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Hintergrund: Es bestehen soziale Unterschiede in der Kenntnis und der Nutzung kommunaler Gesundheitsforderungs- und Praventionsangebote fur Kinder und Familien wie Bewegungsangebote und Elternedukation. Die Einflussfaktoren und mogliche Grunde dieser Unterschiede sind bislang jedoch nicht ausreichend untersucht. Fragestellungen: Der vorgestellten Studie lagen folgende Fragestellungen zugrunde. a) In welchem Umfang kennen soziookonomisch benachteiligte Familien und Familien mit Zuwanderungsgeschichte kommunale Angebote der Gesundheitsforderung und Pravention und nehmen sie in Anspruch? b) Welche Angebotsmerkmale fordern die Akzeptanz und die Teilnahmebereitschaft, welche Zugangsbarrieren wirken? Material und Methode: In den Ruhrgebietsstadten Moers (n = 201) und Oberhausen (n = 353) wurden an Kitas und Grundschulen teilstandardisierte Elternbefragungen zu kommunalen Angeboten aus den Handlungsfeldern Bewegungsforderung, Elternbildung und Sprachforderung durchgefuhrt. Anhand von t‑Tests wurden die Mittelwerte zu Angebotskenntnis und Inanspruchnahme von Elterngruppen verglichen. Bei Vorliegen signifikanter Gruppenunterschiede wurden die Effektstarken berechnet. Offene Elternfragen wurden inhaltsanalytisch ausgewertet. Ergebnisse: Familien, die armutsgefahrdet sind, ein niedriges Bildungsniveau oder einen Migrationshintergrund haben, kennen deutlich weniger Angebote und nehmen signifikant weniger teil. Bei Angeboten der Bewegungsforderung liegen die starksten Unterschiedseffekte vor. Die Antworten auf offene Fragen zeigen, dass Eltern einen Mangel an familienfreundlicher Infrastruktur wie Sport‑, Spiel- und Schwimmstatten identifizieren. Das Angebotsspektrum von Kitas und Grundschulen wird als unzureichend und wenig bedarfsorientiert wahrgenommen. Es werden Schlusselfaktoren evident, die die Angebotsnutzung fordern konnen. Diskussion: Angebote der Bewegungsforderung und Elternbildung mit Komm-Struktur, die eine hohe elterliche Eigenaktivitat erfordern, erreichen Risikogruppen mit hohem Praventionsbedarf kaum. Die sozialen Disparitaten illustrieren, dass individuumbezogene, verhaltenspraventive Masnahmen nicht zur Verringerung der sozialbedingten Ungleichheit von Gesundheitschancen im Kindesalter beitragen. Verhaltenspraventive Masnahmen sollten grundsatzlich in verhaltnispraventive Mehrkomponenten-Ansatze integriert werden, die strukturelle und umweltbezogene Veranderungen der Settings Kita, Schule und Wohnquartier beinhalten.

Motor signs such as dyspraxia and abnormal gait are characteristic features of autism spectrum disorder (ASD). However, motor behavior in adults with ASD has scarcely been quantitatively characterized. In this pilot study, we aim to quantitatively examine motor signature of adults with ASD without intellectual impairment using marker-less visual-perceptive motion capture. 82 individuals (37 ASD and 45 healthy controls, HC) with an IQ > 85 and aged 18 to 65 years performed nine movement tasks and were filmed by a 3D-infrared camera. Anatomical models were quantified via custom-made software and resulting kinematic parameters were compared between individuals with ASD and HCs. Furthermore, the association between specific motor behaviour and severity of autistic symptoms (Autism Diagnostic Observation Schedule 2, Autism Spectrum Quotient) was explored. Adults with ASD showed a greater mediolateral deviation while walking, greater sway during normal, tandem and single leg stance, a reduced walking speed and cadence, a greater arrhythmicity during jumping jack tasks and an impaired manual dexterity during finger tapping tasks (p 0.48) compared to HC. Furthermore, in the ASD group, some of these parameters correlated moderately to severity of ASD symptoms. Adults with ASD seem to display a specific motor signature in this disorder affecting movement timing and aspects of balance. The data appear to reinforce knowledge about motor signs reported in children and adolescents with ASD. Also, quantitative motor assessment via visual-perceptive computing may be a feasible instrument to detect subtle motor signs in ASD and perhaps suitable in the diagnosis of ASD in the future.

Es bestehen soziookonomische Disparitaten in der Inanspruchnahme gesundheitsfordernder und primarpraventiver Masnahmen bei Kindern und Jugendlichen. Ziel ist es, einen breiten Uberblick uber Ansatze zur Erhohung der Reichweite in der Gesundheitsforderung und Pravention bei vulnerablen Kindern und Jugendlichen in Kitas und Schulen zu geben sowie fur die Reichweite forderliche Interventionsmerkmale zu identifizieren. Die Autoren haben ein Scoping Review zu zwischen 2010 und 2018 publizierten peer-reviewten Artikeln und Reviews in den Datenbanken Cochrane Library, DoPHER, PubMed, PsychINFO, SCOPUS und Web of Science durchgefuhrt. Insgesamt wurden 32 Volltexte, davon 16 Interventionsstudien, 10 deskriptive Studien und 6 Reviews eingeschlossen. Ein groses Spektrum an Ansatzen wurde identifiziert, jedoch konnte keine belastbare Evidenz zu Effekten auf die Reichweite eruiert werden. Interventionsmerkmale, die am starksten mit einer erhohten Reichweite unter vulnerablen Kindern und Jugendlichen assoziiert werden, sind 1) universeller Praventionsansatz, 2) Multikomponentendesign, 3) Settingansatz, 4) strukturelle und umweltbezogene Veranderungen, 5) lokaler Governance- und Partnerschaftsansatz, 6) Einbeziehung von Eltern und Geschwistern und 7) masgeschneiderte Masnahmen („tailoring“). Es konnte ein erster Uberblick zu Typen und Wirkweisen von Masnahmen zur Erhohung der Reichweite generiert werden. Bestimmte konzeptionelle Merkmale konnen die Reichweite von Interventionen bei soziookonomisch benachteiligten Kindern und Jugendlichen erhohen. Zentrales Forschungsdesiderat ist, dass die Perspektive sozialer Determinanten von Gesundheit und damit einhergehende methodisch-theoretische Erfordernisse in Interventionsstudien starker berucksichtigt werden mussen.

In 1965 Dr. Harry Angelman reported a neurodevelopmental disorder affecting three unrelated children who had similar symptoms: brachycephaly, mental retardation, ataxia, seizures, protruding tongues, and remarkable paroxysms of laughter. Over the past 50 years, the disorder became Angelman’s namesake and symptomology was expanded to include hyper-activity, stereotypies, and severe sleep disturbances. The sleep disorders in many Angelman syndrome (AS) patients are broadly characterized by difficulty falling and staying asleep at night. Some of these patients sleep less than 4 hours a night and, in most cases, do not make up this lost-sleep during the day—leading to the speculation that AS patients may “need” less sleep. Most AS patients also have severely reduced levels of melatonin, a hormone produced by the pineal gland exclusively at night. This nightly pattern of melatonin production is thought to help synchronize internal circadian rhythms and promote nighttime sleep in humans and other diurnal species. It has been proposed that reduced melatonin levels contribute to the sleep problems in AS patients. Indeed, emerging evidence suggests melatonin replacement therapy can improve sleep in many AS patients. However, AS mice show sleep problems that are arguably similar to those in humans despite being on genetic backgrounds that do not make melatonin. This suggests the hypothesis that the change in nighttime melatonin may be a secondary factor rather than the root cause of the sleeping disorder. The goals of this review article are to revisit the sleep and melatonin findings in both AS patients and animal models of AS and discuss what AS may tell us about the underlying mechanisms of, and interplay between, melatonin and sleep.

Der Forschungsverbund „Gesund Aufwachsen“ hat integrierte Gesamtansatze kommunaler Gesundheitsforderung fur Kinder in den Ruhrgebietsstadten Moers und Oberhausen untersucht. Kommunale Politiken, institutionelle und sozialraumliche Rahmenbedingungen werden unter folgenden Fragestellungen analysiert: Wie ist der Implementierungsstand integrierter Gesundheitsforderung in den Modellkommunen aus Perspektive von a) kommunalen Steuerungsverantwortlichen; b) Leitenden aus Grundschulen, Kindertagesstatten und Familienzentren? Wie schatzen sie die Gesundheitschancen von sozial benachteiligten Familien und Familien mit Zuwanderungsgeschichte ein? Im Rahmen einer Bestandsaufnahme wurden mit kommunalen Steuerungsverantwortlichen sowie Leitungskraften aus Kitas, Familienzentren und Grundschulen Experteninterviews gefuhrt (n = 34). Entwicklungsbedarf besteht besonders bei intersektoraler Steuerung lokaler Praventionspolitiken sowie ihrer adaquaten kommunalpolitischen Mandatierung. Die grosten Hurden in Kitas und Schulen sind marode oder fehlende Infrastruktur sowie unzureichende Ressourcenausstattung. Armut, Inklusion und Integration stellen Fachkrafte in benachteiligten Quartieren vor grose Herausforderungen. Integrierte kommunale Praventionspolitiken stehen noch am Anfang. Ein expliziter gesetzlicher Auftrag und eine damit verbundene gesicherte Finanzierung bestehen nicht. Es gibt deutliche Hinweise, dass Gesundheitschancen von Kindern je nach Stadtquartier und Bildungsinstitution stark variieren. Die Notwendigkeit einer bedarfsorientierten Kita- und Schulfinanzierung wird offensichtlich.

Integrierte Gesamtansatze kommunaler Gesundheitsforderung fur Kinder werden in Nordrhein-Westfalen systematisch gefordert. Ziel ist eine lebenslauforientierte kommunale Gesundheitsforderung und Pravention von der Schwangerschaft bis zum Berufseintritt. Bislang fehlt es jedoch an Erkenntnissen zu Reichweite und moglichen Wirkungen des Ansatzes. Im Mittelpunkt steht die Analyse der integrierten Gesamtansatze in den Modellkommunen Moers und Oberhausen mit Fokus auf die Settings Kita, Grundschule und Stadtquartier. Untersucht werden insbesondere der Implementierungsprozess, die Wahrnehmung und Inanspruchnahme gesundheitsfordernder Masnahmen durch vulnerable Familien sowie die Zusammenhange zwischen Inanspruchnahme und Kindergesundheit. Der vom Bundesministerium fur Forschung und Bildung geforderte Forschungsverbund „Gesund Aufwachsen“ hat ein gemeinsames Untersuchungsdesign entwickelt, das die verschiedenen Dimensionen von Kindergesundheit (i. e. korperlich, seelisch, sozial und verhaltensbezogen) sowie zentrale Einflussfaktoren (Stadtquartier, Kita/Schule, Familie) integriert. Es handelt sich um einen hybriden Forschungsansatz, der ein nicht-randomisiertes, cluster-kontrolliertes Studiendesign mit qualitativen Untersuchungen und partizipativer Qualitatsentwicklung verbindet. Das integrative Vorgehen ermoglicht es, komplexe Hypothesen zur gesunden Entwicklung von Kindern zu uberprufen und Zusammenhange zwischen verschiedenen Gesundheitsdimensionen, kindlichen Entwicklungssettings und Masnahmen der Gesundheitsforderung zu analysieren. Der Forschungsverbund „Gesund Aufwachsen“ tragt dazu bei, die bedarfsorientierte Gestaltung von kommunalen und settingubergreifenden Interventionen der Gesundheitsforderung und Primarpravention fur Kinder konzeptionell und methodisch weiterzuentwickeln.

Objectives Verticality perception is known to be abnormal in Parkinson's disease (PD), but in which stage respective dysfunctions arise and how they relate to postural disorders remains to be settled. These issues were studied with respect to different dimensions of the subjective visual vertical (SVV) in relation to clinical parameters of postural control. Materials & Methods All participants had to orientate a luminous line at random planar orientations to a strictly vertical position using an automated operator system. The SVV was analyzed in 58 PD patients and 28 control subjects with respect to (i) the angle between true and subjective vertical (deviation) and (ii) the variability of this across five measurements (variability). Results were referred to the subjective upright head position (SUH), the disease stage, and clinical gait/balance features assessed by the MDS-UPDRS and the Tinetti test. Results Parkinson's disease patients had significantly higher SVV deviation and variability than controls. With respect to disease stage, deviation developed before abnormal variability. SVV variability was associated with poor balance and gait performance, as well as postural instability. Deficits in SUH and SVV deviation were correlated and mostly unidirectional, but did not correspond to the side of motor symptom dominance. Conclusions Visual verticality perception in PD is deviated already in early stages, conceivably as a relatively static internal misrepresentation of object orientation. Variability about verticality perception emerges in more advanced stages and is associated with postural and balance abnormalities.

Das Fettemboliesyndrom ist eine seltene Komplikation, die durch verschiedenste Traumata, vor allem aber durch Frakturen langer Rohrenknochen, hervorgerufen werden kann. Im Kindesalter wurde das Fettemboliesyndrom bisher nur selten beschrieben. Im Folgenden berichten wir uber einen 16-jahrigen Patienten mit Muskeldystrophie Duchenne. Nach Sturz aus dem Rollstuhl zog sich der Junge eine distale Femurfraktur zu. Kurze Zeit nach stationarer Aufnahme verschlechterte sich der Allgemeinzustand des Kindes durch das Auftreten multipler zerebraler Embolien, einer akuten pulmonalen Hypertension und Petechien. Die Kasuistik zeigt, dass bei einer Kombination aus zerebraler und pulmonaler Symptomatik auch im Kindesalter an ein Fettemboliesyndrom gedacht werden muss.

Next to the typical motor signs, Parkinson's disease (PD) goes along with neuropsychiatric symptoms, amongst others affecting social cognition. Particularly, Theory of Mind (ToM) impairments have mostly been associated with right hemispherical brain dysfunction, so that it might prevail in patients with left dominant PD. Fourty-four PD patients, twenty-four with left and twenty with right dominant motor symptoms, engaged in the Reading the Mind in the Eyes (RME) and the Faux Pas Detection Test (FPD) to assess affective and cognitive ToM. The results were correlated with performance in further cognitive tests, and analyzed with respect to associations with the side of motor symptom dominance and severity of motor symptoms. No association of ToM performance with right hemispheric dysfunction was found. RME results were inversely correlated with motor symptom severity, while FPD performance was found to correlate with the performance in verbal fluency tasks and the overall cognitive evaluation. Affective ToM was found associated with motor symptom severity and cognitive ToM predominantly with executive function, but no effect of PD lateralization on this was identified. The results suggest that deficits in social cognition occur as a sequel of the general corticobasal pathology in PD, rather than as a result of hemisphere-specific dysfunction.

Summary Background Individual patient data from two randomised trials comparing neoadjuvant chemotherapy with upfront debulking surgery in advanced tubo-ovarian cancer were analysed to examine long-term outcomes for patients and to identify any preferable therapeutic approaches for subgroup populations. Methods We did a per-protocol pooled analysis of individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial ( NCT00003636 ) and the Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) trial (ISRCTN74802813). In the EORTC trial, eligible women had biopsy-proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV invasive epithelial tubo-ovarian carcinoma. In the CHORUS trial, inclusion criteria were similar to those of the EORTC trial, and women with apparent FIGO stage IIIA and IIIB disease were also eligible. The main aim of the pooled analysis was to show non-inferiority in overall survival with neoadjuvant chemotherapy compared with upfront debulking surgery, using the reverse Kaplan-Meier method. Tests for heterogeneity were based on Cochran's Q heterogeneity statistic. Findings Data for 1220 women were included in the pooled analysis, 670 from the EORTC trial and 550 from the CHORUS trial. 612 women were randomly allocated to receive upfront debulking surgery and 608 to receive neoadjuvant chemotherapy. Median follow-up was 7·6 years (IQR 6·0–9·6; EORTC, 9·2 years [IQR 7·3–10·4]; CHORUS, 5·9 years [IQR 4·3–7·4]). Median age was 63 years (IQR 56–71) and median size of the largest metastatic tumour at diagnosis was 8 cm (IQR 4·8–13·0). 55 (5%) women had FIGO stage II–IIIB disease, 831 (68%) had stage IIIC disease, and 230 (19%) had stage IV disease, with staging data missing for 104 (9%) women. In the entire population, no difference in median overall survival was noted between patients who underwent neoadjuvant chemotherapy and upfront debulking surgery (27·6 months [IQR 14·1–51·3] and 26·9 months [12·7–50·1], respectively; hazard ratio [HR] 0·97, 95% CI 0·86–1·09; p=0·586). Median overall survival for EORTC and CHORUS patients was significantly different at 30·2 months (IQR 15·7–53·7) and 23·6 months (10·5–46·9), respectively (HR 1·20, 95% CI 1·06–1·36; p=0·004), but was not heterogeneous (Cochran's Q, p=0·17). Women with stage IV disease had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery (median overall survival 24·3 months [IQR 14·1–47·6] and 21·2 months [10·0–36·4], respectively; HR 0·76, 95% CI 0·58–1·00; p=0·048; median progression-free survival 10·6 months [7·9–15·0] and 9·7 months [5·2–13·2], respectively; HR 0·77, 95% CI 0·59–1·00; p=0·049). Interpretation Long-term follow-up data substantiate previous results showing that neoadjuvant chemotherapy and upfront debulking surgery result in similar overall survival in advanced tubo-ovarian cancer, with better survival in women with stage IV disease with neoadjuvant chemotherapy. This pooled analysis, with long-term follow-up, shows that neoadjuvant chemotherapy is a valuable treatment option for patients with stage IIIC–IV tubo-ovarian cancer, particularly in patients with a high tumour burden at presentation or poor performance status. Funding National Cancer Institute and Vlaamse Liga tegen kanker (Flemish League against Cancer).

Individuals with Angelman syndrome (AS) suffer sleep disturbances that severely impair quality of life. Whether these disturbances arise from sleep or circadian clock dysfunction is currently unknown. Here, we explored the mechanistic basis for these sleep disorders in a mouse model of Angelman syndrome (Ube3am−/p+mice). Genetic deletion of the maternalUbe3aallele practically eliminates UBE3A protein from the brain ofUbe3am−/p+mice, because the paternal allele is epigenetically silenced in most neurons. However, we found that UBE3A protein was present in many neurons of the suprachiasmatic nucleus—the site of the mammalian circadian clock—indicating thatUbe3acan be expressed from both parental alleles in this brain region in adult mice. We found that whileUbe3am−/p+mice maintained relatively normal circadian rhythms of behavior and light-resetting, these mice exhibited consolidated locomotor activity and skipped the timed rest period (siesta) present in wild-type (Ube3am+/p+) mice. Electroencephalographic analysis revealed that alterations in sleep regulation were responsible for these overt changes in activity. Specifically,Ube3am−/p+mice have a markedly reduced capacity to accumulate sleep pressure, both during their active period and in response to forced sleep deprivation. Thus, our data indicate that the siesta is governed by sleep pressure, and thatUbe3ais an important regulator of sleep homeostasis. These preclinical findings suggest that therapeutic interventions that target mechanisms of sleep homeostasis may improve sleep quality in individuals with AS.SIGNIFICANCE STATEMENTAngelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of expression of the maternal copy of theUBE3Agene. Individuals with AS have severe sleep dysfunction that affects their cognition and presents challenges to their caregivers. Unfortunately, current treatment strategies have limited efficacy due to a poor understanding of the mechanisms underlying sleep disruptions in AS. Here we demonstrate that abnormal sleep patterns arise from a deficit in accumulation of sleep drive, uncovering theUbe3agene as a novel genetic regulator of sleep homeostasis. Our findings encourage a re-evaluation of current treatment strategies for sleep dysfunction in AS, and suggest that interventions that promote increased sleep drive may alleviate sleep disturbances in individuals with AS.

Objective To estimate the impact of implementing primary human papilloma virus liquid-based cytology (LBC) screening on four-year rates of referral for colposcopy in the British Columbia screening program. Methods We used data on referral for colposcopy from an RCT (HPV FOCAL) comparing HPV testing every four years with LBC testing every two years. We also used data from population screening with conventional cytology among women aged 25 to 69. The predicted effect of adoption of either trial protocol on rates of referral for colposcopy was estimated using trial age-specific result and screening result-specific rates weighted by their screening program distribution. The cumulative age-specific rates of referral for colposcopy over four years were calculated. Results Use of HPV testing initially increased rates of referral for colposcopy in the trial, but over four years the cumulative rates of referral were similar to those for LBC except in women aged 25 to 29, in whom a substantial excess persisted. Four-year rates of referral for colposcopy declined with age in women screened with HPV testing, LBC, and conventional cytology. Extrapolating the trial results to the distribution in the provincial screening program, implementation of either HPV or LBC throughout the provincial population would approximately double the current rates of referral for colposcopy. Conclusion Compared with LBC screening, primary screening for HPV increased rates of referral for colposcopy only among women aged 25 to 29. In contrast to current practice, referral for colposcopy was largely driven by the trial protocol recommendations for the management of abnormal results and not by which screening test was used.

Sleep loss can severely impair the ability to perform, yet the ability to recover from sleep loss is not well understood. Sleep regulatory processes are assumed to lie exclusively within the brain mainly due to the strong behavioral manifestations of sleep. Whole-body knockout of the circadian clock gene Bmal1 in mice affects several aspects of sleep, however, the cells/tissues responsible are unknown. We found that restoring Bmal1 expression in the brains of Bmal1-knockout mice did not rescue Bmal1-dependent sleep phenotypes. Surprisingly, most sleep-amount, but not sleep-timing, phenotypes could be reproduced or rescued by knocking out or restoring BMAL1 exclusively in skeletal muscle, respectively. We also found that overexpression of skeletal-muscle Bmal1 reduced the recovery response to sleep loss. Together, these findings demonstrate that Bmal1 expression in skeletal muscle is both necessary and sufficient to regulate total sleep amount and reveal that critical components of normal sleep regulation occur in muscle. DOI: http://dx.doi.org/10.7554/eLife.26557.001, eLife digest We spend nearly one third of our lives asleep. Sleep plays a critical role in human health and is regulated by multiple brain regions. Genes are some of the factors that control sleep. Recent studies have shown that mice in which a gene called Bmal1 had been completely removed, sleep more than mice that still have the gene. These Bmal1-deficient mice also respond differently to sleep loss. However, until now, it was not known which tissues and cells that carry active (or ‘expressed’) Bmal1 are involved in regulating sleep. To find out if Bmal1 activity in the brain is sufficient to recover from sleep loss, Ehlen, Brager et al. compared genetically modified mice that either expressed Bmal1 only in the brain, or only in the muscle tissue that covers the skeleton. After the mice were kept awake for six hours, their sleep was monitored by measuring electrical signals on the surface of the skull. Contrary to what they expected, Ehlen et al. found that mice with Bmal1 expressed in the skeletal muscle were able to have a normal sleep pattern, while mice with Bmal1 expressed in the brain had an abnormal sleep pattern. Further experiments show that removing Bmal1 from the skeletal muscle of mice, but allowing the gene to be expressed in other tissues, produced sleeping patterns that were similar to those seen in mice that were completely missing the Bmal1 gene. These results indicate that Bmal1 in skeletal muscle is important to help regulate sleep, and that the signal for sleepiness does not only originate from the brain. This is the first study to show that skeletal muscle can regulate sleep. The next step will be to identify the specific signal the muscle uses to trigger the brain to sleep. Understanding the mechanisms that regulate sleep may help to develop new treatments for sleep disorders. DOI: http://dx.doi.org/10.7554/eLife.26557.002

Ethnicity and race are important factors in determining risk, developing diagnostic assessments, and implementing treatment strategies for a variety of disorders. This is no less true for sleep-disordered breathing; however, there are not many epidemiological or clinical studies that include appreciable amounts of non-whites in the United States, and even fewer that make direct comparisons between races. Studies that have investigated race-related disparities in sleep-disordered breathing report that African-Americans have a higher risk for obstructive sleep apnea, particularly men, and are less likely to adhere to continuous positive airway pressure (CPAP). Here, we present a cross-sectional analysis of studies that examine racial disparities in several measures of risk, diagnosis, treatment, and outcomes of obstructive sleep apnea. These studies shed light on the complex interactions between race and the etiology of obstructive sleep apnea and underscore the need for greater inclusion of non-whites, in studies of sleep-disordered breathing.

Brain and muscle-ARNT-like factor (Bmal1/BMAL1) is an essential transcriptional/translational factor of circadian clocks. Loss of function of Bmal1/BMAL1 is highly disruptive to physiological and behavioral processes. In light of these previous findings, we examined if transgenic overexpression of Bmal1/BMAL1 in skeletal muscle could alter metabolic processes. First, we characterized invivo and exvivo metabolic phenotypes of muscle overexpressed mice (male and female) compared to wild-type littermates (WT). Second, we examined invivo and exvivo metabolic processes in the presence of positive and negative homeostatic challenges: high-intensity treadmill running (positive) and acute sleep deprivation (negative). Invivo measures of metabolic processes included body composition, respiratory exchange ratio (RER; VCO2/VO2), energy expenditure, total activity counts, and food intake collected from small animal indirect calorimetry. Exvivo measure of insulin sensitivity in skeletal muscle was determined from radioassays. RER was lower for muscle overexpressed females compared to female WTs. There were no genotype-dependent differences in metabolic phenotypes for males. With homeostatic challenges, muscle overexpressed mice had lower energy expenditure after high-intensity treadmill running. Acute sleep deprivation reduced insulin sensitivity in skeletal muscle in overexpressed male mice, but not male WTs. The present study contributes to a body of evidence showing pleiotropic, non-circadian, and homeostatic effects of altered Bmal1/BMAL1 expression on metabolic processes, demonstrating a critical need to further investigate the broad and complex actions of Bmal1/BMAL1 on physiology and behavior.

Although sleep disruptions that accompany stress reduce quality of life and deteriorate health, the mechanisms through which stress alters sleep remain obscure. Psychological stress can alter sleep in a variety of ways, but it has been shown to be particularly influential on rapid eye movement (REM) sleep. Prolactin (PRL), a sexually dimorphic, stress-sensitive hormone whose basal levels are higher in females, has somnogenic effects on REM sleep. In the current study, we examined the relationship between PRL secretion and REM sleep after restraint stress to determine whether: 1) the ability of stress to increase REM sleep is PRL-dependent, and 2) fluctuating PRL levels underlie sex differences in sleep responses to stress. Because dopamine D2 receptors in the pituitary gland are the primary regulator of PRL secretion, D2 receptor agonist, 1-[(6-allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino) propyl]-3-ethylurea (cabergoline), was used to attenuate PRL levels in mice before 1 hour of restraint stress. Mice were implanted with electroencephalographic/electromyographic recording electrodes and received an ip injection of either 0.3-mg/kg cabergoline or vehicle before a control procedure of 1 hour of sleep deprivation by gentle handling during the light phase. Six days after the control procedure, mice received cabergoline or vehicle 15 minutes before 1 hour of restraint stress. Cabergoline blocked the ability of restraint stress to increase REM sleep amount in males but did not alter REM sleep amount after stress in females even though it reduced basal REM sleep amount in female controls. These data provide evidence that the ability for restraint stress to increase REM sleep is dependent on PRL and that sex differences in REM sleep amount may be driven by PRL.

In diesem Beitrag werden Ergebnisse einer Studie vorgestellt, in der 834 Erzieherinnen und Erzieher zu Arbeitsbedingungen, beruflichen Stressbelastungen und gesundheitlichen Belastungsfolgen befragt wurden. Um das Ausmas psychischer und psychosomatischer Beschwerden sowie das Burnout-Risiko einschatzen zu konnen, wurde das standardisierte Fragebogeninstrument „Burnout Screening Skalen“ (BOSS I) eingesetzt. Die Datenauswertung zeigte u. a., dass ein hoher Anteil der befragten Erzieherinnen ein deutlich erhohtes Stressniveau aufweist; fast ein Funftel kann als Hochrisiko-Gruppe fur Burnout angesehen werden. Als zentrale Stress­quelle konnte die mangelhafte Personalausstattung in vielen Einrichtungen identifiziert werden, einhergehend mit zu grosen Gruppen, einem unzureichenden Betreuungsschlussel, Zeitdruck und „Multi-Tasking“. Auf der Grundlage der Forschungsbefunde werden abschliesend mogliche Entlastungs- und Verbesserungsmasnahmen diskutiert.

Formalin-fixed tissue has been a mainstay of clinical pathology laboratories, but formalin alters many biomolecules, including nucleic acids and proteins. Meanwhile, frozen tissues contain better-preserved biomolecules, but tissue morphology is affected, limiting their diagnostic utility. Molecular fixatives promise to bridge this gap by simultaneously preserving morphology and biomolecules, enabling clinical diagnosis and molecular analyses on the same specimen. While previous reports have broadly evaluated the use of molecular fixative in various human tissues, we present here the first detailed assessment of the applicability of molecular fixative to both routine histopathological diagnosis and molecular analysis of cervical tissues. Ten specimens excised via the Loop Electrosurgical Excision Procedure, which removes conical tissue samples from the cervix, were cut into alternating pieces preserved in either formalin or molecular fixative. Cervical specimens preserved in molecular fixative were easily interpretable, despite featuring more eosinophilic cytoplasm and more recognizable chromatin texture than formalin-fixed specimens. Immunohistochemical staining patterns of p16 and Ki-67 were similar between fixatives, although Ki-67 staining was stronger in the molecular fixative specimens. The RNA of molecular fixative specimens from seven cases representing various dysplasia grades was assessed for utility in expression microarray analysis. Cluster analysis and scatter plots of duplicate samples suggest that data of sufficient quality can be obtained from as little as 50 ng of RNA from molecular fixative samples. Taken together, our results show that molecular fixative may be a more versatile substitute for formalin, simultaneously preserving tissue morphology for clinical diagnosis and biomolecules for immunohistochemistry and gene expression analysis.

Receptor-mediated transfer of IgG and albumin has been suggested to occur also at cerebrospinal fluid interfaces. We point out findings of statistically unchanging IgG/albumin ratios along the lumbar CSF column which propose that such transfer should be absent or very small at cerebrospinal fluid interfaces.

Study objectives Episodes of brief limb ischemia (remote preconditioning) in mice induce tolerance to modeled ischemic stroke (focal brain ischemia). Since stroke outcomes are in part dependent on sleep-wake history, we sought to determine if sleep is critical for the neuroprotective effect of limb ischemia. Methods EEG/EMG recording electrodes were implanted in mice. After a 24 h baseline recording, limb ischemia was induced by tightening an elastic band around the left quadriceps for 10 minutes followed by 10 minutes of release for two cycles. Two days following remote preconditioning, a second 24 h EEG/EMG recording was completed and was immediately followed by a 60-minute suture occlusion of the middle cerebral artery (modeled ischemic stroke). This experiment was then repeated in a model of circadian and sleep abnormalities (Bmal1 knockout [KO] mice sleep 2 h more than wild-type littermates). Brain infarction was determined by vital dye staining, and sleep was assessed by trained identification of EEG/EMG recordings. Results Two days after limb ischemia, wild-type mice slept an additional 2.4 h. This additional sleep was primarily comprised of non-rapid eye movement (NREM) sleep during the middle of the light-phase (i.e., naps). Repeating the experiment but preventing increases in sleep after limb ischemia abolished tolerance to ischemic stroke. In Bmal1 knockout mice, remote preconditioning did not increase daily sleep nor provide tolerance to subsequent focal ischemia. Conclusions These results suggest that sleep induced by remote preconditioning is both sufficient and necessary for its neuroprotective effects on stroke outcome.

In the cervix in vivo multi-excitation multi-emission (AFI) data can have high sensitive (~90% plus) but specificity is affected by confounding tissue structures. OCT-AFI combined imaging has potential to identify these confounding structures.

Background: Round 1 data of human papillomavirus (HPV) FOCAL, a three-arm, randomised trial, which aims to establish the efficacy of HPV DNA testing as a primary screen for cervical cancer, are presented. Methods: The three arms are: Control arm – liquid based cytology with atypical squamous cells of unknown significance (ASC-US) triage with hrHPV testing; Intervention Arm – hrHPV at entry with liquid-based cytology (LBC) triage of hrHPV positives, with exit screen at 4 years; Safety check arm – hrHPV at entry with LBC triage of hrHPV positives with exit screen at 2 years. Results: A total of 6154 women were randomised to the control arm and 12 494 to the HPV arms (intervention and safety check). In the HPV arm, the baseline cervical intraepithelial neoplasia (CIN)2+ and CIN3+ rate was 9.2/1000 (95%CI; 7.4, 10.9) and 4.8/1000 (95%CI; 3.6, 6.1), which increased to 16.1/1000 (95%CI 13.2, 18.9) for CIN2+ and to 8.0/1000 (95%CI; 5.9, 10.0) for CIN3+ after subsequent screening of HPV-DNA-positive/cytology-negative women. Detection rate in the control arm remained unchanged after subsequent screening of ASC-US-positive/hrHPV DNA-negative women at 11.0/1000 for CIN2+ and 5.0/1000 for CIN3+. Conclusion: After subsequent screening of women who were either hrHPV positive/cytology negative or ASC-US positive/HPV negative, women randomised to the HPV arms had increased CIN2+ detection compared with women randomised to the cytology arm.

The goal of this study was to evaluate a mindfulness-based cognitive behavioral intervention for sexual dysfunction in gynecologic cancer survivors compared to a wait-list control group.Thirty-one survivors of endometrial or cervical cancer (mean age 54.0, range 31-64) who self-reported significant and distressing sexual desire and/or sexual arousal concerns were assigned either to three, 90-minute mindfulness-based cognitive behavior therapy sessions or two months of wait-list control prior to entering the treatment arm. Validated measures of sexual response, sexual distress, and mood, as well as laboratory-evoked physiological and subjective sexual arousal were assessed at pre-, one month post-, and 6-months following treatment.There were no significant effects of the wait-list condition on any measure. Treatment led to significant improvements in all domains of sexual response, and a trend towards significance for reducing sexual distress. Perception of genital arousal during an erotic film was also significantly increased following the intervention despite no change in physiologically-measured sexual arousal.A brief mindfulness-based intervention was effective for improving sexual functioning. Geographic restrictions permitted only a select sample of survivors to participate, thus, the generalizability of the findings is limited. Future studies should aim to develop online modalities for treatment administration to overcome this limitation.

Mice with a combined deficiency in the α2β1 and α11β1 integrins lack the major receptors for collagen I. These mutants are born with inconspicuous differences in size but develop dwarfism within the first 4 weeks of life. Dwarfism correlates with shorter, less mineralized and functionally weaker bones that do not result from growth plate abnormalities or osteoblast dysfunction. Besides skeletal dwarfism, internal organs are correspondingly smaller, indicating proportional dwarfism and suggesting a systemic cause for the overall size reduction. In accordance with a critical role of insulin-like growth factor (IGF)-1 in growth control and bone mineralization, circulating IGF-1 levels in the sera of mice lacking either α2β1 or α11β1 or both integrins were sharply reduced by 39%, 64%, or 81% of normal levels, respectively. Low hepatic IGF-1 production resulted from diminished growth hormone-releasing hormone expression in the hypothalamus and, subsequently, reduced growth hormone expression in the pituitary glands of these mice. These findings point out a novel role of collagen-binding integrin receptors in the control of growth hormone/IGF-1-dependent biological activities. Thus, coupling hormone secretion to extracellular matrix signaling via integrins represents a novel concept in the control of endocrine homeostasis.

Objective The objective was to evaluate rates of nodal disease in endometrial cancer within risk groups based on uterine factors, and to estimate the rate of potential undertreatment and impact on survival if nodal status was unknown. Methods This was a population-based retrospective cohort study of endometrioid-type endometrial cancer in British Columbia from 2005 to 2009. All women with a preoperative grade 2/3 cancer underwent hysterectomy, bilateral salpingo-oophorectomy (HBSO) and lymphadenectomy, and those with intermediate- or high-risk disease based on uterine factors after HBSO alone underwent secondary lymphadenectomy. We compared rates of node-positivity and potential undertreatment in each group if nodal status had been unknown (chi-square test), and estimated the survival benefit from lymphadenectomy. Results There were 222 women who underwent primary or secondary lymphadenectomy. Median age was 65 (range 38–86) and median number of lymph nodes was 10 (range 2–39). Of the 66 women with intermediate-risk disease (grade 1 or 2 tumor, deep myometrial invasion), 6 had nodal disease (9.1%) and received adjuvant chemotherapy. They remain disease-free after 24months (range 8–55). They would not have qualified for chemotherapy based on uterine factors alone, and would have been undertreated compared to other risk groups (chi-square p =0.071). A 1% survival benefit was estimated from lymphadenectomy. Conclusion Women with a grade 1 or 2 tumor and deep myometrial invasion have a 9% risk of nodal disease. Lymphadenectomy is significant for this subgroup as they would have been undertreated based on uterine risk factors alone, although the survival benefit is limited.

Brisk walking is a recommended form of exercise for obese individuals. However, lower-extremity joint loads and the associated risk of musculoskeletal injury or pathological disease increase with walking speed. Walking uphill at a slower speed is an alternative form of moderate intensity exercise that may reduce joint loading.The purpose of this study was to quantify the energetics and biomechanics of level and uphill walking in obese adults. We hypothesized that compared to brisk level walking, walking slower up a moderate incline would reduce lower-extremity net muscle moments while providing appropriate cardiovascular stimulus.Twelve obese adult volunteers, with mass of 100.5±15.7 kg and body mass index of 33.4±2.6 kg·m (mean±SD), participated in this study. We measured oxygen consumption, ground reaction forces, and three-dimensional lower-extremity kinematics while subjects walked on a dual-belt force-measuring treadmill at several speed (0.50-1.75 m·s) and grade (0°-9°) combinations. We calculated metabolic rate, loading rates, and net muscle moments at the hip, knee, and ankle for each condition.Metabolic rates were similar across trials and were of moderate intensity (48.5%-59.8% of VO2max). Walking slower uphill significantly reduced loading rates and lower-extremity net muscle moments compared with faster level walking. Peak knee extension and adduction moments were reduced by ∼19% and 26%, respectively, when subjects walked up a 6° incline at 0.75 m·s versus level walking at 1.50 m·s.These results suggest that walking at a relatively slow speed up a moderate incline is a potential exercise strategy that may reduce the risk of musculoskeletal injury/pathological disease while providing proper cardiovascular stimulus in obese adults.

OBJECTIVE: To assess the quality of surgical pathology reports of advanced stage ovarian, fallopian tube and primary peritoneal cancer. This quality assurance project was performed within the EORTC-GCG 55971/NCIC-CTG OV13 study comparing primary debulking surgery followed by chemotherapy with neoadjuvant chemotherapy and interval debulking surgery. METHODS: Four hundred and seventy nine pathology reports from 40 institutions in 11 different countries were checked for the following quality indicators: macroscopic description of all specimens, measuring and weighing of major specimens, description of tumour origin and differentiation. RESULTS: All specimens were macroscopically described in 92.3% of the reports. All major samples were measured and weighed in 59.9% of the reports. A description of the origin of the tumour was missing in 20.5% of reports of the primary debulking group and in 23.4% of the interval debulking group. Assessment of tumour differentiation was missing in 10% of the reports after primary debulking and in 20.8% of the reports after interval debulking. Completeness of reports is positively correlated with accrual volume and adversely with hospital volume or type of hospital (academic versus non-academic). Quality of reports differs significantly by country. CONCLUSION: This audit of ovarian cancer pathology reports reveals that in a substantial number of reports basic pathologic data are missing, with possible adverse consequences for the quality of cancer care. Specialisation by pathologists and the use of standardised synoptic reports can lead to improved quality of reporting. Further research is needed to better define pre- and post-operative diagnostic criteria for ovarian cancer treated with neoadjuvant chemotherapy.

Testing emerging technologies involves the evaluation of biologic plausibility, technical efficacy, clinical effectiveness, patient satisfaction, and cost-effectiveness. The objective of this study was to select an effective classification algorithm for optical spectroscopy as an adjunct to colposcopy and obtain preliminary estimates of its accuracy for the detection of CIN 2 or worse. We recruited 1,000 patients from screening and prevention clinics and 850 patients from colposcopy clinics at two comprehensive cancer centers and a community hospital. Optical spectroscopy was performed, and 4,864 biopsies were obtained from the sites measured, including abnormal and normal colposcopic areas. The gold standard was the histologic report of biopsies, read 2 to 3 times by histopathologists blinded to the cytologic, histopathologic, and spectroscopic results. We calculated sensitivities, specificities, receiver operating characteristic (ROC) curves, and areas under the ROC curves. We identified a cutpoint for an algorithm based on optical spectroscopy that yielded an estimated sensitivity of 1.00 [95% confidence interval (CI) = 0.92-1.00] and an estimated specificity of 0.71 [95% CI = 0.62-0.79] in a combined screening and diagnostic population. The positive and negative predictive values were 0.58 and 1.00, respectively. The area under the ROC curve was 0.85 (95% CI = 0.81-0.89). The per-patient and per-site performance were similar in the diagnostic and poorer in the screening settings. Like colposcopy, the device performs best in a diagnostic population. Alternative statistical approaches demonstrate that the analysis is robust and that spectroscopy works as well as or slightly better than colposcopy for the detection of CIN 2 to cancer.

Diurnal animals occupy a different temporal niche from nocturnal animals and are consequently exposed to different amounts of light as well as different dangers. Accordingly, some variation exists in the way that diurnal animals synchronize their internal circadian clock to match the external 24-hour daily cycle. First, though the brain mechanisms underlying photic entrainment are very similar among species with different daily activity patterns, there is evidence that diurnal animals are less sensitive to photic stimuli compared to nocturnal animals. Second, stimuli other than light that synchronize rhythms (i.e. nonphotic stimuli) can also entrain and phase shift daily rhythms. Some of the rules that govern nonphotic entrainment in nocturnal animals as well as the brain mechanisms that control nonphotic influences on rhythms do not appear to apply to diurnal animals, however. Some evidence supports the idea that arousal or activity plays an important role in entraining rhythms in diurnal animals, either...

Activation of γ-aminobutyric acid (GABA)A receptors in the suprachiasmatic nucleus (SCN) resets the circadian clock during the day and inhibits the ability of light to reset the clock at night. Light in turn acts during the day to inhibit the phase-resetting effects of GABA. Some evidence suggests that Period mRNA changes in the SCN are responsible for these interactions between light and GABA. Here, the hypothesis that light and the GABAA receptor interact by altering the expression of Period 1 and/or Period 2 mRNA in the SCN is tested. The GABAA agonist muscimol was injected near the SCN just prior to a light pulse, during the mid-subjective day and the early and late subjective night. Changes in Period 1 and Period 2 mRNA were measured in the SCN by in situ hybridization. Light-induced Period 1 mRNA was inhibited by GABAA receptor activation in the early and late subjective night, while Period 2 mRNA was only inhibited during the late night. During the subjective day, light had no effect on the ability of muscimol to suppress Period 1 mRNA hybridization signal. Thus, light and GABA A receptor activation inhibit each other's ability to induce behavioral phase shifts throughout the subjective day and night. However, only in the late night are these behavioral effects correlated with changes in Period gene expression. Together, our data support the hypothesis that the interacting effects of light and GABA are the result of the opposing actions of these stimuli on Period mRNA, but only during the subjective night.

This paper discusses the use of the Monopoly board game as a tool to contrast the concept of income from an economic perspective with the financial accounting (GAAP) concept of income. This approach is used in a principles of accounting course to make more efficient use of time in an environment where only one academic term is devoted to presenting basic financial accounting concepts. The use of an engaging and unusual medium early in the principles course helps students build confidence and provides positive reinforcement of understanding in a course that undergraduate business students do not always enjoy. The board game medium allows for a simple presentation of some of the differences in economic and accounting definitions of income. Further, it provides a familiar economic simulation of business activity that saves time in demonstrating the value of accounting information from the users perspective.

Background Cervical cancer remains a major health problem, especially in developing countries. Colposcopic examination is used to detect high-grade lesions in patients with a history of abnormal pap smears. New technologies are needed to improve the sensitivity and specificity of this technique. We propose to test the potential of fluorescence confocal microscopy to identify high-grade lesions. Methods We examined the quantification of ex vivo confocal fluorescence microscopy to differentiate among normal cervical tissue, low-grade Cervical Intraepithelial Neoplasia (CIN), and high-grade CIN. We sought to (1) quantify nuclear morphology and tissue architecture features by analyzing images of cervical biopsies; and (2) determine the accuracy of high-grade CIN detection via confocal microscopy relative to the accuracy of detection by colposcopic impression. Forty-six biopsies obtained from colposcopically normal and abnormal cervical sites were evaluated. Confocal images were acquired at different depths from the epithelial surface and histological images were analyzed using in-house software. Results The features calculated from the confocal images compared well with those features obtained from the histological images and histopathological reviews of the specimens (obtained by a gynecologic pathologist). The correlations between two of these features (the nuclear-cytoplasmic ratio and the average of three nearest Delaunay-neighbors distance) and the grade of dysplasia were higher than that of colposcopic impression. The sensitivity of detecting high-grade dysplasia by analysing images collected at the surface of the epithelium, and at 15 and 30 μm below the epithelial surface were respectively 100, 100, and 92 %. Conclusions Quantitative analysis of confocal fluorescence images showed its capacity for discriminating high-grade CIN lesions vs. low-grade CIN lesions and normal tissues, at different depth of imaging. This approach could be used to help clinicians identify high-grade CIN in clinical settings.

Background Daily rhythms in mammals are programmed by a master clock in the suprachiasmatic nucleus (SCN). The SCN contains two main compartments (shell and core), but the role of each region in system-level coordination remains ill defined. Herein, we use a functional assay to investigate how downstream tissues interpret region-specific outputs by using in vivo exposure to long day photoperiods to temporally dissociate the SCN. We then analyze resulting changes in the rhythms of clocks located throughout the brain and body to examine whether they maintain phase synchrony with the SCN shell or core. Results Nearly all of the 17 tissues examined in the brain and body maintain phase synchrony with the SCN shell, but not the SCN core, which indicates that downstream oscillators are set by cues controlled specifically by the SCN shell. Interestingly, we also found that SCN dissociation diminished the amplitude of rhythms in core clock gene and protein expression in brain tissues by 50–75 %, which suggests that light-driven changes in the functional organization of the SCN markedly influence the strength of rhythms in downstream tissues. Conclusions Overall, our results reveal that body clocks receive time-of-day cues specifically from the SCN shell, which may be an adaptive design principle that serves to maintain system-level phase relationships in a changing environment. Further, we demonstrate that lighting conditions alter the amplitude of the molecular clock in downstream tissues, which uncovers a new form of plasticity that may contribute to seasonal changes in physiology and behavior. Electronic supplementary material The online version of this article (doi:10.1186/s12915-015-0157-x) contains supplementary material, which is available to authorized users.

Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

This chapter will focus on the direct postoperative management after the removal of a posterior fossa tumor. There are general principles that can be applied to any kind of tumor surgery in the posterior fossa and its adjacent structures, but specific aspects depending on the different pathologies found in this region are addressed as well. General principles as well as personal statements reflecting the authors’ experience in the treatment of such entities are presented. A special emphasis is put on early postoperative complications.

Converging evidence indicates that white adipose tissue (WAT) is innervated by the sympathetic nervous system (SNS) based on immunohistochemical labeling of a SNS marker (tyrosine hydroxylase [TH]), tract tracing of WAT sympathetic postganglionic innervation, pseudorabies virus (PRV) transneuronal labeling of WAT SNS outflow neurons, and functional evidence from denervation studies. Recently, WAT para-SNS (PSNS) innervation was suggested because local surgical WAT sympathectomy (sparing hypothesized parasympathetic innervation) followed by PRV injection yielded infected cells in the vagal dorsomotor nucleus (DMV), a traditionally-recognized PSNS brain stem site. In addition, local surgical PSNS WAT denervation triggered WAT catabolic responses. We tested histologically whether WAT was parasympathetically innervated by searching for PSNS markers in rat, and normal (C57BL) and obese ( ob/ob) mouse WAT. Vesicular acetylcholine transporter, vasoactive intestinal peptide and neuronal nitric oxide synthase immunoreactivities were absent in WAT pads (retroperitoneal, epididymal, inguinal subcutaneous) from all animals. Nearly all nerves innervating WAT vasculature and parenchyma that were labeled with protein gene product 9.5 (PGP9.5; pan-nerve marker) also contained TH, attesting to pervasive SNS innervation. When Siberian hamster inguinal WAT was sympathetically denervated via local injections of catecholaminergic toxin 6-hydroxydopamine (sparing putative parasympathetic nerves), subsequent PRV injection resulted in no central nervous system (CNS) or sympathetic chain infections suggesting no PSNS innervation. By contrast, vehicle-injected WAT subsequently inoculated with PRV had typical CNS/sympathetic chain viral infection patterns. Collectively, these data indicate no parasympathetic nerve markers in WAT of several species, with sparse DMV innervation and question the claim of PSNS WAT innervation as well as its functional significance.

We examined Period (Per) mRNA rhythms in the suprachiasmatic nucleus (SCN) of a diurnal rodent and assessed how phase-shifting stimuli acutely affect SCN Per mRNA using semiquantitative in situ hybridization. First, Per1 and Per2 varied rhythmically in the SCN over the course of one circadian cycle in constant darkness: Per1 mRNA was highest in the early to mid-subjective day, while Per2 mRNA levels peaked in the late subjective day. Second, acute light exposure in the early subjective night significantly increased both Per1 and Per2 mRNA. Third, Per2 but not Per1 levels decreased 1 and 2 h after injection of the gamma-aminobutyric acid (GABA)(A) receptor agonist muscimol into the SCN during the subjective day. Fourth, muscimol also reduced the light-induced Per2 in the early subjective night, but Per1 induction by light was not significantly affected. Consistent with previous studies, these data demonstrate that diurnal and nocturnal animals show very similar daily patterns of Per mRNA and light-induced Per increases in the SCN. As with light, muscimol alters circadian phase, and daytime phase alterations induced by muscimol are associated with significant decreases in Per2 mRNA. In diurnal animals, muscimol-induced decreases in Per are associated with phase delays rather than advances. The direction of the daytime phase shift may be determined by the relative suppression of Per1 vs. Per2 in SCN cells. As in nocturnal animals, changes in Per1 and Per2 mRNA by photic and non-photic stimuli appear to be associated with circadian phase alteration.

Hedgehog signaling coordinates a variety of patterning processes during early embryonic development. Drosophila hedgehog and its vertebrate orthologs, Sonic hedgehog, Indian hedgehog, and Desert hedgehog, share a generally conserved signal transduction cascade. However, the particular mechanisms by which the lipid-modified molecules specify embryonic tissues differ substantially. Vertebrate skeletal patterning is one of the most intensively studied biological processes. During skeletogenesis, Sonic and Indian hedgehog provide positional information and initiate or maintain cellular differentiation programs regulating the formation of cartilage and bone. They either signal directly to adjacent cells or form tightly regulated gradients that act over long distances to pattern the axial and appendicular skeleton and regulate crucial steps during endochondral ossification. As a consequence, malfunction of the hedgehog signaling network can cause severe skeletal disorders and tumors.

Objective. Fluorescence spectroscopy is a promising technology for the detection of cervical squamous intraepithelial precancers and cancers. To date, many investigators have focused on point spectroscopy as an adjunct to diagnostic colposcopy. A device that visualizes the whole field of the cervix is needed for screening. To that end, we have developed a multispectral digital colposcope that works through the colposcope to image with white light, UV excitation at 345 nm, and blue light at 440 nm excitation. Here, we report the pilot study that precedes a Phase I trial. Methods. The MDC system is composed of a light source, a colposcope, and a video rate color CCD camera with a frame grabber and takes approximately less than 1 min to make images of the cervix. Patients were measured at baseline and after acetic acid placement with white light, 345 nm excitation, and 440 nm excitation from the xenon arc lamp. The white light is in the visible spectrum, 345 nm excitation is in the UV spectrum and is not visible, and 440 nm excitation is blue light in the visible spectrum. White light generates a pink image of the cervix. 345 nm excitation, the UV light, excites fluorophores to emit a blue image. 440 nm excitation, the blue light, excites fluorophores to emit a green image. The patients underwent a loop excision procedure and the histopathology was inked and cut into 12 sections by the study pathologists. The histopathologic slides were scanned and the images were then reconstructed into maps. A diagnostic algorithm was calculated. The data were preprocessed, transformed, and analyzed by the K-means clustering method. Disease maps were generated using the algorithm and classifier and compared to white light colposcopy and the blue and green images obtained at 345 and 440 nm. Results. Forty-six patients were measured at four clinical sites. Images were made of the cervix with white light, 345 nm excitation, and 440 nm excitation and are presented in the figures. As the study went on, images improved with improvements in the instrument. The white light and fluorescence images are presented with crudely constructed histopathologic maps and algorithmic maps. At 345 nm excitation, the UV light, histologically confirmed CIN appears darker blue; while at 440 nm excitation, the blue light, histologically confirmed CIN appears lighter green. Conclusions. This pilot study shows that MDC images can be matched to both histopathologic and algorithmic maps. The device and the algorithm are evolving but show promise. A Phase I trial is planned.

Objective. To study the pattern of protein expression associated with a predisposition to develop ovarian cancer. Methods. Prophylactic oophorectomy is used to prevent ovarian carcinoma in high-risk populations who have a strong family history of breast/ovarian cancer. In ovarian specimens of these women, the ovarian surface epithelium (OSE), which is tissue of origin of epithelial ovarian cancer, often shows altered morphology, growth patterns and differentiation features that are believed to be preneoplastic. This study has used a proteomic approach, based on two-dimensional gel electrophoresis and mass spectrometry, to compare the protein profiles of OSE from women with a history of familial ovarian cancer (FH-OSE), i.e., at least two first-degree relatives with such cancer and/or testing positive for BRCA1 mutations, to those without such history (NFH-OSE). Results. Of >1500 protein spots, there were 8 proteins whose levels were significantly altered in FH-OSE. Three were known ovarian tumor associated proteins, others were novel changes. A number of the alterations seen were accompanied with protein modifications and have not been previously reported. There was a predominance of sequences related to the stress response pathway. Differential expression of selected genes was confirmed by Western blotting and real-time reverse transcription polymerase chain reaction. Conclusions. Our findings define the OSE phenotype of women at a high risk of developing ovarian cancer. Protein alterations seen in these tissues may represent an early, irreversible, non-mutational step in ovarian epithelial neoplastic progression and may be potential early and sensitive markers for the evaluation of cancer risk.

Circadian rhythms are reset by light during the night or by nonphotic stimuli during the day. Neuropeptide Y (NPY), which appears to mediate at least some nonphotic phase shifts by its actions in the suprachiasmatic nucleus (SCN), induces phase advances during the day and inhibits light-induced phase advances during the night. In this study, we used a highly selective Y5-like agonist to test whether activation of NPY Y5 receptors is sufficient to mimic NPY during the day and late night in Syrian hamsters. We also tested whether NPY in the early night reduces light-induced phase delays in a dose-dependent manner. Microinjection of a selective Y5 receptor agonist, (Ala31, Aib32)-NPY, into the SCN significantly inhibited light-induced phase advances during the late night, but did not induce phase advances during the day. In addition, concentrations of NPY ranging from 0.23 to 23 mM did not attenuate light-induced phase delays in the early night. These results suggest that activation of Y5-like receptors is sufficient to inhibit light-induced phase advances during the late night but is not sufficient to induce phase advances during the day. Furthermore, this study provided no evidence that NPY can inhibit light-induced phase shifts early in the night.

Diurnal (day-active) and nocturnal (night-active) animals have very different daily activity patterns. We recently demonstrated that the suprachiasmatic nucleus (SCN) responds to GABAergic stimulation differently in diurnal and nocturnal animals. Specifically, GABAA receptor activation with muscimol during the subjective day causes phase delays in diurnal grass rats while producing phase advances in nocturnal hamsters. The aim of the following experiments was to determine if diurnal and nocturnal animals differ in their response to GABAB receptor activation in the SCN. Baclofen, a GABAB receptor agonist, was microinjected into the SCN region of grass rats or hamsters under free-running conditions and phase alterations were analyzed. Changes in phase were not detected after baclofen treatment during the subjective day in either grass rats or hamsters. During the night, however, GABAB receptor activation significantly decreased the ability of light to induce phase delays in grass rats. Taken together with previous data from our laboratory, these results demonstrate that, in both hamsters and grass rats, GABAB receptor activation in the SCN significantly affects circadian phase during the night, but not during the day.

Acquired infection is one of the most prevalent sources of concern in neonatal intensive care units (NICUs). Center-to-center variation has been noted by both the National Nosocomial Infection Surveillance System and the Vermont Oxford Network suggesting that site of care influences outcomes including acquired infection.To reduce the acquired infection rate by isolating and then implementing meaningful process differences between high and low infection rate centers.A multistaged observation and intervention study. The primary outcome measure was defined as a positive blood culture, collected more than 3 days after birth. Hospital patient days along with infection episodes were collected for all NICU admissions in the network during the baseline and post-implementation periods. A detailed observation guide was used during site visits to high and low infection rate centers. The observations recorded in the guide allowed the team to isolate meaningful differences, which were shared with the network. Individual NICUs decided which of the meaningful differences, if any, to implement. To estimate the impact on costs, additional data were gathered in a case-matched series of infants in one demonstration site.In all, 15 meaningful differences were isolated and shared with the network. The network rate for acquired infection dropped from 3.8 to 2.9 episodes per 1000 patient days. In the demonstration site, the infection rate dropped from 7.4 to 4.0 per 1000 patient days.Isolation of process level differences between high and low performing centers followed by implementation of these meaningful differences may reduce acquired infections. Other targeted areas of care may benefit from this quality improvement methodology.

Hintergrund. Die inhalative Anwendung von Prostacyclinderivaten stellt einen neuen Behandlungsansatz der pulmonalen Hypertonie dar. Anwendungsbeobachtungen bei kritisch erkrankten Kindern mit vorbestehender pulmonaler Hypertonie und gleichzeitig dekompensierter respiratorischer Erkrankung sind rar. Patienten und Methode. Im vorliegenden Artikel wird uber die inhalative Anwendung von Iloprost bei 2 Patienten mit pulmonaler Hypertonie unterschiedlicher Genese und schwerer respiratorischer Dekompensation berichtet. Die Methode der inhalativen Anwendung von Iloprost und die Integration des Verneblersystems in verschiedene Beatmungssysteme in Kombination mit inhalativem NO werden dargestellt.

Background. In recent years, there has been a move toward using laparoscopy in the management of presumed benign ovarian masses. This paper discusses the use of laparoscopy for ovarian masses (particularly dermoid cysts). The focus is on the implications for unexpected malignancies. Case. We report here a case involving a dermoid cyst that was removed at laparoscopy and was subsequently found to contain a squamous cell carcinoma. Spillage of the cyst's contents occurred at the time of removal. At staging laparotomy, peritoneal implants of the tumor were found, upgrading the tumor from FIGO stage Ia to IIc. Conclusion. Spillage rates of dermoid cyst content with laparoscopic removal are inevitably higher than with excision at laparotomy. It remains controversial whether upstaging from FIGO stage Ia to IIc affects prognosis; however, in this case it led to aggressive adjuvant therapy which imposed significant additional morbidity, including loss of fertility, on the patient. One should be aware of the possibility of unexpected malignancy when the decision to manage an ovarian mass laparoscopically is made.

Here, we provide a detailed account of how to denervate white and brown adipose tissue (WAT and BAT) and how to measure sympathetic nervous system (SNS) activity to these and other tissues neurochemically. The brain controls many of the functions of WAT and BAT via the SNS innervation of the tissues, especially lipolysis and thermogenesis, respectively. There is no clearly demonstrated parasympathetic innervation of WAT or the major interscapular BAT (IBAT) depot. WAT and BAT communicate with the brain neurally via sensory nerves. We detail the surgical denervation (eliminating both innervations) of several WAT pads and IBAT. We also detail more selective chemical denervation of the SNS innervation via intra-WAT/IBAT 6-hydroxy-dopamine (a catecholaminergic neurotoxin) injections and selective chemical sensory denervation via intra-WAT/IBAT capsaicin (a sensory nerve neurotoxin) injections. Verifications of the denervations are provided (HPLC-EC detection for SNS, ELIA for calcitonin gene-related peptide (proven sensory nerve marker)). Finally, assessment of the SNS drive to WAT/BAT or other tissues is described using the alpha-methyl-para-tyrosine method combined with HPLC-EC, a direct neurochemical measure of SNS activity. These methods have proven useful for us and for other investigators interested in innervation of adipose tissues. The chemical denervation approach has been extended to nonadipose tissues as well.