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Objective: With an increasing choice of new treatment options, the management of side effects to maintain a chosen treatment if likely to be effective on the tumor remains important. The perception of side effects however varies between the physician and the patient, leading to possible wrong assumptions on tolerability that result in dose modifications, which may ultimately affect effectiveness. The aim was to assess fatigue in patients with advanced or metastatic renal cell carcinoma (RCC) by comparing the evaluation of the physician to the one provided by their respective patient. In addition, we aimed to assess possible influences of fatigue on parameters of quality of life., Methods: Patients receiving systemic treatment for advanced RCC and their physicians were questioned independently regarding incidence and severity of fatigue and its effect on quality of life., Results: Both physicians and patients completed 98 matching questionnaires. Patients were treated with sunitinib, sorafenib, bevacizumab combined with interferon alpha, temsirolimus, everolimus, or interferon alpha alone. Incidence and severity of fatigue was differently assessed by patients and physicians, with fatigue being more severe when reported by the patient. The severity of fatigue increased with progressing treatment lines. Quality of life was significantly lower in patients experiencing fatigue compared with patients without fatigue. Emotional, functional, and physical well-being were all affected by fatigue, the latter being the most affected subscale. Social well-being was least affected., Conclusion: Fatigue is a complex and cumulative condition of patients treated for advanced RCC, and it considerably affects patient's quality of life. As many of its underlying causes may be treated, the divergent perception of occurrence and severity of fatigue should be integrated in treatment concepts. The active role of the patient in helping to manage ailments through assessment should be implemented when optimizing treatment of RCC., (© 2013 Published by Elsevier Inc.)

We compared the pupil responses originating from outer versus inner retinal photoreception between patients with isolated hereditary optic neuropathy (HON, n = 8) and healthy controls (n = 8). Three different testing protocols were used. For the first two protocols, a response function of the maximal pupil contraction versus stimulus light intensity was generated and the intensity at which half of the maximal pupil contraction, the half-max intensity, was determined. For the third protocol, the pupil size after light offset, the re-dilation rate and re-dilation amplitude were calculated to assess the post-light stimulus response. Patients with HON had bilateral, symmetric optic atrophy and significant reduction of visual acuity and visual field compared to controls. There were no significant mean differences in the response curve and pupil response parameters that reflect mainly rod, cone or melanopsin activity between patients and controls. In patients, there was a significant correlation between the half-max intensity of the red light sequence and visual field loss. In conclusion, pupil responses derived from outer or inner retinal photoreception in HON patients having mild-to moderate visual dysfunction are not quantitatively different from age-matched controls. However, an association between the degree of visual field loss and the half-max intensity of the cone response suggests that more advanced stages of disease may lead to impaired pupil light reflexes., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Endogenous rhythms of circalunar periodicity (∼29.5 days) and their underlying molecular and genetic basis have been demonstrated in a number of marine species [1, 2]. In contrast, there is a great deal of folklore but no consistent association of moon cycles with human physiology and behavior [3]. Here we show that subjective and objective measures of sleep vary according to lunar phase and thus may reflect circalunar rhythmicity in humans. To exclude confounders such as increased light at night or the potential bias in perception regarding a lunar influence on sleep, we retrospectively analyzed sleep structure, electroencephalographic activity during non-rapid-eye-movement (NREM) sleep, and secretion of the hormones melatonin and cortisol found under stringently controlled laboratory conditions in a cross-sectional setting. At no point during and after the study were volunteers or investigators aware of the a posteriori analysis relative to lunar phase. We found that around full moon, electroencephalogram (EEG) delta activity during NREM sleep, an indicator of deep sleep, decreased by 30%, time to fall asleep increased by 5 min, and EEG-assessed total sleep duration was reduced by 20 min. These changes were associated with a decrease in subjective sleep quality and diminished endogenous melatonin levels. This is the first reliable evidence that a lunar rhythm can modulate sleep structure in humans when measured under the highly controlled conditions of a circadian laboratory study protocol without time cues., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose of Review: The discovery of a new class of intrinsically photosensitive retinal ganglion cells (ipRGCs) revealed their superior role for various nonvisual biological functions, including the pupil light reflex, and circadian photoentrainment., Recent Findings: Recent works have identified and characterized several anatomically and functionally distinct ipRGC subtypes and have added strong new evidence for the accessory role of ipRGCs in the visual system in humans., Summary: This review summarizes current concepts related to ipRGC morphology, central connections and behavioural functions and highlights recent studies having clinical relevance to ipRGCs. Clinical implications of the melanopsin system are widespread, particularly as related to chronobiology.

Environmental light synchronizes the primary mammalian biological clock in the suprachiasmatic nuclei, as well as many peripheral clocks in tissues and cells, to the solar 24-hour day. Light is the strongest synchronizing agent (zeitgeber) for the circadian system, and therefore keeps most biological and psychological rhythms internally synchronized, which is important for optimum function. Circadian sleep-wake disruptions and chronic circadian misalignment, as often observed in psychiatric and neurodegenerative illness, can be treated with light therapy. The beneficial effect on circadian synchronization, sleep quality, mood, and cognitive performance depends on timing, intensity, and spectral composition of light exposure. Tailoring and optimizing indoor lighting conditions may be an approach to improve wellbeing, alertness, and cognitive performance and, in the long term, producing health benefits.

Purpose: Nonvisual light-dependent functions in humans are conveyed mainly by intrinsically photosensitive retinal ganglion cells, which express melanopsin as photopigment. We aimed to identify the effects of circadian phase and sleepiness across 24 hours on various aspects of the pupil response to light stimulation., Methods: We tested 10 healthy adults hourly in two 12-hour sessions covering a 24-hour period. Pupil responses to narrow bandwidth red (635 ± 18 nm) and blue (463 ± 24 nm) light (duration of 1 and 30 seconds) at equal photon fluxes were recorded, and correlated with salivary melatonin concentrations at the same circadian phases and to subjective sleepiness ratings. The magnitude of pupil constriction was determined from minimal pupil size. The post-stimulus pupil response was assessed from the pupil size at 6 seconds following light offset, the area within the redilation curve, and the exponential rate of redilation., Results: Among the measured parameters, the pupil size 6 seconds after light offset correlated with melatonin concentrations (P < 0.05) and showed a significant modulation over 24 hours with maximal values after the nocturnal peak of melatonin secretion. In contrast, the post-stimulus pupil response following red light stimulation correlated with subjective sleepiness (P < 0.05) without significant changes over 24 hours., Conclusions: The post-stimulus pupil response to blue light as a marker of intrinsic melanopsin activity demonstrated a circadian modulation. In contrast, the effect of sleepiness was more apparent in the cone contribution to the pupil response. Thus, pupillary responsiveness to light is under influence of the endogenous circadian clock and subjective sleepiness.

Ageing is associated with marked changes in sleep timing, structure and electroencephalographic (EEG) activity. Older people exhibit less slow-wave and spindle activity during non-rapid eye movement (NREM) sleep, together with attenuated levels of rapid eye movement (REM) sleep as compared to young individuals. However, the extent to which these age-related changes in sleep impact on dream processing remains largely unknown. Here we investigated NREM and REM sleep EEG activity prior to dream recall and no recall in 17 young (20-31 years) and 15 older volunteers (57-74 years) during a 40 h multiple nap protocol. Dream recall was assessed immediately after each nap. During NREM sleep prior to dream recall, older participants displayed higher frontal EEG delta activity (1-3 Hz) and higher centro-parietal sigma activity (12-15 Hz) than the young volunteers. Conversely, before no recall, older participants had less frontal-central delta activity and less sigma activity in frontal, central and parietal derivations than the young participants. REM sleep was associated to age-related changes, such that older participants had less frontal-central alpha (10-12 Hz) and beta (16-19 Hz) activity, irrespective of dream recall and no recall. Our data indicate that age-related differences in dream recall seem to be directly coupled to specific frequency and topography EEG patterns, particularly during NREM sleep. Thus, the spectral correlates of dreaming can help to understand the cortical pathways of dreaming., (© 2011 European Sleep Research Society.)

There is mounting evidence for the involvement of the sleep-wake cycle and the circadian system in the pathogenesis of major depression. However, only a few studies so far focused on sleep and circadian rhythms under controlled experimental conditions. Thus, it remains unclear whether homeostatic sleep pressure or circadian rhythms, or both, are altered in depression. Here, the authors aimed at quantifying homeostatic and circadian sleep-wake regulatory mechanisms in young women suffering from major depressive disorder and healthy controls during a multiple nap paradigm under constant routine conditions. After an 8-h baseline night, 9 depressed women, 8 healthy young women, and 8 healthy older women underwent a 40-h multiple nap protocol (10 short sleep-wake cycles) followed by an 8-h recovery night. Polysomnographic recordings were done continuously, and subjective sleepiness was assessed. In order to measure circadian output, salivary melatonin samples were collected during scheduled wakefulness, and the circadian modulation of sleep spindles was analyzed with reference to the timing of melatonin secretion. Sleep parameters as well as non-rapid eye movement (NREM) sleep electroencephalographic (EEG) spectra were determined for collapsed left, central, and right frontal, central, parietal, and occipital derivations for the night and nap-sleep episodes in the frequency range .75-25 Hz. Young depressed women showed higher frontal EEG delta activity, as a marker of homeostatic sleep pressure, compared to healthy young and older women across both night sleep episodes together with significantly higher subjective sleepiness. Higher delta sleep EEG activity in the naps during the biological day were observed in young depressed women along with reduced nighttime melatonin secretion as compared to healthy young volunteers. The circadian modulation of sleep spindles between the biological night and day was virtually absent in healthy older women and partially impaired in young depressed women. These data provide strong evidence for higher homeostatic sleep pressure in young moderately depressed women, along with some indications for impairment of the strength of the endogenous circadian output signal involved in sleep-wake regulation. This finding may have important repercussions on the treatment of the illness as such that a selective suppression of EEG slow-wave activity could promote acute mood improvement.

In sighted humans, light intensity, timing, exposure duration, and spectral composition of light are important to entrain the endogenous circadian pacemaker to the 24-h day-night cycle. We tested the impact of two realistic office lighting conditions during the afternoon on subjective sleepiness, hormonal secretion, and cognitive performance in the early evening hours. Twenty-nine young subjects came twice and spent 8 h (12:00-20:00) in our laboratory, where they were exposed for 6 h to either artificial light (AL) or to mainly daylight (DL). In the early evening, we assessed their salivary cortisol and melatonin secretion, subjective sleepiness, and cognitive performance (n-back test) under dim light conditions. Subjects felt significantly more alert at the beginning of the evening after the DL condition, and they became sleepier at the end of the evening after the AL condition. For cognitive performance we found a significant interaction between light conditions, mental load (2- or 3-back task) and the order of light administration. On their first evening, subjects performed with similar accuracy after both light conditions, but on their second evening, subjects performed significantly more accurately after the DL in both n-back versions and committed fewer false alarms in the 2-back task compared to the AL group. Lower sleepiness in the evening was significantly correlated with better cognitive performance (p < .05). In summary, even short-term lighting conditions during the afternoon had an impact on cognitive task performance in the evening. This rapid effect was only distinguishable on the second day of training, when a difficult task had been sufficiently practiced.

The accumulation of alpha-synuclein in Lewy bodies and Lewy neurites of different neuronal populations is one of the neuropathological hallmarks in Parkinson disease (PD). Overexpression of human wildtype or mutant alpha-synuclein affects the generation of new neurons in the adult dentate gyrus (DG) of the hippocampus in models of PD. Hippocampal dysfunction with reduced neurogenesis plays an important role in the pathogenesis of depression, an important non-motor symptom in PD. Moreover, effective antidepressant treatment is still an unmet need in PD. The present study explored if impaired hippocampal neurogenesis in the A53T transgenic animal model of PD may be restored by chronic oral application of the selective serotonin reuptake inhibitor (SSRI) fluoxetine. First, we determined the expression pattern of transgenic mutant A53T synuclein in developing DG neurons and showed early expression of the transgene linked to a severely impaired neurogenesis. After chronic fluoxetine treatment we observed an increased adult neurogenesis in the hippocampus of more than threefold in treated A53T mice compared with controls. The pro-neurogenic effect of chronic fluoxetine application is predominantly related to an increased proliferation of neural precursor cells in the DG, and to a lesser extent by induction of differentiation into mature neurons. Analysis of the underlying mechanisms revealed an induction of brain-derived and glial cell-derived neurotrophic factor levels as a result of fluoxetine treatment. This study underlines the large potential of SSRI-dependent mechanisms to stimulate adult hippocampal neurogenesis in alpha-synuclein models and may lead to novel means to improve neuropsychiatric symptoms in PD., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Evening bright light exposure is reported to ameliorate daytime sleepiness and age-related sleep complaints, and also delays the timing of circadian rhythms. We tested whether evening light exposure given to older adults with sleep-wake complaints would delay the timing of their circadian rhythms with respect to their sleep timing, thereby reducing evening sleepiness and improving subsequent sleep quality. We examined the impact of evening light exposure from two different light sources on subjective alertness, EEG activity during wakefulness, and sleep stages. Ten healthy older adults with sleep complaints (mean age=63.3 years; 6F) participated in a 13-day study. After three baseline days, circadian phase was assessed. On the evening of days 5-8 the subjects were exposed for 2h to either polychromatic blue-enriched white light or standard white fluorescent light, and on the following day circadian phase was re-assessed. Subjects were allowed to leave the laboratory during all but the two days when the circadian phase assessment took place. Evening assessments of subjective alertness, and wake and sleep EEG data were analyzed. Subjective alertness and wake EEG activity in the alpha range (9.75-11.25 Hz) were significantly higher during light exposures when compared to the pre-light exposure evening (p<0.05). The light exposures produced circadian phase shifts and significantly prolonged latency to rapid eye-movement (REM) sleep for both light groups (p<0.05). The increase in wake EEG alpha activity during the light exposures was negatively correlated with REM sleep duration (p<0.05). Evening light exposure could benefit older adults with early evening sleepiness, without negatively impacting the subsequent sleep episode., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Neuronal currents produce local electromagnetic fields that can potentially modulate the phase of the magnetic resonance signal and thus provide a contrast mechanism tightly linked to neuronal activity. Previous work has demonstrated the feasibility of direct MRI of neuronal activity in phantoms and cell culture, but in vivo efforts have yielded inconclusive, conflicting results. The likelihood of detecting and validating such signals can be increased with (i) fast gradient-echo echo-planar imaging, with acquisition rates sufficient to resolve neuronal activity, (ii) subjects with epilepsy, who frequently experience stereotypical electromagnetic discharges between seizures, expressed as brief, localized, high-amplitude spikes (interictal discharges), and (iii) concurrent electroencephalography. This work demonstrates that both MR magnitude and phase show large-amplitude changes concurrent with electroencephalography spikes. We found a temporal derivative relationship between MR phase and scalp electroencephalography, suggesting that the MR phase changes may be tightly linked to local cerebral activity. We refer to this manner of MR acquisition, designed explicitly to track the electroencephalography, as encephalographic MRI (eMRI). Potential extension of this technique into a general purpose functional neuroimaging tool requires further study of the MR signal changes accompanying lower amplitude neuronal activity than those discussed here., (Copyright © 2010 Wiley-Liss, Inc.)

Endometrial carcinomas (ECs) are classified into type 1 (less aggressive) and type 2 (aggressive) tumours that differ in genetic alterations. So far, reliable immunohistochemical markers that can identify patients with high risk for recurrence are rare. We have defined the expression of L1 cell adhesion molecule (L1CAM), a biomarker previously identified for EC, and compared its expression to oestrogen receptor (ER)/progesterone receptor (PR) and E-cadherin. We found that L1CAM was absent in normal endometrium and the vast majority of endometrioid ECs (type 1) but was strongly expressed in serous and clear-cell ECs, considered as type 2. 78/272 cases were identified as L1CAM-positive endometrioid ECs that were correlated with a poor prognosis. Strikingly, we observed an inverse relationship between L1CAM and ER/PR/E-cadherin expression in all ECs. In mixed ECs, composed of endometrioid (L1CAM(-) ER/PR(+) E-cadherin(+)) and clear-cell/serous (L1CAM(+) ER/PR(-) E-cadherin(-)), both phenotypes were co-expressed. In some of these cases L1CAM was up-regulated at the leading edge of the tumour, where ER/PR and E-cadherin expression were selectively lost. In EC cell lines treated with the epithelial-mesenchymal transition (EMT) inducer TGFbeta1, L1CAM and vimentin were strongly up-regulated, while E-cadherin expression was reduced. The treatment also resulted in an increased expression of the EMT transcription factor Slug and an enhanced cell invasion. Depletion of Slug by siRNA knockdown prevented both L1CAM up-regulation and enhanced cell invasion. According to our analysis, we suggest that L1CAM is a novel marker for EMT in ECs and that L1CAM-typing could identify endometrioid ECs that have type 2-like features and are at high risk for recurrence.

Study Objectives: Healthy aging is associated with changes in sleep-wake regulation, and those changes often lead to problems sleeping, both during the night and during daytime. We aimed to examine the electroencephalographic (EEG) sleep spectra during non-rapid eye movement (NREM) sleep when sleep was scheduled at all times of day., Design/interventions: After three 24-h baseline (BL) days, participants were scheduled to live on 20-hour "days" consisting of 6.7 hours of bed rest and 13.3 hours of wakefulness for 12 consecutive days (forced desynchrony, FD). The EEG was recorded from a central derivation during all scheduled sleep episodes, with subsequent visual scoring and spectral analysis., Setting: Intensive Physiological Monitoring Unit of the Brigham & Women's Hospital General Clinical Research Center., Participants: Twenty-four healthy older subjects (64.2 +/- 6.3 yr; 13 women, 11 men), Measurements and Results: Compared with BL nights, EEG activity in the slow wave (0.5 to 5.25 Hz), theta (6 to 6.25 and 7 Hz), alpha (10 to 11.25 Hz), and high spindle range (14.5 to 15.5 Hz) was significantly greater during FD, when subjects slept across many times of day and night. During FD, there was a significant interaction between homeostatic and circadian factors, such that EEG delta activity (0.5 to 1.5 Hz) was higher in the biological morning/early afternoon than at other times. EEG activity was significantly increased in almost all frequency ranges (0.5 to 21 Hz) during the biological day, as compared with the biological night, except for the lower EEG spindle range (12.25 to 14 Hz). Overall, EEG beta activity was positively correlated with wakefulness and negatively correlated with total sleep time., Conclusion: Our findings provide some new evidence for the underlying mechanisms that contribute to age-related difficulties in sleep consolidation, especially when sleep occurs during the daytime.

Orientation and self-location within the temporal fabric of the environment involves multiple organismic systems. While temporal self-location on the physiological level has been known for some time to be based on a 'biological clock' located within the hypothalamus, the mechanisms that participate in temporal position finding on the cognitive level are not yet fully understood. In order to probe the mechanisms that underlie this faculty, verbal estimates on time-of-day were collected at 3.75-h intervals from 16 young (7 males, 8 females; 20-31 years) and 16 older (8 males, 8 females; 57-74 years) subjects in a balanced crossover design during 40-h epochs of prolonged wakefulness and 40-h epochs of sleep satiation spent under constant routine conditions. An overestimation of clock time during prolonged wakefulness was found in both age-groups, with significantly larger errors for the older group (young: 0.5+/-0.2h; older: 1.5+/-0.2h, p<0.05). In both age-groups, estimation errors ran roughly parallel to the time course of core body temperature. However a significant interaction between time-of-day and age-group was observed (rANOVA, p<0.05): younger subjects exhibited similar estimation errors as the older subjects after 16 h of prior wakefulness, whereas the latter did not manifest decrements under high sleep pressure. Data collected under conditions of sleep satiation also displayed a diurnal oscillation in estimation errors and a general overestimation (young: 0.8+/-0.2h; older: 1.3+/-0.3h, p<0.05). Here however, the age-groups did not differ significantly nor was there an interactive effect between time-of-day and age-group. The effects of age, duration of wake time and circadian phase on temporal position finding are in line with predictions based on the idea that awareness about current position in time is derived from interval timing processes.

Subjective well-being largely depends on mood, which shows circadian rhythmicity and can be linked to rhythms in many physiological circadian markers, such as melatonin and cortisol. In healthy young volunteers mood is influenced by an interaction of circadian phase and the duration of time awake. The authors analyzed this interaction under differential sleep pressure conditions to investigate age and gender effects on subjective well-being. Sixteen healthy young (8 women, 8 men; 20-35 years) and 16 older volunteers (8 women, 8 men; 55-75 years) underwent a 40-h sleep deprivation (high sleep pressure) and a 40-h nap protocol (low sleep pressure) in a balanced crossover design under constant routine conditions. Mood, tension, and physical comfort were assessed by visual analogue scales during scheduled wakefulness, and their average formed a composite score of well-being. Significant variations in well-being were determined by the factors "age," "sleep pressure," and "circadian phase." Well-being was generally worse under high than low sleep pressure. Older volunteers felt significantly worse than the young under both experimental conditions. Significant interactions were found between "sleep pressure" and "age," and between "sleep pressure" and "gender." This indicated that older volunteers and women responded with a greater impairment in well-being under high compared with low sleep pressure. The time course of well-being displayed a significant circadian modulation, particularly in women under high sleep pressure conditions. The results demonstrate age- and/or gender-related modifications of well-being related to sleep deprivation and circadian phase and thus point to specific biological components of mood vulnerability.

Older adults have reduced sleep quality compared with younger adults when sleeping at habitual times and greater sleep disruption when their sleep is at adverse times. The purpose of this analysis was to investigate how subjective measures of sleep relate to objectively recorded sleep in older subjects scheduled to sleep at all times of day. We analyzed data from 24 healthy older (55-74 years) subjects who took part in a 32-day inpatient study where polysomnography was recorded each night and subjective sleep was assessed after each scheduled wake time. The study included baseline nights and a forced desynchrony (FD) protocol when the subjects lived on a 20-h rest activity schedule. Our postsleep questionnaire both included quantitative and qualitative questions about the prior sleep. Under baseline and FD conditions, objective and subjective sleep latency were correlated, subjective sleep duration was related to slow-wave sleep and wake after sleep onset, subjective sleep quality was related to stage 1 and 2 sleep, and sleepiness and refreshment at wake time were related to duration of premature awakening. During FD, most measures of objective and subjective sleep varied with circadian phase and many additional correlations between objective and subjective sleep were present. Our findings show that when sleeping at habitual times, these healthy older subjects did not perceive their generally poor sleep quality, but under FD conditions where sleep quality changed from day-to-day their subjective sleep ratings were more associated with their objective sleep.

The invariant-mass spectrum of e+e- pairs produced in 12C+12C collisions at an incident energy of 2 GeV per nucleon has been measured for the first time. The measured pair production probabilities span over 5 orders of magnitude from the pi(0)-Dalitz to the rho/omega invariant-mass region. Dalitz decays of pi(0) and eta account for all the yield up to 0.15 GeV/c(2), but for only about 50% above this mass. A comparison with model calculations shows that the excess pair yield is likely due to baryon-resonance and vector-meson decays. Transport calculations based on vacuum spectral functions fail, however, to describe the entire mass region.

Learning-dependent increases in sleep spindle density have been reported during nocturnal sleep immediately after the learning session. Here, we investigated experience-dependent changes in daytime sleep EEG activity after declarative learning of unrelated word pairs. At weekly intervals, 13 young male volunteers spent three 24 h sessions in the laboratory under carefully controlled homeostatic and circadian conditions. At approximately midday, subjects performed either one of two word-pair learning tasks or a matched nonlearning control task, in a counterbalanced order. The two learning lists differed in the level of concreteness of the words used, resulting in an easier and a more difficult associative encoding condition, as confirmed by performance at immediate cued recall. Subjects were then allowed to sleep for 4 h; afterward, delayed cued recall was tested. Compared with the control condition, sleep EEG spectral activity in the low spindle frequency range and the density of low-frequency sleep spindles (11.25-13.75 Hz) were both significantly increased in the left frontal cortex after the difficult but not after the easy encoding condition. Furthermore, we found positive correlations between these EEG changes during sleep and changes in memory performance between pre-nap and post-nap recall sessions. These results indicate that, like during nocturnal sleep, daytime sleep EEG oscillations including spindle activity are modified after declarative learning of word pairs. Furthermore, we demonstrate here that the nature of the learning material is a determinant factor for sleep-related alterations after declarative learning.

Light strongly influences the circadian timing system in humans via non-image-forming photoreceptors in the retinal ganglion cells. Their spectral sensitivity is highest in the short-wavelength range of the visible light spectrum as demonstrated by melatonin suppression, circadian phase shifting, acute physiological responses, and subjective alertness. We tested the impact of short wavelength light (460 nm) on sleep EEG power spectra and sleep architecture. We hypothesized that its acute action on sleep is similar in magnitude to reported effects for polychromatic light at higher intensities and stronger than longer wavelength light (550 nm). The sleep EEGs of eight young men were analyzed after 2-h evening exposure to blue (460 nm) and green (550 nm) light of equal photon densities (2.8 x 10(13) photons x cm(-2) x s(-1)) and to dark (0 lux) under constant posture conditions. The time course of EEG slow-wave activity (SWA; 0.75-4.5 Hz) across sleep cycles after blue light at 460 nm was changed such that SWA was slightly reduced in the first and significantly increased during the third sleep cycle in parietal and occipital brain regions. Moreover, blue light significantly shortened rapid eye movement (REM) sleep duration during these two sleep cycles. Thus the light effects on the dynamics of SWA and REM sleep durations were blue shifted relative to the three-cone visual photopic system probably mediated by the circadian, non-image-forming visual system. Our results can be interpreted in terms of an induction of a circadian phase delay and/or repercussions of a stronger alerting effect after blue light, persisting into the sleep episode.

The effects of sleep pressure and circadian phase on neurobehavioral function can be sensitively measured with the psychomotor vigilance task (PVT). We compared PVT performance in 16 young (8 men and 8 women, 20-31 years) and 16 elderly healthy subjects (8 men and 8 women, 57-74 years) during a 40-h sleep deprivation (SD, high sleep pressure) and a 40-h multiple nap protocol (NAP, low sleep pressure) under dim light and constant posture conditions in a balanced crossover design. Independent of age and sleep pressure conditions, women exhibited significantly slower reaction times (RTs) than men. This effect became more apparent with increasing time elapsed into both the 40-h NAP and SD protocol. However, women tended to have fewer premature key presses than men. Independent of gender, the elderly showed slower RTs than the young in the NAP protocol during the biological day (8-24 h) but not during the biological night (24-8 h). In the SD protocol, they had also significantly slower RTs but only during the first 16 h under low to moderate levels of sleep pressure conditions. The relative PVT performance decline after SD was significantly less pronounced in the elderly than in the young, so that both age groups exhibited similar performance decrements after 16 h into the SD protocol. Thus, nighttime- and sleep pressure-related RT slowing in the young "makes them old", or the elderly are less susceptible to circadian and wake-dependent PVT performance decrements. We interpret the gender effect as a different strategy in women when performing the PVT, although the instructions to be 'as fast as possible' were identical. Not only sleepiness and circadian phase, but also age and gender are major factors that may contribute to attentional failures in extended work shifts and during nighttime work shifts.

We developed a non-invasive method to measure and quantify human circadian PER2 gene expression in oral mucosa samples and show that this gene oscillates in a circadian (= about a day) fashion. We also have the first evidence that induction of human PER2 expression is stimulated by exposing subjects to 2 h of light in the evening. This increase in PER2 expression was statistically significant in comparison to a non-light control condition only after light at 460 nm (blue) but not after light exposure at 550 nm (green). Our results indicate that the non-image-forming visual system is involved in human circadian gene expression. The demonstration of a functional circadian machinery in human buccal samples and its response to light opens the door for investigation of human circadian rhythms at the gene level and their associated disorders.

The reduction of electroencephalographic (EEG) slow-wave activity (SWA) (EEG power density between 0.75-4.5 Hz) and spindle frequency activity, together with an increase in involuntary awakenings during sleep, represent the hallmarks of human sleep alterations with age. It has been assumed that this decrease in non-rapid eye movement (NREM) sleep consolidation reflects an age-related attenuation of the sleep homeostatic drive. To test this hypothesis, we measured sleep EEG characteristics (i.e., SWA, sleep spindles) in healthy older volunteers in response to high (sleep deprivation protocol) and low sleep pressure (nap protocol) conditions. Despite the fact that the older volunteers had impaired sleep consolidation and reduced SWA levels, their relative SWA response to both high and low sleep pressure conditions was similar to that of younger persons. Only in frontal brain regions did we find an age-related diminished SWA response to high sleep pressure. On the other hand, we have clear evidence that the circadian regulation of sleep during the 40 h nap protocol was changed such that the circadian arousal signal in the evening was weaker in the older study participants. More sleep occurred during the wake maintenance zone, and subjective sleepiness ratings in the late afternoon and evening were higher than in younger participants. In addition, we found a diminished melatonin secretion and a reduced circadian modulation of REM sleep and spindle frequency-the latter was phase-advanced relative to the circadian melatonin profile. Therefore, we favor the hypothesis that age-related changes in sleep are due to weaker circadian regulation of sleep and wakefulness. Our data suggest that manipulations of the circadian timing system, rather than the sleep homeostat, may offer a potential strategy to alleviate age-related decrements in sleep and daytime alertness levels.

Prefrontal cortex (PFC)-related functions are particularly sensitive to sleep loss. However, their repeated examination is intricate because of methodological constraints such as practice effects and loss of novelty. We investigated to what extent the circadian timing system and the sleep homeostat influence PFC-related performance in differently difficult versions of a single task. Parallel versions of a planning task combined with a control group investigation were used to control for practice effects. Thirteen healthy volunteers (five women and eight men, range 57-74 years) completed a 40-h sleep deprivation (SD) and a 40-h multiple nap protocol (NAP) under constant routine conditions. Each participant performed 11 easy and 11 difficult task versions under either SD or NAP conditions. The cognitive and motor components of performance could be distinguished and analysed separately. Only by thoroughly controlling for superimposed secondary factors such as practice or sequence effects, could a significant influence of circadian timing and sleep pressure be clearly detected in planning performance in the more difficult, but not easier maze tasks. These results indicate that sleep loss-related decrements in planning performance depend on difficulty level, and that apparently insensitive tasks can turn out to be sensitive to sleep loss and circadian variation.

The human circadian pacemaker maintains timing and consolidation of sleep-wake behavior by opposing the build-up of homeostatic sleep pressure during the wake episode, particularly in the evening during the 'wake maintenance zone'. We tested whether age-related changes in sleep are a consequence of a weaker circadian arousal signal in the evening. Circadian rhythms and spectral components of the sleep EEG were investigated in 17 young (20-31 year) and 15 older (57-74 year) volunteers under constant posture conditions during a 40-h nap protocol (75/150 min sleep/wake schedule). Quantitative evidence for a weaker circadian arousal signal in aging arose from significantly more sleep occurring during the wake maintenance zone and higher subjective sleepiness ratings in the late afternoon and evening in the older group. In addition, we found a diminished melatonin secretion and a reduced circadian modulation of REM sleep together with less pronounced day-night differences in the lower alpha and spindle range of sleep EEG activity in the older group. Thus, our data indicate that age-related changes in sleep propensity are clearly related to a reduced circadian signal opposing the homeostatic drive for sleep.

With age, the consolidation of nocturnal sleep decreases, daytime napping increases, and sleep occurs earlier. Sleep regulation is dependent on the interaction between a circadian pacemaker (biological clock) and the sleep homeostat (sleep pressure increasing with duration of time awake). We have shown that in the healthy elderly, the amplitude of circadian rhythms (e. g. melatonin secretion) declines, as does slow wave sleep, parallel with an increase in afternoon sleepiness and a tendency to fall asleep in the early evening when younger subjects do not. Light is the major zeitgeber to stabilise the biological clock: older subjects require sufficient light exposure during daytime and in the evening, and should take no or only brief naps during the day to improve sleep.

Light can elicit acute physiological and alerting responses in humans, the magnitude of which depends on the timing, intensity, and duration of light exposure. Here, we report that the alerting response of light as well as its effects on thermoregulation and heart rate are also wavelength dependent. Exposure to 2 h of monochromatic light at 460 nm in the late evening induced a significantly greater melatonin suppression than occurred with 550-nm monochromatic light, concomitant with a significantly greater alerting response and increased core body temperature and heart rate ( approximately 2.8 x 10(13) photons/cm(2)/sec for each light treatment). Light diminished the distal-proximal skin temperature gradient, a measure of the degree of vasoconstriction, independent of wavelength. Nonclassical ocular photoreceptors with peak sensitivity around 460 nm have been found to regulate circadian rhythm function as measured by melatonin suppression and phase shifting. Our findings-that the sensitivity of the human alerting response to light and its thermoregulatory sequelae are blue-shifted relative to the three-cone visual photopic system-indicate an additional role for these novel photoreceptors in modifying human alertness, thermophysiology, and heart rate.

Sleep loss has marked and selective effects on brain wave activity during subsequent recovery sleep. The electroencephalogram (EEG) responds to sleep deprivation with a relative increase in power density in the delta and theta range during non-rapid eye movement sleep. We investigated age-related changes of the EEG response to sleep deprivation along the antero-posterior axis (Fz, Cz, Pz, Oz) under constant routine conditions. Both healthy young (20-31 years) and older (57-74 years) participants manifested a significant relative increase in EEG power density in the delta and theta range after 40 h of sleep deprivation, indicating a sustained capacity of the sleep homeostat to respond to sleep loss in ageing. However, the increase in relative EEG delta activity (1.25-3.75 Hz) following sleep deprivation was significantly more pronounced in frontal than parietal brain regions in the young, whereas such a frontal predominance was diminished in the older volunteers. This age-related decrease of frontal delta predominance was most distinct at the beginning of the recovery sleep episode. Furthermore, the dissipation of homeostatic sleep pressure during the recovery night, as indexed by EEG delta activity, exhibited a significantly shallower decline in the older group. Activation of sleep regulatory processes in frontal brain areas by an extension of wakefulness from 16 to 40 h appears to be age-dependent. These findings provide quantitative evidence for the hypothesis that frontal brain regions are particularly vulnerable to the effects of elevated sleep pressure ('prefrontal tiredness') and ageing ('frontal ageing').

Allelic imbalance constitutes a major mechanism of genetic aberrations in breast cancer and strongly indicates the involvement of tumor associated genes in the affected chromosomal regions. Preliminary results from our study indicated the existence of a tumor suppressor gene located on chromosomal arm 15q which may be involved in breast cancer progression.1 In the present study, 210 primary breast carcinomas, 30 metastases and 26 local recurrences from primary breast carcinomas have been analyzed with a panel of 18 highly polymorphic microsatellite markers spanning the chromosomal region 15q11-21.3. Allelic imbalance at 15q with at least 1 marker was seen in 36 of 56 (64.3%) metastases and recurrences, but only in 58 of 210 (27.6%) primary tumors (p<0.0001). We identified a subregion defined by microsatellite marker CYP19 (15q21.1) that showed significantly higher frequencies of allelic imbalance in metastases and recurrences (57.6%) when compared to primary carcinomas (8.9%; p<0.0001). Allelic imbalance at 15q was correlated with histopathologic parameters of the patients with primary breast carcinomas. We detected a significant association with established predictors of poor prognosis, i.e., negative estrogen receptor status (p=0.003), negative progesterone receptor status (p=0.028), high grade (p=0.014) and positive axillary lymph nodes (p=0.013). In summary, our data provide further evidence for a novel prognostic marker in breast carcinomas located in the chromosomal region 15q21., (Copyright 2003 Wiley-Liss, Inc.)

We observed well-separated 1s and 2p pi(-) states in 205Pb in the 206Pb(d,3He) reaction at T(d) = 604.3 MeV. The binding energies and the widths determined are B(1s) = 6.762+/-0.061 MeV, Gamma(1s) = 0.764(+0.154)(-0.171) MeV, B(2p) = 5.110+/-0.045 MeV, and Gamma(2p) = 0.321(-0.062)(+0.060) MeV. They are used to deduce the real and imaginary strengths of the s-wave part of the pion-nucleus interaction, which translates into a positive mass shift of pi(-) in 205Pb.

The cholinergic system in rat and human airways and the effects of glucocorticoids were investigated by assay of choline acetyltransferase activity, by high-pressure liquid chromatography measurement of acetylcholine, and by anti-choline acetyltransferase immunocyto-/histochemistry. Human bronchi were obtained at surgery from patients with lung cancer. Group 1 patients did not suffer from additional lung diseases and had not been treated with glucocorticoids. Group 2 patients, who suffered in addition to lung cancer from chronic obstructive bronchitis, had been treated for at least 6 weeks before surgery with four puffs of flusinolid daily. Isolated bronchial epithelial cells as well as intact surface epithelium of human bronchi expressed choline acetyltransferase immunoreactivity and choline acetyltransferase enzyme activity (3 +/- 1 nmol/mg protein per h). Ciliated epithelial cells showed strong choline acetyltransferase immunoreactivity at the basal body and the roolet of cilia. Surface epithelium in group 1 and 2 bronchi contained 23 +/- 6 (n = 14) and 1.8 +/- 0.3 pmol/g acetylcholine) (n = 7, P < 0.001), respectively, whereas the transmural acetylcholine content did not differ significantly between both groups. The amount of choline acetyltransferase immunoreactivity appeared similar in the surface epithelium of both groups. In an animal (rat) study the effects of oral dexamethasone (3 mg/day, 1 week) on choline acetyltransferase activity and acetylcholine levels were investigated. Dexamethasone treatment reduced epithelial acetylcholine in the airways and small intestine by about 80% and inhibited epithelial choline acetyltransferase activity. In conclusion, epithelial cells of human airways possess components of the cholinergic system, i.e., contain the synthesizing enzyme choline acetyltransferase and store acetylcholine. The data obtained from the animal study indicate that glucocorticoids can inhibit epithelial acetylcholine.

Acetylcholine acts as a prominent transmitter in the central and peripheral nervous system. The aim of the present study was to investigate whether mammalian non-neuronal cells can synthesize and store acetylcholine. A cotton tipped applicator (Q-tip) was used to collect surface cells from airways and alimentary tract. Histological inspection indicated that rubbing of the luminal surface of human bronchi did not penetrate the basal membrane. Acetylcholine was measured by an HPLC-method using substrate-specific enzyme reactor-columns. Non-neuronal acetylcholine was found in cells covering inner and outer surfaces of rat and man. For example, acetylcholine was detected in the surface epithelium of human bronchi (33 pmol/g), mouth (female 0.7 and male 8 pmol/sample), small and large intestine (800 and 16 pmol/g, respectively), gall bladder (12 pmol/g), vagina (6 pmol/sample), skin 1000 (pmol/g) and in pulmonary pleura (5 pmol/sample). Somewhat higher amounts of acetylcholine were found in rat tracheal and intestinal epithelium and in rat skin. The synthesizing enzyme choline acetyltransferase (ChAT) was demonstrated in human surface epithelium by immunohistochemistry and by Western blot analysis. Enzymatic ChAT activity was demonstrated in isolated epithelial cells of human bronchi and small intestine (3.5 and 28 nmol/mg protein/h, respectively). Applied acetylcholine (in nM concentrations) increased, whereas inhibition of ChAT activity by bromoacetylcholine (10 microM) reduced the growth of cultured human bronchial epithelial cells. Inhibition of cell growth occurred also in the presence of atropine (1 microM) together with (+/-)-tubocurarine (30 microM). In conclusion, the present experiments demonstrate a widespread existence of non-neuronal acetylcholine in surface cells of man. Non-neuronal acetylcholine may act as a local signalling molecule.

In order to define the usefulness of subzonal sperm insertion (SUZI) and intracytoplasmic sperm injection (ICSI), we studied in a comparative trial 46 consecutive treatment cycles of microassisted fertilisation by SUZI and ICSI. By ICSI 9% of the oocytes in metaphase II were damaged in 26 treatment cycles, by SUZI, however, not one single egg in 20 cycles (p < 0.001). Fertilisation rate after ICSI (65%) was, particularly in cases with combined sperm defects as well, significantly higher than after SUZI (35%; p < 0.001). Additionally, after ICSI a higher transfer (100% vs. 75%; p < 0.05) and pregnancy rate could be obtained (38% vs. 10% per cycle; p < or = 0.05). At the moment, 3 healthy children are born (2 after SUZI, 1 after ICSI), 4 patients are in the 2nd and 3rd trimenon, respectively, the remaining 5 patients aborted. In conclusion, the ICSI technique yields better results than SUZI, especially in cases of very severe male subfertility.

The impairment of sleep quality is a common complaint during pregnancy. To investigate the changes in sleep in the course of pregnancy, the sleep electroencephalogram (EEG) was recorded and analyzed in nine healthy women on 2 consecutive nights during each trimester of pregnancy. Waking after sleep onset increased from the second (TR2) to the third (TR3) trimester, whereas rapid eye movement (REM) sleep decreased from the first trimester (TR1) to TR2. Spectral analysis of the EEG in nonrapid eye movement (NREM) sleep revealed a progressive reduction of power density in the course of pregnancy. In comparison to TR1, the values in TR2 were significantly lower in the 10.25-11.0-Hz and 14.25-17.0-Hz bands. In TR3, the significant reduction extended over the ranges of 1.25-12.0 Hz and 13.25-16.0 Hz. The largest decrease (30%) occurred in the 14.25-15.0-Hz band. In REM sleep, the spindle frequency range was not affected, and a minor reduction of power density in some frequency bins below 12 Hz was present only in TR3. The study documents major alterations of the sleep EEG that are not evident from the sleep scores and that may be associated with the characteristic hormonal changes occurring during pregnancy.

Microinsemination is a new method of treating sterility. It improves the chance of fertilization in cases of severe male subfertility and of unexplained infertility. Fertilization is assisted by opening the zona pellucida with a microneedle (PZD), by introducing a small number of sperms with a micropipette into the perivitelline space (SUZI) or by direct insertion of a spermatozoon into the ooplasm (ICSI). We report on the first delivery achieved by microinsemination (SUZI) at the University Hospital Zurich and, as far as we know, in Switzerland.

A total of 121 patients suffering from erectile dysfunction were evaluated by means of a questionnaire. In all these cases corpus cavernosum autoinjection therapy had been recommended. The aim of the study was to determine the acceptance and complications of the therapy, general level of satisfaction with it, and reasons for refusal. Completed questionnaire were received from 89 patients (75.5%), 56.2% of whom had applied the therapy continuously, while 18% had broken it off and 25.8% had never started on therapy (cumulative dropout rate 43.8%). The complications encountered were temporary hematomas (25.8) and deviations of the penis (10.1%). In 6.1% indurations of the penis were found. The frequency of prolonged erection needing an antidote was 0.07% in the continuous treatment group. The relatively high drop-out rate in the autoinjection therapy group shows the necessity for intensive patient care and the need for alternative therapy options and a more critical view of reports already published of success with autoinjection therapy.

A single 10 mg dose of zolpidem, an imidazopyridine hypnotic, was administered to young, healthy male volunteers prior to bedtime. The drug reduced REM sleep but did not significantly affect other sleep stages and subjective sleep parameters. All-night spectral analysis of the EEG revealed that power density in nonREM sleep was reduced in the low-frequency range (1.25-2.5 Hz; 5.25-10.0 Hz) and increased in the spindle frequency range (12.25-13.0 Hz). Significant changes in the EEG spectrum were present in the first 4 h of sleep. The pattern of the spectral changes was similar to those induced by other hypnotics that bind to the GABAA/benzodiazepine receptor complex. There were no residual effects of zolpidem on psychomotor performance in the morning, on the self-rated state in the morning and at noon, and on sleep and EEG parameters in the subsequent drug-free night.