EXPRESSION OF p53 AND Ki67 IN TYPE 1 AND TYPE 2 ENDOMETRIAL CARCINOMAS AND IN LOW AND HIGH GRADE SEROUS OVARIAN CARCINOMAS

Ovarian cancer is the deadliest of gynecological malignancies, and despite the efforts to improve existing treatment methods and early diagnosis, no progress has been made. Endometrial carcinoma (EC) is the fourth most common malignancy in women. The p53 gene has a leading role in the control of the cell cycle and the initiation of carcinogenesis. The p53 protein induces apoptosis, or cell cycle arrest, which allows the cell to repair genomic damage. Loss of p53 function plays a central role in the development of malignant tumors. P53 is a tumor suppressor gene whose expression in tumors is associated with progression and poor prognosis. Ki67 protein is a cell proliferation marker. Immunohistochemical staining with Ki-67 provides reliable data on the growth fraction of tumors. The Ki67 marker reflects cell proliferation in the tissue being examined. By reading the immunohistochemical expression of Ki67, we can obtain information about the proliferative index and about the growth fraction of tumors. The number of Ki67 positive tumor cells often correlates with the clinical course

Abnormal activity in hypothalamus and amygdala during humour processing in human narcolepsy with cataplexy

Narcolepsy with cataplexy (NC) is a complex sleep-wake disorder, which was recently found to be associated with a reduction or loss of hypocretin (HCRT, also called orexin). HCRT is a hypothalamic peptide implicated in the regulation of sleep/wake, motor and feeding functions. Cataplexy refers to episodes of sudden and transient loss of muscle tone triggered by strong, mostly positive emotions, such as hearing or telling jokes. Cataplexy is thought to reflect the recruitment of ponto-medullary mechanisms that normally underlie muscle atonia during REM-sleep. In contrast, the suprapontine brain mechanisms associated with the cataplectic effects of emotions in human narcolepsy with cataplexy remain essentially unknown. Here, we used event-related functional MRI to assess brain activity in 12 NC patients and 12 controls while they watched sequences of humourous pictures. Patients and controls were similar in humour appreciation and activated regions known to contribute to humour processing, including limbic and striatal regions. A direct statistical comparison between patients and controls revealed that humourous pictures elicited reduced hypothalamic response together with enhanced amygdala response in the patients. These results suggest (i) that hypothalamic HCRT activity physiologically modulates the processing of emotional inputs within the amygdala, and (ii) that suprapontine mechanisms of cataplexy involve a dysfunction of hypothalamic-amygdala interactions triggered by positive emotion

Sodium oxybate in narcolepsy with cataplexy: Zurich sleep center experience

Sodium oxybate (SO; Xyrem®) has been approved in most countries for treatment of narcolepsy and cataplexy. In this study, we present a single-center experience of a series of 18 patients with narcolepsy with cataplexy (18/18 DQB1*0602 positive, 17/17 with low/absent cerebrospinal fluid hypocretin) in whom SO was prescribed. After 26 ± 13 months, 13/18 patients were still on SO at a mean dosage of 6.1 ± 1.2 g (in 8 of them in combination with stimulants). The following significant effects were observed: improved subjective sleepiness (12/13), cataplexy (13/13; median number of attacks from 20 to 1/month), hallucinations (8/10) and sleep paralysis (8/8); increase in mean sleep latency on the Maintenance of Wakefulness Test (from 5.5 to 17.4 min) and sleep/rest efficiency on actigraphy (from 61 to 76%); decrease in Epworth Sleepiness Scale score (from 18 to 14), sleep onset REM periods on the Multiple Sleep Latency Test (from 3.6 to 2.4) and errors in the Steer-Clear Test (from 11 to 2%). Five patients discontinued SO because of insufficient compliance (n = 2), lack of efficiency (n = 1) and side effects (n = 1). These data confirm and expand previous reports on the good effects and tolerability of SO as a treatment for narcolepsy with cataplexy

Recognition and diagnosis of sleep disorders in Parkinson's disease

Contains fulltext : 109296.pdf (publisher's version ) (Open Access)Sleep disturbances are among the most frequent and incapacitating non-motor symptoms of Parkinson's disease (PD), and are increasingly recognized as an important determinant of impaired quality of life. Here we review several recent developments regarding the recognition and diagnosis of sleep disorders in PD. In addition, we provide a practical and easily applicable approach to the diagnostic process as a basis for tailored therapeutic interventions. This includes a stepwise scheme that guides the clinical interview and subsequent ancillary investigations. In this scheme, the various possible sleep disorders are arranged not in order of prevalence, but in a 'differential diagnostic' order. We also provide recommendations for the use of sleep registrations such as polysomnography. Furthermore, we point out when a sleep specialist could be consulted to provide additional diagnostic and therapeutic input. This structured approach facilitates early detection of sleep disturbances in PD, so treatment can be initiated promptly

Mechanisms and therapeutic applications of electromagnetic therapy in Parkinson's disease

© 2015 Vadalà et al. Electromagnetic therapy is a non-invasive and safe approach for the management of several pathological conditions including neurodegenerative diseases. Parkinson's disease is a neurodegenerative pathology caused by abnormal degeneration of dopaminergic neurons in the ventral tegmental area and substantia nigra pars compacta in the midbrain resulting in damage to the basal ganglia. Electromagnetic therapy has been extensively used in the clinical setting in the form of transcranial magnetic stimulation, repetitive transcranial magnetic stimulation, high-frequency transcranial magnetic stimulation and pulsed electromagnetic field therapy which can also be used in the domestic setting. In this review, we discuss the mechanisms and therapeutic applications of electromagnetic therapy to alleviate motor and non-motor deficits that characterize Parkinson's disease

Excessive daytime sleepiness in idiopathic restless legs syndrome: characteristics and evolution under dopaminergic treatment

BACKGROUND/AIMS: Whereas insomnia is frequent in restless legs syndrome (RLS), little is known about daytime sleepiness. We studied a series of 27 consecutive patients with idiopathic RLS in order to identify the characteristics and evolution of excessive daytime sleepiness (EDS) under dopaminergic treatment. METHODS: Patients were assessed by clinical examination, questionnaires and video-polysomnography (PSG). Sleepy patients, as defined by Epworth Sleepiness Scale (ESS) >10, were also assessed by the multiple sleep latency test (MSLT). We excluded RLS patients with other sleep-wake disorders, in particular chronic sleep deprivation. RESULTS: Mean age was 56 years, the mean International RLS Study Group Rating Scale score was 24 at baseline. Ten (37%) of the 27 patients reported EDS. RLS patients with sleepiness had a higher amount of total sleep time (p = 0.029) on PSG and a mean sleep latency of 6.4 min on MSLT. No other differences regarding clinical or polysomnographic parameters were found. RLS severity improved in all patients under dopaminergic treatment (p = 0.001); this was also the case for the ESS score in sleepy patients (p = 0.007). CONCLUSION: In our series of RLS patients, EDS was common, characterized by longer sleep (PSG) and reduced sleep latencies on MSLT. Under dopaminergic treatment, both RLS severity and ESS improved

Diagnostic delay in narcolepsy type 1: combining the patients' and the doctors' perspectives

Narcolepsy type 1 is a neurological disorder characterized by a unique syndrome, including the pathognomonic symptom of cataplexy. The diagnosis can be confirmed by objective measures, such as typical findings in the multiple sleep latency test, reduced or undetectable levels of orexin (hypocretin) in the cerebrospinal fluid, and linkage to a specific HLA haplotype. Nevertheless, the mean time that elapses from symptom onset to the correct diagnosis ranges between 10 and 20 years, and the causes and correlates of this delay are poorly understood. Diagnostic delay was assessed on 52 well-defined patients with narcolepsy type 1, evaluating clinical, electrophysiological and neurochemical parameters and the results of a 41-item questionnaire developed to obtain the patients' perspective on various aspects of the diagnostic process. The mean time gap between disease onset and first medical consultation was 3.2 ± 5.1 years; the mean diagnostic delay was 8.9 ± 11.0 years. Prior to correct diagnosis, patients received a wide variety of misdiagnoses. The self-ratings of the patients revealed that the undiagnosed symptoms caused high levels of anxiety and unjustified criticism by family, friends and employers. Multiple regression analysis identified higher cerebrospinal fluid orexin levels (β = 0.311, P = 0.01), and a longer interval between the onset of excessive daytime sleepiness and cataplexy (β = 0.368, P = 0.002) as independent associates of longer diagnostic delay. The diagnostic delay decreased over the last decades (β = -0.672, P < 0.001). In conclusion, delayed diagnosis of narcolepsy type 1 is very common, associated with many adverse consequences, and requires educational efforts to improve awareness on narcolepsy among healthcare providers and the general population

Cyclic alternating pattern in narcolepsy patients and healthy controls after partial and total sleep deprivation

OBJECTIVE: To investigate the regulation NREM sleep at baseline and in morning recovery sleep after partial and total sleep deprivation (SD) in narcolepsy-cataplexy (NC) using cyclic alternating pattern (CAP). METHODS: Daytime sleep under either increased (no sleep in the previous night) or decreased sleep pressure (allowing 4h of sleep, 23:00-3:00 h) was recorded in ten drug-free, HLA-positive, hypocretin deficient NC patients and ten age, gender and body mass index matched healthy controls. Baseline sleep was also recorded and used for comparison purposes. CAP parameters were scored and analyzed for each subject. RESULTS: Narcolepsy patients had significantly lower CAP rate, CAP index, CAP time, number of CAP cycles, A1 index and number of A1 cycles in comparison to healthy controls at baseline as well as after partial and total SD. In both narcolepsy patients and healthy control subjects there was a significant decrease in these parameters after partial and total SD but the changes followed a similar pattern. CONCLUSION: The persistence of baseline differences in CAP parameters between narcolepsy patients and healthy controls and their similar behavior after partial and total SD suggests similar homeostatic NREM sleep regulation but on a different level. SIGNIFICANCE: CAP analysis demonstrates that NREM sleep homeostasis although altered, is functional in narcolepsy patients

Bound to supine sleep: Parkinson's disease and the impact of nocturnal immobility

BACKGROUND Impaired nocturnal mobility is a well-known problem in Parkinson's disease (PD), and clinical experience suggests a predominance of supine body position during sleep. However, this assumption - and potential consequences - still awaits objective validation by a polysomnography-based and adequately controlled study. METHODS Clinical and polysomnographical analysis of 80 consecutive PD patients and 80 control subjects carefully matched for age, sex, body mass index and apnea-hypopnea index. RESULTS PD patients slept twice as much in supine position than control subjects (62.2 ± 32.9% vs. 34.2 ± 28.5%, p < 0.001). In PD, but not in control subjects, more supine sleep correlated with fewer changes in body position (rho = -0.434, p < 0.001). Longer PD disease duration was an independent predictor of more supine sleep in multiple linear regression analysis (β = 0.389, p < 0.001); conversely, more supine sleep was associated with higher apnea-hypopnea index and daytime sleepiness. CONCLUSIONS We confirmed that supine sleep is common in PD, and increases with longer disease duration. Our findings indicate that supine sleep may contribute to the overall disease burden by deteriorating sleep-disordered breathing and daytime vigilance

Revisiting the impact of REM sleep behavior disorder on motor progression in Parkinson's disease

BACKGROUND Estimation of progression in Parkinson's disease (PD) is useful to guide clinical decisions and to enable patients to plan and manage their life with PD. Rapid eye movement (REM) sleep behavior disorder (RBD) and REM sleep without atonia (RWA) are recognized as early harbingers of neurodegeneration and may precede motor symptoms by years. However, their impact on motor progression remains elusive. METHODS We retrospectively analyzed polysomnographic and clinical data of 59 PD patients, grouping them into patients with RBD (n = 15), RWA (n = 22) and those with normal muscle atonia (n = 22). We compared the three groups with regard to motor progression, defined as changes in Unified Parkinson's Disease Rating Scale (UPDRS) III values per year, and selected PD specific characteristics. RESULTS Motor disability at first visit and time interval between first and last visits were similar between groups. We observed a significantly faster motor progression in PD patients with RBD and RWA than in those with preserved REM sleep atonia. CONCLUSION Our findings suggest that impaired muscle atonia during REM sleep might represent a marker of faster motor progression in PD