No abstract

Daytime sleepiness is a common complaint in blind subjects. Abnormally timed melatonin has been invoked as a possible cause of both daytime sleepiness and nighttime awakening. In free-running blind individuals, there is an opportunity to assess the relationship between endogenous melatonin rhythms and subjective sleepiness and naps. The aim of this study was to characterize melatonin rhythms and simultaneously to evaluate subjective napping. A total of 15 subjects with no conscious light perception (NPL) were studied for 1 month. Prior to the study, sleep disorders were assessed using the Pittsburgh Sleep Quality Index. Cosinor and regression analysis revealed that 9 of the 15 NPL subjects had free-running 6-sulphatoxymelatonin (aMT6s) rhythms (period [tau] range = 24.34 to 24.79 h), 3 were entrained with an abnormal phase, and 3 were normally entrained. Most of the subjects (13 of 15) had daytime naps; the 2 individuals who did not made conscious efforts not to do so. Subjects with abnormal aMT6s rhythms had more naps of a longer duration than did those with normal rhythms. Free-running nap rhythms occurred only in subjects with free-running aMT6s rhythms. The 2 abnormally entrained subjects who napped did so at times that coincided with high levels of aMT6s (mean aMT6s acrophase [phi] +/- SD = 14.30 +/- 1.08 h, 20.30 +/- 0.62 h; mean nap time +/- SD = 14.01 +/- 3.60 h, 18.23 +/- 3.20 h, respectively). Regardless of aMT6s rhythm abnormality, significantly more naps occurred with a 4-h period before and after the estimated aMT6s acrophase. In 4 free-running subjects, aMT6s acrophase (phi) passed through an entire 24-h period. When aMT6s was in a normal phase position (24:00 to 06:00 h), night-sleep duration tended to increase with a significant reduction in the number and duration of naps. Sleep onset and offset times tended to advance and delay as the aMT6s rhythms advanced and delayed. Our results show a striking relationship between the timing of daytime production of melatonin and the timing of daytime naps. This suggests that abnormally timed endogenous melatonin may induce sleepiness in blind subjects.

Blind individuals are not only handicapped by their loss of vision, but are also affected because the loss of sight may have a secondary impact on functioning of their biological clock. The objective of the present study was to determine the impact of visual loss on sleep/wake disorders. A prospective 48-item questionnaire survey was distributed to blind individuals through the French Association Valentin Haüy, which serves blind persons. A control group matched by age, sex, geographical location and professional activity/non-activity was obtained from a panel of 20000 households representative of the French population, and this group also completed the questionnaire. From a potential blind population of 1500 subjects, 1073 questionnaires (71.5%) were completed and usable for analysis, and from a potential 1000 control subjects, 794 (79. 4%) of the questionnaires were returned and analysed. Criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders, 4th revision, and the International Classification of Sleep/Wake Disorders (1990) were used to determine pathology. Individuals determined to be 'totally blind' and 'almost blind' (i.e. with less than 10% vision left in only one eye) presented a significantly higher occurrence of sleep/wake disorders than controls. Nocturnal sleep disruption, daytime somnolence, and (to a lesser degree) a 'free-running' condition are significantly more common in blind individuals. There is an increased use of sleeping pills, and a higher incidence of inappropriate involuntary daily naps. In conclusion, individuals with blindness report a significant curtailment of total sleep time and hence resulting daytime somnolence, which impacts on daytime activities. A 'free-running' condition is also a common sleep/wake impairment that may compound the handicap of blindness.

No abstract

Purpose: Human telomerase reverse transcriptase (hTERT) is highly expressed in >85% of human tumors and is thus considered as a good tumor-associated antigen candidate for vaccine development. We conducted a phase I study to investigate the safety, tolerability, clinical response, and immunogenicity of INVAC-1, a DNA plasmid encoding a modified hTERT protein in patients with relapsed or refractory solid tumors.Patients and Methods: INVAC-1 was either administered by intradermal route followed by electroporation or by Tropis, a needle-free injection system. Safety and tolerability were monitored by clinical and laboratory assessments. Progression-free survival and overall survival were reported using Kaplan-Meier survival analysis. Immunogenicity was studied by ELISpot, Luminex, and Flow Cytometry.Results: Twenty-six patients were treated with INVAC-1 administered at three dose levels (100, 400, and 800 mg). Vaccination was well tolerated and no dose-limiting toxicity was reported. One treatment-related grade 3 SAE was reported. Fifty-eight percent of patients experienced disease stabilization. PFS was 2.7 months, median OS was 15 months, and 1-year survival was reached for 65% of patients. INVAC-1 vaccination stimulated specific anti-hTERT CD4 T-cell response as well as cytotoxic CD8 T-cell response. No evidence of peripheral vaccine-induced immunosuppression was observed.Conclusions: INVAC-1 vaccination was safe, well tolerated, and immunogenic when administered intradermally at the three tested doses in patients with relapsed or refractory cancers. Disease stabilization was observed for the majority of patients (58%) during the treatment period and beyond.See related commentary by Slingluff Jr, p. 529