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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.

Embodied cognition theories posit direct interactions between sensorimotor and mental processing. Various clinical observations have been interpreted in this controversial framework, amongst others, low verb generation in word production tasks performed by persons with Parkinson’s disease (PD). If this were a sequel of reduced motor simulation of prevalent action semantics in this word class, reduced PD pathophysiology should result in increased verb production and a general shift of lexical contents towards particular movement-related meanings. 17 persons with PD and bilateral Deep Brain Stimulation (DBS) of the subhtalamic nucleus (STN) and 17 healthy control persons engaged in a semantically unconstrained, phonemic verbal fluency task, the former in both DBS-off and DBS-on states. The analysis referred to the number of words produced, verb use, and the occurrence of different dimensions of movement-related semantics in the lexical output. Persons with PD produced fewer words than controls. In the DBS-off, but not in the DBS-on condition, the proportion of verbs within this reduced output was lower than in controls. Lowered verb production went in parallel with a semantic shift. In persons with PD in the DBS-off, but not the DBS-on condition, the relatedness of produced words to own body-movement was lower than in controls. In persons with PD, DBS induced-changes of the motor condition appear to go along with formal and semantic shifts in word production. The results support the idea of a direct connection between the motor system and lexical processing.

Background Colorectal cancer is one of the most common malignancies worldwide. There is an urgent need for simple and fast methods to improve tumor detection in the diagnostic and intraoperative setting to avoid complications and provide objective information in distinguishing malignant and benign colorectal tissue. Optical spectroscopy methods have recently shown a great potential for this discrimination in different organs. Materials and methods In this pilot study, fluorescence emission spectra (excitation: 473 nm) and diffuse reflectance spectra (DRS) of normal and tumor tissues from resected colorectal cancer specimen were measured using fiber optical probes in an ex vivo setting, and the data were subjected to multivariate analysis. Results Substantial spectral differences were found in the fluorescence and DRS spectra of colorectal cancer tissue in comparison to benign tissue. The diagnostic potential of a multimode optical system combining both spectroscopic methods was investigated by mathematical combination. Compared with the individual techniques, a higher sensitivity of the joint DRS-fluorescence optical system in the discrimination between malignant and benign colorectal tissue could be observed. Conclusions In the pilot study presented herein, a quick and reliable method to differentiate malignant and benign colorectal tissue ex vivo with different spectroscopic techniques using spectral fiber probes could be established. Joint fluorescence and near-infrared spectroscopy had a higher sensitivity in tissue discrimination and showed to be a promising combination of two spectroscopic methods. Further studies using the synergic effect of fluorescence and DRS spectroscopy are needed to transfer these findings into the in vivo situation.

There are no Food and Drug Administration approved pharmacotherapies for methamphetamine (METH) overdose, thus identifying novel drug targets to prevent this devastating adverse event is a public-health imperative. Previous research suggests that serotonin and sigma receptors may contribute to the adverse effects of METH. The present study assessed whether pretreatment with the 5-HT2A receptor antagonist M100907 or the sigma 1 (σ1) receptor antagonist BD 1047 attenuated METH-induced lethality, hyperthermia, convulsions, and seizures. Male, Swiss-Webster mice received intraperitoneal injections of M100907 (1 and 10 mg/kg), BD 1047 (10 mg/kg), or a combination of M100907 (1 mg/kg) and BD 1047 (10 mg/kg) prior to treatment with METH (78 mg/kg). Convulsions and lethality were assessed by observation, core body temperature was assessed by surgically implanted telemetric probes, and seizures were assessed by electroencephalography. M100907 reduced METH-elicited lethality from 67% to 33%, BD1047 reduced METH-elicited lethality from 67% to 50%, and combined administration of both agents eliminated lethality in all mice tested. Similarly, both agents and their combination reduced METH-elicited seizures and convulsions. None of the treatments decreased METH-induced hyperthermia. This research suggests that reducing METH-induced seizures is an important factor in reducing lethality associated with METH overdose. However, future studies should examine whether M100907 and BD 1047 modulate METH-induced hypertension and other adverse effects that may also contribute to METH overdose. Our data support the continued investigation of compounds that target 5-HT2A and σ1 receptors in METH-induced overdose, including their potential to yield emergency reversal agents.

Age-related macular degeneration (AMD) is the leading cause of vision loss in adults over 60 years old globally. There are two forms of advanced AMD: "dry" and "wet". Dry AMD is characterized by geographic atrophy of the retinal pigment epithelium and overlying photoreceptors in the macular region; whereas wet AMD is characterized by vascular penetrance from the choroid into the retina, known as choroidal neovascularization (CNV). Both phenotypes eventually lead to loss of central vision. The pathogenesis of AMD involves the interplay of genetic polymorphisms and environmental risk factors, many of which elevate retinal oxidative stress. Excess reactive oxygen species react with cellular macromolecules, forming oxidation-modified byproducts that elicit chronic inflammation and promote CNV. Additionally, genome-wide association studies have identified several genetic variants in the age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1 (ARMS2-HTRA1) locus associated with the progression of late-stage AMD, especially the wet subtype. In this review, we will focus on the interplay of oxidative stress and HTRA1 in drusen deposition, chronic inflammation, and chronic angiogenesis. We aim to present a multifactorial model of wet AMD progression, supporting HTRA1 as a novel therapeutic target upstream of vascular endothelial growth factor (VEGF), the conventional target in AMD therapeutics. By inhibiting HTRA1's proteolytic activity, we can reduce pro-angiogenic signaling and prevent proteolytic breakdown of the blood-retina barrier. The anti-HTRA1 approach offers a promising alternative treatment option to wet AMD, complementary to anti-VEGF therapy.

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.

Age-related macular degeneration (AMD) is the most common cause of central vision loss among elderly populations in industrialized countries. Genome-wide association studies have consistently associated two genomic loci with progression to late-stage AMD: the complement factor H (CFH) locus on chromosome 1q31 and the age-related maculopathy susceptibility 2-HtrA serine peptidase 1 (ARMS2-HTRA1) locus on chromosome 10q26. While the CFH risk variant has been shown to alter complement activity, the ARMS2-HTRA1 risk haplotype remains enigmatic due to high linkage disequilibrium and inconsistent functional findings spanning two genes that are plausibly causative for AMD risk. In this review, we detail the genetic and functional evidence used to support either ARMS2 or HTRA1 as the causal gene for AMD risk, emphasizing both the historical development and the current understanding of the ARMS2-HTRA1 locus in AMD pathogenesis. We conclude by summarizing the evidence in favor of HTRA1 and present our hypothesis whereby HTRA1-derived ECM fragments mediate AMD pathogenesis.

Individuals with Autism Spectrum Disorder (ASD) experience a variety of symptoms sometimes including atypicalities in language use. The study explored differences in semantic network organisation of adults with ASD without intellectual impairment. We assessed clusters and switches in verbal fluency tasks (‘animals’, ‘human feature’, ‘verbs’, ‘r-words’) via curve fitting in combination with corpus-driven analysis of semantic relatedness and evaluated socio-emotional and motor action related content. Compared to participants without ASD (n = 39), participants with ASD (n = 32) tended to produce smaller clusters, longer switches, and fewer words in semantic conditions (no p values survived Bonferroni-correction), whereas relatedness and content were similar. In ASD, semantic networks underlying cluster formation appeared comparably small without affecting strength of associations or content.

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.

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.

Cognitive changes including reduced word production in verbal fluency (VF) tasks are frequently observed in Parkinson's disease (PD) with ambiguous effects of dopaminergic medication on these symptoms. Here, we studied the impact of dopaminergic medication on specific cognitive components underlying VF task performance in 21 participants with PD on their regular medication and following dopamine withdrawal compared with healthy controls. We used temporal cluster analysis (TCA) to differentiate phases of VF output relating to fast automatic lexical activation ('clusters') and slower attention-demanding shifts ('switches'). Dopaminergic medication led to increased switching and, in non-alternating VF tasks, to the formation of smaller and shorter word clusters. The number of switches was correlated with higher cognitive scores and showed an inverse relationship with VF error rates. Increased switching operations during VF task performance can be interpreted in view of nigrostriatal dopaminergic roles for balancing system state versus change propensities. The additional effect on word clustering suggests a modulation of semantic spreading activation mechanisms underlying lexical search, presumably involving non-nigrostriatal, e.g., mesocortical dopaminergic networks.

Objectives The complex symptomatology of Parkinson’ disease (PD) usually goes along with reduced physical activity. Previous studies have indicated positive effects of activating therapies on patients’ well‐being. This study, therefore, examined how activity in daily life is related to patients’ subjective condition. Materials and Methods Twenty‐one PD patients rated their condition every two hours during two routine days and documented the duration and type of their activities (based on the PRISCUS‐Physical Activity Questionnaire) during the respective time intervals. They were furthermore assessed regarding motor and nonmotor symptoms, personality factors, and coping strategies. Results Patients spent on average 8.59 ± 2.93 hr per day at physical rest and 5.47 ± 2.93 hr physically active. We found highly significant associations between positive condition ratings (such as happiness, motivation, and concentration) and the duration of subsequent physical activities (adj.r2 = .689) as well as between the duration of these activities and a subsequent improvement in the subjective condition (adj.r2 = .545). This was strongest in patients using active coping strategies and showing agreeable and conscientious personality traits (adj.r2 = .380). Nonmotor symptom severity was weakly inversely related to the daily amount of activities (adj.r2 = .273), whereas no significant association with motor symptom severity was found. Conclusions The results suggest a feedback process between a positive subjective condition and physical activities in PD patients. This appears to depend on the use of active coping strategies and nonmotor symptoms rather than on motor symptom severity. The results should encourage physicians to address the importance of everyday physical activities and to provide patients with behavioral advice.

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.

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.

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.

National Institutes of Health (NIH) Associacao Fundo de Incentivo a Psicofarmacologia (AFIP) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) National Institute of Neurological Disorders and Stroke (NINDS) Purpose Mutations in the voltage-gated sodium channel (VGSC) gene SCN1A are responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. in addition to seizures, patients with SCN1A mutations often experience sleep abnormalities, suggesting that SCN1A may also play a role in the neuronal pathways involved in the regulation of sleep. However, to date, a role for SCN1A in the regulation of sleep architecture has not been directly examined. To fill this gap, we tested the hypothesis that SCN1A contributes to the regulation of sleep architecture, and by extension, that SCN1A dysfunction contributes to the sleep abnormalities observed in patients with SCN1A mutations. Methods Using immunohistochemistry we first examined the expression of mouse Scn1a in regions of the mouse brain that are known to be involved in seizure generation and sleep regulation. Next, we performed detailed analysis of sleep and wake electroencephalography (EEG) patterns during 48 continuous hours of baseline recordings in a knock-in mouse line that expresses the human SCN1A GEFS+ mutation R1648H (RH mutants). We also characterized the sleepwake pattern following 6h of sleep deprivation. Key Findings Immunohistochemistry revealed broad expression of Scn1a in the neocortex, hippocampus, hypothalamus, thalamic reticular nuclei, dorsal raphe nuclei, pedunculopontine, and laterodorsal tegmental nuclei. Co-localization between Scn1a immunoreactivity and critical cell types within these regions was also observed. EEG analysis under baseline conditions revealed increased wakefulness and reduced nonrapid eye movement (NREM) and rapid eye movement (REM) sleep amounts during the dark phase in the RH mutants, suggesting a sleep deficit. Nevertheless, the mutants exhibited levels of NREM and REM sleep that were generally similar to wild-type littermates during the recovery period following 6 h of sleep deprivation. Significance These results establish a direct role for SCN1A in the regulation of sleep and suggest that patients with SCN1A mutations may experience chronic alterations in sleep, potentially leading to negative outcomes over time. in addition, the expression of Scn1a in specific cell types/brain regions that are known to play critical roles in seizure generation and sleep now provides a mechanistic basis for the clinical features (seizures and sleep abnormalities) associated with human SCN1A mutations. Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA Universidade Federal de São Paulo, Dept Psychobiol, São Paulo, Brazil Morehouse Sch Med, Dept Neurobiol, Atlanta, GA 30310 USA Georgia State Univ, Sch Nursing & Hlth Profess, Atlanta, GA 30303 USA Universidade Federal de São Paulo, Dept Psychobiol, São Paulo, Brazil National Institutes of Health (NIH): NS072221 National Institutes of Health (NIH): NS060659 National Institutes of Health (NIH): F31NS074717 FAPESP: 07/50534-0 FAPESP: 98/14303-3 National Institute of Neurological Disorders and Stroke (NINDS): P30N5055077 Web of Science

Background Deep Brain Stimulation (DBS) of the thalamic ventral intermediate nucleus (VIM) is a therapeutic option for patients with essential tremor. Despite a generally low risk of side effects, declines in verbal fluency (VF) have previously been reported. Objectives We aimed to specify effects of VIM-DBS on major cognitive operations needed for VF task performance, represented by clusters and switches. Clusters are word production spurts, thought to arise from automatic activation of associated information pertaining to a given lexical field. Switches are slow word-to-word transitions, presumed to indicate controlled operations for stepping from one lexical field to another. Patients & methods Thirteen essential tremor patients with VIM-DBS performed verbal fluency tasks in their VIM-DBS ON and OFF conditions. Clusters and switches were formally defined by mathematical criteria. All results were compared to those of fifteen healthy control subjects, and significant OFF-ON-change scores were correlated to stimulation parameters. Results Patients produced fewer words than healthy controls. DBS ON compared to DBS OFF aggravated this deficit by prolonging the intervals between words within clusters, whereas switches remained unaffected. This stimulation effect correlated with more anterior electrode positions. Conclusion VIM-DBS seems to influence word output dynamics during verbal fluency tasks on the level of word clustering. This suggests a perturbation of automatic lexical co-activation by thalamic stimulation, particularly if delivered relatively anteriorly. The findings are discussed in the context of the hypothesized role of the thalamus in lexical processing.

Objective Neural interactions between cortex and basal ganglia are pivotal for sensorimotor processing. Specifically, coherency between cortex and subthalamic structures is a frequently studied phenomenon in patients with Parkinson’s disease. However, it is unknown whether cortico-subthalamic coherency might also relate to cognitive aspects of task performance, e.g., language processing. Furthermore, standard coherency studies are challenged by how to efficiently handle multi-channel recordings. Methods In eight patients with Parkinson’s disease treated with deep brain stimulation, simultaneous recordings of surface electroencephalography and deep local field potentials were obtained from bilateral subthalamic nuclei, during performing a lexical decision task. A recent multivariate coherency measure (maximized imaginary part of coherency, MIC) was applied, simultaneously accounting for multi-channel recordings. Results Cortico-subthalamic synchronization (MIC) in 14–35 Hz oscillations positively correlated with accuracy in lexical decisions across patients, but not in 7–13 Hz oscillations. In contrast to multivariate MIC, no significant correlation was obtained when extracting cortico-subthalamic synchronization by “standard” bivariate coherency. Conclusions Cortico-subthalamic synchronization may relate to non-motor aspects of task performance, here reflected in lexical accuracy. Significance The results tentatively suggest the relevance of cortico-subthalamic interactions for lexical decisions. Multivariate coherency might be effective to extract neural synchronization from multi-channel recordings.

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.

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.

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.

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.

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.

Complex amplitude dynamics of dominant alpha oscillations (8–13 Hz) in the cortex can be captured with long-range temporal correlations (LRTC) in healthy subjects and in various diseases. In patients with Parkinson’s disease (PD), intra-nuclear coherence was demonstrated in dominant beta rhythms (10–30 Hz) in the basal ganglia. However, so far the relation between cortical LRTC (across tens of seconds) and subcortical coherence (millisecond scale) is unknown. We addressed these “multiscale interactions” by simultaneous recordings of surface electroencephalography (EEG) and deep local field potentials (LFP) from the bilateral subthalamic nucleus (STN) in eight patients with severe PD eligible for deep brain stimulation, who performed a lexical decision task on medication. In the continuous data set LRTC up to 20 s were calculated in the amplitude envelope of 8–13-Hz EEG oscillations (across whole scalp), and subcortical coherence was assessed with measures being insensitive to volume conduction artifacts (imaginary part of coherency; iCOH) in 10–20 and 21–30-Hz oscillations in STN–LFP. We showed a significant positive correlation across patients between cortical LRTC (8–13 Hz) and subcortical iCOH selectively in 10–20-Hz oscillations in the left STN. Our results suggest a relation between neural dynamics in the most dominant rhythms in the cortex and basal ganglia in PD, extending across multiple time scales (milliseconds vs. tens of seconds). Furthermore, the investigation of multiscale interactions might contribute to our understanding of cortical–subcortical neural coupling in PD.

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.

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.

Roles of subcortical structures in language processing are vague, but, interestingly, basal ganglia and thalamic Deep Brain Stimulation can go along with reduced lexical capacities. To deepen the understanding of this impact, we assessed word processing as a function of thalamic versus subthalamic Deep Brain Stimulation. Ten essential tremor patients treated with thalamic and 14 Parkinson׳s disease patients with subthalamic Deep Brain Stimulation performed an acoustic Lexical Decision Task ON and OFF stimulation. Combined analysis of task performance and event-related potentials allowed the determination of processing speed, priming effects, and N400 as neurophysiological correlate of lexical stimulus processing. 12 age-matched healthy participants acted as control subjects. Thalamic Deep Brain Stimulation prolonged word decisions and reduced N400 potentials. No comparable ON–OFF effects were present in patients with subthalamic Deep Brain Stimulation. In the latter group of patients with Parkinson’ disease, N400 amplitudes were, however, abnormally low, whether under active or inactive Deep Brain Stimulation. In conclusion, performance speed and N400 appear to be influenced by state functions, modulated by thalamic, but not subthalamic Deep Brain Stimulation, compatible with concepts of thalamo-cortical engagement in word processing. Clinically, these findings specify cognitive sequels of Deep Brain Stimulation in a target-specific way.

We report on a 4 month old male infant with respiratory syncytial virus (RSV) infection leading to acute respiratory distress syndrome (ARDS). A diagnostic algorithm including extended infectiological and immunological work-up revealed absence of CD40-ligand. ARDS was treated successfully with a complex respiratory therapy plus intravenous immunoglobulin substitution. Molecular analysis detected mutations in the CD40L gene (Hyper-IgM syndrome Type 1). The case underlines the importance of an extended diagnostic work-up in an uncommonly severe course of respiratory infection in early infancy.

Cervical intra-epithelial glandular lesions have a morphological spectrum (akin to squamous) that ranges from mild changes to severe abnormalities. The entire spectrum is referred to as "cervical intra-epethilial glandular neoplasia" and is abbreviated as CIGN, CGIN or GIN. The diagnosis of adenocarcinoma in situ (ACIS) is made by some method of excision. The specimen, preferably cylindrical in shape, must have negative (disease free) lateral and upper margins. The ratio of adenocarcinoma in situ to severe squamous dysplasia/carcinoma in situ averages 1:50 (meaning that glandular comprises roughly 2% of in situ cases) whereas the malignant glandular lesions make up six to 18 percent of all invasive cervical cancers. In both stages, 46 to 72 percent of lesions contain a counterpart squamous component (being, therefore, of mixed type). Screening and invasive detection methods used to identify lesions and determine the presence of persistent or recurrent disease (cytology, colposcopy, biopsy and endocervical curettage) are inaccurate and unreliable. This is because of inadequate cytologic sampling in some cases, the existence of various colposcopic mimics (the most commonly encountered being metaplasia, condylomata, invasive adenocarcinoma, invasive squamous cancer and microglandular hyperplasia), most colposcopists' lack of experience with these lesions (due to their rarity) and the inadequacy of endocervical curettage in some cases. Adenocardnoma in situ has a length (the distance over the tissue surface between caudal and cephalad edges) not usually exceeding 15 mm. The underlying cervical crypt ("gland") involvement does not usually exceed four millimetres. Although ACIS has many architectural and histological patterns, management is not influenced by these patterns. The management of ACIS continues to be controversial. Cervical excision (like the traditional "conization" but with the specimen cylindrical in shape) is proposed as conservative management for patients desirous of future fertility. The excised specimen must have negative margins, meaning that the outer and upper margins of the specimen are free of disease and that the disease is completely contained within the excised tissue. Follow-up cytology, colposcopy and endocervical curettage may not be accurate in identifying persistent disease and/or detecting recurrent disease. If fertility is not an issue, simple routine hysterectomy is advocated, even though the specimen contains negative margins. Although disease can still be present in the hysterectomy specimen, it is usually ACIS and rarely an invasive adenocarcinoma. In the case of positive margins, meaning disease is noted at the upper and/or outer surface of the excised specimen, the probability of finding an invasive lesion in the extirpated specimen is enhanced. Patients who choose conservative management must be counselled about the importance of compliance and the potential risks of early undetected persistent or recurrent glandular disease, despite negative screening and invasive detection methods. This is because some cases of persistent or recurrent glandular disease have been reported after excision, despite negative specimen margins.

In recent years, advances in minimally invasive surgery have modified the management of the adnexal mass. Laparoscopic surgery offers advantages over conventional laparotomy which are beneficial to the patient and society: minimal scarring, decreased pain, and shorter hos-pitalization and recovery times. Consequently, this surgical approach has gained widespread popularity. More recendy, reports of undiagnosed ovarian cancers managed laparoscopically with unfortunate consequences have been published. These cases have prompted a re-evaluation of the management of the adnexal mass. Although most adnexal masses are benign and can be managed by hparoscopy, the challenge that remains is how to identify the ones which would be managed best by laparotomy. The objective of this guideline is to define, based on published data, clinical and surgical criteria which could help to distinguish a high-risk from a low^risk adnexal mass. There are two steps in the evaluation of the adnexal mass: the pre-operative and the intra-operative assessments. These will be reviewed in detail in this guideline. Observing strict criteria and using rigorous surgical technique will ensure the appropriate management of most adnexal masses.

This article describes the use of a cuffed pediatric endotracheal tube occluding selectively the air leakage resulting from tracheoesophageal fistula in a preterm neonate with esophageal atresia and severe respiratory failure due to respiratory distress syndrome. The gastric distension resolved completely within 4 hours. Surgical correction was performed on the third day of life after respiratory stabilization.

Department of General Paediatrics, Centre of Paediatrics and Neonatology, Asklepios Clinic, Arnold Janssen Strasse 29, 53575 Sankt Augustin, Germany Institute of Medical Virology and Epidemiology of Viral Diseases, University Hospital of Tuebingen, Elfriede Aulhorn Strasse 6, 72076 Tuebingen, Germany Virology Laboratory, Children Hospital of Mexico Federico Gomez, Doctor Marquez 162 Doctores, Cuauhtemoc, 06720 Mexico City, Distrito Federal, Mexico Department of Paediatric Pathology, University Clinic Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany Department of Neonatology and Paediatric Intensive Care, Centre of Paediatrics and Neonatology, Asklepios Clinic, Arnold Janssen Strasse 29, 3575 Sankt Augustin, Germany

Although thalamic deep brain stimulation is an effective treatment for patients with essential tremor, little is known about its effect on cortical neural dynamics. Therefore, we investigated long-range temporal correlations and spectral power in electroencephalographic recordings of patients during OFF versus ON bilateral thalamic deep brain stimulation in comparison with healthy controls. Cortical dynamics were analyzed in the range of 6-30 Hz. We found the presence of long-range temporal correlations up to 20 s in patients and controls. Thalamic deep brain stimulation was associated with increased long-range temporal correlations in the high beta band (21-30 Hz) and decreased power in the low beta band (13-20 Hz) compared with OFF stimulation and healthy controls. Long-range temporal correlations in the 6-10 Hz range were increased with OFF stimulation compared with the controls. Importantly, deep brain stimulation-induced changes in long-range temporal correlations within 6-10 Hz and in the beta ranges (13-20, 21-30 Hz) were correlated with OFF-ON changes in the tremor severity and with the disease duration, respectively. The differential reactivity of long-range temporal correlations and spectral power to deep brain stimulation might suggest that both measures reflect distinct aspects of cortical dynamics and might represent biomarkers for stimulation-induced modulations of neural dynamics in electroencephalography. The fact that long-range temporal correlations, but not spectral power, were correlated with clinical information might suggest long-range temporal correlations as a potential marker for disease severity in essential tremor.

We aimed at gaining insights into principles of subcortical lexical processing. Therefore, effects of deep brain stimulation (DBS) in different target structures on verbal fluency (VF) were tested. VF was assessed with active vs. inactivated DBS in 13 and 14 patients with DBS in the vicinity of the thalamic ventral intermediate nucleus (VIM) and, respectively, of the subthalamic nucleus (STN). Results were correlated to electrode localizations in postoperative MRI, and compared to those of 12 age-matched healthy controls. Patients' VF performance was generally below normal. However, while activation of DBS in the vicinity of VIM provoked marked VF decline, it induced subtle phonemic VF enhancement in the vicinity of STN. The effects correlated with electrode localizations in left hemispheric stimulation sites. The results show distinct dependencies of VF on DBS in the vicinity of VIM vs. STN. Particular risks for deterioration occur in patients with relatively ventromedial thalamic electrodes.

Introduction The thalamus is thought to contribute to language-related functions, but specifications of this notion remain vague. Objectives An assessment of potential effects of thalamic deep brain stimulation (DBS) on spontaneous language may help to delineate respective functions. Patients and methods For this purpose, we analysed spontaneous language samples from thirteen (six female/seven male) patients with essential tremor (ET) treated with DBS of the thalamic ventral intermediate nucleus (VIM) in their respective ON vs. OFF conditions. Samples were obtained from semi-structured interviews and examined on multidimensional linguistic levels. The main results were correlated with a more general score of cognitive function. Results In the VIM-DBS ON condition, participants produced significantly less hypotactic sentences compared to the OFF condition. This reduction correlated with the variation of the general cognitive score. Further, active VIM-DBS led to a decreased use of words from the open class. In conclusion, VIM-DBS appears to induce the use of a simplified syntactic and lexical structure. The findings are discussed in relation to the proposed functions of the thalamus for language-related cognitive behavior.

Familial ovarian cancer has been gaining extensive coverage in the lay press recently, posing a counselling dilemma to physicians in general and gynaecologists in particular. The literature on this topic has exploded with publications since 1991 when the first indication surfaced that a gene responsible for the development of epithelial ovarian cancer (EOC) is located on chromosome 17. 1 As the same gene also appears to have a close link to the development of breast cancer, 2 large numbers of women are potential gene carriers as breast cancer alone affects 10 percent of the female population. The search for the breast ovarian cancer gene (BRCA1), therefore, has become a focus of genetic research around the world. At the same time, the questions asked by patients centre around the possibility of early diagnosis and prevention in those women found to be potential gene carriers. While our knowledge of the exact genetic mechanism involved in the development of this cancer is still in its embryonic state, it is important that we scrutinize carefully our recommendations to patients, who are anxious and vulnerable. Often informed reassurance may be more helpful than well meaning intervention.

Aerosolized iloprost is now used as a therapeutic option in the treatment of pulmonary hypertension. We report on the administration of this derivative of prostacycline in treating severe pulmonary hypertension of the newborn. The combination of iloprost instilled endotracheally and inhaled was chosen as a last attempt at treatment in a critically ill patient who did not respond to advanced conventional treatments, including high frequency oscillation and inhalation of nitric oxide. The use of iloprost converted permanently the right-to-left shunting, leading to a substantial improvement in oxygenation.

We report clinical imaging results for an MDC that has been applied to more than 50 patients with suspected cervical precancer and analyze against matched histopathology results. For high grade dysplasia: sensitivity ~90%, specificity ~55%.

Advanced ovarian cancer has a poor prognosis. De-bulking surgery and platinum-based chemotherapy are the cornerstones of the treatment. Primary debulking surgery has been the standard of care in advanced ovarian cancer. Recently a new strategy with neoadjuvant chemotherapy followed by interval debulking surgery has been developed. In a recently published randomised trial of the EORTC-NCIC (European Organisation for Research and Treatment of Cancer - National Cancer Institute Canada) in patients with extensive stage IIIc and IV ovarian cancer it was shown that the survival was similar for patients randomised to neoadjuvant chemotherapy followed by interval debulking compared to primary debulking surgery, followed by chemotherapy. The post-operative complications and mortality rates were lower after interval debulking than after primary debulking surgery. The most important independent prognostic factor for overall survival was no residual tumour after primary or interval debulking surgery. In some patients obtaining the goal of no residual tumour at interval debulking is difficult due to chemotherapy-induced fibrosis. On the other hand the patients randomised had very extensive stage IIIc and IV disease and in patients with metastases smaller than 5 cm the survival tended to be better after primary debulking surgery. Hence, selection of the correct patients with stage IIIc or IV ovarian cancer for primary debulking or neoadjuvant chemotherapy followed by interval debulking surgery is important. Besides imaging with CT, diffusion MRI and/or PET-CT, also laparoscopy can play an important role in the selection of patients. It should be emphasised that the group of patients included in this study had extensive stage IIIc or IV disease. Surgical skills, especially in the upper abdomen, remain pivotal in the treatment of advanced ovarian cancer. However, very aggressive surgery should be tailored according to the general condition and extent of the disease of the patients. Otherwise, this type of aggressive surgery will result in unnecessary postoperative morbidity and mortality without improving survival. Hence, neoadjuvant chemotherapy should not be an easy way out, but is in some patients with stage IIIc or IV ovarian cancer a better alternative treatment option than primary debulking. According to the current treatment algorithm at the University Hospitals Leuven about 50% of the patients with stage IIIc or IV ovarian cancer are selected for neoadjuvant chemotherapy.