Prokineticin 2 Regulates the Electrical Activity of Rat Suprachiasmatic Nuclei Neurons

Neuropeptide signaling plays roles in coordinating cellular activities and maintaining robust oscillations within the mammalian suprachiasmatic nucleus (SCN). Prokineticin2 (PK2) is a signaling molecule from the SCN and involves in the generation of circadian locomotor activity. Prokineticin receptor 2 (PKR2), a receptor for PK2, has been shown to be expressed in the SCN. However, very little is known about the cellular action of PK2 within the SCN. In the present study, we investigated the effect of PK2 on spontaneous firing and miniature inhibitory postsynaptic currents (mIPSCs) using whole cell patch-clamp recording in the SCN slices. PK2 dose-dependently increased spontaneous firing rates in most neurons from the dorsal SCN. PK2 acted postsynaptically to reduce γ-aminobutyric acid (GABA)-ergic function within the SCN, and PK2 reduced the amplitude but not frequency of mIPSCs. Furthermore, PK2 also suppressed exogenous GABA-induced currents. And the inhibitory effect of PK2 required PKC activation in the postsynaptic cells. Our data suggest that PK2 could alter cellular activities within the SCN and may influence behavioral and physiological rhythms

Differential arousal regulation by prokineticin 2 signaling in the nocturnal mouse and the diurnal monkey

The temporal organization of activity/rest or sleep/wake rhythms for mammals is regulated by the interaction of light/dark cycle and circadian clocks. The neural and molecular mechanisms that confine the active phase to either day or night period for the diurnal and the nocturnal mammals are unclear. Here we report that prokineticin 2, previously shown as a circadian clock output molecule, is expressed in the intrinsically photosensitive retinal ganglion cells, and the expression of prokineticin 2 in the intrinsically photosensitive retinal ganglion cells is oscillatory in a clock-dependent manner. We further show that the prokineticin 2 signaling is required for the activity and arousal suppression by light in the mouse. Between the nocturnal mouse and the diurnal monkey, a signaling receptor for prokineticin 2 is differentially expressed in the retinorecipient suprachiasmatic nucleus and the superior colliculus, brain projection targets of the intrinsically photosensitive retinal ganglion cells. Blockade with a selective antagonist reveals the respectively inhibitory and stimulatory effect of prokineticin 2 signaling on the arousal levels for the nocturnal mouse and the diurnal monkey. Thus, the mammalian diurnality or nocturnality is likely determined by the differential signaling of prokineticin 2 from the intrinsically photosensitive retinal ganglion cells onto their retinorecipient brain targets

Historical and projected hysterectomy rates in the USA: Implications for future observed cervical cancer rates and evaluating prevention interventions

BACKGROUND. SEER-reported cervical cancer incidence rates reflect the total female population including women no longer at risk due to hysterectomy. Hysterectomy rates have been declining in the United States as alternative treatments have become available, which could result in an apparent increase in SEER-reported cervical cancer rates. We aimed to obtain nationally representative historical data on hysterectomy rates in USA, use trends analysis to project rates back to 1935 and forward to 2035, and then predict the impact of changing hysterectomy rates on SEER-reported cervical cancer rates. METHODS. We performed a systematic search of Medline, Embase, Premedline, Cochrane Central databases and extracted nationally-representative hysterectomy incidence data from 1965 to 2009, including data on the number of cervix-preserving (subtotal) procedures. We then projected rates back to 1935, and forward to 2035 based on trends from joinpoint regression. These rates were then used to estimate hysterectomy prevalence out to 2035, and then to predict the impact of changing hysterectomy rates on SEER-reported cervical cancer rates to 2035. We examined alternative assumptions regarding projected hysterectomy incidence rates out to 2035, including a scenario in which rates decline no further from 2009 rates, and a scenario where rates decline at twice the baseline rate. RESULTS. Estimated age-standardized hysterectomy incidence increased from 2.4 to 10.6 per 1000 women between 1935 and 1975. Thereafter, rates are predicted to fall to 3.9 per 1000 by 2035. Subtotal hysterectomy procedures declined from being the predominant method in 1935 to less than 12% of procedures from 1970 onwards. Consequently, holding all else constant, an increase in SEER-reported age-standardized cervical cancer incidence rates (ages 0–85+) of 9% is expected from 2009 to 2035. The predictions were minimally impacted by alternative scenarios for future hysterectomy rates. CONCLUSIONS. Declining hysterectomy rates have implications for the interpretation of SEER-reported cervical cancer rates. A background increase in cervical cancer rates due to decreasing population hysterectomy exposure may partially offset expected decreases from recent cervical screening changes recommended by the US Preventive Services Task Force. Evaluations of new cervical cancer prevention opportunities should consider the background impact of historical and projected hysterectomy rates