bluuebunny/crossref_metadata_2025 huggingface dataset:
U-Series Chronology of Lacustrine Deposits in Death Valley, California
Authors: Ku Teh-Lung , Luo Shangde , Lowenstein Tim K. , Li Jianren , Spencer Ronald J.
Published: September 2002

Uranium-series dating on a 186-m core (DV93-1) drilled from Badwater Basin in Death Valley, California, and on calcareous tufas from nearby strandlines shows that Lake Manly, the lake that periodically flooded Death Valley during the late Pleistocene, experienced large fluctuations in depth and chemistry over the last 200,000 yr. Death Valley has been occupied by a long-standing deep lake, perennial shallow saline lakes, and a desiccated salt pan similar to the modern valley floor. The average sedimentation rate of about 1 mm/yr for core DV93-1 was punctuated by episodes of more-rapid accumulation of halite. Arid conditions similar to the modern conditions prevailed during the entire Holocene and between 120,000 and 60,000 yr B.P. From 35,000 yr B.P. to the beginning of the Holocene, a perennial saline lake existed, over 70 m at its deepest. A much deeper and longer lasting perennial Lake Manly existed from about 185,000 to 128,000 yr B.P., with water depths reaching about 175 m, if not 330 m. This lake had two significant “dry” excursions of 102–103yr duration about 166,000 and 146,000 yr B.P., and it began to shrink to the point of halite precipitation between 128,000 and 120,000 yr B.P. The two perennial lake periods correspond to marine oxygen isotopic stages (OIS) 2 and 6. Based on the shoreline tufa ages, we do not rule out the possible existence ∼200,000 yr ago of yet a third perennial lake comparable in size to the OIS 6 lake. The234U/238U data suggest that U in tufa owes its origin mainly to Ca-rich springs fed by groundwater that emanated along lake shorelines in southern Death Valley, and that an increase of this spring-water input relative to the river-water input apparently occurred during OIS 6.
Point-Counting Technique for Fission-Track Dating of Tephra Glass Shards, and Its Relative Standard Error
Authors: Bigazzi Giulio , Galbraith Rex F.
Published: September 2002

Fission-track dating of glass is potentially an efficient technique for tephrochronological studies. However, most glasses from Quaternary tephra have very low spontaneous track densities and track counting is laborious. The point-counting technique is a simplified procedure for evaluating fission-track areal densities in a glass shard population that allows the analyst to count larger numbers of tracks in significantly shorter times. A field of view is coded as 1 if its center is on glass and is 0 otherwise, and the total area of glass is estimated by counting the number of 1's. Under simple assumptions, the binomial distribution appears to provide a reasonable evaluation of the additional experimental error in a fission-track density determination by this technique. Glass shard populations have been simulated, assuming that glass areas are random samples from distributions analogous to real ones. The effect of variation in glass area on the relative standard error of the estimated track density is found to be small. The point-counting technique significantly enhances the potential of fission-track dating, especially for very low track densities typical of most Quaternary tephra, as the additional error associated with its use is largely counterbalanced by the greater number of tracks that can be counted.
Timing of the Last-Interglacial High Sea Level on the Seychelles Islands, Indian Ocean
Authors: Israelson Carsten , Wohlfarth Barbara
Published: September 2002

Corals from the Seychelles Islands, Indian Ocean, occur mainly as small coralline algae–vermetid remnants found in cavities adhering to the rock surface, and they rarely attain more than 2 m2 in area. Samples of Goniastrea and Porites from elevations between 1.7 and 6 m above present mean sea level were dated by TIMS 238U–234U–230Th techniques. The ages from well-preserved corals lie between 131,000 and 122,000 yr B.P., in agreement with most other observations of the last-interglacial sea level. Field evidence and dating from high marine limestones from two sections at La Digue Island indicate a period of coral buildup until 131,000 yr B.P., followed by a drop in sea level between 131,000 and 122,000 yr B.P.
Dendrochronology and Late Holocene History of Bering Piedmont Glacier, Alaska
Authors: Wiles Gregory C. , Post Austin , Muller Ernest H. , Molnia Bruce F.
Published: September 2002

Fluctuations of the piedmont lobe of Bering Glacier and its sublobe Steller Glacier over the past two millennia are reconstructed using 34 radiocarbon dates and tree-ring data from 16 sites across the glaciers' forelands. The general sequence of glacial activity is consistent with well-dated fluctuations of tidewater and land-terminating glaciers elsewhere along the Gulf of Alaska. Extensive forested areas along 25 km of the Bering ice margin were inundated by glacio-lacustrine and glacio-fluvial sediments during a probable ice advance shortly before 500 cal yr A.D. Regrowth of forests followed the retreating ice as early as the 7th century A.D., with frequent interruptions of tree growth due to outwash aggradation. Forests overrun by ice and buried in outwash indicate readvance about 1080 cal yr A.D. Retreat followed, with ice-free conditions maintained along the distal portions of the forefield until the early 17th century after which the ice advanced to within a few kilometers of its outer Neoglacial moraine. Ice reached this position after the mid-17th century and prior to 200 yr ago. Since the early 20th century, glacial retreat has been punctuated by periodic surges. The record from forests overrun by the nonsurging Steller Lobe shows that this western ice margin was advancing by 1250 A.D., reaching near its outer moraine after 1420 cal yr A.D. Since the late 19th century, the lobe has dominantly retreated.
Petaloid Organs Preserved in an Arctic Plant Macrofossil Assemblage from Full-Glacial Sediments in Southeastern Minnesota
Authors: Baker R. G. , Mason J. A. , Maher L. J.
Published: September 2002

A small suite of plant macrofossils indicates that southeastern Minnesota supported subarctic to arctic vegetation 18,700 yr B.P. Fossil tepals of Polygonum viviparum are exceptionally well preserved; they occur with more fragmentary remains of Dryas integrifolia, Vaccinium uliginosum var. alpinum, and probable species of arctic Salix, S. cf. herbacea, and S. cf. arctica. The pollen spectrum from this site is dominated by Picea, Pinus, and Cyperaceae, which are typical of midwestern full-glacial sequences. Tundra-like conditions with permafrost were present in southeastern Minnesota during full-glacial time. Local environments 18,700 yr B.P. reconstructed from both physical and paleobotanical evidence include wind-swept ridge tops with thin loess, outcrops of dolostone and sandstone on valley walls, colluvial slopes, sandy to gravelly floodplains, shallow floodplain pools, wet meadows, and peaty turfs, all in a treeless or nearly treeless environment.
A Holocene Record of Atmospheric Dust Deposition on the Penny Ice Cap, Baffin Island, Canada
Authors: Zdanowicz Christian M. , Zielinski Gregory A. , Wake Cameron P. , Fisher David A. , Koerner Roy M.
Published: September 2002

An >11,550-yr-long record of atmospheric dust deposition was developed from an ice core (P95) drilled through the Penny ice cap, Baffin Island. The P95 record documents environmental changes that affected the production and transport of dust in the eastern Canadian Arctic during the late Pleistocene and Holocene. Dust deposition on the Penny ice cap was greatest in late-glacial time when the climate was dry and windy and comparatively low in the Holocene. Microparticles deposited during late-glacial time are finer than in Greenland cores, suggesting distinct dust sources and transport trajectories to each region. Dust deposition at the P95 site increased after ca. 7800 yr ago as the Penny ice cap receded and distance from local dust sources was reduced. Deflation of newly exposed marine sediments on southwestern Baffin Island may have contributed to this dust increase. The P95 and GISP2 (Greenland) dust records show diverging trends in the middle to late Holocene, reflecting the growing influence of regional environmental conditions (e.g., dust source area, snow cover extent) on atmospheric dust deposition. This study further demonstrates how valuable records of regional-scale paleoenvironmental changes can be developed from small circum-Arctic ice caps, even those affected by considerable melt.
Holocene Earthquakes Inferred from a Fan-Delta Sequence in the Dead Sea Graben
Authors: Enzel Yehouda , Kadan Galit , Eyal Yehuda
Published: September 2002

The Holocene sequence of the fan-delta of Nahal Darga, in Israel, records deformation associated with earthquakes related to the Dead Sea Transform in general and to the Jericho Fault in particular. The fan-delta sequence is well exposed, and 20 radiocarbon ages help to date the earthquakes that are inferred from (a) displacement along faults, (b) liquefaction features associated with 11 separate sandy and silty layers, and (c) slumped allocthonous bodies of sediments located directly above one of the main splays of the Jericho Fault. On average, an earthquake larger thanM5.5 has occurred approximately every 600 years. This estimate is based on the earthquake record of the complete stratigraphic sequence, with erosional hiatuses omitted from the calculations. The most recently deformed layer is related to the 1927 Jericho (ML6.2) earthquake. This layer provides a modern analog for the style of soft-sediment deformation associated with earthquakes in the late Pleistocene and Holocene silty sand beds of the fan-delta complexes of the Dead Sea and its predecessor, Lake Lisan.
North Atlantic Climate–Ocean Variations and Sea Level in Long Island Sound, Connecticut, Since 500 cal yr A.D.
Authors: van de Plassche Orson
Published: September 2002

A record of detrended mean high water (MHW) variations from Hammock River marsh, Connecticut, is extended from ca. 850 to ca. 500 cal yr A.D. and correlated with summer-temperature reconstructions from northern Fennoscandia and northern Eurasia, Greenland Ice Sheet Project 2 δ18O, and Greenland Ice Core Project borehole-temperature variations from central Greenland, a Sargasso Sea sea-surface temperature (SST) record, and a proxy record for deep-ocean flow south of Iceland. The records from northern Fennoscandia/Eurasia and central Greenland document century-scale intervals of warming (four) and cooling (three) since ca A.D. 850. The MHW fluctuations lag behind these climate intervals by 0–100 yr, with the two larger MHW rises corresponding to the two larger temperature increases. This positive correlation suggests that surface air temperature (SAT) is a dominant variable controlling sea level in the northwestern North Atlantic since ca. A.D. 850. The SST variations parallel the MHW fluctuations back to ca. 950 cal yr A.D. A positive correlation is found also for (sub)century-scale SAT and MHW variations during the period A.D. 500–850, but this result is less firm. MHW–SST correlation over this time interval is not consistent.
Speleothem Evidence for Changes in Indian Summer Monsoon Precipitation over the Last ∼2300 Years
Authors: Denniston Rhawn F. , González Luis A. , Asmerom Yemane , Sharma Ram H. , Reagan Mark K.
Published: September 2002

Speleothems from a well-ventilated dolomitic cave in the Pokhara Valley, central Nepal, preserve a mineralogic record of Indian summer monsoon variability over the past 2300 yr. Annually deposited aragonite layers formed between 2300 and 1500 yr B.P., indicating reduced monsoon precipitation and increased cave aridity, whereas alternating calcite/aragonite laminae deposited after 1500 yr B.P. record elevated summer monsoon precipitation and increased cave humidity. Dense, optically clear calcite layers deposited from 450 ± 5 to 360 ± 20 yr B.P. (1550 to 1640 A.D.) indicate a less-evaporative cave environment and suggest moister and/or cooler conditions, possibly related to climatic change associated with the onset of the Little Ice Age.
Holocene Foraminifera as Indicators of Relative Estuarine-Lagoonal and Oceanic Influences in Estuarine Sediments of the River Murray, South Australia
Authors: Cann John H. , Bourman Robert P. , Barnett Elizabeth J.
Published: September 2002

In southeastern South Australia, the River Murray debouches through a coastal barrier separating euryhaline estuarine-lagoonal waters from the Southern Ocean. Depending upon the relative freshwater outflow of the river and ingress of the ocean, water salinity varies greatly within the lower estuary.Ammonia beccariiandElphidium articulatumare euryhaline species of foraminifera that characterize the estuary and back-barrier Coorong Lagoon. The inner-shelf marine environment hosts an assemblage in whichDiscorbis dimidiatus, E. crispum, E. macelliforme,and various cibicidid species predominate. In cored sediments recovered from the shallow lower estuary, the relative abundance ofA. beccarii + E. articulatumwas compared with that ofD. dimidiatus + E. crispum + E. macelliforme+ other species. These data, and AMS radiocarbon ages determined for foraminifera and ostracods, provide evidence of a change from maximum oceanic influence (5255 ± 60 yr B.P.) to maximum estuarine influence (3605 ± 70 yr B.P.). Over this same time interval, sea level fell relatively by about 2 m. However, the event was also contemporaneous with falling water levels in several Victorian lakes, and it is thus attributed to onset of climatic aridity. Reduced precipitation in the River Murray catchment and reduced freshwater outflow enhanced development of the flood-tide delta and constriction of the mouth.
Warm Period Growth of Travertine during the Last Interglaciation in Southern Germany
Authors: Frank Norbert , Braum Margarethe , Hambach Ulrich , Mangini Augusto , Wagner Günther
Published: September 2002

Late-Quaternary travertine at two sites near Stuttgart formed entirely during interglacial periods. The travertine contains structures from growth induced by bacteria, and such structures have been dated by 230Th/U mass spectrometry. The resulting ages from both sites imply growth episodes of short duration, with growth rates up to 5 mm yr−1, at 99,800 ± 1300 yr B.P. (2σ n = 8) and 105,900 ± 1300 yr B.P. (2σ n = 7). These episodes were likely part of marine isotope stage (MIS) 5.3. Deposition of silt interrupted travertine growth at one of the sites ∼105,000 yr B.P. Likely correlatives of this silt are the St. Germain I-B stade recorded in the Grand Pile peat bog and a cold episode ∼1000 yr long recorded by δ18O values in the GRIP ice core. Travertine also formed during stage 5.5 (∼115,000 yr) and during the early Holocene. We found no evidence for travertine accumulation in stages 2, 3, 4, and 5.1. At both sites, the Sr/U ratio and the initial 234U/238U activity ratio resemble those of modern spring water. However, the sites differ in the chemical composition of spring water and in stratigraphic sequence of travertine accumulation.
Macrofossil Record of a Middle Holocene Drop in Relative Sea Level at the St. Lawrence Estuary, Québec
Authors: Bhiry Najat , Garneau Michelle , Filion Louise
Published: September 2002

Macrofossil analysis of a peat layer overlying shallow-water estuarine sediments allows the reconstruction of vegetation changes between 7000 and 6000 14C yr B.P. near Montmagny, Québec. About 7500–7000 14C yr B.P., the study site was brackish and intertidal. Next, a cattail marsh dominated by Typha changed into a terrestrial fire-prone environment that contained xero-mesophilous tree species (Pinus/Tsuga) and lasted a few hundred years, until about 6800 14C yr B.P. This rapid change may have resulted from land tilting associated with the northward migration of the postglacial forebulge. An abrupt change from a Pinus/Tsuga-dominated cover to shrubby vegetation was due to a fire that affected the site 6800 14C yr B.P. Fossil mosses at the site reflect local wetness likely produced by a rise in the water table starting about 6600 14C yr B.P. By 6500–6400 14C yr B.P., seawater returned and freshwater plants were replaced by semihalophilous and halophilous plants. Thinning of annual rings in fossil larch reflects this change from a terrestrial peatland to a treeless coast.
Evidence from 40Ar/39Ar Ages of Individual Hornblende Grains for Varying Laurentide Sources of Iceberg Discharges 22,000 to 10,500 yr B.P.
Authors: Hemming Sidney R. , Bond Gerard C. , Broecker Wallace S. , Sharp Warren D. , Klas-Mendelson Mieczyslawa
Published: September 2002

The abundance and lithic content of ice rafted detritus in glacial North Atlantic sediment cores vary abruptly on millennial time scales that have been correlated to Dansgaard-Oeschger cycles in the Greenland ice cores. There is growing evidence that various ice sheet outlets contributed increased iceberg fluxes at multiple discrete intervals, and the relative timing of iceberg discharges from different sources is important for understanding interactions between oceans and ice sheets. We present a provenance study based on 40Ar/39Ar dates of individual hornblende grains from 20 samples taken at 600 to 700 yr spacing between 10,500 and 22,000 yr B.P., from Orphan Knoll core EW9303-GGC31. Heinrich layers are characterized by a dominant Paleoproterozoic hornblende provenance consistent with published studies. A change in provenance between Heinrich events H2 and H1 indicates contributions of iceberg calving from the Newfoundland and southern Labrador margins. Between H1 and the Younger Dryas interval, Paleoproterozoic ice rafted grains remained dominant. The dominance of Baffin Island (or Greenland?) sources to the ice rafted detritus is ascribed to the retreat of the southern Laurentide ice sheet at about the time of H1—a retreat that isolated Newfoundland and southern Labrador ice from the shelf-slope boundary.
Holocene Climate Inferred from Oxygen Isotope Ratios in Lake Sediments, Central Brooks Range, Alaska
Authors: Anderson Lesleigh , Abbott Mark B. , Finney Bruce P.
Published: September 2002

Analyses of sediment cores from two lakes in the central Brooks Range provide temperature and moisture balance information for the past ∼8500 cal yr at century-scale resolution. Two methods of oxygen isotope analysis are used to reconstruct past changes in the effective moisture (precipitation minus evaporation) and temperature. Effective moisture is inferred from oxygen isotope ratios in sediment cellulose from Meli Lake (area ∼0.13 km2, depth 19.4 m). The lake has a low watershed-to-lake-area ratio (7) and significant evaporation relative to input. Summer temperature shifts are based on oxygen isotope analyses of endogenic calcite from Tangled Up Lake (area ∼0.25 km2, depth 3.5 m). This basin has a larger watershed-to-lake-area ratio (91) and less evaporation relative to input. Sediment oxygen isotope analyses from the two sites indicate generally more arid conditions than present prior to ∼6000 cal yr B.P. Subsequently, the region became increasingly wet. Temperature variability is recorded minimally at centennial scale resolution with values that are generally cool for the past ∼6700 cal yr. The timing and direction of climate variability indicated by the oxygen isotope time series from Meli and Tangled Up lakes are consistent with previously established late Holocene glacier advances at ∼5000 cal yr B.P. in the central Brooks Range, and high lake-levels at Birch Lake since ∼5500 cal yr B.P. This unique use of oxygen isotopes reveals both moisture balance and temperature histories at previously undetected high-resolution temporal scales for northern Alaska during the middle to late Holocene.
Fossil Rotifers and the Early Colonization of an Antarctic Lake
Authors: Swadling Kerrie M. , Dartnall Herbert J. G. , Gibson John A. E. , Saulnier-Talbot Émilie , Vincent Warwick F.
Published: September 2002

Early Holocene sediments from a continental Antarctic lake (Ace Lake, Vestfold Hills, East Antarctica) contained abundant fossil rotifers of the genus Notholca. The fossil is similar to specimens of Notholca sp. present in modern-day Ace Lake and other fresh and brackish lakes of the Vestfold Hills. Cyanobacteria and protists (chrysophyte cysts, dinoflagellate cysts, and rhizopod tests) were also recovered from the core samples. These sediments were deposited early in the freshwater phase of Ace Lake, soon after deglaciation of the area. The occurrence of this trophically diverse assemblage of organisms at an early stage in the evolution of the lake suggests either that they were part of an endemic Antarctic flora and fauna which pre-dated the last glacial maximum and survived in glacial refugia or that efficient intercontinental dispersal had occurred.
Diatom, Pollen, and Chemical Evidence of Postglacial Climatic Change at Big Lake, South-Central British Columbia, Canada
Authors: Bennett Joseph R. , Cumming Brian F. , Leavitt Peter R. , Chiu Marian , Smol John P. , Szeicz Julian
Published: September 2002

Postglacial climatic conditions were inferred from cores taken from Big Lake in southern British Columbia. Low concentrations of nonarboreal pollen and pigments near the base of the core suggest that initial conditions were cool. Increases in both aquatic and terrestrial production suggest warmer and moister conditions until ∼8500 cal yr B.P. Hyposaline diatom assemblages, increases in nonarboreal pollen, and increased concentrations of pigments suggest the onset of arid conditions from ∼8500 to ∼7500 cal yr B.P. Slightly less arid conditions are inferred from ∼7500 until ∼6660 cal yr B.P. based on the diatoms, small increases and greater variability in biogenic silica and pigments, and higher percentages of arboreal pollen. At ∼6600 cal yr B.P., changes in diatoms, pigments, biogenic silica, and organic matter suggest that Big Lake became fresh, deep, and eutrophic until ∼3600 cal yr B.P., when water levels and nutrients decreased slightly. Our paleoclimatic inferences are similar to pollen-based studies until ∼6600 cal yr B.P. However, unlike these studies, our multiple lines of evidence from Big Lake imply large changes in effective moisture since 6000 cal yr B.P.
Radiocarbon Dating, Chronologic Framework, and Changes in Accumulation Rates of Holocene Estuarine Sediments from Chesapeake Bay
Authors: Colman Steven M. , Baucom Pattie C. , Bratton John F. , Cronin Thomas M. , McGeehin John P. , Willard Debra , Zimmerman Andrew R. , Vogt Peter R.
Published: September 2002

Rapidly accumulating Holocene sediments in estuaries commonly are difficult to sample and date. In Chesapeake Bay, we obtained sediment cores as much as 20 m in length and used numerous radiocarbon ages measured by accelerator mass spectrometry methods to provide the first detailed chronologies of Holocene sediment accumulation in the bay. Carbon in these sediments is a complex mixture of materials from a variety of sources. Analyses of different components of the sediments show that total organic carbon ages are largely unreliable, because much of the carbon (including coal) has been transported to the bay from upstream sources and is older than sediments in which it was deposited. Mollusk shells (clams, oysters) and foraminifera appear to give reliable results, although reworking and burrowing are potential problems. Analyses of museum specimens collected alive before atmospheric nuclear testing suggest that the standard reservoir correction for marine samples is appropriate for middle to lower Chesapeake Bay. The biogenic carbonate radiocarbon ages are compatible with 210Pb and 137Cs data and pollen stratigraphy from the same sites.

Post-settlement changes in sediment transport and accumulation is an important environmental issue in many estuaries, including the Chesapeake. Our data show that large variations in sediment mass accumulation rates occur among sites. At shallow water sites, local factors seem to control changes in accumulation rates with time. Our two relatively deep-water sites in the axial channel of the bay have different long-term average accumulation rates, but the history of sediment accumulation at these sites appears to reflect overall conditions in the bay. Mass accumulation rates at the two deep-water sites rapidly increased by about fourfold coincident with widespread land clearance for agriculture in the Chesapeake watershed.
Role of mitogen‐activated protein kinase family in serum‐induced leukaemia inhibitory factor and interleukin‐6 secretion by bone marrow stromal cells
Authors: Nakao Takafumi , Kim Shokei , Ohta Kensuke , Kawano Hitomi , Hino Masayuki , Miura Katsuyuki , Tatsumi Noriyuki , Iwao Hiroshi
Published: September 2002

In the haematopoietic microenvironment, bone marrow stromal cells play an important role in regulating haematopoiesis by expressing various cytokines, including leukaemia inhibitory factor (LIF) and interleukin‐6 (IL‐6). However, the intracellular signal that regulates cytokine secretion in bone marrow stromal cells has not been determined. The aim of this study was to evaluate the role of mitogen‐activated protein kinase (MAPK) family in serum‐induced secretion of LIF and IL‐6 by bone marrow stromal cells.

Transformed human bone marrow stromal cells (HS‐5) were stimulated with foetal calf serum (FCS) to produce LIF and IL‐6. FCS also induced activation of extracellular signal‐regulated kinase (ERK), p38 MAPK and c‐Jun NH2‐terminal kinase (JNK).

Both PD98059 (MAPK/ERK kinase inhibitor) and SB203580 (p38 MAPK inhibitor) attenuated FCS‐induced LIF protein production and gene expression. SB203580 decreased IL‐6 production and gene expression, but PD98059 had no effect on IL‐6 production and gene expression.

Expression of a dominant‐negative mutant form of JNK1 that blocked FCS‐induced JNK activity had no effect on protein production and gene expression of these cytokines.

These findings demonstrate that both ERK and p38 MAPK are involved in FCS‐induced LIF secretion, whereas only p38 MAPK is important for IL‐6 secretion, and that FCS‐induced activation of JNK has no effect on the production of LIF and IL‐6. We conclude that, in spite of their similar biological effects, they are differentially regulated at the level of MAPK activity in bone marrow stromal cells.

British Journal of Pharmacology (2002) 136, 975–984. doi:10.1038/sj.bjp.0704797
Protein nitration in cutaneous inflammation in the rat: essential role of inducible nitric oxide synthase and polymorphonuclear leukocytes
Authors: Greenacre S A B , Rocha F A C , Rawlingson A , Meinerikandathevan S , Poston R N , Ruiz E , Halliwell B , Brain S D
Published: September 2002

We have examined the relationship between neutrophil accumulation, NO• production and nitrated protein levels in zymosan‐mediated inflammation in rat skin in vivo.

Rats were anaesthetized and cutaneous inflammation was induced by zymosan (injected intradermally, i.d.). Experiments were carried out up to 48 h, in recovery procedures as appropriate. Assays for neutrophil accumulation (measurement of myeloperoxidase), nitric oxide (assessment of NO2−/NO3−) and nitrated proteins (detected by ELISA and Western blot) were performed in skin extracts.

The results demonstrate a close temporal relationship between these parameters. Samples were assayed at 1, 4, 8, 24 and 48 h after i.d. injection of zymosan. The highest levels measured of each parameter (P<0.001 compared with vehicle) were found at 4–8 h, with a reduction towards basal levels by 24 h.

Selective depletion of circulating neutrophils with anti‐neutrophil antibody abolished neutrophil accumulation and protein nitration. In addition substantially decreased NO levels were found.

A selective inducible nitric oxide synthase (iNOS) inhibitor, N‐3‐aminomethyl‐benzyl‐acetamidine‐dihydrochloride (1400W) also significantly reduced neutrophil levels and NO production and substantially inhibited protein nitration.

We conclude that the neutrophil leukocyte plays an essential role in the formation of iNOS‐derived NO and nitrated proteins in inflammation, in a time‐dependent and reversible manner. The NO‐derived iNOS also has a role in stimulating further neutrophil accumulation into skin. This suggests a close mechanistic coupling between neutrophils, NO production and protein nitration.

British Journal of Pharmacology (2002) 136, 985–994. doi:10.1038/sj.bjp.0704798
Differential coupling of 5‐HT1 receptors to G proteins of the Gi family
Authors: Lin Stanley L , Setya Shilpy , Johnson‐Farley Nadine N , Cowen Daniel S
Published: September 2002

Since all 5‐HT1 receptors couple to Gi–type G proteins and inhibit adenylyl cyclase, the functional significance of five distinct subtypes of 5‐HT1 receptors has been unclear.

In previous studies we have used transfected cells to demonstrate that 5‐HT1B receptors can couple more efficiently than 5‐HT1A receptors to activation of extracellular signal‐regulated kinase (ERK) and to inhibition of adenylyl cyclase. These findings suggested the possibility that individual 5‐HT1 receptors differentially couple to isoforms of Giα.

In the present study we utilized a model system in which pertussis toxin resistant forms of human Giα1, Giα2, and Giα3 were used to directly compare the coupling of human 5‐HT1A, 5‐HT1B, and 5‐HT1D receptors to each Giα in transfected human HeLa cells.

5‐HT1A receptors displayed a preference for Giα1 and Giα2, relative to Giα3. Pertussis toxin resistant forms of Giα1, Giα2, and Giα3 rescued 73%, 76%, and 44%, respectively, of the ERK activation stimulated by 5‐HT in the absence of pertussis toxin.

In contrast, pertussis toxin resistant forms of Giα1, Giα2, and Giα3 rescued 32%, 118%, and 35% of 5‐HT1B receptor‐stimulated activity, respectively, indicating that 5‐HT1B receptors coupled primarily through Giα2. A similar preference for Giα2 was found in studies of the 5‐HT1D receptor, where toxin resistant Giα1, Giα2, and Giα3 rescued 30%, 70%, and 40% of activity, respectively.

In conclusion, the observed differential coupling of 5‐HT1 receptors to isoforms of Giα, provides additional evidence for our previous findings that the subtypes of 5‐HT1 receptors exhibit similar, but distinct, functions.

British Journal of Pharmacology (2002) 136, 1072–1078. doi:10.1038/sj.bjp.0704809
Effect of prolonged incubation with copper on endothelium‐dependent relaxation in rat isolated aorta
Authors: Chiarugi Alberto , Pitari Giovanni Mario , Costa Rosa , Ferrante Margherita , Villari Loredana , Amico‐Roxas Matilde , Godfraind Théophile , Bianchi Alfredo , Salomone Salvatore
Published: September 2002

We investigated the effects of prolonged exposure to copper (Cu2+) on vascular functioning of isolated rat aorta.

Aortic rings were exposed to CuSO4 (3–24 h) in Dulbecco's modified Eagle medium with or without 10% foetal bovine serum (FBS) and then challenged with vasoconstrictors or vasodilators in the absence of Cu2+.

Exposure to 2 μM Cu2+ in the absence of FBS did not modify the response to phenylephrine (PE) or acetylcholine (ACh) in aortic rings incubated for 24 h. Identical exposure in the presence of FBS increased the contractile response to 1 μM PE by 30% (P<0.05) and impaired the relaxant response to 3 μM ACh or 1 μM A23187 (ACh, from 65.7±7.1 to 6.2±1.1%, n=8; A23187, from 74.6±8.2 to 12.0±0.8%, n=6; P<0.01 for both). Cu2+ exposure did not affect the relaxant response to NO‐donors.

Impairment of vasorelaxation appeared 3 h after incubation with 2 μM Cu2+ and required 12 h to attain a steady state. Vasorelaxation to ACh was partially restored by 1 mM tiron (intracellular scavenger of superoxide ions; maximum relaxation 34.2±6.4%, n=10, P<0.01 vs Cu2+ alone), whereas catalase, superoxide dismutase or cycloheximide were ineffective.

Twenty‐four hour‐exposure to 2 μM Cu2+ did not affect endothelium integrity or eNOS expression, and increased the Cu content in arterial rings from 6.8±1.1 to 18.9±2.9 ng mg−1 wet weight, n=8; P<0.01.

Our results show that, in the presence of FBS, prolonged exposure to submicromolar concentrations of Cu2+ impaired endothelium‐dependent vasorelaxation in aortic rings, probably through an intracellular generation of superoxide ions.

British Journal of Pharmacology (2002) 136, 1185–1193. doi:10.1038/sj.bjp.0704816
Calcium channel subtypes contributing to acetylcholine release from normal, 4‐aminopyridine‐treated and myasthenic syndrome auto‐antibodies‐affected neuromuscular junctions
Authors: Giovannini F , Sher E , Webster R , Boot J , Lang B
Published: September 2002

Acetylcholine release at the neuromuscular junction relies on rapid, local and transient calcium increase at presynaptic active zones, triggered by the ion influx through voltage‐dependent calcium channels (VDCCs) clustered on the presynaptic membrane. Pharmacological investigation of the role of different VDCC subtypes (L‐, N‐, P/Q‐ and R‐type) in spontaneous and evoked acetylcholine (ACh) release was carried out in adult mouse neuromuscular junctions (NMJs) under normal and pathological conditions.

ω‐Agatoxin IVA (500 nM), a specific P/Q‐type VDCC blocker, abolished end plate potentials (EPPs) in normal NMJs. However, when neurotransmitter release was potentiated by the presence of the K+ channel blocker 4‐aminopyridine (4‐AP), an ω‐agatoxin IVA‐ and ω‐conotoxin MVIIC‐resistant component was detected. This resistant component was only partially sensitive to 1 μM ω‐conotoxin GVIA (N‐type VDCC blocker), but insensitive to any other known VDCC blockers. Spontaneous release was dependent only on P/Q‐type VDCC in normal NMJs. However, in the presence of 4‐AP, it relied on L‐type VDCCs too.

ACh release from normal NMJs was compared with that of NMJs of mice passively injected with IgGs obtained from patients with Lambert‐Eaton myasthenic syndrome (LEMS), a disorder characterized by a compromised neurotransmitter release. Differently from normal NMJs, in LEMS IgGs‐treated NMJs an ω‐agatoxin IVA‐resistant EPP component was detected, which was only partially blocked by calciseptine (1 μM), a specific L‐type VDCC blocker.

Altogether, these data demonstrate that multiple VDCC subtypes are present at the mouse NMJ and that a resistant component can be identified under ‘pharmacological’ and/or ‘pathological’ conditions.

British Journal of Pharmacology (2002) 136, 1135–1145. doi:10.1038/sj.bjp.0704818
Characterization of the anandamide induced depolarization of guinea‐pig isolated vagus nerve
Authors: Kagaya Manabu , Lamb Jasmine , Robbins Jon , Page Clive P , Spina Domenico
Published: September 2002

There is considerable interest in elucidating potential endogenously derived agonists of the vanilloid receptor and the role of anandamide in this regard has received considerable attention. In the present study, we have used an electrophysiological technique to investigate the mechanism of activation of vanilloid receptors in an isolated vagal preparation.

Both capsaicin and anandamide depolarized de‐sheathed whole vagal nerve preparations that was antagonized by the VR1 antagonist, capsazepine (P<0.05) whilst this response was unaltered by the cannabinoid (CB1) selective antagonist SR141716A or the CB2 selective antagonist, SR144528, thereby ruling out a role for cannabinoid receptors in this response.

The PKC activator, phorbol‐12‐myristate‐13‐acetate (PMA) augmented depolarization to both anandamide and capsaicin and this response was significantly inhibited with the PKC inhibitor, bisindolylmaleimide (BIM) (P<0.05).

The role of lipoxygenase products in the depolarization to anandamide was investigated in the presence of the lipoxygenase inhibitor, 5,8,11‐Eicosatriynoic acid (ETI). Depolarization to anandamide and arachidonic acid was significantly inhibited in the presence of ET1 (P<0.05). However, in the absence of calcium depolarization to anandamide was not inhibited by ETI.

Using confocal microscopy we have demonstrated the presence of vanilloid receptors on both neuropeptide containing nerves and nerves that did not stain for sensory neuropeptides.

These results demonstrate that anandamide evokes depolarization of guinea‐pig vagus nerve, following activation of vanilloid receptors, a component of which involves the generation of lipoxygenase products. Furthermore, these receptors are distributed in both neuropeptide and non‐neuropeptide containing nerves.

British Journal of Pharmacology (2002) 137, 39–48. doi:10.1038/sj.bjp.0704840
Direct and indirect inhibition by nociceptin/orphanin FQ on noradrenaline release from rodent cerebral cortex in vitro
Authors: Siniscalchi Anna , Rodi Donata , Morari Michele , Marti Matteo , Cavallini Sabrina , Marino Silvia , Beani Lorenzo , Bianchi Clementina
Published: September 2002

The modulation exerted by nociceptin/orphanin FQ (NC) on noradrenaline (NE) release in rodent cerebral cortex slices and synaptosomes was studied.

Rat, mouse and guinea‐pig cortical slices and synaptosomes were preincubated with 0.1 μM [3H]‐NE and superfused. NE release was evoked by 2 min of electrical (3 Hz) stimulation in slices and by 1 min pulse of 10 mM KCl in synaptosomes.

In rat cortical slices, 0.01–3 μM NC reduced the evoked [3H]‐NE efflux (Emax−54%), with a bell‐shaped concentration‐response curve, which regained its monotonic nature in the presence of either 0.1 μM naloxone (NX) or 30 μM bicuculline. In synaptosomes, the NC effect curve was sygmoidal in shape and reached a plateau at 1 μM concentration.

In the rat, both 1 μM [Phe1ψ(CH2‐NH)Gly2]NC(1‐13)NH2 and 10 μM [Nphe1]NC(1‐13)NH2 (NPhe) antagonised NC‐induced inhibition, without per se modifying [3H]‐NE efflux. The effects of 0.3–1 μM NC concentrations were partially prevented by 1 μM NX; 1 μM D‐Phe‐Cys‐Thr‐D‐Trp‐Orn‐Thr‐Pen‐Thr‐NH2 (CTOP) was also an effective antagonist, but 0.1 μM norbinaltorphimine was not.

In the mouse cerebral cortex, NC‐induced inhibition of NE release (pEC50 6.87, Emax−61%, in the slices) was prevented by Nphe but was NX‐insensitive. In guinea‐pig cortical slices, NC effect (pEC50 6.22, Emax−38%) was prevented by Nphe, but was NX‐insensitive.

These findings demonstrate that NC inhibits NE release from rodent cerebral cortex via presynaptically located ORL1 receptors. In the rat, μ opioid and GABAA receptors are involved as well.

British Journal of Pharmacology (2002) 136, 1178–1184. doi:10.1038/sj.bjp.0704841
Prospective randomized study of the efficacy of hydrogel, hydrocolloid, and saline solution—moistened dressings on the management of pressure ulcers
Authors: Mulder Gerit D. , Altman Morton , Seeley Jeannie E. , Tintle Tess
Published: September 2002

A total of 67 patients with pressure ulcers were randomized into one of three treatment modalities: hydrogel sheet dressing, hydrocolloid, or wet‐to‐moist gauze. Safety, efficacy, and physical attributes of the three dressings were evaluated. No statistical significance was found in wound healing rate among the three treatments. Hydrogel sheets were advantageous in allowing wound visualization without dressing or wound disruption.
Increased gene expression of scatter factor—hepatocyte growth factor and basic fibroblast growth factor in granulation tissue in the rat
Authors: Steenfos Henrik , Tarnow Peter , Aram Mahdieh , Nakamura Toshikazu , Jansson John‐Olov
Published: September 2002

Scatter factor—hepatocyte growth factor is a protein secreted by fibroblasts which disperses colonies of epithelial cells and keratinocytes in culture. The factor is also a patent mitogen for hepatocytes, synthesized in the liver. Basic fibroblast growth factor, another heparin‐binding factor, is most abundant in the brain but also plays a role in wound healing. Using a solution hybridization/RNAase protection assay, we have measured the abundance of messenger RNA for scatter factor—hepatocyte growth factor and basic fibroblast growth factor in granulation tissue obtained from subcutaneously Hunt‐Schilling wound cylinders. The levels of scatter factor—hepatocyte growth factor messenger RNA increased after weeks 2 through 4 to a twofold higher level in weeks 5 through 7 after implantation of the cylinders, whereas no changes in basic fibroblast growth factor messenger RNA levels were noticed. At week 3 after implantation of the cylinders, scatter factor—hepatocyte growth factor messenger RNA levels in granulation tissue were more than threefold higher than in skin dermis fibroblasts but markedly lower than in the liver. The abundance of basic fibroblast growth factor messenger RNA was also significantly increased in granulation tissue compared with dermis but, as expected, markedly lower than in the brain. In conclusion, the gene expression of the scatter factor—hepatocyte growth factor, as well as basic fibroblast growth factor, is increased in granulation tissue. Because there was a time‐dependent increase in the expression of scatter factor—hepatocyte growth factor, it is hypothesized that scatter factor—hepatocyte growth factor acts as a signal from fully developed granulation tissue to stimulate skin epithelial cells to scatter over the wound.
Fibronectin gene expression differs in normal and abnormal human wound healing
Authors: Sible Jill C. , Eriksson Elof , Smith Steven P. , Oliver Noelynn
Published: September 2002

The overproduction of fibronectin and type I collagen in keloids and hypertrophic scars implicates altered regulation of extracellular matrix components as an important aspect of these wound healing pathologies. However, little is known about the similarities and differences in extracellular matrix gene expression during normal and abnormal wound healing. This study compared the content of fibronectin messenger RNA and rates of fibronectin protein biosynthesis in fibroblasts derived from normal skin, normal scar, keloid, and hypertrophic scar. Fibronectin expression was enhanced in cells from both normal and abnormal wounds relative to cells from quiescent normal skin. Matched pairs of normal and keloid fibroblasts from the same individuals were also compared, and three of the four pairs showed higher fibronectin expression by the keloid cells at the levels of messenger RNA and protein synthesis. This was consistent with previous studies showing elevated steady state content of fibronectin in keloid cells relative to normal cells from the same individual. Fibronectin messenger RNA and protein content in the tissues from which these cells were derived was examined by in situ hybridization and immunohistochemistry. These studies revealed that in vivo, the steady state content of fibronectin messenger RNA and protein was highest in abnormal wounds, less in most normal scars, and lowest in normal skin. Thus, fibroblasts from keloids and hypertrophic scars overexpressed fibronectin in vivo relative to normal skin and normal scar and retain this characteristic in vitro relative to normal skin. Although normal scars contained little fibronectin protein and messenger RNA, cultured fibroblasts derived from these scars had contents of fibronectin messenger RNA and rates of biosynthesis in vitro similar to those of keloid fibroblasts. This indicates that the fibronectin regulatory pathway in scar fibroblasts is influenced by the tissue environment. These results are discussed with respect to the relationship of fibronectin expression in keloids, hypertrophic scars, and normal wounds in human beings.
The combination of platelet‐derived growth factor‐BB and insulin‐like growth factor‐I stimulates bone repair in adult Yucatan miniature pigs
Authors: Lynch Samuel E. , Trippel Stephen B. , Finkelman Richard D. , Hernandez Rafael A. , Kiritsy Christopher P. , Antoniades Harry N.
Published: September 2002

The combination of insulin‐like growth factor‐I and platelet‐derived growth factor‐BB has previously been shown to stimulate healing of soft tissue wounds and the formation of bone and ligament around teeth. The purpose of the present study was to evaluate the effects of platelet‐derived growth factor‐BB and insulin‐like growth factor‐I individually and in combination on the healing of osseous wounds. Four standardized cortical wounds were created in each tibia of 11 adult Yucatan miniature pigs. The wounds in one tibia per animal were treated with either purified recombinant human insulin‐like growth factor‐I, platelet‐derived growth factor‐BB, or both in a methylcellulose gel. The wounds in each contralateral tibia received placebo gel alone. Coded serial sections of each wound were evaluated by computer‐aided histomorphometry 21 days after surgery. The area and perimeter of the newly formed mineralized callus, the thickness of the total callus, and the percentage of mineralized tissue within the callus were significantly increased compared with the values of matched controls only in wounds treated with a combination of insulin‐like growth factor‐I and platelet‐derived growth factor‐BB. No significant differences in the measured parameters of callus formation were found in wounds treated with either insulin‐like growth factor‐I or platelet‐derived growth factor‐BB alone. Cartilage was present only in sites treated with insulin‐like growth factor‐I alone. These results suggest that the combination of platelet‐derived growth factor‐BB and insulin‐like growth factor‐I stimulates bone formation in wounds in long bones of adult animals and that these growth factors act via different pathways during the repair process.
Safety and effect of transforming growth factor‐β2 for treatment of venous stasis ulcers
Authors: Robson M. C. , Phillip L. G. , Cooper D. M. , Lyle W. G. , Robson L. E. , Odom L. , Hill D. P. , Hanham A. F. , Ksander G. A.
Published: September 2002

Transforming growth factor‐β2 promotes healing in a variety of animal models and exhibits clinical effects thought to be mediated by connective tissue formation. Two clinical trials were conducted to evaluate the safety and effect of transforming growth factor‐β2 purified from bovine bone and delivered topically to venous stasis ulcers three times per week for up to 6 weeks by means of a lyophilized collagen vehicle. The first was an open‐label trial comparing transforming growth factor‐β2 purified from bovine bone (0.5 µg/cm2) with a placebo consisting of lyophilized collagen vehicle‐without active drug. After no safety issues arose in that trial, a prospectively randomized, closed‐label, observer‐blinded, three‐armed trial was conducted to compare bovine transforming growth factor‐β2 (2.5 µg/cm2) with the collagen matrix placebo vehicle and with a standard dressing. Standardized elastic compression was applied to all test extremities. The rate of reduction of ulcer area as measured by planimetry was the primary measure of effect. No serious safety‐related events occurred in either trial. Clinical evaluation suggested that improvement in the quality and quantity of granulation tissue appeared to precede epithelialization of ulcers treated with bovine transforming growth factor‐β2. In both studies, treatment with bovine transforming growth factor‐β2 appeared to have a positive effect on the rate of ulcer closure, whereas ulcers in the control groups continued to exhibit impaired healing. In the open‐label study, the mean rate of closure of ulcers treated with bovine transforming growth factor‐β2 was significantly greater than that of ulcers treated with placebo. There was likewise enhanced reduction in ulcer area in the ulcers treated with bovine transforming growth factor‐β2 in the second trial. However, because of a higher variability in patient response and a greater placebo effect, the difference was not significant. The placebo was not worse than the standard care arm, thereby showing that the vehicle is not injurious to healing. The combined results of the two trials suggest that, at doses of 0.5 to 2.5 µg/cm2, bovine transforming growth factor‐β2 is safe as a topically applied agent in a collagen matrix vehicle and can have a positive effect on closure of venous stasis ulcers. Large multicenter trials appear to be indicated to evaluate fully the potential utility of transforming growth factor‐β2 in accelerating closure of chronic dermal ulcers.