Neuropilin 1 is the specific receptor for Sema3A and plays a role in nerve fiber guidance. We report that neuropilin 1 and Sema3A mutant mouse embryos, generated by targeted gene disruption, showed displacement of sympathetic neurons and their precursors and abnormal morphogenesis in the sympathetic trunk. We also show that Sema3A suppressed the cell migration activity of sympathetic neurons from wild-type but not neuropilin 1 mutant embryos in vitro and instead promoted their accumulation into compact cell masses and fasciculation of their neurites. These findings suggest that the neuropilin 1-mediated Sema3A signals regulate arrest and aggregation of sympathetic neuron precursors and sympathetic neurons themselves at defined target sites and axon fasciculation to produce the stereotyped sympathetic nerve pattern.
Neural crest cells leave the neural tube, migrate for long distances along defined paths, and subsequently settle at appropriate positions where they differentiate into diverse cell types (for reviews, see Bronner-Fraser, 1995; Anderson, 2000). Therefore, this cell population is a good experimental model to investigate mechanisms underlying cell migration, as well as cell differentiation.
Extensive analyses have been done to elucidate migratory patterns of neural crest cells in several vertebrate species, and have shown that progenitors of autonomic neurons of the sympathetic ganglia (neural crest cells of sympathetic neuron lineage) emerge from the neural crest at trunk level, and migrate ventrally (the ventral migratory pathway) through the rostral but not caudal halves of the sclerotomes to the dorsal aorta where they cease migration (Weston, 1963; Le Douarin and Teillet, 1974; Thiery et al., 1982; Rickmann et al., 1985; Bronner-Fraser, 1986; Loring and Erickson, 1987; Lallier and Bronner-Fraser, 1988; Serbedzija et al., 1990). The neural crest cell descendants then proliferate and differentiate into neurons that are aggregated into segmentally distinct groupings, the sympathetic ganglia. The sympathetic ganglia are interconnected by communicating rami to give rise to the sympathetic trunk.
Over the last decade, several molecules that influence the patterned migration of neural crest cells have been identified. Extracellular matrix molecules such as fibronectin and laminin are distributed along the neural crest cell migration routes and thought to be permissive substrates for cell migration (for a review, see Perris and Perissinotto, 2000). However, peanut agglutinin (PNA)-binding molecules (Oakley and Tosney, 1994; Krull et al., 1995), chondroitin sulfate proteoglycans (Henderson et al., 1997; Kubota et al., 1999; Perissinotto et al., 2000) (for a review, see Perris and Perissinotto, 2000), and ephrinB1 and ephrinB2, which are the ligands of Eph-related receptor tyrosine kinases (Krull et al., 1997; Smith et al., 1997; Wang and Anderson, 1997), are expressed in tissues lining the neural crest cell migratory pathways such as the caudal sclerotome and/or the perinotochordal mesenchyme and are thought to function as barriers that repel neural crest cells and limit their migration routes. However, as the influence of these molecules on neural crest cell migration has mainly been elucidated in vitro, their roles in vivo are mostly unknown. Moreover, little is known about molecules that control the arrest of particular neural crest cell descendants at defined target sites, for example, the arrest of neural sympathetic neuron precursors at the dorsal aorta.
Sema3A is a member of the class 3 secreted semaphorin (Semaphorin Nomenclature Committee, 1999) and has been shown to be a potent neuronal chemorepellent that induces growth cone collapse or repels sensory axons of the dorsal root ganglia in vitro (Luo et al., 1993; Fan and Raper, 1995). Neuropilin 1 is a receptor for Sema3A (He and Tessier-Lavigne, 1997; Kolodkin et al., 1997; Kitsukawa et al., 1997) (for a review, see Fujisawa and Kitsukawa, 1998), and propagates Sema3A signals into cells after forming receptor complexes with plexins (Takahashi et al., 1999; Rohm et al., 2000). Targeted inactivation of the Sema3A gene (Taniguchi et al., 1997) or the neuropilin 1 gene (Kitsukawa et al., 1997) in mice induced disruption of the patterned pathways and projections of the peripheral nerve fibers, indicating the importance of neuropilin 1-mediated Sema3A signals to the directional guidance of nerve fibers in vivo.
Our previous study (Kawakami et al., 1996) showed that neuropilin 1 is expressed not only in the sensory neurons of the dorsal root ganglia but also in autonomic neurons of the sympathetic ganglia, both of which derive from a common progenitor, the trunk neural crest cells of the ventral migratory pathway. A recent study has shown that Sema3A suppresses migration of the avian trunk neural crest cells in vitro (Eickholt et al., 1999). Sema3A transcripts are limited to the caudal half of sclerotomes in avian embryos (Shepherd et al., 1996; Eickholt et al., 1999) and rodent embryos (Adams et al., 1996; Giger et al., 1996). Furthermore, Sema3A inhibits extension of neurites of sympathetic neurons in vitro (Püschel et al., 1995; Chen et al., 1998). These findings suggest that neuropilin 1-mediated Sema3A signals also play roles in the migration and/or arrest of neural crest cells of the sympathetic neuron lineage and the formation of the sympathetic nervous system.
We have closely examined the sympathetic nervous system of neuropilin 1 mutant mouse embryos (Kitsukawa et al., 1997) and Sema3A mutant mouse embryos (Taniguchi et al., 1997), and report that, in these mutant embryos, many tyrosine hydroxylase (TH)-positive sympathetic neurons are displaced, and the pattern of the sympathetic nervous system is severely disrupted. We also report that, in these two mutant embryos, MASH1-positive sympathetic neuron precursors are not accumulated at their target sites around the dorsal aorta but dispersed widely, even though the migratory pathways of their progenitors within the sclerotomes are normal. To elucidate further the role of the neuropilin 1-mediated Sema3A signals in the formation of the sympathetic nervous system, we co-cultured sympathetic ganglia with Sema3A-secreting cells, and report that Sema3A suppresses cell migration activity of the sympathetic neurons from the wild-type but not neuropilin 1 mutant mouse embryos, and instead promotes their aggregation into compact cell masses and fasciculation of their neurites into thick fiber bundles. These findings suggest that the neuropilin 1-mediated Sema3A signals function not only as a stop signal to prohibit migration of the neural crest cells of sympathetic neuron lineage into inappropriate regions of embryos but also as a signal to promote aggregation of sympathetic neurons and probably their precursors into tightly packed cell masses, the sympathetic ganglia, at defined target sites and fasciculation of sympathetic neuron axons into a thick fiber bundle, the sympathetic trunk.
Production of the neuropilin 1 mutant mice and Sema3A mutant mice by targeted gene disruption and determination of genotypes by polymerase chain reaction was reported elsewhere (Kitsukawa et al., 1997; Taniguchi et al., 1997). The present study used neuropilin 1 mutant mice created in the ICR strain, and Sema3A mutant mice in the C57BL/6 strain. Noon on the day on which a copulation plug was found was designated as embryonic day 0.5 (E0.5).
To detect sympathetic neurons in sections, embryos were fixed with 4% paraformaldehyde in 10 mM phosphate-buffered saline pH 7.4 (PBS) overnight at 4°C. Cryostat sections (14 μm thick) were thaw-mounted on poly-L-lysine (PLL: SIGMA)-coated glass slides and incubated with a rabbit anti-TH antibody (Nagatsu et al., 1977) (1:1,000 dilution with TBST (10 mM Tris-HCl pH 7.4, 130 mM NaCl, 0.1% Tween 20) containing 5% skimmed milk). The bound antibodies were visualized with biotinylated goat anti-rabbit Ig antibody (Amersham Pharmacia Biotech; 1:500 dilution with TBST) and streptavidin-HRP complex (Vectastain ABC elite kit, Vector Labs). HRP activity was detected with 0.025% diaminobenzidine (DAB) and 0.03% H2O2 in TBST. In some specimens, the bound antibodies were visualized with Cy3-labeled anti-rabbit IgG antibody (Amersham Pharmacia Biotech; 1:500 dilution). To detect sympathetic neurons in whole-mounted specimens, embryos were fixed with paraformaldehyde, internal organs were removed, and they were then processed for immunohistochemistry following the procedures reported (Klymkowsky and Hanken, 1991; Kitsukawa et al., 1997). The specimens were treated with the anti-TH-antibody (1:100 dilution with TBST containing 5% skimmed milk, 5% DMSO and 0.1% NaN3) for 2 days at room temperature. Immunostaining of sections with a rabbit anti-neuropilin 1 antibody (Kawakami et al., 1996) and a rat anti-neurofilament monoclonal antibody 2H3 (Dodd et al., 1988) was carried out using the Cy3-labeled anti-rabbit antibody and anti-rat Ig antibody as secondary antibodies, respectively. To detect neural crest cells within the sclerotomes, embryos were fixed with 100% methanol containing 0.1% formaldehyde for 5-10 minutes at 4°C. Cryostat sections were incubated with a rat anti-mouse monoclonal antibody 4E9R (Kubota et al., 1996)(1:5 dilution of hybridoma culture supernatant) and biotin-labeled isolectin-B4 (Sigma; 10 μg/ml in TBST) overnight at 4°C. The bound 4E9R and isolectin-B4 were detected by treatment of sections with Cy3-labeled anti-mouse Ig antibody and fluorescein-conjugated streptavidin (Amersham Pharmacia Biotech; 1:200 dilution with TBST) each for 30 minutes at room temperature.
The sequence encoding the mouse Sema3A protein (amino acids 26-773) (Püschel et al., 1995) was amplified and a his tag added at the 5′ end by PCR. The sequence encoding the signal sequence of the mouse Sema3A (amino acids 1-25) was amplified and a myc tag added at the 3′ end by PCR. The PCR products were fused and cloned into the expression vector pCEP4 (Invitrogen). The plasmid was used to obtain a stable HEK293T-EBNA cell line (Invitrogen) that secretes the Sema3A-myc-his fusion protein (Sema3A-secreting cells), as described (Shirasaki et al., 1996). The empty pCEP4 vector was used to produce a control HEK293T-EBNA cell line (control cells). HEK293T cells were cultured in Dulbecco's modified Eagle's medium (DMEM; Nissui, Japan) containing 10% FCS (FBS; JRH Bioscience).
Small fragments of the sympathetic ganglia and dorsal root ganglia from E12.5 embryos were cultured in a medium containing 45% DMEM, 45% Ham's F12 (Nissui, Japan), 10% FBS and 2.5S NGF (30 ng/ml; Wako, Japan), in culture dishes (30-mm: Nunc) which had been incubated with a mixture of PLL (100 μg/ml) and mouse laminin (Gibco-BRL; 20 μg/ml) for 2 hours at room temperature. The cultures were fixed with paraformaldehyde and processed for immunostaining with anti-TH antibody and/or 2H3.
In situ hybridization with digoxigenin-labeled rat Mash1 cRNA probe (a gift from Dr Kageyama) and mouse Sema3A cRNA on cryostat sections (10 μm thick) was performed, following procedures reported previously (Schaeren-Wiemers and Gerfin-Moser, 1993). The bound probes were visualized with alkaline phosphatase-conjugated anti-digoxigenin Fab fragment (Boehringer Mannheim) and its color-indicated substrate.
Sympathetic neurons contain catecholamines and are detected by immunoreactivity for the catecholamine synthetic enzyme, tyrosine hydroxylase (TH). In the wild-type (Nrp-1+/+) and heterozygous neuropilin 1 mutant (Nrp-1+/–) embryos at E12.5, TH-positive cells accumulated to form sympathetic ganglia at positions dorsolateral to the dorsal aorta (Fig. 1A,D). In contrast, in the homozygous neuropilin 1 mutant (Nrp-1–/–) embryos, TH-positive cells did not accumulate but distributed widely within embryos. Several TH-positive cells were detected in regions more medial to the original sites of the sympathetic ganglia (Fig. 1B,E), in shoulder (Fig. 1B,F), upper arm, axilla, and sometimes the abdominal wall. As most of the ectopic TH-positive cells possessed axon-like processes (Fig. 1E,F), we assume these cells to be sympathetic neurons. Dislocation of sympathetic neurons was also observed in the homozygous Sema3A mutant (Sema3A–/–) embryos (Fig. 1C) but not the wild-type (Sema3A+/+) or heterozygous mutant (Sema3A+/–) embryos. A double immunostaining with anti-TH antibody and anti-neurofilament antibody 2H3 (Dodd et al., 1988) revealed that the ectopic sympathetic neurons were always associated with spinal nerve fibers and sprouted cell processes along the nerves (Fig. 1G).
Dislocation of TH-positive sympathetic neurons in the neuropilin 1 and Sema3A mutant embryos. (A-F) Frontal sections of the wild-type (A), neuropilin 1 homozygous mutant (B) and Sema3A homozygous mutant (C) embryos at E12.5, immunostained with anti-TH antibody. (D,F) High-magnification views of the boxed areas in A and B, respectively. (E) A high-magnification view of the medial part of an embryo in a section adjacent to B. Arrows in C indicate TH-positive neurons in the upper arm and axilla. (G) A double immunostaining of a section from the Nrp-1–/– embryo at E12.5, with anti-TH antibody (red) and anti-neurofilament antibody 2H3 (green). (H,I) The wild-type (H) and homozygous neuropilin 1 mutant (I) embryos at E12.5, immunostained in whole-mount with anti-TH antibody. Arrows indicate TH-positive neurons at ectopic positions. nt, the neural tube; da, the dorsal aorta; SCG, the superior cervical ganglion; fl, the forelimb. Scale bar: 200 μm (A-C); 200 μm (D,E); 100 μm (F,G); 500 μm (H,I).
Immunostaining of whole-mounted embryos with anti TH-antibody clearly demonstrated the overall pattern of the sympathetic nervous system. In Nrp-1+/+ (Fig. 1H), TH-positive neurons formed ganglia and sympathetic trunks bilaterally to the vertebra. In contrast, in the Nrp-1–/– embryos, many TH-positive neurons were located at ectopic positions, formed irregular cell masses and extended cell processes in various directions (Fig. 1I). As a whole, the sympathetic trunk was severely disorganized.
Quantitative analysis revealed that the total number of TH-positive neurons (an average number of neurons per section) in the Nrp-1–/– embryos was 60% of that in the Nrp-1+/+ or Nrp-1+/– embryos, and 51.2% of the neurons were located at the original sites of the sympathetic ganglia (Fig. 2A). In the Sema3A–/– embryos, the total number of TH-positive neurons was 86.3% of that in the wild-type embryos, and 35.9% of the neurons were located at the original sites of the sympathetic ganglia (Fig. 2B).
Quantitative analysis on the distribution of TH-positive sympathetic neurons. The average number of TH-positive neurons per section was calculated from around 20 serial frontal sections that were made at the cervical level of embryos at E12.5. Open and filled columns indicate the number of TH-positive neurons located at the original sites of the sympathetic ganglia and ectopic positions, respectively. (A) neuropilin 1 mutant embryos. 100%, 99.4% and 51.2% of TH-positive neurons are located at the original sites of the sympathetic ganglia in the wild-type embryo (1 embryo), heterozygous mutant embryos (2 embryos) and homozygous mutant embryos (3 embryos), respectively. (B) The Sema3A mutant embryos. 97.6% and 35.9% of TH-positive neurons are located at the original sites of the sympathetic ganglia in the wild-type embryos (3 embryos) and homozygous mutant embryos (2 embryos), respectively.
Neuropilin 1 is expressed in cultured mouse trunk neural crest cells (Fig. 3A). Furthermore, Sema3A is expressed in the caudal half of the sclerotomes in the mouse embryos (Adams et al., 1996). These findings suggest that the neuropilin 1-expressing neural crest cells avoid Sema3A expressed in the caudal half of each sclerotome to give rise to the metameric migratory pattern. Therefore, we examined whether the migratory pathways of neural crest cells within the sclerotomes are disorganized in the neuropilin 1 and Sema3A mutant embryos.
Migratory pathways of neural crest cells within the sclerotome. (A) Neural crest cells from the wild-type embryo at E8.5 in vitro, immunostained with a neural crest cell-specific monoclonal antibody 4E9R (red) and anti-neuropilin 1 antibody (green). (B-E) Distribution of neural crest cells within the sclerotomes at the cervical level of E9.0 embryos. (B) A diagram indicating 9 regions of the sclerotome defined by different colors. (C-E) Histograms showing relative number (percentages) of neural crest cells contained within each region of the sclerotome shown in B, in the wild-type (C), neuropilin 1 homozygous mutant (D) and Sema3A homozygous mutant (E) embryos. d, dorsal; v, ventral; r, rostral; c, caudal; nt, neural tube; n, notochord; s, sclerotome. Scale bar: 50 μm in A.
As progenitors of sympathetic neurons start to emigrate from the neural tube at around E8.5 to E9.5 (Serbedzija et al., 1990), we made serial sagittal sections through the sclerotomes in embryos at E9.0 and detected neural crest cells by immunohistochemistry using a monoclonal antibody 4E9R, which is a marker for neural crest cells (Kubota et al., 1996) (Fig. 3A). As 4E9R cross-reacts with endothelial cells, we performed a double-immunostaining using 4E9R and isolectin B4, which binds to endothelial cells (Kawasaki et al., 1999) but not neural crest cells. We divided each sclerotome into 9 areas (Fig. 3B), and counted the number of 4E9R-positive and isolectin B4-negative cells in each area.
As shown in Fig. 3C-E, there was no clear difference in the distribution pattern of neural crest cells within the sclerotome between the mutant and wild-type embryos; neural crest cells in both the neuropilin 1 and Sema3A mutant embryos were mainly distributed in the rostral sclerotome, as in the wild-type embryos. These results indicate that the migratory pathways of neural crest cells within the sclerotomes are mostly normal in the neuropilin 1-deficient and Sema3A-deficient mouse embryos, and suggest that the displacement of the sympathetic neuron progenitors would occur after they have left the sclerotomes.
To examine whether sympathetic neuron progenitors that left the sclerotomes are displaced in the neuropilin 1 and Sema3A mutant embryos, we performed in situ hybridization analysis using Mash1 cRNA as a probe. Mash1 encodes a basic helix-loop-helix protein that is a mammalian homologue of the Drosophila achaete-scute proteins and is expressed in the precursors of sympathetic neurons that have arrived at the dorsal aorta but not migrating neural crest cells within the sclerotomes (Johnson et al., 1990; Lo et al., 1991). As neural crest cells of the sympathetic neuron lineage arrive at the dorsal aorta by E9 to E10 (Serbedzija et al., 1990), we analyzed the embryos at E9.25 (10-20 somites stage).
In the Nrp-1+/+ (Fig. 4A) and Nrp-1+/– embryos (4 embryos each), most cells with Mash1 transcripts accumulated at the dorsal aorta. In contrast, in the Nrp-1–/– embryos (8 embryos), Mash1-positive cells distributed widely within embryos, not only at the dorsal aorta but also in the proximal part of the forelimbs and regions more medial to the original sites of the sympathetic ganglia (Fig. 4B). In the Sema3A mutant embryos Mash1-positive cells were also displaced in a similar pattern to that in the neuropilin 1 mutant embryos (data not shown). Immunohistochemistry with 2H3 in adjacent sections revealed that 2H3-positive spinal nerve fibers were limited to the vicinity of the neural tube in the Nrp-1+/+ (Fig. 4C), Nrp-1+/– and Nrp-1–/– (Fig. 4D) embryos. The findings indicate that the emigration of sympathetic neuron precursors from the neural tube to the dorsal aorta precedes the sprouting of the spinal nerve fibers, and suggest that sympathetic neuron precursors arrive at the dorsal aorta independently of spinal nerve fibers. We further examined expression patterns of Sema3A by in situ hybridization, and observed strong signals for the Sema3A transcripts in the forelimb and the dermamyotome (Fig. 4E). These results indicate that, in the neuropilin 1-deficient embryos, sympathetic neuron precursors have migrated into regions where Sema3A is expressed, such as the forelimbs (compare Fig. 4B,E).
Distribution of sympathetic neuron precursors, spinal nerve fibers, and Sema3A transcripts in E9.25 embryos. (A,B) In situ hybridization analysis on frontal sections of the wild-type (A) and neuropilin 1 homozygous mutant (B) embryos, using an antisense cRNA probe for Mash1. Arrows indicate cells with the Mash1 transcripts. (C,D) Detection of spinal nerve fibers by immunostaining with 2H3 in sections adjacent to A and B. 2H3-positive fibers (arrows) are limited around the neural tube (nt). The staining in blood cells and the internal surface of the digestive tracts is non-specific. (E) In situ hybridization analysis on a frontal section of a wild-type embryo, using an anti-sense cRNA probe for Sema3A. An arrow indicates the notochord. da, dorsal aorta; fl, the forelimb; dm, dermamyotome; nt, neural tube. Scale bar: 100 μm (A-E).
Next, we examined whether Sema3A suppress cell migration in vitro. Because isolation of sympathetic neuron precursors was technically difficult, we co-cultured small explants of the sympathetic ganglia (SG explant) from E12.5 embryos or dorsal root ganglia (DRG explant) from E12.5 embryos with Sema3A-secreting HEK293T cells generated by the EBNA system using an expression vector pCEP4, and examined the effect of Sema3A on neuronal cell migration. HEK293T cells transfected with the empty vector were used as a control (control cells). In the present culture conditions, TH-positive sympathetic ganglion neurons strongly expressed neuropilin 1 (see Fig. 5E).
Effect of Sema3A on migration of dorsal root ganglia neurons and sympathetic neurons in vitro. (A-D) Co-cultures of the dorsal root ganglia explants from the wild-type (A,B) and homozygous neuropilin 1 mutant (C,D) embryos at E12.5 with the control HEK293T cells (A,C) and the Sema3A-secreting HEK293T cells (B,D) (2,000 cells/cm2 each). (E) A cultured sympathetic ganglion neuron, immunostained with anti-neuropilin 1 antibody (green) and anti-TH antibody (originally red but yellow after merging). (F-I) Co-culture of the sympathetic ganglion explants from the wild-type (F,G) and homozygous neuropilin 1 mutant (H,I) embryos at E12.5 with the control HEK293T cells (F,H) and the Sema3A-secreting HEK293T cells (G,I) (2,000 cells/cm2 each). Cultures were immunostained with anti-TH antibody. (J-M) Co-culture of the sympathetic ganglion explants from the wild-type embryos at E12.5 with the control HEK293T cells (J,L) or the Sema3A-secreting HEK293T cells (K,M) (800 cell/cm2 each). The cultures were immunostained with anti-TH antibody (red) and 2H3 (green). J and K are phase-contrast micrographs. L and M correspond to the boxed regions in J and K, respectively. Arrows in A-D, J and K indicate the HEK293T cells. Scale bar: 100 μm (A-D); 25 μm (E); 200 μm (F-I); 200 μm (J,K); 200 μm (L,M).
First, we analyzed cell migration activity in the presence of a relatively high concentration of Sema3A; we seeded the Sema3A-secreting cells or control cells (2,000 cells/cm2 each) 12 hours before inoculation of the SG explants or DRG explants, and cultured then for 12 hours. In these culture conditions, neurite outgrowth was completely blocked by Sema3A in the DRG explants from the Nrp-1+/+ embryos (Fig. 5A,B) but not Nrp-1–/– embryos (Fig. 5C,D), even though several non-neuronal cells grew out from the explants. Neurite outgrowth and migration of TH-positive neurons from the SG explants of the Nrp-1+/+ embryos occurred in the co-culture with the control cells (Fig. 5F) but was completely blocked in the co-culture with the Sema3A-secreting cells (Fig. 5G). In contrast, neurite outgrowth and migration of TH-positive neurons was not suppressed in the co-culture of the SG explants from the Nrp-1–/– embryos with the control cells (Fig. 5H) and Sema3A-secreting cells (Fig. 5I).
In the explant culture of the sympathetic ganglia, outgrowth of neurites preceded migration of neuronal cells. TH-positive neurons always migrated from the explants along with the preformed neurites. As neurite outgrowth from the SG explants was completely suppressed with Sema3A under the above co-culture conditions (see Fig. 5G), we cannot say whether Sema3A primarily suppresses cell migration activity of sympathetic neurons. Therefore, we then examined migration activity of sympathetic neurons in the presence of a lower concentration of Sema3A that does not inhibit neurite outgrowth; we inoculated the SG explants from the wild-type embryos with Sema3A-secreting cells or control cells (800 cells/cm2 each) simultaneously and cultured then for 2 days. In the co-culture with the control cells, many TH-positive neurons migrated from the SG explants along with neurites (Fig. 5J,L). In contrast, no TH-positive neurons migrated from the SG explants in the co-culture with the Sema3A-secreting cells, even though several neurites grew from the explants (Fig. 5K,M). These results suggest that neuropilin 1-mediated Sema3A signals suppress the cell migration activity of sympathetic neurons.
It has been reported that Sema3A induces neuronal apoptosis in cultured sympathetic neurons (Shirvan et al., 1999). Therefore, we performed TUNEL staining and Hochst dye staining of the SG explants, but found no apparent increase in apoptotic cells in the explants co-cultured with Sema3A-secreting cells (data not shown), suggesting that the prevention of neuron migration from the SG explants is not due to cell death.
In addition to the suppression of sympathetic neuron migration, Sema3A influenced the morphology of SG explants and neurites. When the SG explants from the wild-type embryos were co-cultured with the control cells, the explants were gradually spread out, and neurites sprouted without apparent fasciculation (Fig. 6A-C, also see Fig. 5F,J,L). In contrast, when the SG explants were co-cultured with the Sema3A-secreting cells (800 cells/cm2), cells in the explants were gradually aggregated into compact cell masses (Fig. 6D-F, also see Fig. 5K,M). In addition, neurites that had initially been dispersed became fasciculated into thick fiber bundles (Fig. 6D-F, also see Fig. 5K,M). The Sema3A-mediated cell aggregation and neurite fasciculation were observed in the SG explants from the wild-type embryos (23 explants form 3 independent experiments) but not neuropilin 1 mutant embryos (see Fig. 5I).
Effects of Sema3A on morphology of sympathetic ganglion explants and neurites. The sympathetic ganglion explants from the wild-type embryos at E12.5 were co-cultured with the control HEK293T cells (A-C) or the Sema3A-secreting HEK293T cells (D-F) (800 cells/cm2 each). Phase-contrast micrographs of the explants at 12 hour (A,D), 24 hour (B,E) and 48 hour (C,F) in culture. Arrows indicate the HEK293T cells. Scale bar: 100 μm (A-F).
The present analysis showed that many sympathetic neurons are located at ectopic positions in the neuropilin 1 and Sema3A mutant embryos at E12.5. The neural crest cells of the ventral migratory pathway are multipotent, and become restricted in phenotype either during their migration or at their sites of localization into sensory neurons of the dorsal root ganglia, Schwann cells, neurons in the sympathetic ganglia, chromaffin cells of the adrenal medulla, or enteric neurons of the digestive tracts (Stern et al., 1991; Bronner-Fraser and Fraser, 1991; Durbec et al., 1996) (for reviews, see Le Douarin et al., 1993; Selleck et al., 1993; Bronner-Fraser, 1995; Anderson, 1993; Anderson, 2000). Therefore, it is possible that the sympathetic neurons located at ectopic positions were produced by the change of phenotype of neural crest cells into sympathetic neurons. However, the reduction of TH-positive sympathetic neurons, in particular, the marked reduction of the neurons at the original sites for the sympathetic ganglia in the neuropilin 1 and Sema3A mutant embryos (see Fig. 2) suggests that the distribution of sympathetic neurons at ectopic positions accounted for the displacement of the sympathetic neuron progenitors and/or sympathetic neuron themselves but not for the phenotypic conversion of neural crest cells, which would differentiate other cell types into bona fide sympathetic neurons.
It is well documented that factors in the local environment derived from the dorsal aorta such as BMP2/4/7 are required for the expression of the sympathetic neuron phenotype in neural crest cells (Reissmann et al., 1996; Shah et al., 1996; Varley and Maxwell, 1996). However, the localization of TH-positive neurons at ectopic positions such as the limb bud and abdominal wall in the neuropilin 1 and Sema3A mutant embryos suggests that neural crest cells can express the sympathetic neuron phenotype, the expression of TH, at sites far from the dorsal aorta. The number of TH-positive cells located at ectopic positions in the neuropilin 1 mutant embryos was smaller than that in the Sema3A mutant embryos. This may be attributable primarily to the regression of embryonic vessel formation in the neuropilin 1 mutant embryos (Kawasaki et al., 1999). The vascular defect may result in the reduction of cell proliferation of sympathetic neuron precursors or neuronal cell death.
Which steps of neural crest cell migration are disrupted in the neuropilin 1 and Sema3A mutant embryos?
The selective expression of Sema3A in the caudal half of each sclerotome in the avian embryos (Shepherd et al., 1996; Eickholt et al., 1999) and rodent embryos (Adams et al., 1996; Giger et al., 1996) has led us to speculate that Sema3A affects the metameric migratory patterns of neural crest cells (Adams et al., 1996; Eickholt et al., 1999). The present study, however, showed no apparent abnormal distribution of neural crest cells within the sclerotomes in the neuropilin 1 and Sema3A mutant embryos. As several extracellular matrix molecules and the Eph family transmembrane ligands, which would inhibit neural crest cell migration, are redundantly expressed in the caudal half of the sclerotomes (for reviews, see Robinson et al., 1997; Perris and Perissinotto, 2000) and work in concert, the effect of deprivation of a single inhibitory molecule may be negated. We previously reported that cell packaging in the dorsal root ganglia was slightly loose in the neuropilin 1 mutant embryos, even though the number of dorsal root ganglion and their location within embryos were nearly normal (Kitsukawa et al., 1997). Therefore, we cannot exclude the possibility that the migratory pathways of the neural crest cells at somite level are slightly disorganized in the mutant embryos.
The in situ hybridization analysis indicates that MASH1-positive sympathetic neuron precursors were distributed widely in the neuropilin 1 and Sema3A mutant embryos, suggesting that displacement of the progenitors of sympathetic neurons occurs after they have left the sclerotomes. It has been reported that, in avian embryos, neural crest cells leave the sclerotomes and then closely associate with newly emerging ventral root fibers (Rickmann et al., 1985; Loring and Erickson, 1987). As reported previously (Kitsukawa et al., 1997; Taniguchi et al., 1997), pathways of the spinal nerves in the neuropilin 1 and Sema3A mutant embryos are severely disorganized. In addition, in the neuropilin 1 and Sema3A mutant embryos at E12.5, displaced sympathetic neurons were always associated with spinal nerve fibers (see Fig. 1G). These findings raised the possibility that the displacement of sympathetic neuron precursors in the mutant mouse embryos is a side effect of the disorganization of the spinal nerve fiber pathways. However, the present finding that MASH1-positive sympathetic neuron precursors arrive at their final target sites before the sprouting of the spinal nerve fibers (see Fig. 4) excludes this possibility.
Progenitors of sympathetic neurons that arrive at the dorsal aorta migrate 2 segments rostrally and 3 segments caudally along the aorta and then accumulate to form ganglia (Yip, 1986), suggesting the importance of the dorsal aorta in migration and/or accumulation of sympathetic neuron precursors. However, the present study showed that the displacement of sympathetic neurons occurs to nearly the same extent in the neuropilin 1 mutant embryos in which segments of the dorsal aorta are often regressed (Kawasaki et al., 1999) and the Sema3A mutant embryos in which the morphogenesis of the dorsal aorta is apparently normal (unpublished). Therefore, the displacement of sympathetic neuron precursors in these mutant embryos seems to be induced independently of the dorsal aorta.
Taken collectively, the results obtained by histological analyses on the neuropilin 1 and Sema3A mutant embryos suggest that the progenitors of sympathetic neurons migrate along normal paths within the sclerotomes but fail to arrive at their target sites and disperse widely within embryos.
Why do sympathetic neurons and their precursors in the neuropilin 1- and Sema3A-deficient embryos not accumulate at the dorsal aorta but are displaced, even though their migratory pathways within the sclerotomes are normal?
A most likely answer is that Sema3A functions as a stop signal for the migration of sympathetic neurons and their precursors. The co-culture of the sympathetic ganglions with Sema3A-secreting cells showed that Sema3A suppressed neuron migration from the sympathetic ganglion explants. Though we did not directly test the effect of Sema3A on the sympathetic neuron precursors, for technical reasons, the precursors may also be responsible to Sema3A and suppressed their migration activity. In the mouse embryos at E9.5 when the sympathetic neuron precursors have just arrived at the dorsal aorta (Serbedzija et al., 1990), Sema3A transcripts are expressed in the dermamyotome and the forelimb, as well as the caudal sclerotome (see Fig. 4E). In addition, several studies have shown that, in the mouse embryos at E10 (Adams et al., 1996) and rat embryos at corresponding developmental stages (Wright et al., 1995), Sema3A is also expressed in paraxial mesenchymal tissues. As Sema3A is a secreted protein, the Sema3A produced in these tissues may diffuse within embryos and make a concentration gradient with the lowest point at the lateral part of the dorsal aorta. On this assumption, we speculate that, in the wild-type embryos, the diffused Sema3A suppresses the migration activity of sympathetic neuron precursors and arrests them at the bottom of the Sema3A gradient, the lateral part of the dorsal aorta (Fig. 7A). In contrast, in the neuropilin 1 and Sema3A mutant embryos, sympathetic neuron precursors may migrate further following the permissive routes for these cells into diverse regions, even into the areas where Sema3A is originally expressed (Fig. 7B,C).
Possible roles of Sema3A in migration and arrest of sympathetic neuron precursors. (A) In the wild-type embryo, Sema3A (blue) production in the dermamyotome (dm), forelimb (fl) and paraxial mesenchymal tissue forms a concentration gradient. Sympathetic neuron precursors (red spots), which have migrated through the ventral migratory pathway (a green arrow), are arrested at the bottom of the Sema3A gradient, the lateral part of the dorsal aorta (da). (B,C) Sympathetic neuron precursors in the neuropilin 1-deficient embryo (B) and the Sema3A-deficient embryo (C) do not stop at the lateral part of the dorsal aorta but migrate further along the permissive route. nt, neural tube; n, notochord.
The co-culture of the sympathetic ganglions with Sema3A-secreting cells also suggests a function of Sema3A other than as the stop signal, that is, Sema3A promotes aggregation of sympathetic neurons into compact cell masses. The cell aggregation activity of Sema3A may play a role in the aggregation of differentiated sympathetic neurons into ganglia and probably the aggregation of sympathetic neuron precursors into compact cell masses at the dorsal aorta. In the Sema3A and neuropilin 1 mutant embryos, sympathetic neuron precursors may fail to be aggregated but disperse widely and give rise to sympathetic neurons at ectopic positions. The differentiated sympathetic neurons may migrate further or be pulled by growing spinal nerve fibers into places far from the original target sites, such as the upper arm and the abdominal wall.
The present in vitro study also showed that Sema3A promotes neurite fasciculation. This result led us to speculate that Sema3A, expressed in paraxial mesenchymal tissues surrounding the sympathetic trunk, functions not only as a signal to inhibit sprouting of sympathetic neuron axons into the medial part of embryos but also as a signal to promote their fasciculation into a thick fiber bundle, the sympathetic trunk, along the rostro-caudal axis of embryos. The lack of Sema3A from the tissues surrounding sympathetic neurons or neuropilin 1 from the sympathetic neurons may cause defasciculation of axons and their sprouting in random directions, as found in the neuropilin 1 (see Fig. 1I) and Sema3A mutant embryos.
It is open to question how Sema3A suppresses cell migration activity and promotes cell aggregation in the sympathetic neurons and their precursors. Sema3A paralyses growth cones and stops their migration, probably through depolymerization of actin (Fan et al., 1993). A similar molecular mechanism might be exerted in the suppression of cell migration. We have previously reported that neuropilin 1 mediates cell adhesion after interacting with unknown ligands (Takagi et al., 1995; Shimizu et al., 2000). More recently, neuropilin 1 has been shown to form a complex with a neuronal cell adhesion molecule, L1 (Castellani et al., 2000). Therefore, Sema3A may modify the interaction of neuropilin 1 with L1 or other cell adhesion molecules and increase cell adhesiveness. Several studies have shown that repulsive signals regulate axon fasciculation (Bray et al., 1980; Winberg et al., 1998; Ringstedt et al., 2000; Yu et al., 2000), and suggested that axon fasciculation versus defasciculation appears to be determined by a balance of attractive (or adhesive) and repulsive forces on the axons relative to their surrounding environment (Tessier-Lavigne and Goodman, 1996). The repulsive function of Sema3A expressed in the tissues surrounding sympathetic neurons might promote fasciculation of their axons. It is also likely that Sema3A directly increases the adhesiveness of the axons.
Whatever the mechanisms, the results obtained in the present in vivo and in vitro studies emphasize the central role of neuropilin 1-mediated Sema3A signals in the migration of neural crest cells of sympathetic neuron lineage, their arrest at defined target sites and accumulation into the sympathetic ganglia, and fasciculation of sympathetic neuron axons into the sympathetic trunk.
This work was funded by grants from the CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Corporation (JST). We thank Dr Ryuichiro Kageyama (Kyoto University) for the gift of rat Mash1 cDNA and Drs Tetsuichiro Saito (Kyoto University), Noriko Osumi (Tohoku University) and Takahiro Kunisada (Gifu University) for valuable technical advice and discussion.
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There are many different opinions on Pro Football Talk, but one thing is certain – Michael Florio is an excellent journalist. He has the mind of a lawyer, yet writes in a conversational tone. He updates the site daily and analyses everything from minor transactions to emerging trends. If you are looking for scoops, check out his site. Is it worth the price? Let's find out! Below, you'll find some of my favorite quotes from the site.
ProFootballTalk Live will move to a new timeslot starting in mid-April. The show will air weekdays from 6-9 a.m. ET, with a repeat showing during West Coast drive time from 6:00-8:00 a.m. PT (9 a.m.-noon ET). It will be simulcast on NBCSN and streamed on NBC Sports Live Extra.
As a result of the move, the show's time slot will change, too. Weekdays from 6-9 a.m. ET will now be the primetime time for ProFootballTalk Live. A second episode will air in the early afternoon during West Coast drive time. The show will air live in both regions, and will be simulcast on NBCSN and NBC Sports Live Extra through mid-April.
PFT has expanded its reach to new mediums. The show will continue to air its radio show from 6-9 a.m. ET. The show will also air an encore in the West Coast drive time from 6-9 a.m. PT (9 a.m.-noon ET). The show will continue to be simulcast on NBCSN and NBC Sports Live Extra through mid-April. It will also be simulcast on NBCSN, which will also be available for streaming on NBC Sports Live Extra.
Another new format for ProFootballTalk is the move from its weekly radio show to NBC Sports TV. The show will be a morning show that will feature interviews with top athletes and breaking news from all over the world. The show will also be available on NBC Sports Live Extra on NBCSN. While it is primarily a radio show, the TV show is a great way to get sports-related news.
With the move to the new time slot, ProFootballTalk will continue to grow its reach. The show will be on NBCSN from 6 a.m. ET to 9 a.m. ET on the West Coast. The show will be streamed on NBC Sports Live Extra until mid-April. While the radio show will continue to be available on NBCSN, it will be on NBC Sports TV on a weekly basis.
In addition to its radio program, PFT is also on NBC Sports TV. The show will feature interviews with top athletes and breaking news, and the show will air weekdays at 6 a.m. on the East Coast. It will be simulcast on NBCSN from 6 a.m. to noon. The television show will also be streamed on NBC Sports Live Extra through mid-April. There are other shows on NBCSN that are similar to ProFootballTalk.
Mike Florio's PFT radio show has moved to NBC Sports TV. The show will air weekdays from 6 a.m. ET to noon ET, with an encore at 10 a.m. PT. It will also be simulcast on NBCSN and NBC Sports Live Extra from mid-April onward. Until then, the show is available on NBCSN and a variety of other channels.
The radio show is now moving to a new time slot on NBC. The new show airs weekdays from 6-9 a.m. ET, with an encore in West Coast drive time at 9 a.m. PT. During the week, PFT will also be simulcast on NBCSN. During the spring, the show will be streamed on NBC Sports Live Extra through mid-April.
is now on NBC Sports. Its new timeslot was determined by the demand for its show. The show will air weekdays from 6-9 a.m. ET. An encore in West Coast drive time will air from 6-9 a.m. PT. NBCSN will also simulcast the show on NBC Sports Live Extra until mid-April. In addition, PFT will be simulcast on NBCSN and NBC Sports Live Extra.
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Set in Combe Martin, Poplars Hotel provides a seasonal outdoor swimming pool, garden and terrace. Among the various facilities of this property are a shared lounge and a bar. Both free WiFi and private parking are accessible at the bed and breakfast. All rooms in Poplars Hotel are equipped with a flat-screen TV. Rooms include a private bathroom with a shower, while selected rooms here will provide you with a balcony and others also boast sea views. All units will provide guests with a wardrobe and a kettle. Guests at the accommodation can enjoy a continental breakfast. You can play billiards at Poplars Hotel. Swansea is 47 km from the bed and breakfast, while Barnstaple is 14 km from the property. The nearest airport is Cardiff Airport, 53 km from the property.
You will be charged a prepayment of the first night in the 14 days before arrival.
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John DiPace (né le  à Clinton Township, dans l'état du Michigan aux États-Unis) est un joueur américain de hockey sur glace.

Carrière de joueur
Il commence sa carrière en 2002 avec le Lightning de Détroit dans la Continental Elite Hockey League.

Statistiques de carrière
Pour les significations des abréviations, voir statistiques du hockey sur glace.

|2002-2003 || Lightning de Détroit || CEHL ||50 ||35 ||42 ||77 ||309 ||- ||- ||- ||- ||-
|-
|2003-2004 || Generals de Flint || UHL ||70 ||16 ||31 ||47 ||84 ||3 ||2 ||2 ||4 ||2
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|2004-2005 || Generals de Flint || UHL ||79 ||20 ||25 ||45 ||229 ||- ||- ||- ||- ||-
|-
|2005-2006 || Riverdogs de Richmond || UHL ||74 ||31 ||36 ||67 ||224 ||- ||- ||- ||- ||-
|-
|2006-2007 || Rage de Rocky Mountain || LCH ||62 ||15 ||20 ||35 ||163 ||- ||- ||- ||- ||-
|-
|2007-2008 || Generals de Flint || LIH ||70 ||24 ||31 ||55 ||238 ||5 ||4 ||2 ||6 ||12
|-
|2008-2009 || Generals de Flint || LIH ||48 ||24 ||27 ||51 ||159 ||- ||- ||- ||- ||-
|-
|2008-2009 || Lumberjacks de Muskegon || LIH ||26 ||13 ||18 ||31 ||81 ||9 ||2 ||5 ||7 ||16
|-
|2009-2010 || Lumberjacks de Muskegon || LIH ||58 ||25 ||39 ||64 ||87 ||7 ||1 ||3 ||4 ||18
|-
|2010-2011 || IceMen d'Evansville || LCH || 38|| 5|| 12|| 17|| 53|| -|| -|| -|| -|| -

Notes et références

Naissance en avril 1982
Naissance dans le comté de Macomb
Joueur américain de hockey sur glace
Joueur du Lightning de Détroit
Joueur des Generals de Flint
Joueur des RiverDogs de Richmond
Joueur du Rage de Rocky Mountain
Joueur des Lumberjacks de Muskegon (1992-2010)
Joueur des IceMen d'Evansville
Attaquant de hockey sur glace

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About Elder-Geek
Champions Online Going Free to Play
Following successful transition into free-to-play titles of games like Lord of the Rings Online and Dungeon and Dragons Online, Cryptic Studios has announced that its action-oriented MMORPG Champions Online will also be going free to play in the near future. The game was originally launched in September 2009, and an Xbox 360 version of the game was cancelled earlier this year for an unspecified reason.
The transition from subscription-based to free-to-play will be combined with a major game update, which introduces many new features and adapts existing gameplay elements to make the game more accessible to newcomers. A closed beta will be set up early November, and will feature these upcoming changes. It is currently not clear when Champions Online can be expected to make a full transition to free-to-play.
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Dear Santa Hot Chocolate Drink Mix is the perfect addition to your next holiday party.
Sweeten up your holidays with Dear Santa Hot Chocolate Drink Mix. This package of delicious and creamy hot chocolate features a fun Santa hat sticker that will include your custom wording.


My Madder Fatter Diary is the second collection of diary entries Rae Earl wrote as a teenager. It follows the events after My Fat, Mad Teenage Diary.
It's 1990. Rae has to face her A Levels and figure out what she can and wants to do next. But figuring yourself out is a tall order even when you don't struggle with your mother, have mental health issues and no proper help with that, when you aren't fat or in love with the most gorgeous guy on earth. That means that life's a tall order for Rae, but at least she has the big personality to match it.
My Madder Fatter Diary manages to bring Rae's story to a nice conclusion (as much as you can bring a life story that doesn't end in death to a conclusion). It's a hugely enjoyable and emotional read that I absolutely loved.
My Madder Fatter Diary feels a lot more unguarded than the first volume of Earl's diaries. Especially with regards to her mental illness – I'd say she suffers from obsessive compulsive disorder, though I don't think that she mentions a diagnosis in the book. She both shows more clearly how the illness affected her and in the afterword that clears up some of the last open points, she makes it very clear that she would have needed therapy at that time already, but she only got the proper help only many years later.
The afterword was generally important, and not only for closing those story threads. In it, Earl also states without a doubt that losing the weight wasn't the point of her journey that made life better for her. And that she kept losing and gaining weight for pretty much most of her adult life, moving away from the narrative that if you just get thin, all other problems will magically disappear – a narrative that often haunts fat people.
The book also clearly shows how much Rae grew up in that year and that she finally gets to a point where she's ready to face her own life – even if it's [SPOILER] without Haddock [/SPOILER]. Which was, all things considered, a good thing for me: she developed and did her own thing. It's another great argumentation for gap years. If there's any way you can afford it, do it. Give yourself that time to grow.
And all of that with the wonderful sense of humor I've come to expect from Earl. It's simply a lovely read and will speak to anyone who was/is fat, mentally ill and/or a teen.
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text:
Q: Counting and filtering Arrow for HXT I'm trying to parse an XML, but I want to filter and extract only a determinate number of children from a given node. For example:
<root>
    <node id="a" />
    <node id="b" />
    <node id="c" />
    <node id="d" />
</root>

And then if I execute the arrow getChildren >>> myFilter 2, I would get back only the nodes with id "a" and "b".
Intuition gives that I should use a State Arrow to keep track, but I don't know how to do that.
I tried to do it myself but it's not exactly what I want, doesn't look very elegant, and doesn't work. I try to run my chain of arrows with runSLA and a integer parameter as initial state, and then defining:
takeOnly :: IOSLA Int XmlTree XmlTree
takeOnly = changeState (\s b -> s-1)
             >>> accessState (\s b -> if s >= 0 then b else Nothing)

But of course I can't return Nothing, I need to return a XmlTree. But I don't want to return anything at all!
There's probably a better way out there. Can you help me?
Thanks for your time and help!

A: It would probably be more idiomatic to use the combinators in Control.Arrow.ArrowList to handle this kind of thing.
The package specifically provides (>>.) :: a b c -> ([c] -> [d]) -> a b d, which is a "combinator for converting the result of a list arrow into another list". This allows us to use the take function that we already have for lists in this context.
Here's a quick version of how you might use it:
module Main where

import Text.XML.HXT.Arrow

takeOnly :: (ArrowXml a) => Int -> a XmlTree XmlTree
takeOnly n = getChildren >>. take n

main = do
  let xml = "<root><node id='a' /><node id='b' />\
                  \<node id='c' /><node id='d' /></root>"

  print =<< runX (readString [] xml >>> getChildren >>> takeOnly 2)

This I believe does approximately what you're looking for:
travis@sidmouth% ./ArrowTake
[NTree (XTag (LP node) [NTree (XAttr (LP id)) [NTree (XText "a") []]]) [],
 NTree (XTag (LP node) [NTree (XAttr (LP id)) [NTree (XText "b") []]]) []]

No IOSLA required. Note that I've also changed the function type a little—this version seems nicer to me, but you could easily convert it to something more like the type in your version.

redpajama_set_name: RedPajamaStackExchange


We have enjoyed beginning our topic 'The Heart' and have been impressed with your enthusiasm so far. We would like you to further your knowledge by creating something from the list below. They are just suggestions so if you can think of anything else that inspires you, then go for it! As long as the theme is the Heart, you can be as creative as you like.
You could create a scientific 3D model of the heart.
You could create a quiz for friends or teachers to complete.
You could create a fact file with interesting facts that you have learnt.
You could create a rap about how the heart works.


Helsinki (Finnish pronunciation places stress on the first syllable: ), is used to refer to the city in most languages, but not in Swedish.
The Swedish name Helsingfors ( or ) is the original official name of the city of Helsinki (in the very beginning, spelled Hellssingeforss). The Finnish language form of the name probably originates from Helsinga and similar names used for the river that is currently known as the Vantaa River as documented already in the 14th century. Helsingfors comes from the name of the surrounding parish, Helsinge (source for Finnish Helsinki) and the rapids (Swedish: fors), which flowed through the original village.
Another suggestion is that the name Helsinge may have originated with medieval Swedish settlers who came from Hälsingland in Sweden. Others have proposed that the name derives from the Swedish word hals (neck), referring to the narrowest part of the river, i.e. the rapids.


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text:
ICH GCP | Clinical Trials Registry
Clinical Trials: SEARCH[Study] TILT[Study:StudyFirstPostDate] AREA[InterventionSearch] Placebo
Fill in any or all of the fields below.
Click on a label to the left for further explanation or read the Help.
Basic Terms:
All Studies Open Studies Closed Studies Exclude Unknown Status
Study Results:
All Studies Studies With Results Studies Without Results
All Studies Interventional Studies Observational Studies Expanded Access Studies
Targeted search:
Interventions:
Outcome Measures:
Sponsor/Collaborators:
Sponsor (Lead):
Study IDs:
State 1:
--- Optional --- United States, Alabama United States, Alaska United States, Arizona United States, Arkansas United States, California United States, Colorado United States, Connecticut United States, Delaware United States, District of Columbia United States, Florida United States, Georgia United States, Hawaii United States, Idaho United States, Illinois United States, Indiana United States, Iowa United States, Kansas United States, Kentucky United States, Louisiana United States, Maine United States, Maryland United States, Massachusetts United States, Michigan United States, Minnesota United States, Mississippi United States, Missouri United States, Montana United States, Nebraska United States, Nevada United States, New Hampshire United States, New Jersey United States, New Mexico United States, New York United States, North Carolina United States, North Dakota United States, Ohio United States, Oklahoma United States, Oregon United States, Pennsylvania United States, Rhode Island United States, South Carolina United States, South Dakota United States, Tennessee United States, Texas United States, Utah United States, Vermont United States, Virginia United States, Washington United States, West Virginia United States, Wisconsin United States, Wyoming Canada, Alberta Canada, British Columbia Canada, Manitoba Canada, New Brunswick Canada, Newfoundland and Labrador Canada, Nova Scotia Canada, Ontario Canada, Prince Edward Island Canada, Quebec Canada, Saskatchewan Australia, Australian Capital Territory Australia, New South Wales Australia, Northern Territory Australia, Queensland Australia, South Australia Australia, Tasmania Australia, Victoria Australia, Western Australia
Country 1:
--- Optional --- United States Afghanistan Albania Algeria American Samoa Andorra Angola Argentina Armenia Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bolivia Bosnia and Herzegovina Botswana Brazil Brunei Darussalam Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Central African Republic Chad Chile China Colombia Congo Congo, The Democratic Republic of the Costa Rica Croatia Cuba Cyprus Czech Republic Côte D`Ivoire Denmark Djibouti Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Estonia Ethiopia Fiji Finland Former Serbia and Montenegro Former Yugoslavia France French Polynesia Gabon Gambia Georgia Germany Ghana Greece Grenada Guadeloupe Guatemala Guinea Guinea-Bissau Guyana Haiti Honduras Hong Kong Hungary Iceland India Indonesia Iran, Islamic Republic of Iraq Ireland Israel Italy Jamaica Japan Jordan Kazakhstan Kenya Korea, Republic of Kuwait Kyrgyzstan Lao People`s Democratic Republic Latvia Lebanon Lesotho Liberia Libyan Arab Jamahiriya Lithuania Luxembourg Macau Macedonia, The Former Yugoslav Republic of Madagascar Malawi Malaysia Mali Malta Martinique Mauritania Mauritius Mexico Moldova, Republic of Monaco Mongolia Montenegro Morocco Mozambique Myanmar Nepal Netherlands Netherlands Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Northern Mariana Islands Norway Oman Pakistan Panama Papua New Guinea Paraguay Peru Philippines Poland Portugal Puerto Rico Qatar Romania Russian Federation Rwanda Réunion Saint Kitts and Nevis Saudi Arabia Senegal Serbia Sierra Leone Singapore Slovakia Slovenia Solomon Islands South Africa Spain Sri Lanka Sudan Swaziland Sweden Switzerland Syrian Arab Republic Taiwan Tanzania Thailand Togo Trinidad and Tobago Tunisia Turkey Uganda Ukraine United Arab Emirates United Kingdom Uruguay Uzbekistan Venezuela Vietnam Virgin Islands (U.S.) Yemen Zambia Zimbabwe
Location Terms:
Additional Criteria:
All Studies Studies with Female Participants Studies with Male Participants
Child (birth-17) Adult (18-65) Senior (66+)
Phase 1 Phase 2 Phase 3 Phase 4
NIH Industry
Other U.S. Federal Agency All others (Individual, University, Organization, ... )
Safety Issue:
Has an outcome measure designated as a safety issue.
First Received:
From To (MM/DD/YYYY)
First Previous 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 … 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 Next Last
NCTID/Status
Measure the Effects of Specific Thoracic Chiropractic Adjustments on Blood Pressure and Pulse Rate
Conditions: Hypertension
Intervention: Activator IV Adjusting Instrument
Travatan Versus Timoptic in Treating Open-angle Glaucoma or Ocular Hypertension
Conditions: Glaucoma
Intervention: Travoprost 0.004% Ophthalmic Solution (Travatan), Timolol 0.5% Ophthalmic Solution (Timoptic)
Long-Term Dopamine Transporter Imaging and Clinical Assessment of Parkinson's Disease Progression
Conditions: Parkinson Disease
Intervention: [123I]B-CIT SPECT Imaging
Comparison of Covered and Bare Stent in TIPS
Conditions: Cirrhosis
Intervention: Covered Stent, Bare Stent
A Phase 1a/1b Study of CB4211 in Healthy Non-obese Subjects and Subjects With Nonalcoholic Fatty Liver Disease
Conditions: Nonalcoholic Fatty Liver Disease
Intervention: CB4211 Dose 1, CB4211 Dose 2, CB4211 Dose 3, CB4211 Dose 4, CB4211 Dose 5, CB4211 Dose 6, CB4211 Dose TBD, Placebo
Effects of Dexmedetomidine on Quality of Recovery and Analgesia After Video-assisted Thoracoscopic Surgery
Conditions: Lung Cancer; Video-assisted Thoracoscopic Surgery
Intervention: Dexmedetomidine, Normal Saline
Study to Evaluate the Long-Term Safety, Tolerability and Efficacy of Dalfampridine.
Conditions: Post-ischemic Stroke
Intervention: Dalfampridine-ER 7.5 Mg, Dalfampridine-ER 10 Mg
chemQbiosciences:Manual Liquid Based Cytology
Conditions: Cervical Dysplasia; Cervical Cancer
Intervention: Pap Smear
Sirolimus and Familial Adenomatous Polyposis (FAP)
Conditions: Adenomatous Polyposis Coli
Intervention: Sirolimus
Evaluation of the Effect of TMS on Primary Dysmenorrhea
Conditions: Primary Dysmenorrhea
Intervention: Active RTMS, Sham RTMS
Application of Detecting Circulating Tumor Cells in the Accurate Treatment of Early Stage Lung Adenocarcinoma
Conditions: Lung Adenocarcinoma, Stage I; Diagnoses Diseases; Circulating Tumor Cells; Treatment
Intervention: Lobectomy, Segmentecomy, Chemotherapy(pemetrexed+CISPLATIN), Lymphadenectomy, CanPatrolTM To Detect CTCs
Oral Ketamine as an Adjuvant to Opioids for Pain Treatment in Cancer Patients
Conditions: Cancer; Pain; Tolerance
Intervention: Oral Ketamine
Phase III Efficacy and Tolerability Trial of the Fixed Dose Combination of Etodolac 400 mg and Cyclobenzaprine 10 mg Versus Isolated Active Substances in Pain Control After Impacted Third Molar Extraction
Conditions: Pain, Acute
Intervention: Fixed Dose Combination, Etodolac, Cyclobenzaprine
EMDR in the Treatment of Specific Phobia.
Conditions: Specific Phobia
Intervention: EMDR (Eye Movement Desensitization And Reprocessing), Exposure Therapy
"E4/DRSP Endocrine Function, Metabolic Control and Hemostasis Study"
Conditions: Contraception; Liver Metabolism; Hemostasis Parameter
Intervention: 15 Mg E4/3 Mg DRSP, 30 Mcg EE/150 Mcg LNG, 20 Mcg EE/3 Mg DRSP
Efficacy and Safety of Oral NOMAC-E2 in Indian Women (P07057/MK-8175A-017)
Conditions: Contraception
Intervention: Nomegestrol Acetate (NOMAC), Estradiol (E2)
Feel Breathe, Restriction Device Ventilatory Nasal
Conditions: Mouth Breathing; Restrictive Breathing Pattern
Intervention: Feel Breathe, Restriction Device Ventilatory Nasal
Hemodynamic Response to Exercise in HFpEF Patients After Upregulation of SERCA2a
Conditions: Heart Failure, Congestive
Intervention: Istaroxime, Exercise
Effects of Growth Hormone Administration on Muscle Strength and Body Composition in Men Over 50 Years Old
Conditions: Healthy
Intervention: Growth Hormone
An Open Label Study for Participants With Rheumatoid Arthritis
Conditions: Rheumatoid Arthritis
Intervention: LY2127399
Safety, Pharmacokinetic (PK), Pharmcodynamic (PD), and Drug-Drug Interaction of PLX3397 in Patients With Rheumatoid Arthritis Who Are Receiving Methotrexate
Intervention: PLX3397
A Multinational Phase III Study of CS-8958 (MARVEL)
Conditions: Influenza, Human
Intervention: CS-8958, CS-8958, Oseltamivir Phosphate
Secretin Activates Human Brown Fat and Induces Satiation.
Conditions: Obesity
Intervention: Secretin Human, Saline Solution, Cold Exposure
EBV Positive Nasopharyngeal Carcinoma Treated With Concurrent Chemo-radiotherapy With or Without Anti-Viral Drug
Conditions: Drug Use for Unapproved Schedule
Intervention: Acyclovir 800 MG, Radiotherapy And Chemotherapy
Study Of Dacomitinib (PF-00299804) In Advanced NSCLC Patients (Post Chemo Or Select First Line) To Evaluate Prophylactic Intervention On Derm And GI AEs And PRO
Conditions: Non Small Cell Lung Cancer (NSCLC)
Intervention: Dacomitinib, Dacomitinib, Doxycycline, Probiotic, Alclometasone Cream
Mitochondrial Function in Septic Patients
Conditions: Sepsis; Septic Shock
Intervention: Hydrocortisone
Inorganic Nitrate and OSA
Conditions: Obstructive Sleep Apnea
Intervention: Pre-beetroot Juice Supplementation, Post-beetroot Juice Supplementation
Does Topical Ophthalmic Anesthetic Prior to Probing and Irrigation Decrease Pain?
Conditions: Epiphora; Dacryostenosis; Dacryocystitis
Intervention: Proparacaine Hydrochloride Ophthalmic Solution, USP 0.5%, Balanced Salt Solution
Effects of Massage on the Immune System of Preterm Infants
Conditions: Premature Birth; Stress
Intervention: Massage Therapy, Sham
Evaluation of Ingenol Mebutate for Actinic Cheilitis Treatment
Conditions: Actinic Cheilitis
Intervention: Ingenol Mebutate Gel
A Study of Psilocybin for Major Depressive Disorder (MDD)
Conditions: Depressive Disorder, Major
Intervention: Psilocybin, Niacin
Clinical Study of R744 to Hemodialysis Patients
Conditions: Hemodialysis Patients
Intervention: R744, R744, RHuEPO, RHuEPO, R744 Placebo, RHuEPO Placebo
Inflammatory Response to Salt in Essential Hypertension
Conditions: Essential Hypertension.
Intervention: High Salt Intake
Effects of Photobiomodulation on Superficial Sensitivity and Muscle Activity of Individuals With Myelomeningocele
Conditions: Myelomeningocele Without Hydrocephalus; Sensory Defect; Motor Activity
Intervention: Low Level Laser Therapy
Assessing Tele-Health Outcomes in Multiyear Extensions of PD Trials
Exploring Advanced Imaging Techniques to Characterize Botulinum Toxin Diffusion in Human Muscle
Conditions: Stroke; Muscle Spasticity
Intervention: Botox (botulinum Toxin)
Interpretive Biases in Children With Social Anxiety
Conditions: Social Anxiety; Social Anxiety Disorder
Intervention: Online Interpretation Training Condition 1, Online Interpretation Training Condition 2
Augmenting Effects of L-DOPS With Carbidopa and Entacapone
Conditions: Parkinson Disease; Multiple System Atrophy; Autonomic Nervous System Diseases
Intervention: Droxidopa, Carbidopa, Entacapone
Efficacy and Safety of Odanacatib in Postmenopausal Women Previously Treated With Alendronate (MK-0822-050)
Conditions: Osteoporosis; Postmenopausal Osteoporosis
Intervention: Odanacatib, Alendronate, Placebo (odanacatib), Cholecalciferol (Vitamin D3), Calcium Carbonate, Placebo (alendronate)
Prevention of Silent Cerebral Thromboembolism by Oral Anticoagulation With Dabigatran After Pulmonary Vein Isolation for Atrial Fibrillation
Conditions: Atrial Fibrillation; Cardioembolic Events; Oral Anticoagulation
Intervention: Dabigatran
Fecal Microbiota Transplantation for Ulcerative Colitis
Conditions: Ulcerative Colitis; Fecal Microbiota Transplantation
Intervention: Fecal Microbiota Transplantation, Infusion Of Saline, 5-Aminosalicylic Acid(5-ASA) And/or Prednisone
Preoperative Chemotherapy With Bevacizumab For Potentially Resectable Gastric Cancer With Liver Metastasis
Conditions: Gastric Cancer; Liver Metastasis
Intervention: Oxaliplatin;Capecitabine, Oxaliplatin;Capecitabine;Bevacizumab
Nebivolol Versus Metoprolol: Sodium Sensitivity
Intervention: Nebivolol, Metoprolol
Evaluation of the Tolerance and Acceptability of Rasagiline in the Treatment of Early-stage Parkinson's Disease
Conditions: Early-stage Parkinson's Disease
Intervention: Rasagiline, Pramipexole
Effects of Exemestane on Bone Strength
Conditions: Osteoporosis; Breast Cancer
Celecoxib for Primary Prophylaxis of Combat-Related Heterotopic Ossification
Conditions: Ossification, Heterotopic
Intervention: Celecoxib
Fecal Microbiota Transplantation for Irritable Bowel Syndrome
Conditions: Irritable Bowel Syndrome; Fecal Microbiota Transplantation
Intervention: Fecal Microbiota Transplantation, Infusion Of Sham, Probiotics, Antibiotics Or Antidepressants
Medications Development for Drug Abuse Disorders
Conditions: Opioid Related Disorders; Opioid Dependence; Opioid Addiction
Intervention: Buprenorphine/naloxone, Clonidine, Tramadol ER
Phase 3 Study of RPC1063 in Relapsing MS
Conditions: Multiple Sclerosis
Intervention: RPC1063, Beta Interferon
MuscleCare™ Pain Relief Therapy vs. Voltaren® in the Relief of Trapezius Trigger Point Musculoskeletal Pain.
Conditions: Pain
Intervention: MuscleCare Topical Product, Voltaren Topical, Nivea, Topical Cream
The last updated date is the most recent date when changes to a clinical trial were submitted to ClinicalTrials.gov. There is often a delay of a few days before the updated trial is available on the clinical trials website.
Specify a From date to find the most recently changed trials. Specify both From and To dates to find trials changed during a certain period. If no dates are given, all trials will be included.
Dates should be given in a MM/DD/YYYY format, as in 1/1/2006 or 8/17/2004.
First Received
The first received date is the date when the clinical trial was first submitted to ClinicalTrials.gov. There is often a delay of a few days before the trial is available on the clinical trials website.
Clinical trial records are often updated after they have been published. The first received, last updated, start, and end dates are all displayed in the full text view of the clinical trial.
Specify a From date to find the most recent trials. Specify both From and To dates to find trials submitted during a certain period. If no dates are given, all trials will be included.
If selected, restricts search results to those studies which have an outcome measure designated as a safety issue. Note that this is a poor estimate of the safety of a treatment or intervention, but it is all we have now.
Studies are supported by one or more organizations called sponsors. Support includes contributions of facilities, expertise, and/or financial resources. All sponsors in the database have been assigned one of the following organization types:
Other U.S. Federal Agency - Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC), Department of Veterans Affairs (VA), etc.
Industry - the pharmaceutical companies
University/Organization - all others, including community-based organizations
Click the check box to the left of each organization type that you wish to include in your search. You can select more than one organization type. If you do not select any type, all types will be included.
Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions that study is seeking to answer:
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.
Click the check box to the left of each study phase that you wish to include in your search. You can select more than one study phase. If you do not select a any phase, all phases will be included.
Studies may be designed for participants of particular ages:
Children (birth-17 yrs old)
Adults (18-65 yrs old)
Senior (66+ yrs old)
Click the check box to the left of each age group that you wish to include in your search. You can select more than one age group. If you do not select a any group, all groups will be included.
Searches can be restricted to studies which accept female or male participants.
Location Terms
If you are interested in a specific city (such as Los Angeles) or facility name (such as the Mayo Clinic), enter it as a location term. Not all studies include this level of detail, but if they do, this will find them.
Countries and States
Trials are often conducted at many locations around the world. Select up to three locations to find trials conducted in specific countries. Some countries (currently limited to the United States, Canada, and Australia), locations can be narrowed further by selecting a state.
Study IDs
Each trial is assigned one or more identification numbers by the institute, agency, or organization sponsoring the trial. In addition, clinical trials assigns a unique NCT identifier of the form NCTxxxxxxxx where each x is a numeric digit. Use this box to search for a trial by NCT identifier or any other study identification numbers.
97-h-0197
ia0006
actg 076
Sponsor (Lead)
Use this box to specify the name of an institute, organization, or company that is conducting a trial.
It is common for several organizations to collaborate by providing funding, facilities, experimental treatments, etc. Which organization is considered the sponsor is decided by the data provider.
A search in this area will check only the sponsor field. To also look for collaborators, use the Sponsor/Collaborators search box.
When the Exact Match checkbox is checked, the sponsor name in the study must exactly match the sponsor name in the search. For example, if unchecked, a search for Merck in the lead sponsor field will find Merck, Merck KGaA, Dupont Merck, and Merck Sharp & Dohme. When checked, only Merck, with no other words in the name, will be found.
Sponsor/Collaborators
Use this box to specify institutes, organizations, or companies that are conducting or otherwise supporting a trial.
Searching this area will look in both the sponsor field and in the collaborators field. To only look in the sponsor field, use the Sponsor (Lead) search box.
When the Exact Match checkbox is checked, the name in the study must exactly match the name in the search. For example, if unchecked, a search for Merck will find Merck, Merck KGaA, Dupont Merck, and Merck Sharp & Dohme. When checked, only Merck, with no other words in the name, will be found.
Outcome measures are used to evaluate trial results. For example, an obesity treatment might be evaluated by a measure of weight loss after 6 months. Measures can also be used to quantify side effects, such as number of myocardial infarctions, number of patients with heart arrhythmia, number of suicides, etc.
Use this box to specify an outcome measure used to evaluate trial results.
Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied. Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Use this box to specify drugs, devices, procedures, or vaccines used in a trial.
clofibrate
Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov, conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Use this box to specify the conditions being studied.
risk factors for breast cancer
There are three types of studies available in ClinicalTrials.gov:
Interventional:
Studies where individuals are assigned to receive specific interventions. Participants may receive diagnostic, therapeutic or other types of interventions. Assignment of the intervention may or may not be random. Individuals are tracked and biomedical and/or health outcomes are assessed.
Observational:
Studies without an intervention. Studies where biomedical and/or health outcomes are assessed in a pre-defined group of individuals. Participants may receive diagnostic, therapeutic, or other interventions, but the investigator does not assign specific interventions to the participants of the study.
Expanded Access:
Records describing the procedure for obtaining an experimental drug or device for patients who are failing on currently available treatments for their condition and also are unable to participate in ongoing clinical trials. Expanded Access records are used to register all types of non-protocol access to experimental treatments, including protocol exception, single-patient IND, treatment IND, compassionate use, emergency use, continued access and parallel track.
Searches can be restricted to studies with or without results.
The inclusion of study results is a relatively new feature of ClinicalTrials.gov. Collection of results began in September of 2008. Almost all older studies and some newer studies do not include results. As time goes on, there will be more results available.
Recruitment Status
Also known as Enrollment Status.
Not all clinical trials in this database are accepting new participants. If you are looking for studies that are currently recruiting participants, will be recruiting in the future, or are about drugs that are available for expanded access, select Open Studies in the recruitment menu.
If you are interested in all trials, whether they are recruiting new participants or not, leave the menu with All Studies selected.
Trials may not be recruiting because they are full, completed, or halted for various reasons. In addition, some trials have very restrictive eligibility requirements and must seek participants by invitation only. To see these studies, Select Closed Studies in the recruitment menu.
Full list of all possible recruitment status values:
Open recruitment status values:
Recruiting,
Not yet recruiting, or
Available for expanded access.
Closed recruitment status values:
Active, not recruiting,
Completed,
Terminated,
Withdrawn,
Enrolling by invitation,
Temporarily not available for expanded access,
No longer available for expanded access,
Approved for marketing, or
Values are color coded (as shown) in the search results.
Use this box to specify general search terms found anywhere in the trial record.
Multiple terms can be separated by an AND (all uppercase).
heart attacks in older adults
nhlbi AND heart disease
Cisplatin AND safety study
Help for Searching clinical trials
Search Expressions
Basic Search:
On the Basic Search page, enter a word or word(s) that you want to use to find studies. These may include diseases, interventions, and/or locations.
Medical terms are often several words long, such as Percutaneous Coronary Intervention. To only find studies where the words are together as a phrase, put the term in quotes (e.g., "Percutaneous Coronary Intervention"). If you search for a multi-word term without quotes, studies with all words together as a phrase will appear higher in the results list than studies where the words are separated and spread throughout the document. For example, a search for Heart Attack will list a study about,
Use of a Pacemaker Following a Heart Attack.
higher than the study,
Heart Defects and Transient Ischemic Attacks
A search for "Heart Attack" would not find the second study. Synonyms are known for some terms and are used where possible. For example, a search for Heart Attack will also find occurrences of Myocardial Infarction.
Many searches are a single term and can be performed with a few words in the search box. But, sometimes you need more control. Click on the Advanced Search tab (if starting a new search) or Refine Search tab (if modifying an existing search) to show additional search fields.
The additional search fields can be used to limit your search results. Note that it is not necessary to fill in all the fields, only those that are needed for your search. If you are finding too few studies, consider clearing a field and searching again.
Performs a general search in all sections of the study record, including title, description, conditions, interventions, locations, etc. Terms in this field are searched the same as Basic Search.
Limits search results to studies that are open or closed. New volunteers may be able to participate in open studies, but not closed studies.
Limits search results based on whether the study has results or not:
All Studies,
Studies With Results, or
Studies Without Results
The inclusion of Study Results is a new feature of ClinicalTrials.gov. Only a few studies have results available.
Limits search results to any of the following study types:
Interventional,
Observational, or
Performs a search on fields describing the diseases or conditions being studied.
Performs a search on fields listing the drugs or interventions being studied.
Outcomes Measures:
Performs a search on fields listing the outcome measures used to quantify study results.
Performs a search on fields listing the sponsor and collaborators of a study.
When the Exact Match checkbox is checked, the sponsor/collaborator name in the study must exactly match the name in the search. For example, if unchecked, a search for Merck in the sponsor/collaborator field will find Merck, Merck KGaA, Dupont Merck, and Merck Sharp & Dohme. When checked, only Merck, with no other words in the name, will be found.
Performs a search on the sponsor field of a study.
It is common for several organizations to collaborate by providing funding, facilities, experimental treatments, etc. Which organization is considered the "sponsor" is decided by the data provider.
When the Exact Match checkbox is checked, the lead sponsor name in the study must exactly match the lead sponsor name in the search. For example, if unchecked, a search for Merck in the lead sponsor field will find Merck, Merck KGaA, Dupont Merck, and Merck Sharp & Dohme. When checked, only Merck, with no other words in the name, will be found.
Performs a search on fields listing ID numbers.
Trials are often conducted at many locations around the world. Select up to three locations to find trials conducted in specific countries. Some countries (currently limited to the United States, Canada, and Australia), locations can be narrowed further by selecting a state (e.g., United States, Alabama).
Finds studies in specific locations such as a city (Los Angeles) or facility (Mayo Clinic). Not all studies include this level of detail, but if they do, this will find them.
Limits search results to those studies that accept female or male participants.
Limits search results to those studies that include at least one of the specified age ranges. More than one age group can be selected.
Limits search results to studies that are labeled with at least one of the specified phases. More than one Phase can be selected.
Limits search results to studies that have at least one sponsor of the specified types. More than one sponsor type can be selected.
Limits search results to studies that have at least one outcome measure designated as a safety issue.
Limits search results to studies that were received by clinical trials within a specified date range. The "From" or "To" field can be left blank.
Limits search results to studies that were modified within a specified date range. The "From" or "To" field can be left blank.
Searches display a list of studies found (List Results tab). If you are not content with the search results, click on the Refine Search tab at the top of the list to modify your search.
Add terms to empty fields to search within your current result. You can also add terms to fields that contain terms. For best results, use an AND (all upper case) as a separator between terms in the same field.
heart attack AND aspirin
heart attack AND aspirin AND older adults
heart attack AND aspirin AND older adults AND California
When you are done making changes, click Search to display the new results.
Search Expressions:
Use AND (all upper case) to find study records that contain all terms connected by AND.
prostate cancer AND radiation
heart disease AND stroke AND California
Use OR (all upper case) to find study records that contain either term connected by OR.
Aspirin OR ibuprofen
heart disease OR heart attack
Use NOT (all upper case) to find study records that do not contain the term following NOT.
Immunodeficiency NOT AIDS
Likewise, AND, OR, NOT, and parentheses can be used to create more complicated search expressions.
prostate cancer AND NOT ( radiation OR homeopathic remedies )
( heart disease OR heart attack ) AND ( stroke OR clot )
Note that the use of AND and OR as logical operators can be confusing.
An appropriate search for a list such as,
Ear, Nose, and Throat Conditions
is the expression
( Ear OR Nose OR Throat ) AND Conditions
Fortunately, search will do a pretty good job of finding the right studies either way.
To search for AND as a word, instead of using it as an operator, put it in quotes.
Likewise, you can quote OR, NOT, and parentheses.
Quality Assurance Auditor 1 - GLP Tox
Shrewsbury, MA, US, 01545
Client Services Coordinator
Malvern, PA, US, 19355
Clinical research organizations
PharmaFacts
Hyperion Biotechnology
IATEC
Novatia
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