The effects of varying the timing of inputs on a neural oscillator

The gastric mill network of the stomatogastric ganglion of the crab Cancer borealis is comprised of a set of neurons that require modulatory input from outside the stomatogastric ganglion and input from the pyloric network of the animal in order to oscillate. Here we study how the frequency of the gastric mill network is determined when it receives rhythmic input from two different sources but where the timing of these inputs may differ. We find that over a certain range of the time difference one of the two rhythmic inputs plays no role what so ever in determining the network frequency, while in another range, both inputs work together to determine the frequency. The existence and stability of periodic solutions to model sets of equations are obtained analytically using geometric singular perturbation theory. The results are validated through numerical simulations. Comparisons to experiments are also presented

Leukoencephalopathy and cerebral edema as the presenting manifestations of SLE in an ANA-negative adolescent female: a case report and review of literature

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with various clinical manifestations involving multiple organ systems. Neuropsychiatric manifestations of SLE have been associated with increased morbidity and mortality, thus it is important to recognize and diagnose the disease entity and treat early. When neuropsychiatric symptoms are involved, typically there are many other systemic features to aid in the diagnosis of SLE. Many autoantibodies have been discovered and are used to help diagnose SLE. The antibody present in most cases of pediatric SLE, as well as in many other rheumatic diseases, is the nonspecific antinuclear antibody (ANA). The ANA is a commonly used screening tool by primary care physicians when evaluating a patient with a possible rheumatic disorder. However, a small subset of SLE patients, 1-5%, present with a negative ANA, and it is important to keep SLE on the differential diagnosis in specific instances when a thorough infectious, metabolic and neurological workup has been completed and proven to be inconclusive. Case presentation: This case involves a Hispanic adolescent female with a negative ANA who presented with diffuse cerebral edema secondary to leukoencephalopathy due to SLE with central nervous system involvement. She was normotensive on presentation and relatively symptom free aside from headache. She had an extensive workup while inpatient involving metabolic, infectious disease, rheumatology, and neurology prior to obtaining the diagnosis of SLE. She was treated with cyclophosphamide and rituximab with appropriate disease response. Conclusions: A review of the literature revealed 12 cases with SLE presenting with or developing diffuse cerebral edema and/or leukoencephalopathy. Our patient's case differs in that she was also ANA negative despite other autoantibody positivity. While she did have low complements and transient leukopenia, she did not present with other signs of organ involvement, which made the diagnosis of SLE with neuropsychiatric involvement quite challenging. We discuss the importance of keeping SLE on the differential diagnosis despite a negative ANA in complex cases after thorough workup has been unrevealing, and to consider initial screening with not only the ANA but also dsDNA and complements to avoid missed diagnoses

Persönlichkeitsstile von studentischen Teilnehmerinnen an Hypnoseexperimenten im Vergleich zu Hypnoseanwendern

Zweck: Bei einer Befragung zu Persönlichkeitsstilen bei 203 deutschsprachigen Hypnoseanwendern (v.a. Psychotherapeuten, Ärzte und Zahnärzte) hatten sich signifikante, jedoch nicht klinisch auffällige Abweichungen zur Normstichprobe gezeigt. Dabei war unklar, ob diese auf Selektionseffekten in der Stichprobe selbst beruhten, oder ob es sich dabei um berufliche Sozialisations- oder Selektionseffekte handelte. Weil zur Persönlichkeit von Studierenden im Fachbereich Psychologie wenig bekannt ist, sollten Persönlichkeitsstile bei einer Stichprobe von Studentinnen, die an Hypnoseexperimenten teilnahmen, erfasst werden, um diese im Anschluss mit denen der Hypnoseanwender zu vergleichen. Methoden: Die Persönlichkeitsstile von 52 Studentinnen aus den Fächern Psychologie und Pädagogik wurden mit dem Persönlichkeits- Stil-und Störungs-Inventar (PSSI) erhoben. Das PSSI erfasst 14 verschiedene Persönlichkeitsstile, zum Teil im Sinne von nicht-pathologischen Entsprechungen der in DSM-IV und ICD-10 beschriebenen Persönlichkeitsstörungen. Ergebnisse und Schlussfolgerungen: Die durchschnittlichen Persönlichkeitsprofile lagen bei beiden Gruppen im klinisch unauffälligen Bereich. Während bei den Hypnoseanwendern jedoch relativ viele extreme Ausprägungen gefunden wurden, und zwar vor allem im Sinne von unterdurchschnittlich ausgeprägten Persönlichkeitsstilen, zeigten die Studentinnen gemäßigtere Profile und bewegten sich näher am Normdurchschnitt. Insgesamt glichen sich die Profile im Verlauf, bis auf einige Aus nahmen. So fiel auf, dass die Studentinnen relativ hilfsbereit-selbstlos waren, während dieser Stil bei den Hypnoseanwendern signifikant unterdurchschnittlich ausgeprägt war. Dies könnte durch berufliche Sozialisationsprozesse zu erklären sein, wenngleich einige methodische Probleme in dieser Untersuchung die Interpretation erschweren.Aim: Existing data on personality styles of 203 German-speaking practitioners of hypnosis and hypnotherapy (mainly psychologists, physicians and dentists) showed significant deviations from the normative sample, within non-clinical ranges, however. It was unclear whether these effects resulted from selection bias in the sample, or from job-related socialisation or choice of profession. Also, little is known on personality styles of undergraduates in psychology. Therefore, personality styles were assessed in a sample of female undergraduates that participated in hypnosis experiments, and compared to the personality styles of the hypnosis practitioners. Methods: Personality styles of 52 female undergraduates (psychology and educational sciences) were assessed using the Personality-Styles- and Disorders-Inventory (PSSI). The PSSI measures 14 personality styles, covering also non-clinical expressions of personality disorders as described in DSM-IV and ICD-10. Results and conclusion: The average personality profiles of both groups were within non-clinical ranges. Whereas practitioners often showed more extreme scores, students’ profiles were less pronounced. Overall, the profiles were more similar than different. Remarkable was a difference between the two groups concerning the scale “helpful-selfless” with students being rather helpful whereas practitioners had significantly lower scores than students and norms alike. Professional training and socialisation might explain this pronounced difference, although methodological shortcomings of the study hamper conclusions

Persönlichkeitsstile von studentischen Teilnehmerinnen an Hypnoseexperimenten im Vergleich zu Hypnoseanwendern

Zweck: Bei einer Befragung zu Persönlichkeitsstilen bei 203 deutschsprachigen Hypnoseanwendern (v.a. Psychotherapeuten, Ärzte und Zahnärzte) hatten sich signifikante, jedoch nicht klinisch auffällige Abweichungen zur Normstichprobe gezeigt. Dabei war unklar, ob diese auf Selektionseffekten in der Stichprobe selbst beruhten, oder ob es sich dabei um berufliche Sozialisations- oder Selektionseffekte handelte. Weil zur Persönlichkeit von Studierenden im Fachbereich Psychologie wenig bekannt ist, sollten Persönlichkeitsstile bei einer Stichprobe von Studentinnen, die an Hypnoseexperimenten teilnahmen, erfasst werden, um diese im Anschluss mit denen der Hypnoseanwender zu vergleichen. Methoden: Die Persönlichkeitsstile von 52 Studentinnen aus den Fächern Psychologie und Pädagogik wurden mit dem Persönlichkeits- Stil-und Störungs-Inventar (PSSI) erhoben. Das PSSI erfasst 14 verschiedene Persönlichkeitsstile, zum Teil im Sinne von nicht-pathologischen Entsprechungen der in DSM-IV und ICD-10 beschriebenen Persönlichkeitsstörungen. Ergebnisse und Schlussfolgerungen: Die durchschnittlichen Persönlichkeitsprofile lagen bei beiden Gruppen im klinisch unauffälligen Bereich. Während bei den Hypnoseanwendern jedoch relativ viele extreme Ausprägungen gefunden wurden, und zwar vor allem im Sinne von unterdurchschnittlich ausgeprägten Persönlichkeitsstilen, zeigten die Studentinnen gemäßigtere Profile und bewegten sich näher am Normdurchschnitt. Insgesamt glichen sich die Profile im Verlauf, bis auf einige Aus nahmen. So fiel auf, dass die Studentinnen relativ hilfsbereit-selbstlos waren, während dieser Stil bei den Hypnoseanwendern signifikant unterdurchschnittlich ausgeprägt war. Dies könnte durch berufliche Sozialisationsprozesse zu erklären sein, wenngleich einige methodische Probleme in dieser Untersuchung die Interpretation erschweren.Aim: Existing data on personality styles of 203 German-speaking practitioners of hypnosis and hypnotherapy (mainly psychologists, physicians and dentists) showed significant deviations from the normative sample, within non-clinical ranges, however. It was unclear whether these effects resulted from selection bias in the sample, or from job-related socialisation or choice of profession. Also, little is known on personality styles of undergraduates in psychology. Therefore, personality styles were assessed in a sample of female undergraduates that participated in hypnosis experiments, and compared to the personality styles of the hypnosis practitioners. Methods: Personality styles of 52 female undergraduates (psychology and educational sciences) were assessed using the Personality-Styles- and Disorders-Inventory (PSSI). The PSSI measures 14 personality styles, covering also non-clinical expressions of personality disorders as described in DSM-IV and ICD-10. Results and conclusion: The average personality profiles of both groups were within non-clinical ranges. Whereas practitioners often showed more extreme scores, students’ profiles were less pronounced. Overall, the profiles were more similar than different. Remarkable was a difference between the two groups concerning the scale “helpful-selfless” with students being rather helpful whereas practitioners had significantly lower scores than students and norms alike. Professional training and socialisation might explain this pronounced difference, although methodological shortcomings of the study hamper conclusions

FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes.

Mutations in the transcription factor FOXA1 define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown1-9. Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression

Arbeitsprofile deutschsprachiger Anwender von Hypnose und Hypnotherapie

Zweck: Nach mehr als 30 Jahren der Verbreitung von Techniken und theoretischen Konzepten moderner Hypnose und Hypnotherapie war es interessant, etwas über deren konkrete Anwendung in der psychotherapeutischen, ärztlichen und zahnärztlichen Praxis zu erfahren, wobei vor allem auch die Anwendung direkter und indirekter Techniken untersucht werden sollte. Hierzu wurden die Arbeitsprofile von 203 Anwendern von Hypnose und Hypnotherapie aus deutschsprachigen Hypnosegesellschaften untersucht. Es handelte sich dabei hauptsächlich um psychologische und ärztliche Psychotherapeuten, Ärzte und Zahnärzte. Methoden: Der ein gesetzte Fragebogen mit insgesamt 70 Items umfasste Fragen zu soziodemographischen Merkmalen, zu ausbildungs- und hypnosebezogenen Daten sowie Fragen zur Verwendung von indirekten und direkten Techniken. In Bezug auf letztere interessierten besonders Anwendungshäufigkeit sowie Erfahrungen und Einstellungen, die die Anwendungshäufigkeit und den Anwendungserfolg beeinflussen. Ergebnisse: Hypnose wird von den Teilnehmern der Studie insgesamt sehr häufig eingesetzt, wobei viele der Teilnehmer ihre Arbeit gebietsübergreifend sehen. Jeweils ca. 43 % der Befragten benutzen dabei ihren Klienten gegenüber explizit das Wort Hypnose bzw. tun dies nicht. Etwa 90% der Befragten schätzen sich selber als mittel bis hoch hypnotisierbar ein. Die Ergebnisse zeigen zudem, dass überwiegend in direkte und vergleichsweise wenig direkte Techniken eingesetzt werden. Etwa 30% geben an, die direkten Techniken nicht ausreichend zu beherrschen; Faktoren wie Sicherheit und Wohlbefinden, Angst vor Fehlern und Manipulation, eigene Erfahrungen, Überzeugung bzgl. der Vorteile sowie Erfolgserlebnisse beeinflussen die Anwendung direkter Techniken. Schlussfolgerungen: Die Faktoren erworbene Kompetenz durch fundierte Ausbildung und gute persönliche Erfahrungen scheinen im Sinne einer Steigerung der professionellen Selbstwirksamkeit für den Einsatz direkter Techniken von zentraler Bedeutung. Limitationen der Studie und mögliche Implikationen für die Ausbildung in Hypnose und Hypnotherapie werden diskutiert.Aim: After more than 30 years of dissemination of techniques and theoretical concepts of modern hypnosis and hypnotherapy, it was interesting to learn more about their practical application in psychotherapy, medical and dental practice and to investigate the use of direct and indirect techniques. For this reason, work patterns of 203 practitioners of hypnosis and hypnotherapy from German-speaking hypnosis organizations were examined. There were mainly medical and psychological psychotherapists, physicians and dentists involved. Methodology: A 70 item questionnaire was administered, including questions on socio-demographic characteristics, educational and hypnosis related information and questions regarding the use of indirect and direct techniques. Concerning the latter, the frequency of use as well as experiences and attitudes that influence the frequency of application and the application success were of particular interest. Results: Participants indicated an overall frequent use of hypnosis, with many of the participants perceiving their work areas as overlapping. About 43% of the respondents each do or do not make explicit use of the word “hypnosis” when working with their clients. About 90% of the respondents consider themselves as medium to high hypnoti-zable. Furthermore, results show that indirect techniques are used predominantly while there is comparatively little use of direct techniques. About 30% of the participants indicated deficient competences in using direct techniques; factors such as feelings of safety and well-being, fear of making mistakes and manipulating, private experiences, opinions regarding potential advantages and experiences of success influence the application of direct techniques. Conclusions: Two factors, expertise acquired through extensive training and positive personal experience, both providing an increase of professional self-efficacy, seem to be of central importance for the use of direct techniques. Limitations of the study and possible implications for professional training in hypnosis and hypnotherapy are discussed

Arbeitsprofile deutschsprachiger Anwender von Hypnose und Hypnotherapie

Zweck: Nach mehr als 30 Jahren der Verbreitung von Techniken und theoretischen Konzepten moderner Hypnose und Hypnotherapie war es interessant, etwas über deren konkrete Anwendung in der psychotherapeutischen, ärztlichen und zahnärztlichen Praxis zu erfahren, wobei vor allem auch die Anwendung direkter und indirekter Techniken untersucht werden sollte. Hierzu wurden die Arbeitsprofile von 203 Anwendern von Hypnose und Hypnotherapie aus deutschsprachigen Hypnosegesellschaften untersucht. Es handelte sich dabei hauptsächlich um psychologische und ärztliche Psychotherapeuten, Ärzte und Zahnärzte. Methoden: Der ein gesetzte Fragebogen mit insgesamt 70 Items umfasste Fragen zu soziodemographischen Merkmalen, zu ausbildungs- und hypnosebezogenen Daten sowie Fragen zur Verwendung von indirekten und direkten Techniken. In Bezug auf letztere interessierten besonders Anwendungshäufigkeit sowie Erfahrungen und Einstellungen, die die Anwendungshäufigkeit und den Anwendungserfolg beeinflussen. Ergebnisse: Hypnose wird von den Teilnehmern der Studie insgesamt sehr häufig eingesetzt, wobei viele der Teilnehmer ihre Arbeit gebietsübergreifend sehen. Jeweils ca. 43 % der Befragten benutzen dabei ihren Klienten gegenüber explizit das Wort Hypnose bzw. tun dies nicht. Etwa 90% der Befragten schätzen sich selber als mittel bis hoch hypnotisierbar ein. Die Ergebnisse zeigen zudem, dass überwiegend in direkte und vergleichsweise wenig direkte Techniken eingesetzt werden. Etwa 30% geben an, die direkten Techniken nicht ausreichend zu beherrschen; Faktoren wie Sicherheit und Wohlbefinden, Angst vor Fehlern und Manipulation, eigene Erfahrungen, Überzeugung bzgl. der Vorteile sowie Erfolgserlebnisse beeinflussen die Anwendung direkter Techniken. Schlussfolgerungen: Die Faktoren erworbene Kompetenz durch fundierte Ausbildung und gute persönliche Erfahrungen scheinen im Sinne einer Steigerung der professionellen Selbstwirksamkeit für den Einsatz direkter Techniken von zentraler Bedeutung. Limitationen der Studie und mögliche Implikationen für die Ausbildung in Hypnose und Hypnotherapie werden diskutiert.Aim: After more than 30 years of dissemination of techniques and theoretical concepts of modern hypnosis and hypnotherapy, it was interesting to learn more about their practical application in psychotherapy, medical and dental practice and to investigate the use of direct and indirect techniques. For this reason, work patterns of 203 practitioners of hypnosis and hypnotherapy from German-speaking hypnosis organizations were examined. There were mainly medical and psychological psychotherapists, physicians and dentists involved. Methodology: A 70 item questionnaire was administered, including questions on socio-demographic characteristics, educational and hypnosis related information and questions regarding the use of indirect and direct techniques. Concerning the latter, the frequency of use as well as experiences and attitudes that influence the frequency of application and the application success were of particular interest. Results: Participants indicated an overall frequent use of hypnosis, with many of the participants perceiving their work areas as overlapping. About 43% of the respondents each do or do not make explicit use of the word “hypnosis” when working with their clients. About 90% of the respondents consider themselves as medium to high hypnoti-zable. Furthermore, results show that indirect techniques are used predominantly while there is comparatively little use of direct techniques. About 30% of the participants indicated deficient competences in using direct techniques; factors such as feelings of safety and well-being, fear of making mistakes and manipulating, private experiences, opinions regarding potential advantages and experiences of success influence the application of direct techniques. Conclusions: Two factors, expertise acquired through extensive training and positive personal experience, both providing an increase of professional self-efficacy, seem to be of central importance for the use of direct techniques. Limitations of the study and possible implications for professional training in hypnosis and hypnotherapy are discussed

A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma

AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma (MM) cells. This phase 2 study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory MM

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

BACKGROUND: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration. METHODS: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets. FINDINGS: Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990. INTERPRETATION: Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action. FUNDING: Bill & Melinda Gates Foundation