Low-level constitutional mosaicism of a de novoBRCA1 gene mutation.

BACKGROUND: Pathogenic BRCA1 mutations are usually inherited. Constitutional low-level BRCA1 mosaicism has never been reported. METHODS: Next-generation sequencing (NGS) of cancer gene panel of germline and tumour DNA in a patient with early onset, triple-negative breast cancer. RESULTS: Constitutional de novo mosaicism (5%) for a pathogenic (c.1953dupG; p.Lys652Glufs*21) BRCA1mutation was detected in leukocytes, buccal tissue and normal breast tissue DNA, with ∼50% mutation in tumorous breast tissue. CONCLUSION: This is the first reported case of low-level, multiple tissue, constitutional mosaicism in BRCA1, and highlights the need to consider deep sequencing in affected individuals clinically suspected of having cancer predisposition whose tumours display a BRCA mutation.

Repeated nocturnal sleep latencies in narcoleptic, sleepy and alert subjects.

OBJECTIVES: The purpose of this study was to assess nocturnal sleep latencies among narcoleptics. METHODS: Thirteen narcoleptics and matched sleepy and alert controls participated in this study. Subjects were awakened three times on each of two experimental nights. The latencies to sleep and rapid eye movement sleep were evaluated at the beginning of the night and following each experimental awakening. RESULTS: The alert group (AG) had a significantly longer mean nocturnal sleep latency than the narcoleptic (NG) and sleepy groups (SG). The sleep latencies at 23:00 and 01:10 h were significantly longer than the latencies at 03:10 and 05:10 h. The interaction between group and time of night demonstrated longer latencies at 23:00 and 03:10 h for the AG when compared to the SG and the NG. At 01:10 and 05:10 h all groups had comparable latencies. The number of subjects in the NG who had multiple sleep onset REM periods (SOREMPs) was significantly higher than in either the AG or the SG. CONCLUSIONS: Narcoleptics were found to have a heightened propensity to fall asleep and increased number of SOREMPs during nocturnal sleep opportunities. These characteristics are consistent with the daytime polysomnographic findings known in this patient population.

Characterization of the chicken GCAP gene array and analyses of GCAP1, GCAP2, and GC1 gene expression in normal and rd chicken pineal.

PURPOSE: This study had three objectives: (1) to characterize the structures of the chicken GCAP1 and GCAP2 genes; (2) to determine if GCAP1, GCAP2, and GC1 genes are expressed in chicken pineal gland; (3) if GC1 is expressed in chicken pineal, to determine if the GC1 null mutation carried by the retinal degeneration (rd) chicken is associated with degenerative changes within the pineal glands of these animals. METHODS: GCAP1 and GCAP2 gene structures were determined by analyses of chicken cosmid and cDNA clones. The putative transcription start points for these genes were determined using 5'-RACE. GCAP1, GCAP2 and GC1 transcripts were analyzed using Northern blot and RT-PCR. Routine light microscopy was used to examine pineal morphology. RESULTS: Chicken GCAP1 and GCAP2 genes are arranged in a tail-to-tail array. Each protein is encoded by 4 exons that are interrupted by 3 introns of variable length, the positions of which are identical within each gene. The putative transcription start points for GCAP1 and GCAP2 are 314 and 243 bases upstream of the translation start codons of these genes, respectively. As in retina, GCAP1, GCAP2 and GC1 genes are expressed in the chicken pineal. Although the GC1 null mutation is present in both the retina and pineal of the rd chicken, only the retina appears to undergo degeneration. CONCLUSIONS: The identical arrangement of chicken, human, and mouse GCAP1/2 genes suggests that these genes originated from an ancient gene duplication/inversion event that occurred during evolution prior to vertebrate diversification. The expression of GC1, GCAP1, and GCAP2 in chicken pineal is consistent with the hypothesis that chicken pineal contains a functional phototransduction cascade. The absence of cellular degeneration in the rd pineal gland suggests that GC1 is not critical for pineal cell survival.

The detection of brief daytime sleep episodes.

INTRODUCTION: In the present study we evaluated the characteristics of sleep-onset detection (during daytime nap opportunities) as a function of differing sleep lengths among healthy, asymptomatic subjects. METHODS: Twenty subjects were randomized into a Latin square design in which each subject received 1, 5, 10, and 20 minutes of sleep during an MSLT. Subjects were asked after each nap if they fell asleep. The rate of sleep detection was analyzed as a function of sleep duration. RESULTS: Three subjects detected sleep onset after 1 minute of sleep, 7 subjects after 5 minutes of sleep, 10 subjects after 10 minutes of sleep, and 14 after 20 minutes of sleep (chi 2 = 9.63, p < .05). CONCLUSIONS: The present data indicate the importance of sleep duration in an individual's ability to detect the occurrence of sleep. Importantly, only three subjects detected sleep after 1 minute of sleep, emphasizing the dangerous nature of brief sleep episodes in the context of public safety.

The perception of sleep as a function of the level of daytime sleepiness among patients with obstructive sleep apnea.

Subjective estimates of sleep onset among patients with a variety of sleep disorders have been shown to be inaccurate. This inability in perceiving sleep onset is potentially dangerous for this population, in particular, for individuals who are required to drive long distances or operate heavy machinery as part of their daily activities. This study evaluated the perception of sleep among 237 consecutive patients diagnosed with obstructive sleep apnea. Patients completed an overnight sleep-laboratory evaluation followed by an objective evaluation of sleep propensity. The latter was done using the Multiple Sleep Latency Test (MSLT). Patients with an accurate perception of having slept on the MSLT were found to have shorter sleep latencies when compared with those with an inaccurate perception of their sleep. The results of this study suggest that the rapidity with which sleep is manifested is an important contributor to the accurate perception of sleep.

The effects of REM sleep deprivation on the level of sleepiness/alertness.

STUDY OBJECTIVES: The purpose of this study was to evaluate the effects of acute REM deprivation on daytime sleepiness/alertness, as measured by the MSLT. PARTICIPANTS: Twenty-six healthy, normal volunteers (14 males and 12 females) participated in this study. Participating subjects were in good physical and psychological health and were asymptomatic as to sleep/wake complaints. INTERVENTIONS: Subjects spent 5 nights and 5 days in the laboratory. The first night and day were utilized for screening purposes. The remaining stay in the laboratory consisted of a baseline night and day, 2 deprivation nights and days, and a recovery night and day. Each night, a nocturnal polysomnogram was employed to monitor subjects' sleep. Each day, subjects underwent an MSLT to evaluate their sleepiness/alertness. Subjects were randomized into REM-deprivation (RD) and yoked-control (YC) groups. On deprivation nights, RD subjects were awakened each time they entered stage REM sleep, and the YC subjects were awakened concomitantly with the RD subjects, assuming they were not in stage REM sleep. RESULTS: The REM-deprived subjects did not demonstrate any changes in MSLT scores across experimental days. In contrast, the YC subjects documented significantly lower MSLT scores on deprivation days due to decreased total sleep time. CONCLUSION: The REM-deprivation procedure antagonized the effects of sleep loss on daytime sleepiness, resulting in increased alertness for RD subjects compared to YC subjects. The mechanism by which REM deprivation exerts its alerting effects is unknown and will require future research.

Daytime CPAP titration: a viable alternative for patients with severe obstructive sleep apnea.

OBJECTIVE: Continuous positive airway pressure (CPAP) is the treatment of choice for patients diagnosed with severe obstructive sleep apnea (OSA). The implementation of CPAP therapy has traditionally been based on full-night titration studies or split-night protocols. This study compared a group of patients who received a regular nocturnal CPAP titration with patients who received a daytime CPAP titration. The objective of the study was to determine if daytime CPAP titration is a viable alternative for the implementation of CPAP treatment in patients with severe OSA. STUDY DESIGN: Fourteen patients (13 men and one woman) received a daytime CPAP titration (day group). The day group was matched to 18 patients (17 men and one woman) who were titrated under a full-night regular nocturnal study (night group). Eligible patients were those with severe OSA (respiratory event index > 40). The groups were matched by age, sex, and body mass index. RESULTS: Daytime and nocturnal CPAP titration studies yielded sufficient amounts of rapid eye movement (REM) and non-REM sleep to help determine CPAP settings. Importantly, the diurnal and nocturnal CPAP titrations resulted in comparable therapeutic pressures as well as comparable resolution of sleep-disordered breathing. After 1 week of treatment, the groups exhibited similar CPAP use and comparable improvements in subjective sleepiness as indicated by their increase in sleep/wake activity inventory scores. CONCLUSIONS: Daytime CPAP titration studies may be a viable alternative for the efficient and expedient implementation of CPAP therapy among some patients with severe OSA.