Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening

Central Control of Circadian Phase in Arousal-Promoting Neurons

<div><p>Cells of the dorsomedial/lateral hypothalamus (DMH/LH) that produce hypocretin (HCRT) promote arousal in part by activation of cells of the locus coeruleus (LC) which express tyrosine hydroxylase (TH). The suprachiasmatic nucleus (SCN) drives endogenous daily rhythms, including those of sleep and wakefulness. These circadian oscillations are generated by a transcriptional-translational feedback loop in which the <i>Period</i> (<i>Per</i>) genes constitute critical components. This cell-autonomous molecular clock operates not only within the SCN but also in neurons of other brain regions. However, the phenotype of such neurons and the nature of the phase controlling signal from the pacemaker are largely unknown. We used dual fluorescent <i>in situ</i> hybridization to assess clock function in vasopressin, HCRT and TH cells of the SCN, DMH/LH and LC, respectively, of male Syrian hamsters. In the first experiment, we found that <i>Per1</i> expression in HCRT and TH oscillated in animals held in constant darkness with a peak phase that lagged that in AVP cells of the SCN by several hours. In the second experiment, hamsters induced to split their locomotor rhythms by exposure to constant light had asymmetric <i>Per1</i> expression within cells of the middle SCN at 6 h before activity onset (AO) and in HCRT cells 9 h before and at AO. We did not observe evidence of lateralization of <i>Per1</i> expression in the LC. We conclude that the SCN communicates circadian phase to HCRT cells via lateralized neural projections, and suggests that <i>Per1</i> expression in the LC may be regulated by signals of a global or bilateral nature.</p></div

Representative confocal images taken at the level of the (A) SCN, (B) perifornical LH/DMH, (C) LC.

<p>Within each brain region, top row shows cells detected in the Alexa488 channel, middle row shows the HNPP/FR signal indicating <i>Per1</i> and bottom row is the merged image. A single ∼1micron thick section of a 10 section z-stack was selected as a representative image. Scale bar equals 100 microns. Within each brain region, a section taken from representative animals killed at CT3, CT9, CT12.5 or CT22 is shown.</p

<i>Per1</i> intensity quantified by category of intensity within HCRT cells.

<p>Distribution of cells expressing high (<i>left</i>), moderate (<i>center</i>) or low (<i>right</i>) levels of <i>Per1</i> in the (A) medial, (B) perifornical and (C) lateral regions of the <i>HCRT</i>-expressing cells of the LH/DMH. * p<0.05 vs. low side.</p

Expression of haPer1 and haBmal1 in Syrian Hamsters: Heterogeneity of Transcripts and Oscillations in the Periphery

The molecular biology of circadian rhythms has been extensively studied in mice, and the widespread expression of canonical circadian clock genes in peripheral organs is well established in this species. In contrast, much less information about the peripheral expression of haPer1, haPer2, and haBmal1 is available in Syrian hamsters despite the fact that this species is widely used for studies of circadian organization and photoperiodic responses. Furthermore, examination of oscillating expression of these genes in mouse testis has generated discrepant results, and little is known about gonadal expression of haPer1 and haBmal1 or their environmental control. To address these questions, the authors examined the pattern of haPer1 and haBmal1 in heart, kidney, liver, muscle, spleen, and testis of hamsters exposed to DD. In most organs, Northern blots suggested the existence of single transcripts of each of these messenger RNAs (mRNAs). haPer1 peaked in late subjective day and haBmal1 during the late subjective night. Closer inspection of SCN and muscle haPer1, however, revealed the existence of two major transcripts of similar size, as well as minor transcripts that varied in the 3′-untranslated region. In hamster testis, two haPer1 transcripts were found, both of which are truncated relative to the corresponding mouse transcript and both of which contain a sequence homologous to intron 18 of mPer1. Neither testis transcript contains a nuclear localization signal, and haPer1 transcripts lacked the putative C-terminal CRY1-binding domain. Furthermore, the testis deviated from the general pattern in that haPer1 and haBmal1 both peaked in the subjective night. In situ hybridization revealed that haPer1, but not haBmal1, showed a heterogeneous distribution among seminiferous tubules. Hamster testis also expresses 2 haPer2 transcripts, but no circadian variation is evident. In a second experiment, long-term exposure to DD sufficient to induce gonadal regression was found to eliminate circadian oscillations of both testicular haPer1 transcripts. In contrast, gonadal regression was accompanied by a more robust rhythm of haBmal1

Assessment of <i>Per1</i> expression in experiment 1.

<p>Left panels show mean colocalization of <i>Per1</i>, and right panels indicate distribution of <i>Per1</i> expression intensities at each circadian phase, for <i>AVP</i>, <i>HCRT</i>, and <i>TH</i> cells in the brain areas examined. Normalized mean (± SEM) intensity values of <i>Per1</i> expression is depicted within (A) <i>AVP</i>-expressing cells of the SCN, (B) <i>HCRT-</i>expressing cells of the LH/DMH and (C) <i>TH</i>-expressing cells of the LC. Percent of cells expressing highest 25% (<i>black</i>), moderate (<i>grey</i>), or lowest 25% (<i>white</i>) levels of <i>Per1</i> within (D) <i>AVP</i>-expressing cells of the SCN, (E) <i>HCRT-</i>expressing cells of the LH/DMH and (F) TH-expressing cells of the LC. a- p<0.05 vs. CT9, 12.5, 22; b- p<0.05 vs. CT9; c- p<0.05 vs. CT3, 12.5; d- p<0.05 vs. CT3; e- p<0.05 vs. 12.5.</p

<i>Per1</i> intensity quantified by category of intensity within TH cells.

<p>Distribution of cells expressing high (<i>black</i>), moderate (<i>grey</i>) or low (<i>white</i>) levels of <i>Per1</i> in the <i>TH</i>-expressing cells of the LC. * P<0.05 vs. 3 hours before activity onset.</p

Differential control of peripheral circadian rhythms by suprachiasmatic-dependent neural signals

Although dependent on the integrity of a central pacemaker in the suprachiasmatic nucleus of the hypothalamus (SCN), endogenous daily (circadian) rhythms are expressed in a wide variety of peripheral organs. The pathways by which the pacemaker controls the periphery are unclear. Here, we used parabiosis between intact and SCN-lesioned mice to show that nonneural (behavioral or bloodborne) signals are adequate to maintain circadian rhythms of clock gene expression in liver and kidney, but not in heart, spleen, or skeletal muscle. These results indicate that the SCN regulates expression of circadian oscillations in different peripheral organs by diverse pathways

Behavioral and neurochemical sources of variability of circadian period and phase: studies of circadian rhythms of npy-/- mice

The cycle length or period of the free-running rhythm is a key characteristic of circadian rhythms. In this study we verify prior reports that locomotor activity patterns and running wheel access can alter the circadian period, and we report that these treatments also increase variability of the circadian period between animals. We demonstrate that the loss of a neurochemical, neuropeptide Y (NPY), abolishes these influences and reduces the interindividual variability in clock period. These behavioral and environmental influences, from daily distribution of peak locomotor activity and from access to a running wheel, both act to push the mean circadian period to a value < 24 h. Magnitude of light-induced resetting is altered as well. When photoperiod was abruptly changed from a 18:6-h light-dark cycle (LD18:6) to LD6:18, mice deficient in NPY were slower to respond to the change in photoperiod by redistribution of their activity within the prolonged dark and eventually adopted a delayed phase angle of entrainment compared with controls. These results support the hypothesis that nonphotic influences on circadian period serve a useful function when animals must respond to abruptly changing photoperiods and point to the NPYergic pathway from the intergeniculate leaflet innervating the suprachiasmatic nucleus as a circuit mediating these effects