bluuebunny/crossref_metadata_2025 huggingface dataset:
The Concord gabbro-syenite complex, North Carolina
Authors: McSween Harry Y.
Published: November 2007

Two stops (Fig. 1) southwest of the town of Concord, Cabarrus County, North Carolina (Fig. 1). No special permission is needed for either stop. Site 1 is a quarry located in the southwestern corner of the Concord 7½-minute Quadrangle, and is accessible via Cavalier Court, an unpaved road connecting with Rock Hill Church Road (Rd. 1414) 0.2 mi (0.3 km) northwest of its intersection with U.S. 29. Cars and vans can be parked at the quarry (0.4 mi or 0.6 km down Cavalier Court), but buses should be parked near the radio tower. Site 2 is an exposure along Coddle Creek at Weddington Road in the Kannapolis quadrangle. A bridge crosses the creek 0.2 mi (0.3 km) southwest of the Weddington Road (Rd. 1431) and Concord Farms Road (Rd. 1432) intersection. Park at the turnout on the south side of thbridge, cross the fence on the opposite side of the road, and walk upstream on the right side of the creek for approximately 300 ft (90 m) to a small waterfall. The outcrop is a field of large gabbro boulders and is not visible from the road.
Carolina slate belt near Albemarle, North Carolina
Authors: Butler James Robert
Published: November 2007

Two regionally important stratigraphic units in the Carolina slate belt are exposed along North Carolina 24-27 on both sides of Lake Tillery (Pee Dee River), about 7 mi (11 km) east of Albemarle, Stanly and Montgomery Counties, Morrow Mountain 7½-minute quadrangle (Fig. 1). Site A (Fig. 2) is 1.7 miles (2.7 km) east of the Lake Tillery bridge and 0.6 mile (1 km) east of the intersection of North Carolina 24-27 and State Road 1150. At Site B (Fig. 2), mudstone of the Tillery Formation and a metagabbro sill are exposed along North Carolina 24-270.3 mi (0.5 km) west of the Lake Tillery bridge. Since traffic conditions at Site B are dangerous, extreme caution must be used when stopping.
Geology of the Haile Gold Mine, Lancaster County, South Carolina
Authors: Bell Henry
Published: November 2007

Three miles east of Kershaw, Lancaster County, South Carolina, there are two groups of mine workings referred to collectively as the Haile Gold Mine. Their location on opposite sides of Haile Gold Mine Creek and the surrounding mine area is shown on Figure 1. The mine is easily accessible from U.S. 601, South Carolina 188, and unpaved county roads. There are several property owners; however, in early 1984 the property was operated by Mineral Mining Corporation, Kershaw, South Carolina.
The Pumpkinvine Creek Formation at the type locality
Authors: Abrams Charlotte E. , McConnell Keith I.
Published: November 2007

The type locality of the Pumpkinvine Creek Formation is located on I-75, approximately 32 mi (51 km) north of downtown Atlanta, and approximately 1.5 mi (2.4 km) north of where I-75 crosses Lake Allatoona (Fig. 1). Outcrop is readily apparent on both sides of the highway, but exposures of the Pumpkinvine Creek Formation are more extensive and less weathered on the east side of the highway. Do notattempt to cross the highway.
Petrography and structural geology of Uchee Belt Rocks in Columbus Georgia, and Phenix City, Alabama
Authors: Hanley Thomas B.
Published: November 2007

Uchee Belt rocks are well exposed in the vicinity of Columbus, Georgia. Stops A and B are on the banks of the Chattahoochee River in Phenix City, Alabama, and Stop C is located on the campus of Columbus College, Columbus, Georgia (Fig. 1).
Mitchell Dam amphibolite along Alabama Highway 22, east-central Chilton and west-central Coosa Counties, Alabama
Authors: Rheams Karen F. , Allison David , Tull James F.
Published: November 2007

The Mitchell Dam Amphibolite is located along the Coosa River 9 miles (14.5 km) east of Clanton near the center of the Mitchell Dam 7½-minute quadrangle, Chilton and Coosa Counties, Alabama (Fig. 1). Two excellent outcrops illustrate the mineralogical, textural, and structural complexity of the amphibolite. Both exposures are easily accessible, located near the shoulder of Alabama 22.
Olistostromal unit of the Silurian-Lower Devonian Lay Dam Formation, Talladega Slate Belt, Chilton County, Alabama
Authors: Tull James F. , Telle Whitney R.
Published: November 2007

One of the better exposures of an olistostromal sequence (metadiamictite facies) in the Lay Dam Formation lies immediately west of the Coosa River Bridge on Chilton County Road 55, approximately 12 mi ( 19 km) east of Jemison, Alabama (Fig. 1). To reach the site from the Lay Dam Exit on I-65, proceed north on Alabama 145 approximately 2 mi (3.2 km) to Chilton County Road 55. Turn right (east) and proceed approximately 6 mi ( 10 km) to the new Coosa River Bridge at Mire's Ferry. All access roads are improved and readily accessible. The stop is located in the SE¼ of Section 24, T 23 N, R 15 E, Chilton County, Alabama, and may be found on the Lay Dam, Alabama 7½-minute quadrangle. The metadiamictite is exposed on both sides of the highway. Good exposures of the metadamictite also may be found on the east side of the bridge and at the old Mire's Ferry Landing south of the bridge.
Mesozoic and Cenozoic compressional faulting along the Coastal Plain margin, Fredericksburg, Virginia
Authors: Rader Eugene K. , Newell Wayne L. , Mixon Robert B.
Published: November 2007

Exposures of the Stafford fault system are located south and southwest of Fredericksburg, Spotsylvania County, Virginia on or adjacent to U.S. 1 (Fig. 1).
The Chandler Bridge Formation (Upper Oligocene) of the Charleston, South Carolina, region
Authors: Weems Robert E. , Sanders Albert E.
Published: November 2007

Charleston, South Carolina, region U.S. Geological Survey, Reston, Virginia 22092 The Charleston Museum, Charleston, South Carolina 29403 The Chandler Bridge Formation is exposed near the northcentral border of the Ladson 7½-minute quadrangle (Fig. 1), 15 mi (24 km) northwest of Charleston, South Carolina. From I-26, take U.S. 78 exit (eastbound), proceed 1.9 mi (3. 1 km) to U.S. 52 and turn left (north) on 52. Go 1.8 mi (2.9 km) to traffic light at intersection of U.S. 52 and U.S. 178, bear left onto 178 at traffic light (45 degrees left to northwest) and go 0.6 mi ( 1.0 km) to a pair of large overhead power lines. On far (northwest) side of power lines turn left (southwest) onto road paralleling power lines, go 0.7 mi (1. 1 km) to ditch on left (southeast).
Devil’s Mill Hopper, Alachua County, Florida
Authors: Scott Thomas M.
Published: November 2007

Devil's Mill Hopper is a large, impressive solution collapse feature located in west-central Alachua County, Florida, northwest of Gainesville (Gainesville West 7½-minute quadrangle). The State of Florida has incorporated the Devil's Mill Hopper sinkhole and the land surrounding it into the Devil's Mill Hopper State Geological Site. Figure 1 shows the location of Devil's Mill Hopper in relation to I-75 and Gainesville. Access to the sinkhole is limited to the designated trails and a boardwalk to the bottom of the sink. Please follow all the site regulations. Sampling permits may be obtained for research purposes by contacting the Bureau Chief, Bureau of Park Programs, Division of Recreation and Parks, Florida Department of Natural Resources, 3900 Commonwealth Boulevard, Tallahassee, Florida 32303.
The Central Florida Phosphate District
Authors: Scott Thomas M.
Published: November 2007

The Central Florida Phosphate District is located in west-central Florida in parts of Polk, Hillsborough, Manatee, and Hardee counties (Fig. 1). The vast majority of phosphate mines occur within Polk County. 7½-minute topographic quadrangles covering the area of the phosphate district and the near-future southern expansion of the district include: Plant City, Lakeland, Auburndale, Nichols, Mulberry, Bartow, Keysville, Bradley Junction, Homeland, Fort Lonesome, Duette N. E., Baird, Bowling Green, Bereah, Duette, Fort Green, Wauchula and Griffins Corner.
Alum Bluff Liberty County, Florida
Authors: Schmidt Walt
Published: November 2007

Alum Bluff is located about two miles north-northwest of Bristol, in Liberty County, Florida. The bluff occurs along the east bank of the Apalachicola River in the NE¼ and SE¼ SW.24, T. 1N., R.8W. (Fig. 1). The Nature Conservancy owns the Bluff area and adjacent land. Their land is protected by fence and locked gates. Permission to enter can be obtained by contacting their Bristol Office at P.O. Box 789, Bristol, Florida 32321, or calling (904) 893-4153.
Sedimentary facies of the Upper Cretaceus Tuscaloosa Group in eastern Alabama
Authors: Reinhardt Juergen , Smith L. W. , King D. T.
Published: November 2007

These sedimentary facies are exposed in three, related stops in the eastern Gulf Coastal Plain in west-central Alabama, in the vicinity of Tuskegee eastward to Auburn. Specific stop locations are shown on the detailed topographic inset maps (Fig. 1). Except for one locality, the described exposures are along paved rights-of-way. No permission is required to view these outcrops and conventional transportation (car, bus, or van) is appropriate, although parking safely may be difficult along some of the secondary roads.
Cretaceous-Tertiary boundary southeast of Braggs, Lowndes County, Alabama
Authors: Copeland Charles W. , Mancini Ernest A.
Published: November 2007

The Cretaceous-Tertiary boundary is exposed in a highway cut along the southwest side of Alabama 263,4.6 mi (7.4 km) southeast of the intersection of Alabama 21 and 263 at Braggs, in the southwestern part of Lowndes County, Alabama. The exposure is 3.8 mi (6.1 km) northwest of the Lowndes-Butler County boundary in the NE¼ NW¼ sec. 22, T. 12 N., R. 13 E. (Fig. 1). The cuts along Alabama 263 were first opened by highway construction in 1968.
Dobys Bluff tongue of the Kosciusko Formation and the Archusa Marl Member of the Cook Mountain Formation at Dobys Bluff on the Chickasawhay River, Clarke County, Mississippi
Authors: Dockery David T.
Published: November 2007

The Dobys Bluff Tongue of the Kosciusko Formation and the Archusa Marl Member of the Cook Mountain Formation are exposed on the east bank of the Chickasawhay River just below a large bend in the river south of Quitman, Mississippi, at the center of the north line of the NW¼SW½NW¼, Sec.18, T.2N., R.16E., Clarke County, Quitman 7½-minute quadrangle (Fig. 1). The exposure is accessible by boat or taking Mississippi 514 east from Quitman, turning south 0.75 mi (1.3 km) outside of the city limits onto a paved road leading to the Archusa Creek Water Park camp ground, continuing south past the camp ground and past Shiloh Church to a dirt road in Sec. 18 that veers southwest, and taking this road west along the ridgetop (avoiding logging trails leading in other directions) to a high bluff on the Chickasawhay River.
Shelf marls and chalks in the Marine Section of the Upper Cretaceus
Authors: Russell Ernest E.
Published: November 2007

Shelf marls and chalks in the marine section of the Upper Cretaceus of Mississippi are exposed west of Tombigbee River in western Lowndes County and eastern Oktibbeha County, eastcentral Mississippi. An additional optional stop is located in northern Noxubee County (Figure 1). The four stops require approximately 40 mi (66.7 km) of driving mostly on gravel roads. The first two outcrops require short walks (5 to 10 minutes). The outcrops are steep and they are slick when wet.
The Cockfield (Claiborne Group), Moodys Branch and Yazoo (Jackson Group) Formations at the Riverside Park locality in Jackson, Mississippi
Authors: Dockery David T.
Published: November 2007

The Riverside Park locality is a steep-sided ravine along the eastern side of a golf course in northeast Jackson, Mississippi, in the NE¼ NW¼ NW¼, sec. 36, T. 6 N., R. 1 E., Hinds County, Jackson 7½-minute quadrangle (Fig. 1). It is readily accessible by taking the Lakeland Dr. east exit off of I-55 at Jackson, then turning south on Highland Dr. at the first traffic light, and continuing to the intersection with Riverside Dr. and Riverside Park Circle. At this intersection take Riverside Park Circle east, and after the circle turns north, stop in the parking lot on the right. This lot is next to the entrance of a nature trail and uphill from a golf course. The locality can be reached by walking east-northeast for a short distance over a part of the golf course to a ravine below a small pond.
The Vicksburg Group at the Haynes Bluff Quarry
Authors: Dockery David T.
Published: November 2007

The Vicksburg Group is exposed in a rock quarry on east side of Mississippi 3 north of Redwood, Mississippi, in the NW¼, sec. 26, T. 18 N., R. 4 E., Warren County, Onward 15-minute Quadrangle (Fig. 1). Readily accessible by taking 1-20 to the U.S. 61 bypass east of Vicksburg, traveling north on U.S. 61 bypass to Redwood, then continuing north on Mississippi 3 to dirt road on right opposite the office building of the inactive Mississippi Valley Portland Cement Company, and then following the dirt road by foot to the northernmost of two inactive quarries.
The Florida Parishes of southeastern Louisiana
Authors: Autin Whitney J. , Alford J. J. , Miller Bobby J. , Self Robert P.
Published: November 2007

The Florida Parishes of southeastern Louisiana (Fig. 1) are bounded on the west by the Mississippi River, on the east by the Pearl River, on the north by the Louisiana-Mississippi state line, and on the south by the Mississippi River deltaic plain. Principal cities include Baton Rouge and New Orleans.
Red River Gorge Geological Area (Daniel Boone National Forest) and Natural Bridge State Park, east-central Kentucky
Authors: Dever Garland R. , Barron Lance S.
Published: November 2007

The Red River Gorge Geological Area and Natural Bridge State Park are located 32.8 and 40 mi (55 and 67 km) southeast of I-64 on Mountain Parkway and Kentucky 11 and 715; Menifee, Powell and Wolfe Counties; Slade and Pomeroyton 7½-minute Quadrangles (Fig. 1).
Physiography of Louisiana Salt Domes (The Five Islands)
Authors: Kupfer Donald H.
Published: November 2007

The Five Islands are a line of topographic mounds parallel to and southwest of U.S. Highway 90 between New Iberia and Morgan City, Louisiana (Fig. 1). They are 25 to 60 mi (42 to 100 km) from I-10 at Lafayette, Louisiana. Belle Isle is only accessible by boat: the others are 5 to 18 mi (8.3 to 30 km) by rural roads, from U.S. 90. All are privately owned, and the public is no longer admitted to any of the associated salt mines.
Selected depositional environments of the Mississippi River deltaic plain
Authors: Roberts Harry H.
Published: November 2007

Depositional environments of the Mississippi River deltaic plain can be studied in a series of exposures in the Barataria Basin (upper deltaic plain) and in the Balize delta lobe (lower deltaic plain). Stops 1 and 2 are in Barataria Basin, which is an interdistributary basin defined by alluvial ridges of the modern Mississippi River on the east and Bayou Lafourche on the west (Fig. 1 ).

Stops designated for the lower delta are accessible only by boats suitable for safely navigating the river from Venice to the mouth of South Pass.
Pennsylvanian-age distributary-mouth bar in the Breathitt Formation of eastern Kentucky
Authors: Chesnut Donald R. , Cobb James C.
Published: November 2007

A Pennsylvanian-age distributary-mouth bar in the Breathitt Formation can be seen at two localities in Knott County, Kentucky. The northwest locality is on Kentucky 80,500 ft (152 m) west of the intersection of Kentucky 80 and the Hindman access road (“Hindman Spur”) (Fig. 1). This stop is located in Carter coordinate section 16-K-79, in the northwestern comer of the Hindman 7½-minute Quadrangle. The multilane highway offers easy accessibility by vehicle, and buses may park along the shoulder of Kentucky 80, between the road cut and the intersection of the Hindman access road.

The southeast locality is a road cut located on the Hindman access road about 0.5 mi (0.8 km) south of the intersection of Kentucky 80 and the access road. This stop is in the northwestern comer of the Hindman 7½-minute Quadrangle in Carter coordinate section 25-K-79. Buses may park in the large flat area on the southwestern side of the road just west of the road cut.
Pennsylvanian System stratotype sections, West Virginia
Authors: Englund Kenneth J. , Arndt Harold H. , Schweinfurth Stanley P. , Gillespie William H.
Published: November 2007

The establishment of a standard reference section for the Pennsylvanian System in the Appalachian basin was necessitated by inconsistencies and variations in the application and correlation of the loosely defined Lower, Middle, and Upper Pennsylvanian Series. To provide rock-representative definitions for these units, the Pennsylvanian System stratotype study was undertaken in consultation with interested geologists and paleontologists from State geological surveys, U.S. Geological Survey, academia, and industry. An essential criterion for the designation of the stratotype section was the selection of the most complete and continuous sequence of Pennsylvanian strata that are also conformable with underlying and overlying systems. This requirement was only met in West Virginia where Pennsylvanian rocksextend from the Mississippian strata of the Pocahontas coal field to the Permian strata of the Dunkard basin, a location that follows the recommendation of the Pennsylvanian Subcommittee of the National Research Committee on Stratigraphy that the best standard section for Pennsylvanian rocks in the Appalachian basin would be in West Virginia (Moore and others, 1944, p. 665).

The Pennsylvanian System is defined by a composite stratotype consisting of 14 outcrop sections extending from the base to the top of the system over a distance of 100 mi (160 km). Fieldguide site 14 includes a description of strata in the Lower Pennsylvanian Series at three successive sites; A, A-B, and B-C in south-central West Virginia (Fig. 1). Field guide site 13 includes descriptions of strata in the Middle and Upper Pennsylvanian Series. Corroborative investigations include (1) geologic mapping of areas between
Greenland Gap, Grant County, West Virginia
Authors: Avary Katharine Lee
Published: November 2007

Greenland Gap is located in Grant County, West Virginia (Fig. 1), and are on the Greenland Gap and Medley 7½-minute Quadrangles (Fig. 2). The exposures are along West Virginia 42 and 93, west of Scherr, and along Grant County Rt. 1 (Greenland Road) and Grant County Rt. 3/3 (Greenland Gap Road), east of Scherr.
The biostratigraphical and palaeogeographical framework of the earliest diversification of tetrapods (Late Devonian)
Authors: Blieck A. , Clement G. , Blom H. , Lelievre H. , Luksevics E. , Streel M. , Thorez J. , Young G. C.
Published: November 2007

The earliest diversification of tetrapods is dated as Late Devonian based on 10 localities worldwide that have yielded bone remains. At least 18 different species are known from these localities. Their ages span the ‘middle’–late Frasnian to latest Famennian time interval, with three localities in the Frasnian, one at the F/F transition (though this one is not securely dated) and six in the Famennian. These localities encompass a wide variety of environments, from true marine conditions of the nearshore neritic province, to fluvial or lacustrine conditions. However, it does not seem possible to characterize a freshwater assemblage in the Upper Old Red Sandstone based upon vertebrates. Most of the tetrapod-bearing localities (8 of 10) were situated in the eastern part of Laurussia (=Euramerica), one in North China and one in eastern Gondwana (Australia), on a pre-Pangean configuration of the Earth, when most oceanic domains, except Palaeotethys and Panthalassa, had closed.
Brachiopod faunal changes across the Devonian–Carboniferous boundary in NW Sahara (Morocco, Algeria)
Authors: Brice D. , Legrand-Blain M. , Nicollin J.-P.
Published: November 2007

Based on previous systematic studies of productid, rhynchonellid and spiriferid brachiopods from NW Sahara (Morocco and Algeria), we recognize three successive faunas near the Devonian–Carboniferous boundary. A ‘Lower Fauna’, late Famennian in age [IV(?)-V and lower VI(?) Zones], and an ‘Upper Fauna’, early Tournaisian in age, are present in southern Morocco (Assa, Akka, Zemoul areas) and in Algeria, Timimoun area. A third ‘Intermediate Fauna’, with few taxa, and differing according to the areas, is identified in southern Morocco. Northwards, in Tafilalt–Ma'der basins, rare brachiopods, found above a ‘Hangenberg Black Shale’ equivalent, are in spite of taxonomic differences related to the ‘Upper Fauna’. This important renewal of faunas could be in relation to the main lithological variations.
Neritic–pelagic correlation in the Lower and basal Middle Devonian of the Dra Valley (Southern Anti-Atlas, Moroccan Pre-Sahara)
Authors: Jansen U. , Lazreq N. , Plodowski G. , Schemm-Gregory M. , Schindler E. , Weddige K.
Published: November 2007

Marine Lower Devonian successions are widely exposed in the Dra Valley (Southern Anti-Atlas, Moroccan Pre-Sahara). Resulting from new studies, especially on brachiopods, conodonts, and dacryoconarid tentaculitids, the chronostratigraphic assignments of the Lower Devonian formations are revised. Thanks to lateral and vertical facies variations, it is possible to correlate pelagic and neritic successions and corresponding biostratigraphies. Pelagic conodont, dacryoconarid and goniatite faunas allow correlations and dating in the sense of the Bohemian and global chronostratigraphies, whereas units of the traditional Rhenish subdivision can be identified by means of neritic brachiopods.
Persistent depositional sequences and bioevents in the Eifelian (early Middle Devonian) of eastern Laurentia: North American evidence of the Kačák Events?
Authors: DeSantis M. K. , Brett C. E. , Ver Straeten C. A.
Published: November 2007

The late Eifelian–earliest Givetian interval (Middle Devonian) represents a time of significant faunal turnover in the eastern Laurentia and globally. A synthesis of biostratigraphic, K-bentonite and sequence stratigraphic data indicates that physical and biotic events in the Appalachian foreland basin sections in New York are coeval with the predominantly carbonate platform sections of southern Ontario and Ohio. The upper Eifelian (
australis
to
ensensis
conodont zones) Marcellus Subgroup in New York comprises two large-scale (3rd-order) composite depositional sequences dominated by black shale, which are here assigned to the Union Springs and Oatka Creek Formations. The succession includes portions of three distinctive benthic faunas or ecological–evolutionary sub-units (EESUs): ‘Onondaga’, ‘Stony Hollow’ and ‘Hamilton’. In the northern Appalachian Basin in New York, the boundaries of these bioevents show evidence of abrupt, widespread extinctions, immigration and ecological restructuring. In the Niagara Peninsula of Ontario and from central to northern Ohio, the same sequence stratigraphic pattern and bioevents are recognized in coeval, carbonate-dominated facies.

The correlations underscore a relatively simple pattern of two major sequences and four subsequences that can be recognized throughout much of eastern Laurentia. Moreover, the biotic changes appear to be synchronous across the foreland basin and adjacent cratonic platform. However, the degree of change differs substantially, being less pronounced in carbonatedominated mid-continent sections. Finally, we make the case that the two major faunal changes align with regional sequence stratigraphic patterns as well as with the global Kačák bioevents.
Recognizing the Kačák Event in the Devonian terrestrial environment and its implications for understanding land–sea interactions
Authors: Marshall J. E. A. , Astin T. R. , Brown J. F. , Mark-Kurik E. , Lazauskiene J.
Published: November 2007

The Kačák Event is a late Eifelian (Mid-Devonian) episode of marine dysoxia/anoxia with associated extinctions. It has been widely recognized in the shelf seas that surrounded the Old Red Sandstone continent. It was contemporary with the lacustrine Orcadian Basin in Scotland. This basin contains the distinctive Achanarras lake horizon that contains a rich and diverse fish fauna. The Achanarras lake was wide and deep and would have been filled by rainfall from a monsoon system at an insolation maximum. Faunal elements within the lake are in common with the Kernavė Member in Estonia and this level can be conodont dated as late Eifelian
eiflius
or
ensensis
Zone. Therefore the group of lacustrine flooding climatic events that occur at and above the Achanarras level can be correlated with the marine Kačák Event (
sensu lato
) and both can be regarded as having a common climatic cause and driven by an insolation maximum. A reconstruction of the Orcadian Basin drainage system and a water balance model based on the calcium flux within the lake shows that a very significant volume of water would have been seasonally discharged to the Rheic Ocean and would have caused an additional environmental effect.
Rats in the genomic era
Authors: Worley K. C. , Weinstock G. M. , Gibbs R. A.
Published: November 2007

The rat genome project and the resources that it has generated are transforming the translation of rat biology to human medicine. The rat genome was sequenced to a high quality “draft,” the structure and location of the genes were predicted, and a global assessment was published (Gibbs RA et al., Nature 428: 493–521, 2004). Since that time, researchers have made use of the genome sequence and annotations and related resources. We take this opportunity to review the currently available rat genome resources and to discuss the progress and future plans for the rat genome.
A nonstop mutation in the factor (F)X gene of a severely haemorrhagic patient with complete absence of coagulation FX
Authors: Channell Cynthia , Crenshaw Valerie , Fernstrom Karl , Khachidze Manana , Duncan Alexander , Fuchs Sebastien , Ameri Afshin , Machiah Deepa , Tran Thuy , Howard Tom
Published: November 2007

We identified a previously unknown mutation by sequencing the factor (F)X gene in a severely haemorrhagic 14-year-old maleAfrican-American individual with undetectable plasma FX-activity and -antigen levels. This mutation, called F10-Augusta, was homozygote and is a combination of an 8bp insertion in flanking 3’-genomic-DNA and a 5bp terminal exon-8 deletion involving codons 437 and 438. Sequencing of RT-PCR and 3’-RACE products showed that the F10-Augusta transcript is normally processed but lacks an in-frame stop codon. An allele specific 3’-RACE-based RFLP assay demonstrated that the steady-state concentration of the mutant transcript was markedly lower than that of the wild-type message in total-RNA samples from the patient’s unaffected heterozygous parents. The recently discovered nonstop decay mechanism, a component pathway of the mRNA surveillance system, is a possible explanation for the reduced concentration of the mutant FX transcript. This is the first report implying such a mechanism in the pathogenesis of inherited bleeding disorders.
Enhanced platelet aggregation and activation under conditions of hypothermia
Authors: Xavier Ruben , White Ann , Fox Susan , Wilcox Robert , Heptinstall Stan
Published: November 2007

The effects on platelet function of temperatures attained during hypothermia used in cardiac surgery are controversial. Here we have performed studies on platelet aggregation in whole blood and platelet-rich plasma after stimulation with a range of concentrations of ADP, TRAP, U46619 and PAF at both 28°C and 37°C. Spontaneous aggregation was also measured after addition of saline alone. In citrated blood, spontaneous aggregation was markedly enhanced at 28°C compared with 37°C. Aggregation induced by ADP was also enhanced. Similar results were obtained in hirudinised blood. There was no spontaneous aggregation in PRP but ADP-induced aggregation was enhanced at 28°C. The P2Y12 antagonist AR-C69931 inhibited all spontaneous aggregation at 28°C and reduced all ADP-induced aggregation responses to small, reversible responses. Aspirin had no effect. Aggregation was also enhanced at 28°C compared with 37°C with low but not high concentrations of TRAP and U46619. PAF-induced aggregation was maximal at all concentrations when measured at 28°C, but reversal of aggregation was seen at 37°C. Baseline levels of platelet CD62P and CD63 were significantly enhanced at 28°C compared with 37°C. Expression was significantly increased at 28°C after stimulation with ADP, PAF and TRAP but not after stimulation with U46619. Overall, our results demonstrate an enhancement of platelet function at 28°C compared with 37°C, particularly in the presence of ADP.
Disulfide bond disruption by a β3-Cys549Arg mutation in six Jordanian families with Glanzmann thrombasthenia causes diminished production of constitutively active αIIbβ3
Authors: Peretz Hava , Landau Meytal , Coller Barry , Awidi Abdalla , Mor-Cohen Ronit , Rosenberg Nurit , Seligsohn Uri
Published: November 2007

αIIbβ3 integrin mediates platelet aggregation following its activation. Its absence or dysfunction causes Glanzmann thrombasthenia (GT), an inherited bleeding disorder that is rare worldwide but relatively frequent in several populations with high rates of consanguinity, including Arabs in Israel and Jordan. Cysteine residues in the β3 epidermal growth factor (EGF) domains are involved in αIIbβ3 formation and activation. In this study we present a novel Cys549Arg mutation in β3 identified in six Jordanian families, which in the homozygous state is manifested by severe GT. The mutation is located in EGF-3 of β3 predicting disruption of a conserved disulfide bond between Cys549 and Cys558. Haplotype analysis disclosed a common founder whose age estimate was 120–150 years. Flow cytometry revealed 1–14% of normal αIIbβ3 expression at the patients' platelet surface. The Cys549Arg or artificial Cys549Ser mutations were introduced into a β3 expression vector. Co-transfection of baby hamster kidney cells with normal or mutant β3 along with normal αIIb demonstrated reduced surface expression of αIIbβ3 by both mutants. The mutants were constitutively active as demonstrated by 20-fold increased binding of the ligand-mimetic antibody PAC-1. Immunoblotting and immunoprecipitation experiments showed reduced β3 and αIIbβ3 expression and a higher than normal ratio of pro-αIIb to mature αIIb. Immunofluorescence experiments showed that β3 and αIIbβ3 were mostly retained in the endoplasmic reticulum. In conclusion, the novel ancestral mutation found in a cluster of Jordanian GT patients disrupts a conserved Cys549-Cys558 bond which results in reduced production of constitutively active αIIbβ3.
The significance of vasodilator-stimulated phosphoprotein for risk stratification of stent thrombosis
Authors: Stellbrink Katja , de Taeye Anita , Müller Robert , Kiefer Paul , Yagmur Eray , Weber Christian , Kelm Malte , Hoffmann Rainer , Blindt Rüdiger
Published: November 2007

Low-response to the P2Y12 adenosine diphosphate (ADP)-receptor antagonist clopidogrel was suggested to correspond to a higher incidence of stent thrombosis (ST). This prospective observational study assessed the capability of two platelet function assays, e.g. direct measurement of the phosphorylation status of vasodilator-stimulated phosphoprotein (VASP) and ADP-induced platelet aggregation for definition of the individual risk to develop ST. Ninety-nine patients with an elevated high risk to develop ST were enrolled. All patients received a dual antiplatelet therapy consisting of 100 mg aspirin and 75 mg clopidogrel during an observation period of six months. Flow cytometry of VASP phosphorylation and densitometrically-determined measurement of ADP-induced platelet aggregation was performed 72–96 hours after stent implantation. These data were related to angiographically confirmed ST. Nine patients suffered from angiographically confirmed ST (9.1%). The meanVASP-platelet reactivity indices (VASP-PRI) and values for ADP-induced platelet aggregation in the ST group were significantly higher (60.8 ± 13.0 and 60.9 ± 13.1, respectively) compared to patients without ST (41.3 ± 14.0 and 50.8 ± 14.4, P<0.001 vs. 0.048, respectively). There was a fair correlation between both methods using non-linear regression analysis (r=0.332). In a multivariate analysis, VASP was the only independent predictor of ST and was superior to previously identified angiographic parameters. Receiver- operator characteristic (ROC) curve analysis revealed a cut-off value for VASP-PRI of <48% to be associated with low risk of ST. In conclusion, determination ofVASP phosphorylation is superior to conventional platelet aggregometry and angiographic parameters for assessing the risk of ST. Patients with a VASP-PRI >48% seem to have a significantly increased risk.
Coronary artery in-stent stenosis persists despite inhibition of the von Willebrand factor - collagen interaction in baboons
Authors: Badenhorst Philip , Pieters Henry , Lamprecht Seb , Roodt Jan , Janssens Stefan , Meiring Muriel , Vanhoorelbeke Karen , Bruwer André , Brown Stephen , De Meyer Simon , Staelens Stephanie , Deckmyn Hans
Published: November 2007

Revascularization techniques, such as angioplasty and stent implantation, frequently lead to restenosis due to the formation of neointima after platelet activation and the concomittant release of various smooth muscle cell mitogenic and attractant factors. We here investigate whether inhibition of initial platelet adhesion after stent implantation can decrease neointima formation in a clinically relevant baboon model of in-stent stenosis using standard treatment with aspirin, clopidogrel and heparin. Inhibition of platelet adhesion was established by administration of the anti-von Willebrand factor (VWF) monoclonal antibody 82D6A3, which inhibits VWF binding to collagen. Administration of 82D6A3 resulted in a complete inhibition of VWF binding to collagen during the first three days after stent implantation. No thrombocytopenia or prolongation of the bleeding time was observed. Our results show that the formation of neointima was not affected in the group of baboons where primary platelet adhesion was abolished with 82D6A3 when compared to the control group. Vascular injury scores were the same in both groups. Inhibition of platelet adhesion during the first three days after stenting, on top of standard treatment with aspirin, clopidogrel and heparin, had no effect on neo-intima formation in a baboon model of in-stent stenosis. During the last decade, attempts to translate seemingly effective therapies based on smaller animal experimentation to the clinic have consistently failed. This study, using a non-human primate model that more closely resembles the clinical situation, presents a model that may be of further clinical interest for studying the prevention of restenosis.
Prediction of recurrent venous thromboembolism by measuring ProC Global
Authors: Hron Gregor , Hirschl Mirko , Bialonczyk Christine , Minar Erich , Kollars Marietta , Kyrle Paul , Eichinger Sabine
Published: November 2007

In patients with venous thromboembolism (VTE) a laboratory assay that globally measures the overall thrombophilic tendency is not available. We hypothesized that determination of ProC® Global, a plasma assay which tests the global function of the protein C pathway, could be used to stratify patients according to their risk of recurrent VTE. We prospectively followed 774 patients with first spontaneous VTE for a mean time of 52 months. ProC Global normalized ratio (NR) was measured in plasma by use of a commercially available assay based on activated partial thromboplastin time. Ninety-eight of the 774 patients had recurrent VTE. Patients with ProC Global NR ≥ 0.75 had a relative risk of recurrence of 0.59 (95% CI 0.40–0.87) as compared with those with lower ratio. After four years, cumulative probability of recurrence was 8.6% in patients with ProC Global NR ≥ 0.75 and 17.4% in patients with a lower ratio (p=0.006). Patients with a high ProC Global NR have a low risk of recurrent VTE. ProC Global NR can be used to stratify patients with a first unprovoked VTE according to their risk of recurrence.
Catechol-O-methyltransferase genotype is associated with plasma total homocysteine levels and may increase venous thrombosis risk
Authors: Vermeulen Sita , Hermus Ad , Blom Henk , Gellekink Henkjan , Muntjewerff Jan-Willem , Heijer Martin den
Published: November 2007

A disturbed methylation has been proposed as a mechanism via which homocysteine is associated with diseases like vascular disease, neural tube defects and mental disorders. Catechol- O-methyltransferase (COMT) is involved in the S-adenosylmethionine- dependent methylation of catecholamines and catecholestrogens and in this way contributes to homocysteine synthesis. COMT dysfunction has been related to schizophrenia and breast cancer. We hypothesized that COMT dysfunction by virtue of functional genetic polymorphisms may affect plasma total homocysteine (tHcy). Our primary objective was to study the association between common COMT polymorphisms and tHcy. Secondly, we evaluated these polymorphisms as a risk factor for recurrent venous thrombosis. We obtained genotype data from four polymorphisms in the COMT gene (rs2097603, rs4633, rs4680 [324G>A] and rs174699) from 401 populationbased controls. We performed haplotype analysis to investigate the association between common haplotypes and tHcy. In addition, we assessed the rs4680 variant as a genetic risk factor in a case-control study on recurrent venous thrombosis (n= 169). We identified a common haplotype that was significantly associated with tHcy levels. This effect was largely explained by the rs4680 variant, resulting in an increase in tHcy of 10.4% (95% CI 0.01 to 0.21, p=0.03) for 324AA compared with 324GG subjects. Interestingly, we found that the 324AA genotype was more common in venous thrombosis patients (OR 1.61 [95% CI 0.97 to 2.65], p=0.06) compared to control subjects. We show that the COMT rs4680 variant modulates tHcy, and might be associated with venous thrombosis risk as well.
Venous thromboembolism in patients undergoing surgery: Low rates of prophylaxis and high rates of filter insertion
Authors: Seddighzadeh Ali , Zurawska Urszula , Shetty Ranjith , Goldhaber Samuel
Published: November 2007

Patients who undergo surgery are at a high risk of developing venous thromboembolism (VTE). To further define the demographics, comorbidities, and risk factors of VTE in patients undergoing major surgery, we analyzed 1,375 hospitalized non-orthopedic surgery patients in a prospective registry of 5,451 patients with ultrasound confirmed deep vein thrombosis (DVT) from 183 hospitals in the United States. Extremity edema (67.9%), extremity discomfort (44.9%), and dyspnea (18.9%) were among the most common presenting symptoms among these surgical patients. Compared to medical patients, surgical patients presented with a more occult clinical picture and complained less often of extremity edema (67.9% vs. 73.7%; p=0.0001), extremity discomfort (44.9% vs. 56.4%; p<0.0001), or difficulty walking (6.6% vs. 11.2%; p<0.0001). Immobility within 30 days of DVT diagnosis, prior hospitalization within 30 days of DVT diagnosis, presence of an indwelling central venous catheter, obesity (BMI >30 kg/m2), and previous smoking were the most common VTE risk factors among surgical patients. Among surgical patients who developed DVT, some form of prophylaxis had been used in only 44%. Once diagnosed with DVT, surgical patients received IVC filters more often than medical patients (20.0% vs. 14.1%; p<0.0001; adjusted OR=1.49, 95% CI=1.17–1.92; p<0.001). In conclusion, VTE prophylaxis remains underutilized in surgical patients. The IVC filter utilization rate in surgical patients is significantly higher than in medical patients. Future studies should focus on devising mechanisms to improve implementation of prophylaxis and investigate the long-term safety and efficacy of IVC filters in surgical patients.
Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography
Authors: chaikovski Svetlana , van Vliet Huib , Thomassen M.Christella , Bertina Rogier , Rosendaal Frits , Sandset Per-Morten , Helmerhorst Frans , Tans Guido , Rosing Jan
Published: November 2007

In a study population consisting of healthy men (n=8), women not using oral contraceptives (OC) (n=28) and women using different kinds of OC (n=187) we used calibrated automated thrombography (CAT) in the absence and presence of added activated protein C (APC) to compare parameters that can be obtained from thrombin generation curves, i.e. lag time, time to peak, peak height and endogenous thrombin potential (ETP). Both with and without APC, plasmas of OC users exhibited the shortest lag time and time to peak, and the highest peak height and ETP. In the absence of APC none of these parameters differed between users of OC containing different progestogens. In contrast, in the presence of APC shorter lag times and time to peak, and higher peak height and ETP were observed in plasma of users of gestodene-,desogestrel-,drospirenone- and cyproterone acetate-containing OC than in plasma of users of levonorgestrel-containing OC. The ETP determined in the absence of APC (ETP-APC) had no predictive value for the APCsr (r=0.11; slope 0.9×10–3; 95%CI: –0.1×10–3 to 2.0×10–3) whereas the ETP measured in the presence of APC (ETP+APC) showed an excellent correlation with the APCsr (r=0.95; slope 6.6×10–3; 95%CI: 6.3×10–3 to 6.9×10–3) indicating that the APCsr is entirely determined by the ETP+APC. In conclusion, OC use increases thrombin generation, but differential effects of second and third generation OCs on the protein C system likely determine the differences in the risk of venous thrombosis between these kinds of OC.
The fine-tuning of anti-oxidized low-density lipoprotein antibodies in cardiovascular disease and thrombosis
Authors: de Carvalho Jozélio Freire , Sherer Yaniv , Shoenfeld Yehuda
Published: November 2007

Anti-oxidised low-density lipoprotein (anti-oxLDL) antibodies are a heterogeneous group of autoantibodies including both pathogenic and protective subsets. Whereas in most studies the levels of anti-oxLDL antibodies were associated with enhanced atherosclerosis as evaluated by different methods, immunization with oxLDL leads to elevated levels of anti-oxLDL and protection against atherosclerosis. Anti-oxLDL can also be used for immunomodulation of atherosclerosis (i.e. possible therapeutic use of intravenous immunoglobulin, oral tolerance). More specific autoantibodies out of total anti-oxLDL should be selected, for instance, anti-oxLDL/beta-2-glycoprotein I complex, hence defining the fine-tuning of anti-oxLDL antibodies might detect which autoantibodies are pathogenic and which can be used therapeutically.
Cardiac Glycosides Regulate Endothelial Tissue Factor Expression in Culture
Authors: Stähli Barbara E. , Breitenstein Alexander , Akhmedov Alexander , Camici Giovanni G. , Shojaati Kushiar , Bogdanov Nikolay , Steffel Jan , Ringli Daniel , Lüscher Thomas F. , Tanner Felix C.
Published: November 2007

Background—

Tissue factor (TF) plays an important role in acute coronary syndromes and stent thrombosis. This study investigates whether Na
+
/K
+
-ATPase regulates TF expression in human endothelial cells.

Methods and Results—

Ouabain inhibited tumor necrosis factor (TNF)-α–induced endothelial TF protein expression; maximal inhibition occurred at 10
−5
mol/L, reached more than 70%, and was observed throughout the 5 hours stimulation period. The decrease in protein expression was paralleled by a reduced TF surface activity. Similarly, lowering of extracellular potassium concentration inhibited TNF-α–induced TF protein expression. In contrast, ouabain did not affect TNF-α–induced expression of full-length TF mRNA for up to 5 hours of stimulation; instead, expression of alternatively-spliced TF mRNA was upregulated after 3 and 5 hours of stimulation. Ouabain did not affect TNF-α–induced activation of the MAP kinases p38, extracellular signal-regulated kinase (ERK), and c-Jun terminal NH
2
kinase; activation of Akt and p70S6 kinase remained unaltered as well. Similar to the MAP kinases, ouabain did not affect TNF-α–induced degradation of IκB-α. Ouabain had no effect on TF protein degradation.

Conclusions—

Na
+
/K
+
-ATPase is required for protein translation of endothelial TF in culture. This observation provides novel insights into posttranscriptional regulation of TF expression.
Does Comorbidity Account for the Excess Mortality in Patients With Major Bleeding in Acute Myocardial Infarction?
Authors: Spencer Frederick A. , Moscucci Mauro , Granger Christopher B. , Gore Joel M. , Goldberg Robert J. , Steg Philippe Gabriel , Goodman Shaun G. , Budaj Andrzej , FitzGerald Gordon , Fox Keith A.A.
Published: November 2007

Background—

Analyses from randomized controlled trials suggest that bleeding in patients with acute myocardial infarction is associated with poor outcomes. Because these data are not generalizable to all patients with acute myocardial infarction, we sought to better understand the scope of this problem in a “real-world” setting.

Methods and Results—

We examined the frequency of major bleeding in 40 087 patients with acute myocardial infarction enrolled in the Global Registry of Acute Coronary Events. Regression analyses were used to examine the association between patient and treatment characteristics, bleeding, and hospital and postdischarge outcomes. Major bleeding occurred in 2.8% of patients. These patients were older, more severely ill, and more likely to undergo invasive procedures. Patients with bleeding were more likely to die during hospitalization (hazard ratio, 1.9; 95% confidence interval, 1.6 to 2.2) but not after discharge (hazard ratio, 0.8; 95% confidence interval, 0.6 to 1.0) than patients who did not bleed. Continuation of antithrombotic therapies after day 1 was lower in patients who experienced early bleeding. Moreover, in patients who bled, hospital mortality was increased in those who discontinued aspirin, thienopyridines, or low–molecular-weight heparins.

Conclusions—

Major bleeding occurred in 1 in 35 patients with acute myocardial infarction; these patients accounted for ≈10% of all hospital deaths. Nevertheless, risk of hospital mortality associated with bleeding was much lower than reported in randomized controlled trials. These data suggest that although bleeding may be causally related to adverse outcomes in some patients in the real-world setting, it is often merely a marker for patients at higher risk for adverse outcomes.