Partial FlexiBAL® (CPF, Group B, both Heinz Kurz GmbH, Dusslingen, Germany) between 2012 and 2020 were studied retrospectively.274 patients made up our study sample (148 men, 126 women, male to female ratio: 1.17). Their mean age at the time of first surgery was 39.6 years (range: 4-79 years). The mean preoperative air-bone gap (ABG) was 22.7dΒ ± 10.5 dB. Mean follow-up was approximately 4 months (1-12 months). The mean postoperative ABG was 15.7 ± 8.1 dB. In total, the postoperative ABG was significantly improved compared to preoperative values (P 0.001). Surgical success, defined as an ABG ≤ 20 dB, was achieved in the majority of our study patients (210/274, 76.6%). Extrusion of the prosthesis was detected in 3/216 CPF and 5/58 CPPDT cases (p = 0.012). Comparison of both prosthesis groups revealed a significantly better audiological outcome for the patients with ossicular reconstruction using CPF. A significantly better audiological outcome was detected in the cases with a normal aeration of the middle ear.Titanium clip partial ossiculoplasty is a reliable component of modern tympanoplasty, allowing a satisfying audiologic outcome. The higher adaptability of the CPF to the changing postoperative circumstances and the frequently defective aeration of the middle ear is reflected in the better audiologic outcome for this prosthesis.

Background Asymptomatic carotid artery stenosis (ACS) has a low risk of stroke. To achieve an advantage over noninterventional best medical treatment (BMT), carotid endarterectomy (CEA) or carotid artery stenting (CAS) must be performed with the lowest possible risk of stroke. Therefore, an analysis of risk-elevating factors is essential. Grade of ipsilateral and contralateral stenosis as well as plaque morphology are known risk factors in ACS. Methods The randomized, controlled, multicenter SPACE-2 trial had to be stopped prematurely after recruiting 513 patients. 203 patients were randomized to CEA, 197 to CAS, and 113 to BMT. Within one year, risk factors such as grade of stenosis and plaque morphology were analyzed. Results Grade of contralateral stenosis (GCS) was higher in patients with any stroke (50%ECST vs. 20%ECST; p=0.012). Echolucent plaque morphology was associated with any stroke on the day of intervention (OR 5.23; p=0.041). In the periprocedural period, any stroke was correlated with GCS in the CEA group (70%ECST vs. 20%ECST; p=0.026) and with echolucent plaque morphology in the CAS group (6% vs. 1%; p=0.048). In multivariate analysis, occlusion of the contralateral carotid artery (CCO) was associated with risk of any stroke (OR 7.00; p=0.006), without heterogeneity between CEA and CAS. Conclusion In patients with asymptomatic carotid artery stenosis, GCS, CCO, as well as echolucent plaque morphology were associated with a higher risk of cerebrovascular events. The risk of stroke in the periprocedural period was increased by GCS in CEA and by echolucent plaque in CAS. Due to small sample size, results must be interpreted carefully.

Background The purpose of this study was to demonstrate the feasibility of physician driven planning in intensity modulated radiotherapy (IMRT) with a multicriteria optimization (MCO) treatment planning system and template based plan optimization. Exploiting the full planning potential of MCO navigation, this alternative planning approach intends to improve planning efficiency and individual plan quality. Methods Planning was retrospectively performed on 12 brain tumor and 10 post-prostatectomy prostate patients previously treated with MCO-IMRT. For each patient, physicians were provided with a template-based generated Pareto surface of optimal plans to navigate, using the beam angles from the original clinical plans. We compared physician generated plans to clinically delivered plans (created by dosimetrists) in terms of dosimetric differences, physician preferences and planning times. Results Plan qualities were similar, however physician generated and clinical plans differed in the prioritization of clinical goals. Physician derived prostate plans showed significantly better sparing of the high dose rectum and bladder regions (p(D1)

Objective Ribosomal protein S6 Kinase-1 (S6K1) has been linked to resistance exercise-mediated improvements in glycemia. We hypothesized that S6K1 may also play a role in regulating glycemic control in response to endurance exercise training. Methods S6k1-knockout (S6K1KO) and WT mice on a 60 cal% high-fat diet were trained for 4 weeks on treadmills, metabolically phenotyped, and compared to sedentary controls. Results WT mice showed improved glucose tolerance after training. In contrast, S6K1KO mice displayed equally high glucose tolerance already in the sedentary state with no further improvement after training. Similarly, training decreased mitochondrial ROS production in skeletal muscle of WT mice, whereas ROS levels were already low in the sedentary S6K1KO mice with no further decrease after training. Nevertheless, trained S6K1KO mice displayed an increased running capacity compared to trained WT mice, as well as substantially reduced triglyceride contents in liver and skeletal muscle. The improvements in glucose handling and running endurance in S6K1KO mice were associated with markedly increased ketogenesis and a higher respiratory exchange ratio. Conclusions In high-fat fed mice, loss of S6K1 mimics endurance exercise training by reducing mitochondrial ROS production and upregulating oxidative utilization of ketone bodies. Pharmacological targeting of S6K1 may improve the outcome of exercise-based interventions in obesity and diabetes., Highlights • Absence of S6k1 upregulates oxidative substrate utilization under HFD consumption. • S6k1 knockout mice show enhanced running performance and improved glycemia already in the sedentary state. • Aerobic endurance exercise training of S6k1 knockout mice further improves running performance but not glycemia. • Metabolic improvements are associated with lower rates of TCA-linked mitochondrial H2O2 production and increased ketogenesis.

There exist no uniform decision criteria for conservative organ preservation treatments in head and neck cancer patients. Even withDecrease in SUVmax inResidual SUVmax (resSUVmax) values were uniformly distributed across five cut-off levels (0-0.2 vs.0.2-0.4 vs.0.4-0.6 vs.0.6-0.8 vs.0.8) containing 20%, 25% 25%, 15% and 15% of patients. Patients were stratified into three response categories according to residual SUVmax (Group A: 0-0.4 = high response Group B:0.4-0.8 = moderate response, Group C 0.8 = non-response), 5-year local control rates were 90.5% (Group A) vs. 78.9% (Group B; univariate p = 0.07, multivariate: HR: 3.6, p = 0.03) vs. 49.4% (Group C vs. B; univariate p = 0.04, multivariate: HR 5.5, p 0.01). After IC-1, Group A received chemoradiotherapy (CRT) only. Group B received surgery plus either (chemo)radiotherapy (B_S + RT/CRT) or chemoradiotherapy (B_CRT), yielding local control rates of 100% and 74.2% (p = 0.11). Group C received surgery plus CRT or CRT alone; both achieved equally poor local control (p = 0.71). Group C had significantly worse distant metastasis-free survival and overall survival than Groups A and B (p 0.05).Metabolic response after IC-1 differentiates HNC patients into three subgroups predicting local tumor control. Non-response was associated with a poor outcome.

Prenatal stress exposure is associated with risk for psychiatric disorders later in life. This may be mediated in part via enhanced exposure to glucocorticoids (GCs), which are known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on messenger RNA (mRNA) expression and DNA methylation (DNAm) profiles. GC exposure induced changes in DNAm at 27,812 CpG dinucleotides and in the expression of 3,857 transcripts (false discovery rate [FDR] = 1.15). HPC expression and GC-affected DNAm profiles were enriched for changes observed during human fetal brain development. Differentially methylated sites (DMSs) with GC exposure clustered into 4 trajectories over HPC differentiation, with transient as well as long-lasting DNAm changes. Lasting DMSs mapped to distinct functional pathways and were selectively enriched for poised and bivalent enhancer marks. Lasting DMSs had little correlation with lasting expression changes but were associated with a significantly enhanced transcriptional response to a second acute GC challenge. A significant subset of lasting DMSs was also responsive to an acute GC challenge in peripheral blood. These tissue-overlapping DMSs were used to compute a polyepigenetic score that predicted exposure to conditions associated with altered prenatal GCs in newborn's cord blood DNA. Overall, our data suggest that early exposure to GCs can change the set point of future transcriptional responses to stress by inducing lasting DNAm changes. Such altered set points may relate to differential vulnerability to stress exposure later in life.

Objectives/hypothesis To evaluate the demographics, clinical features, management, and prognostic indicators of tracheoesophageal puncture complications in patients undergoing placement of voice prosthesis following cancer treatment. Study design Retrospective analysis. Methods A retrospective analysis was conducted of cases from a tertiary referral center diagnosed between 1996 and 2015. Multivariate logistic regression was used to determine factors associated with tracheoesophageal puncture (TEP) and voice prostheses-complication-free survival (TEP/VP-CFS). Results One hundred fourteen cases were identified. Most patients were males (92.9%) with pT3 (26.8%) or pT4 (58.1%) N+ (53.6%) tumors. All patients received laryngectomy as the primary treatment, with 75% of patients receiving adjuvant radiation therapy or chemoradiotherapy. Complications with TEP were common (65.2%). The most frequent problem was salivary leakage (50.0%), which at the same time was the most common reason for changing the prosthesis. On univariate regression analysis, prosthesis placement time after adjuvant radiotherapy (hazard ratio [HR]: 4.17, 95% confidence interval [CI]: 2-8.69), secondary prosthesis placement after primary surgery (HR: 3.97, 95% CI: 1.99-7.9), and laryngectomy with flap reconstruction (HR: 1.96, 95% CI: 0.99-3.89) were significant prognosticators for complications. Multivariate regression analysis revealed secondary prosthesis placement after adjuvant radiotherapy (HR: 3.66, 95% CI: 1.39-9.68) or after primary surgery (HR: 2.57, 95% CI: 0.92-7.2) to be the strongest predictors of reduced TEP/VP-CFS. Conclusions Secondary prosthesis placement after primary surgery, placement after previous irradiation, and laryngectomy with flap reconstruction are predictors of poor TEP/VP-CFS. Planned adjuvant radiotherapy is not a contraindication for TEP with prosthetic placement, but it is very important to place the prosthesis during the primary surgery or at least before scheduled radiotherapy. Level of evidence 4 Laryngoscope, 2020.

The response to induction chemotherapy (IC) predicts local control after conservative treatment of laryngeal, meso- and hypopharyngeal head and neck squamous cell carcinoma (HNSCC) and can thus help to avoid surgery. Single-cycle induction chemotherapy may help to maintain a low local recurrence rate while keeping the overall toxicity manageable. However, long-term data on single-cycle IC response by tumor location is lacking. N = 102 patients with functionally inoperable primary HNSCC of the larynx (n = 43), hypopharynx (n = 42) or mesopharynx/tongue (n = 17) received one cycle of docetaxel (75 mg/m2, d1) plus cisplatin (30 mg/m2, d1-3) or carboplatin (AUC 1.5, d1-3) and a response evaluation 3 weeks later. Responders (≥ 30% tumor size reduction and ≥ 20% SUVmax decrease in 18F-FDG PET/CT) were recommended chemoradiotherapy (CRT), and non-responders surgery. The overall response rate was 72.5%. All 74 responders and 10 non-responders received primary CRT, and 18 patients received primary surgery after single-cycle IC. Overall 10-year local recurrence-free survival (LRFS) was 73.7%. Three-year LRFS was 88.2% (mesopharynx/tongue), 88.2% (larynx), and 73.3% (hypopharynx); p = 0.17. 3-year distant metastasis-free survival (DMFS) was 94.1% (mesopharynx/tongue), 88.0% (larynx) and 76.4% (hypopharynx); p > 0.05. This influenced the 3-year cancer-specific survival (CSS) for larynx (91.2%) vs. hypopharynx tumors (60.8%); p = 0.003, but CSS was not different to tumors in the mesopharynx/tongue (81.4%); p > 0.05. A single-cycle induction chemotherapy for HNSCC enables surgery plus adjuvant therapy as well as chemoradiotherapy. The long-term local and distant disease control was good but varied between tumors in the larynx and mesopharynx/tongue vs. hypopharynx.

The current study describes the results obtained from clinical examination of over 4700 suckling piglets from 19 individual herds in Germany. In this cohort the prevalence of inflammation and necrosis in the tails, ears, claw coronary bands, heels and teats was determined using a pre-defined scoring system. Results show that already in the 1st days of life, piglets were affected by inflammation and necrosis of the heels (80%), claw coronary bands (50%) and tail base (20%). The praevalences of these alterations in piglets were influenced by genetics (P

Background: The insertion of the stapes piston within the vestibule provides the physical basis for a successful stapedotomy. An insertion depth of 0.5 mm is recommended to avoid the dislocation of...

Objectives The ultrasonic NO PAIN technology (Electro Medical Systems, Nyon, CH) promises minimal pain during debridement due to linear oscillating action combined with a sinusoidal power output and feedback control. The aim of the present study was to measure pain perception on a visual analogue scale (VAS) during supportive periodontal therapy including debridement of hypersensitive teeth. Two ultrasonic scalers were used, one with and one without NO PAIN technology. Material and methods In a randomized-controlled clinical study with split-mouth design, 100 hypersensitive teeth matched for air blast hypersensitivity were either treated with the ultrasonic device Piezon Master 700 or the Mini Piezon (both EMS, Nyon, CH). Pain perception during debridement was assessed by a VAS (range 0–10). Results The average VAS for the test device Piezon Master 700 with NO PAIN technology was 3.16 ± 2.10, and for the control device Mini Piezon without NO PAIN technology 3.40 ± 2.59 (p = 0.490). Placing an arbitrary threshold at the VAS score of 3 for significant pain experience, 60 % of the subjects experienced no significant pain with either instrument. Conclusion No statistically significant difference in perceived pain between the instruments used was found. Clinical relevance Both ultrasonic devices showed very small pain intensities during debridement of highly hypersensitive teeth and can therefore be recommended for supportive periodontal therapy.

The aim was to examine to what extent the dimensions of the BPS map the five factors derived from the PANSS in order to explore the level of agreement of these alternative dimensional approaches in patients with schizophrenia. 149 inpatients with schizophrenia spectrum disorders were recruited. Psychopathological symptoms were assessed with the Bern Psychopathology Scale (BPS) and the Positive and Negative Syndrome Scale (PANSS). Linear regression analyses were conducted to explore the association between the factors and the items of the BPS. The robustness of patterns was evaluated. An understandable overlap of both approaches was found for positive and negative symptoms and excitement. The PANSS positive factor was associated with symptoms of the affect domain in terms of both inhibition and disinhibition, the PANSS negative factor with symptoms of all three domains of the BPS as an inhibition and the PANSS excitement factor with an inhibition of the affect domain and a disinhibition of the language and motor domains. The results show that here is only a partial overlap between the system-specific approach of the BPS and the five-factor PANSS model. A longitudinal assessment of psychopathological symptoms would therefore be of interest.

The endogenous neuropeptide galanin is ubiquitously expressed throughout the mammalian brain. Through the galanin receptors GalR1-3, galanin has been demonstrated to modulate both glutamatergic and GABAergic neurotransmission, and this appears to be important in epilepsy and seizure activity. Accordingly, galanin analogues are likely to provide a new approach to seizure management. However, since peptides are generally poor candidates for therapeutic agents due to their poor metabolic stability and low brain bioavailability, a search for alternative strategies for the development of galanin-based anti-convulsant drugs was prompted. Based on this, a rationally designed GalR1 preferring galanin analogue, NAX-5055, was synthesized. This compound demonstrates anti-convulsant actions in several animal models of epilepsy. However, the alterations at the cellular level leading to this anti-convulsant action of NAX-5055 are not known. Here we investigate the action of NAX-5055 at the cellular level by determining its effects on excitatory and inhibitory neurotransmission, i.e. vesicular release of glutamate and GABA, respectively, in cerebellar, neocortical and hippocampal preparations. In addition, its effects on cell viability and neurotransmitter transporter capacity were examined to evaluate potential cell toxicity mediated by NAX-5055. It was found that vesicular release of glutamate was reduced concentration-dependently by NAX-5055 in the range from 0.1 to 1000 nM. Moreover, exposure to 1 μM NAX-5055 led to a reduction in the extracellular level of glutamate and an elevation of the extracellular level of GABA. Altogether these findings may at least partly explain the anti-convulsant effect of NAX-5055 observed in vivo.

Background Oral anticoagulants can cause potentially serious adverse events. Therefore, before prescribing oral anticoagulants for ischemic stroke prevention in patients with atrial fibrillation (AF), stroke risk assessment is required to identify patients that are likely to benefit from treatment. Current guidelines recommend the CHA2DS2-VASc-score for stroke risk assessment. The CHA2DS2-VASc-score is based on observational studies from different treatment settings and countries. As ischemic stroke risk differs by setting and region, the aim of this study is to estimate ischemic stroke risk (stratified by the CHA2DS2-VASc-score) for a broadly representative population with AF from southern Germany and compare them to results from previous studies. Methods The study design is a retrospective cohort study on patients with atrial fibrillation based on secondary data. We calculated CHA2DS2-VASc-score based on patient’s diagnoses recorded in the year 2014 and assessed outcomes in 2015–2016. The primary outcome is hospitalization for ischemic stroke. The secondary outome is hospitalizations for any thromboembolic event, including ischemic stroke, transient ischemic attack, peripheral arterial embolism, pulmonary embolism, and mesenterial embolism. We estimated the incidence rates of the outcomes (and corresponding 95%-confidence intervals) stratified by CHA2DS2-VASc-score. Results The primary endpoint occurred in 961 of the 30,299 patients constituting the study population, resulting in a total incidence rate of 2.2 per 100 person-years. The secondary endpoint occurred in 1553 patients (3.6 per 100 person-years). Ischemic stroke rates stratified by the CHA2DS2-VASc-score tended to be lower than those reported previously. Thromboembolic event rates stratified tended to be similar to those reported previously. Conclusions Our results show that the performance of the CHA2DS2-VASc-score differs in the German population, as compared to internationally published data, with an overall trend towards lower risk of ischemic stroke in uncoagulated patients with AF. These results should not be practice changing, but they emphasize that stroke risk estimation in patients with atrial fibrillation should be further refined.

The understanding of mechanisms linking psychological stress to disease risk depend on reliable stress biomarkers. Circulating cell-free DNA (cfDNA) has emerged as a potential biomarker of cellular stress, aging, inflammatory processes, and cell death. Recent studies indicated that psychosocial stress and physical exercise might also influence its release. We compared the effects of acute psychosocial and physical exercise stress on cfDNA release by exposing 20 young, healthy men to both an acute psychosocial laboratory stressor and an acute physical exercise stressor. Venous blood and saliva samples were collected before and after stress exposure. Cell-free DNA was extracted from plasma and quantified by qPCR. Furthermore, cfDNA fragment length was analyzed and cfDNA methylation patterns were assayed across time. In addition, release of stress hormones and subjective stress responses were measured. Results showed a twofold increase of cfDNA after TSST and fivefold increase after exhaustive treadmill exercise, with an overabundance of shorter cfDNA fragments after physical exhaustion. Interestingly, cell-free mitochondrial DNA showed similar increase after both stress paradigms. Furthermore, cfDNA methylation signatures—used here as a marker for diverse cellular origin—were significantly different post stress tests. While DNA methylation decreased immediately after psychosocial stress, it increased after physical stress, suggesting different cellular sources of active DNA release. In summary, our results suggest stimulus and cell-specific regulation of cfDNA release. Whereas the functional role of stress-associated cfDNA release remains elusive, it might serve as a valuable biomarker in molecular stress research as a part of the psychophysiological stress response.

Background Although polypharmacy can cause adverse health outcomes, patients often know little about their medication. A regularly conducted medication review (MR) can help provide an overview of a patient’s medication, and benefit patients by enhancing their knowledge of their drugs. As little is known about patient attitudes towards MRs in primary care, the objective of this study was to gain insight into patient-perceived barriers and facilitators to the implementation of an MR. Methods We conducted a qualitative study with a convenience sample of 31 patients (age ≥ 60 years, ≥3 chronic diseases, taking ≥5 drugs/d); in Hesse, Germany, in February 2016. We conducted two focus groups and, in order to ensure the participation of elderly patients with reduced mobility, 16 telephone interviews. Both relied on a semi-structured interview guide dealing with the following subjects: patients’ experience of polypharmacy, general design of MRs, potential barriers and facilitators to implementation etc. Interviews were audio-recorded, transcribed verbatim, and analysed by two researchers using thematic analysis. Results Patients’ average age was 74 years (range 62–88 years). We identified barriers and facilitators for four main topics regarding the implementation of MRs in primary care: patient participation, GP-led MRs, pharmacist-led MRs, and the involvement of healthcare assistants in MRs. Barriers to patient participation concerned patient autonomy, while facilitators involved patient awareness of medication-related problems. Barriers to GP-led MRs concerned GP’s lack of resources while facilitators related to the trusting relationship between patient and GP. Pharmacist-led MRs might be hindered by a lack of patients’ confidence in pharmacists’ expertise, but facilitated by pharmacies’ digital records of the patients’ medications. Regarding the involvement of healthcare assistants in MRs, a potential barrier was patients’ uncertainty regarding the extent of their training. Patients could, however, imagine GPs delegating some aspects of MRs to them. Conclusions Our study suggests that patients regard MRs as beneficial and expect indications for their medicines to be checked, and possible interactions to be identified. To foster the implementation of MRs in primary care, it is important to consider barriers and facilitators to the four identified topics. Electronic supplementary material The online version of this article (10.1186/s12875-017-0707-0) contains supplementary material, which is available to authorized users.

Producción Científica, Most lung cancer deaths are related to metastases, which indicates the necessity of detecting and inhibiting tumor cell dissemination. Here, we aimed to identify miRNAs involved in metastasis of lung adenocarcinoma as prognostic biomarkers and therapeutic targets. To that end, lymph node metastasis– associated miRNAs were identified in The Cancer Genome Atlas lung adenocarcinoma patient cohort (sequencing data; n ¼ 449) and subsequently validated by qRT-PCR in an independent clinical cohort (n ¼ 108). Overexpression of miRNAs located on chromosome 14q32 was associated with metastasis in lung adenocarcinoma patients. Importantly, Kaplan–Meier analysis and log-rank test revealed that higher expression levels of individual 14q32 miRNAs (mir-539, mir-323b, and mir487a) associated with worse disease-free survival of never-smoker patients. Epigenetic analysis including DNA methylation microarray data and bisulfite sequencing validation demonstrated that the induction of 14q32 cluster correlated with genomic hypomethylation of the 14q32 locus. CRISPR activation technology, applied for the first time to functionally study the increase of clustered miRNA levels in a coordinated manner, showed that simultaneous overexpression of 14q32 miRNAs promoted tumor cell migratory and invasive properties. Analysis of individual miRNAs by mimic transfection further illustrated that miR-323b-3p, miR-487a-3p, and miR-539-5p significantly contributed to the invasive phenotype through the indirect regulation of different target genes. In conclusion, overexpression of 14q32 miRNAs, associated with the respective genomic hypomethylation, promotes metastasis and correlates with poor patient prognosis in lung adenocarcinoma

In this study, linear poly(ethylene glycol) (PEG) and novel linear-hyperbranched, amphiphilic polyglycerol (hbPG) polymers with cholesterol (Ch) as a lipid anchor moiety were radiolabeled with fluorine-18 via copper-catalyzed click chemistry. In vivo investigations via positron emission tomography (PET) and ex vivo biodistribution in mice were conducted. A systematic comparison to the liposomal formulations with and without the polymers with respect to their initial pharmacokinetic properties during the first hour was carried out, revealing remarkable differences. Additionally, cholesterol was directly labeled with fluorine-18 and examined likewise. Both polymers, Ch-PEG27-CH2-triazole-TEG-(18)F and Ch-PEG30-hbPG24-CH2-triazole-TEG-(18)F (TEG: triethylene glycol), showed rapid renal excretion, whereas the (18)F-cholesten displayed retention in lung, liver, and spleen. Liposomes containing Ch-PEG27-CH2-triazole-TEG-(18)F revealed a hydrodynamic radius of 46 nm, liposomal Ch-PEG30-hbPG24-CH2-triazole-TEG-(18)F showed a radius of 84 nm and conventional liposomes with (18)F-cholesten 204 nm, respectively. The results revealed fast uptake of the conventional liposomes by liver, spleen, and lung. Most importantly, the novel hbPG-polymer stabilized liposomes showed similar behavior to the PEG-shielded vesicles. Thus, an advantage of multifunctionality is achieved with retained pharmacokinetic properties. The approach expands the scope of polymer tracking in vivo and liposome tracing in mice via PET.

In daily practice, vitreomacular traction (VMT) is described by the horizontal diameter of its attachment site implying a regular round shape of VMT. We investigated the deviation from this circular area of vitreous traction in patients with VMT. A retrospective analysis of optical coherence tomography (OCT) scans was performed. The area of vitreomacular attachment was determined using six radial OCT scans (Ameasured). The assumed circular area of traction was calculated based on measuring the maximal horizontal diameter for comparison (Acircular). Thirty-seven eyes of 37 patients with pure VMT were included. Patients’ mean age was 72.8 ± 8.2 years. Mean horizontal VMT diameter was 400.8 ± 230.5 μm (median 361 μm; range 44–991 μm). While there was no difference between mean areas of traction for Acircular and Ameasured (P = 0.93), the individual difference (|Acircular − Ameasured|) was 0.042 (± 0.044) mm2 in mean or relative 73.0% (± 135.8%). A difference of ≥ 30% of Ameasured to Acircular was found in 16 eyes (43.2%) and ≥ 100% in 7 eyes (18.9%), respectively. Vitreous attachment sites possess an irregular non-circular shape in a significant number of eyes with VMT. Consequently, the area of traction appears inaccurately described by its horizontal VMT diameter alone. As the area of traction is important for therapeutic recommendation, our results emphasize the need for a more precise description of the area of traction in eyes with VMT.

Objective To describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog (PTEN), a tumor suppressor gene associated with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases. Methods We performed whole-exome sequencing in the patient's genomic DNA validated by Sanger sequencing. Immunoblotting, in vitro enzymatic assay, and label-free shotgun proteomic profiling were performed in the patient's fibroblasts. Results The predominant clinical presentation of the patient was a childhood onset, asymmetric progressive multifocal motor neuropathy. In addition, he presented with macrocephaly, autism spectrum disorder, and skin hamartomas, considered as clinical criteria for PTEN-related hamartoma tumor syndrome. Extensive tumor screening did not detect any malignancies. We detected a novel de novo heterozygous c.269T>C, p.(Phe90Ser) PTEN variant, which was absent in both parents. The pathogenicity of the variant is supported by altered expression of several PTEN-associated proteins involved in tumorigenesis. Moreover, fibroblasts showed a defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4-trisphosphate. In support of our findings, focal hypermyelination leading to peripheral neuropathy has been reported in PTEN-deficient mice. Conclusion We describe a novel phenotype, PTEN-associated multifocal demyelinating motor neuropathy with a skin hamartoma syndrome. A similar mechanism may potentially underlie other forms of Charcot-Marie-Tooth disease with involvement of the phosphatidylinositol pathway.

Background: A neurobiologically informed, system-specific psychopathological approach has been suggested for use in schizophrenia. However, to our knowledge, such an approach has not been used to prospectively describe the course of schizophrenia. Sampling and Methods: We assessed psychopathology in a well-described sample of 100 patients with schizophrenia or schizoaffective disorder with the Bern Psychopathology Scale (BPS) at 6-month intervals for up to 18 months. The BPS groups symptoms into the 3 domains language, affectivity and motor behaviour; each domain is rated as being normal, inhibited or disinhibited. In addition, we collected qualitative psychopathological data in the form of case reports. Results: Forty-eight patients completed at least 2 assessments over the course of at least 1 year. Of these, 16 patients (33.3%) showed a bipolar course pattern (i.e., a switch from inhibited to disinhibited or vice versa) in 1 domain and 6 patients (12.5%) in more than 1 domain. Shifts from 1 dominant domain to another were seen frequently (n = 20, 41.7%), but shifts between 1 dominant domain and a combination of dominant domains were more common (n = 33, 68.8%). Conclusions: The course of schizophrenia is heterogeneous and shows frequent changes in psychopathology. This should be taken into account in the communication with patients and in the research on underlying illness mechanisms and treatment. A major limitation of this study is the small sample size.

The aim of this study was to investigate the benefits and potential pitfalls of transcervical extracapsular dissection in the treatment of parotid gland tumours in the parapharyngeal space. We retrospectively evaluated the records of all patients with parapharyngeal parotid gland lesions treated between 2000 and 2015 by transcervical extracapsular dissection. Patients having revision operations and patients whose records were not complete were excluded, leaving 49 patients in the study. We found acceptable oncological and functional outcomes throughout. Special attention should be paid in cases with multilobular growth of the tumour on magnetic resonance imaging, satellite tumours of pleomorphic adenomas, tumours in broad contact with the inner surface of the deep lobe, and lesions suspected of malignancy. Extracapsular dissection in the parapharyngeal region is associated with acceptable oncological and functional outcomes. These outcomes can be expected only after a thorough assessment of patient’s history and preoperative imaging.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders, all of which impair neuromuscular transmission. Epidemiological data and frequencies of gene mutations are scarce in the literature. Here we describe the molecular genetic and clinical findings of sixty-four genetically confirmed CMS patients from Spain. Thirty-six mutations in the CHRNE, RAPSN, COLQ, GFPT1, DOK7, CHRNG, GMPPB, CHAT, CHRNA1, and CHRNB1 genes were identified in our patients, with five of them not reported so far.. These data provide an overview on the relative frequencies of the different CMS subtypes in a large Spanish population. CHRNE mutations are the most common cause of CMS in Spain, accounting for 27% of the total. The second most common are RAPSN mutations. We found a higher rate of GFPT1 mutations in comparison with other populations: Remarkably, several founder mutations made a large contribution to CMS in Spain: RAPSN c.264C > A (p.Asn88Lys), CHRNE c.130insG (Glu44Glyfs*3), CHRNE c.1353insG (p.Asn542Gluf*4), DOK7 c.1124_1127dup (p.Ala378Serfs*30), and particularly frequent in Spain in comparison with other populations, COLQ c.1289A > C (p.Tyr430Ser). Furthermore, we describe phenotypes and distinguishing clinical signs associated with the various CMS genes which might help to identify specific CMS subtypes to guide diagnosis and management. (C) 2017 Elsevier B.V. All rights reserved.

Little is known about the accumulation of persistent organic pollutants (POPs) and its consequences for seabirds in the Mediterranean basin. We characterised the plasma contaminant profile (polychlorinated biphenyls ΣPCBs; organochlorine pesticides ΣOCPs; polybrominated diphenyl ethers ΣPBDEs) of a population of the seabird Scopoli's shearwater (Calonectris diomedea) that breeds in the southern Mediterranean (Linosa Island) and investigated (i) whether sex, stable isotope ratios (related to diet), reproductive phase (early incubation vs. late breeding season) and body mass explained variation in contaminant burden and (ii) whether they predict health-related variables. The predominant category of POPs was ΣPCBs contributing between 53.0 and 92.4% of the total POPs in each shearwater. The percentage contribution of ΣOCPs to total POPs ranged between 7.6 and 47.0%, while that of ΣPBDEs ranged between < 1% and 22.1%. Near the end of the breeding season, concentrations of ΣPCBs, ΣOCPs and ΣPOPs were significantly higher than at the beginning of the incubation period. ΣPBDEs were higher in males than females near the end of the breeding season, while they were higher in females than males at the beginning of the egg incubation period. Carbon- and nitrogen isotope ratios and individual body mass were not significantly associated with any contaminant class. Mates differed in the concentration of POPs, but they had similar stable isotope values. There was little evidence for a connection between contaminants and blood-based markers of oxidative balance. None of the contaminants predicted the probability of a bird being resighted as a breeder the following year. Thus, although POPs were present at high concentrations in some individuals, our study suggests little concern regarding POP exposure for this shearwater population.

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous disorders characterized by a neuromuscular transmission defect. In recent years, causative mutations have been identified in atleast 15 genes encoding proteins of the neuromuscular junction. Mutations in MUSK are known as a very rare genetic cause of CMS and have been described in only three families, world-wide. Consequently, the knowledge about efficient drug therapy is very limited. We identified a novel missense mutation (p.Asp38Glu) heteroallelic to a genomic deletion affecting exons 2–3 of MUSK as cause of a limb-girdle CMS in two brothers of Turkish origin. Clinical symptoms included fatigable limb weakness from early childhood on. Upon diagnosis of a MUSK-related CMS at the age of 16 and 13 years, respectively, treatment with salbutamol was initiated leading to an impressive improvement of clinical symptoms, while treatment with esterase inhibitors did not show any benefit. Our findings highlight the importance of a molecular diagnosis in CMS and demonstrate considerable similarities between patients with MUSK and DOK7-related CMS in terms of clinical phenotype and treatment options.

Signaling through the mammalian target of rapamycin complex 1 (mTORC1) and its effectors the S6-kinases (S6K) in the hypothalamus is thought to be involved in nutrient sensing and control of food intake. Given the anatomical proximity of this pathway to circuits for the hormone ghrelin, we investigated the potential role of the mTORC1/S6K pathway in mediating the metabolic effects of ghrelin. We found that ghrelin promoted phosphorylation of S6K1 in the mouse hypothalamic cell line N-41 and in the rat hypothalamus after intracerebroventricular administration. Rapamycin, an inhibitor of mTORC1, suppressed ghrelin-induced phosphorylation of hypothalamic S6K1 and increased food intake and insulin in rats. Chronic peripheral administration of ghrelin induced a significant increase in body weight, fat mass and food efficiency in wild-type and S6K2-knockout but not in S6K1-knockout mice. We therefore propose that ghrelin-induced hyperphagia, adiposity and insulin secretion are controlled by a central nervous system involving the mTORC1/S6K1 pathway.

Feed intake behavior was studied between 9 weeks of age and slaughter in a total of 36 gilts, 32 immunocastrates, 33 surgically castrated barrows and 33 boars from 36 litters. Consequences for the concentration of substances contributing to off odor of pork (skatole, indole) were evaluated. Animals were kept in groups of 12 pigs of the same sex and treatment and fed ad libitum (13.4 MJ ME, 17% CP, 1.1% lysine). Individual feed intake behavior was recorded continuously by an electronic feeder. Immunocastration was carried out with two injections of Improvac with at least 4 weeks between both injections (1st: 12 to 17 weeks of age, 2nd: 19 to 21 weeks of age). Feed intake/day increased from an average of 0.91 ± 0.02 kg/day up to 3.15 ± 0.04 kg/day before slaughter. This increase was associated with a 50% reduction in the number of meals/day (from 15.8 ± 0.44 to 7.2 ± 0.29 meals/day). The larger meal sizes resulted from an increase in both, the duration of feed intake/meal and the feed intake rate (g/min). In addition, sex and treatment differences were observed: Feed intake in boars was lower than in all other groups due to a reduction in the number of meals/day and in the time spent feeding/day. In females, time spent feeding/day was quite similar to boars, but resulted from a higher number of meals of shorter duration. Barrows had a significantly higher feed intake because of a higher number of meals/day resulting in more time spent feeding/day. The feed intake rate was similar in boars, gilts and barrows and showed an increasing trend during the study, starting from about 15 g/min up to four times the amount. Immunocastration affected feed intake behavior severely, especially the meal size increased dramatically because of higher feed intake rate, which exceeded that of all other groups by 25% at the end of the study. The number of meals/day was not influenced by immunocastration and was almost identical to that of boars. Highest skatole concentrations were measured in fat of boars, whereas indole concentrations were higher in immunocastrates than in all other groups. In gilts and barrows, skatole concentrations were related to growth rate. Additionally, the feeding rate was an important factor explaining the variability in skatole/indole concentrations in adipose tissue. The physiological mechanisms however need further clarification.

Endoprostheses of the ankle joint show higher revision rates of 3.29 revisions per 100 component years. The aims of this study were the application and modification of the consensus classification of the synovia-like interface membrane (SLIM) for periprosthetic failure of the ankle joint, the etiological clarification of periprosthetic pseudocysts and a detailed measurement of proliferative activity (Ki67) in the region of osteolysis.Tissue samples from 159 patients were examined according to the criteria of the standardized consensus classification. Of these, 117 cases were derived from periprosthetic membranes of the ankle. The control group included 42 tissue specimens from the hip and knee joints. Particle identification and characterization were carried out using the particle algorithm. An immunohistochemical examination with Ki67 proliferation was performed in all cases of ankle pseudocysts and 19 control cases.The consensus classification of SLIM is transferrable to endoprosthetic failure of the ankle joint. Periprosthetic pseudocysts with the histopathological characteristics of the appropriate SLIM subtype were detectable in 39 cases of ankle joint endoprostheses (33.3%). The mean value of the Ki67 index was 14% and showed an increased proliferation rate in periprosthetic pseudocysts of the ankle (p-value 0.02037).In periprosthetic pseudocysts an above average higher detection rate of type 1 SLIM induced by abrasion (51.3%) with an increased Ki67 proliferation fraction (p-value 0.02037) was found, which can be interpreted as local destructive intraosseus synovialitis. This can be the reason for formation of pseudocystic osteolysis caused by high mechanical stress in ankle endoprostheses. A simplified diagnostic classification scoring system of dysfunctional endoprostheses of the ankle is proposed for collation of periprosthetic pseudocysts, ossifications and the Ki67 proliferation fraction.

Objectives To determine feasibility and repeatability of measuring the anatomic regurgitant orifice area (AROA) using real-time three-dimensional transthoracic echocardiography (RT3DE) in dogs with myxomatous mitral valve disease (MMVD), and to investigate differences in the AROA of dogs with different disease severity and in different American College of Veterinary Internal Medicine (ACVIM) stages. Animals Sixty privately-owned dogs diagnosed with MMVD. Methods The echocardiographic database of our institution was retrospectively searched for dogs diagnosed with MMVD and RT3DE data set acquisition. Dogs were classified into mild, moderate, or severe MMVD according to a Mitral Regurgitation Severity Score (MRSS), and into stage B1, B2 or C according to ACVIM staging. The RT3DE data sets were imported into dedicated software and a short axis plane crossing the regurgitant orifice was used to measure the AROA. Feasibility, inter- and intra-observer variability of measuring the AROA was calculated. Differences in the AROA between dogs in different MRSS and ACVIM stages were investigated. Results The AROA was measurable in 60 data sets of 81 selected to be included in the study (74%). The inter- and intra-observer coefficients of variation were 26% and 21%, respectively. The AROA was significantly greater in dogs with a severe MRSS compared with dogs with mild MRSS (p=0.045). There was no difference between the AROA of dogs in different ACVIM clinical stages. Conclusions Obtaining the AROA using RT3DE is feasible and might provide additional information to stratify mitral regurgitation severity in dogs with MMVD. Diagnostic and prognostic utility of the AROA deserves further investigation.

In practice, the content of standardized ileal digestible AA in complex feeds for pigs is calculated on the basis of tabulated values for individual feedstuffs. It comes into question, however, whether this truly reflects an accurate content based upon the estimate made for the individual feedstuffs. The objective of this study was to compare standardized ileal digestibility (SID) of crude protein (CP) and selected AA in complex feeds for grower and finisher pigs either calculated or experimentally determined. Six diets with increasing AA levels were prepared for grower (BW from 30 to 70 kg) and finisher (BW from 70 to 120 kg) feed. Crystalline L-lys, DL-met and L-thr were added to both diets, L-trp and L-val only to the grower feed. SID of both CP and AA was calculated from feed tables and experimentally determined in six adult minipigs (MINILEWE) with ileorectal anastomosis. With increasing AA levels, experimentally determined SID of supplemented AA increased (p

To manage patients with high intracranial pressure (ICP), clinicians need to know the critical cerebral perfusion pressure (CPP) required to maintain cerebral blood flow (CBF). Historically, the critical CPP obtained by decreasing mean arterial pressure (MAP) to lower CPP was 60 mm Hg, which fell to 30 mm Hg when CPP was reduced by increasing ICP. We examined whether this decrease in critical CPP was due to a pathological shift from capillary (CAP) to high-velocity microvessel flow or thoroughfare channel (TFC) shunt flow. Cortical microvessel red blood cell velocity and NADH fluorescence were measured by in vivo two-photon laser scanning microscopy in rats at CPP of 70, 50, and 30 mm Hg by increasing ICP or decreasing MAP. Water content was measured by wet/dry weight, and cortical perfusion by laser Doppler flux. Reduction of CPP by raising ICP increased TFC shunt flow from 30.4±2.3% to 51.2±5.2% (mean±SEM, p