Neural tube patterning in vertebrates is controlled in part by locally secreted factors that act in a paracrine manner on nearby cells to regulate proliferation and gene expression. We show here by in situ hybridization that genes for the neuropeptide pituitary adenylate cyclaseactivating peptide (PACAP) and one of its high-affinity receptors (PAC 1 ) are widely expressed in the mouse neural tube on embryonic day (E) 10.5. Transcripts for the ligand are present in differentiating neurons in much of the neural tube, whereas the receptor gene is expressed in the underlying ventricular zone, most prominently in the alar region and f loor plate. PACAP potently increased cAMP levels more than 20-fold in cultured E10.5 hindbrain neuroepithelial cells, suggesting that PACAP activates protein kinase A (PKA) in the neural tube and might act in the process of patterning. Consistent with this possibility, PACAP down-regulated expression of the sonic hedgehog-and PKA-dependent target gene gli-1 in cultured neuroepithelial cells, concomitant with a decrease in DNA synthesis. PACAP is thus an early inducer of cAMP levels in the embryo and may act in the neural tube during patterning to control cell proliferation and gene expression.Recent studies suggest that phenotypic determination in the developing nervous system results from interactions of patterning genes conserved through evolution (1). For example, sonic hedgehog (shh) is one of three mammalian homologs to the segment polarity gene hedgehog (hh). shh has been implicated as a notochord-and floor plate-secreted factor that controls dorsal͞ventral patterning in the vertebrate neural tube (1-4). Abundant genetic and molecular evidence in flies (5), fish (6), and mice (7) indicates that hh and its homologs act by antagonizing cAMP-dependent protein kinase A (PKA) signaling. Although shh may act in the ventral tube by blocking constitutive PKA activity, it is possible that physiological activators of the cAMP͞PKA pathway are important in patterning.We considered that pituitary adenylate cyclase-activating peptide (PACAP) might be involved in patterning for several reasons. First, although PACAP originally was discovered as a hypothalamic factor that potently increased cAMP in the pituitary through G protein-coupled receptors (8), peptide expression later was localized to many central and peripheral neuronal populations as well as the developing embryo (9). Second, the 27-aa form of the peptide, PACAP-27, is conserved 100% in species ranging from fish to humans. Finally, our tissue culture studies indicated that PACAP and a closely related peptide vasoactive intestinal peptide stimulate cAMP production, regulating proliferation, differentiation, and͞or survival of multiple neuronal precursors (10-14). The current studies indicate that a functional PACAP ligand͞receptor cAMP signaling system is expressed in the neural tube at the onset of neurogenesis, raising the possibility that PACAP might be involved in neural tube patterning. MATERIALS AND METHODS In Situ Hybridi...

Hypothesis: Early laparoscopic cholecystectomy (LC) results in a shorter length of stay and acceptable conversion and complication rates when compared with antibiotic therapy plus interval LC or percutaneous cholecystostomy in patients admitted to a surgical service because of acute cholecystitis. However, actual practice does not conform to current evidence. Design: Retrospective cohort study. Setting: Urban teaching hospital. Methods: Data were abstracted from the medical records of all patients with acute cholecystitis admitted to the surgical service via the emergency department during 36 months (October 1, 2002, to September 30, 2005). Patients were divided into 5 groups on the basis of treatment received. Length of stay, duration of symptoms, major complications, and conversion rates were analyzed. Results: Of 173 patients with acute cholecystitis, 71 (41%) underwent early LC. Of 102 patients treated with antibiotic therapy alone (59%), 57 were discharged; antibiotic therapy was unsuccessful in 45 patients. Of the patients in whom antibiotic therapy was unsuccessful, 26 underwent late LC and 19 underwent percutaneous cholecystostomy. Interval LC was eventually performed in 55 patients who did not undergo surgery during the index admission. Length of stay was significantly shorter in the early LC group compared with the interval LC group (PϽ.001). Conversion rates were not statistically different for the 3 LC groups (early LC, 5.6%; late LC, 11.5%; and interval LC, 9.1%). The only biliary complication occurred in the interval LC group. Conclusions: Early laparoscopic cholecystectomy resulted in a significantly reduced length of stay, no major complications, and no significant difference in conversion rates when compared with initial antibiotic treatment and interval LC. Despite these advantages, early LC is not the most common treatment for acute cholecystitis in practice.

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It has been demonstrated that pituitary adenylate cyclase activating polypeptide (PACAP) promotes the survival of neurons in culture and can inhibit neuronal cell death after experimental injury. Furthermore, peripheral axotomy results in increased PACAP gene expression in sensory and sympathetic neurons, suggesting that PACAP might be a mediator in the injury response in certain parts of the nervous system. However, changes in PACAP expression have not been reported in injured motor neurons, despite the significant problem of motor neuron degeneration in injury and in several neurological diseases. We examined here changes in gene expression of PACAP and two high-affinity PACAP receptors, PAC(1) and VPAC(2), in adult rat motor neurons after facial nerve axotomy by in situ hybridization. PACAP gene expression was very low in facial motor neurons of normal rats. However, a robust time-dependent increase in PACAP mRNA was observed in the facial motor nucleus in most or all axotomized motor neurons. This induction was detectable 6 hr after axotomy, and peaked at 48 hr, when expression on the injured side averaged more than 20-fold higher than that on the contralateral side. Thereafter, PACAP mRNA levels decreased slightly, but remained more than 10-fold elevated for as long as 30 days after axotomy. In contrast to PACAP, gene expression for both the PAC(1) and VPAC(2) receptor was high in facial motor neurons of normal rats. No significant change was observed for VPAC(2) receptor gene expression in facial motor neurons after axotomy, whereas gene expression for the PAC(1) receptor became significantly decreased. The results indicate that the PACAP ligand receptor system is tightly regulated in the facial motor nucleus after axotomy, providing evidence that PACAP may be involved in motor injury responses.

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