bluuebunny/crossref_metadata_2025 huggingface dataset:
GISP2 Oxygen Isotope Ratios
Authors: Stuiver Minze , Grootes Pieter M.
Published: September 2002

The GISP2 oxygen isotope record, with its high-resolution detail, yields crucial information on past climate change. The glacial δ18O oscillations of the GISP2 core, with their very fast onsets, are templates of a prototype oscillation of variable duration with an amplitude of 3.9‰. The halfway mark of the cold–warm transition is reached in 2 years; the top is reached in 50 years. The δ18O–time gradient of the leading front is about 7.8‰ per 100 yr. After reaching the top, δ18O slowly declines by −0.14‰ per 100 yr. The duration of δ18O decline varies from a couple of centuries for fast oscillations to about 4000 yr for slower ones. The subsequent δ18O downturn during the warm–cold transition has a δ18O–time gradient of −3.2‰ per 100 yr and lasts about 80 yr.
Millennial-Scale Rhythms in Peatlands in the Western Interior of Canada and in the Global Carbon Cycle
Authors: Campbell Ian D. , Campbell Celina , Yu Zicheng , Vitt Dale H. , Apps Michael J.
Published: September 2002

A natural ∼1450-yr global Holocene climate periodicity underlies a portion of the present global warming trend. Calibrated basal radiocarbon dates from 71 paludified peatlands across the western interior of Canada demonstrate that this periodicity regulated western Canadian peatland initiation. Peatlands, the largest terrestrial carbon pool, and their carbon-budgets are sensitive to hydrological fluctuations. The global atmospheric carbon-budget experienced corresponding fluctuations, as recorded in the Holocene atmospheric CO2 record from Taylor Dome, Antarctica. While the climate changes following this ∼1450-yr periodicity were sufficient to affect the global carbon-budget, the resultant atmospheric CO2 fluctuations did not cause a runaway climate–CO2 feedback loop. This demonstrates that global carbon-budgets are sensitive to small climatic fluctuations; thus international agreements on greenhouse gasses need to take into account the natural carbon-budget imbalance of regions with large climatically sensitive carbon pools.
Deriving Response Matrices from Central American Modern Pollen Rain
Authors: Bush Mark B.
Published: September 2002

Modern pollen samples collected from 80 locations and representing a wide array of mature habitats in Panama and Costa Rica provide analogs to assist in the interpretation of fossil pollen records. Pollen spectra accurately reflect changes in actual forest types. Upslope transport of pollen of anemophilous species is evident in the sparsely vegetated montane samples. However, the corresponding downslope transport of these prolific pollen producers is masked by local pollen production. Mean pollen representation across gradients of mean annual temperature (MAT; 4°C increments) and mean annual precipitation (MAP; 500 mm increments) for 17 pollen types are presented as response matrices. Although preliminary in nature, these response matrices present a clearer image of pollen representation than can be obtained by considering gradients of MAT or MAP alone.
Late Quaternary Upwelling Variations in the Eastern Equatorial Atlantic Ocean as Inferred from Dinoflagellate Cysts, Planktonic Foraminifera, and Organic Carbon Content
Authors: Höll Christine , Kemle-von Mücke Sylvia
Published: September 2002

Analysis of multiple proxies shows that eastern equatorial Atlantic upwelling was subdued during isotope stage 5.5, more intense during stages 4, 5.2, 5.4, and 6, and most intense early in stage 2. These findings are based on proxy measures from a core site about 600 km southwest of Liberia. The proxies include total organic carbon content, the ratio of peridinoid and oceanic organic-walled dinoflagellate cyst species, accumulation rates of calcareous dinoflagellates, estimates of sea surface paleotemperatures, the difference in stable oxygen isotope composition between two species of planktonic foraminifera that live at different water depths, and the abundance of the planktonic foraminifera Neogloboquadrina dutertrei. Most of these parameters consistently vary directly or inversely with one another. Slight discrepancies between the individual parameters show the usefulness of a multiple proxy approach to reconstruct paleoenvironments. Our data confirm that northern summer insolation strongly influences upwelling in the eastern equatorial Atlantic Ocean.
Phytoliths from Archaeological Sites in the Tropical Forest of Ituri, Democratic Republic of Congo
Authors: Mercader Julio , Runge Freya , Vrydaghs Luc , Doutrelepont Hughes , Ewango Corneille E. N. , Juan-Tresseras Jordi
Published: September 2002

Phytoliths record late Quaternary vegetation at three archaeological sites in the Ituri rain forest. The oldest deposits, dated to ca. 19,000 to 10,00014C yr B.P., contain abundant phytoliths of grasses but also enough arboreal forms to show that the landscape was forested. The late-glacial forests may have had a more open canopy than today's. Younger phytolith assemblages show that the northeast Congo basin was densely forested throughout the Holocene. Archaeological materials among the phytoliths show that people lived in this region during the Pleistocene. Therefore, Pleistocene and Holocene prehistoric foragers probably inhabited tropical forests of the northeast Congo basin many millennia before farming appeared in the region.
A Holocene Ice-Core Pollen Record from Ellesmere Island, Nunavut, Canada
Authors: Bourgeois Jocelyne C. , Koerner Roy M. , Gajewski Konrad , Fisher David A.
Published: September 2002

A Holocene record of pollen deposition was obtained from an ice core drilled through the Agassiz Ice Cap. The pollen records long-range atmospheric transport to the ice cap. Pollen concentrations were highest in the early Holocene (∼15 grains/L), decreased in the mid-Holocene (∼6 grains/L), and increased in the late Holocene (∼9 grains/L). In the early Holocene, the higher concentration of tree pollen at a time when large parts of Canada were still ice-covered, and when forest was generally farther away, implies that atmospheric circulation was stronger than at present. Following deglaciation, as vegetation migrated north in central and eastern Canada, sources of pollen were closer to the Agassiz Ice Cap. However, the concentration of tree pollen decreased on the ice cap. This was followed by several relatively rapid changes after 3500 yr ago. Until ca. 3500 yr ago, the pollen concentration curves resembled the ice core δ18O and summer melt layer curves, both regarded as temperature proxies.
Significance of Two New Pleistocene Plant Records from Western Europe
Authors: Field Michael H. , Velichkevich Felix Y. , Andrieu-Ponel Valerie , Woltz Phillipe
Published: September 2002

The first records of extinctCaulinia goretskyi(Dorofeev) Dorofeev (synonymNajas goretskyiDorofeev) in western Europe and ofPotamogeton occidentalisM.H. Field sp. nov. were obtained from plant macrofossil analyses of Middle Pleistocene temperate stage deposits exposed at Trez Rouz, Brittany, France. Palynological assemblages recovered suggest correlation with the Holsteinian Stage. This discovery greatly expands the western limit of the paleogeographical distribution ofCaulinia goretskyi.The record ofPotamogeton occidentalisindicates an affinity with the eastern Asiatic flora, as the fruits resemble those of the extantPotamogeton maackianusA. Bennett. Other extinct Pleistocene species related toP. maackianushave been described, and it is possible to follow the development of this group through the Pleistocene in the European fossil record. These new finds illustrate the importance of a complete paleobotanical approach (both plant macrofossil and palynological analyses). The plant macrofossil assemblages not only provide detailed insight into local vegetation and environment, because they are often not transported long distances (in temperate areas) and can frequently be identified to species level; they can also offer the opportunity to investigate Pleistocene evolutionary trends.
Reconstruction of Prehistoric Landfall Frequencies of Catastrophic Hurricanes in Northwestern Florida from Lake Sediment Records
Authors: Liu Kam-biu , Fearn Miriam L.
Published: September 2002

Sediment cores from Western Lake provide a 7000-yr record of coastal environmental changes and catastrophic hurricane landfalls along the Gulf Coast of the Florida Panhandle. Using Hurricane Opal as a modern analog, we infer that overwash sand layers occurring near the center of the lake were caused by catastrophic hurricanes of category 4 or 5 intensity. Few catastrophic hurricanes struck the Western Lake area during two quiescent periods 3400–5000 and 0–1000 14C yr B.P. The landfall probabilities increased dramatically to ca. 0.5% per yr during an “hyperactive” period from 1000–3400 14C yr B.P., especially in the first millennium A.D. The millennial-scale variability in catastrophic hurricane landfalls along the Gulf Coast is probably controlled by shifts in the position of the jet stream and the Bermuda High.
Dominance of an ∼150-Year Cycle of Sand-Supply Change in Late Holocene Dune-Building along the Eastern Shore of Lake Michigan
Authors: Loope Walter L. , Arbogast Alan F.
Published: September 2002

Outcrops of buried soils on lake-plains and glacial headlands along Lake Michigan's eastern shore suggest that periodic dune-building has occurred there after relatively long (≥100 yr) periods of low sand supply. We located, described, and radiocarbon dated 75 such buried soils that crop out in 32 coastal dune fields beside the lake. We assume that peaks in probability distributions of calibrated 14C ages obtained from wood, charcoal, and other organic matter from buried A horizons approximate the time of soil burial by dunes. Plotted against a late Holocene lake-level curve for Lake Michigan, these peaks are closely associated with many ∼150-yr lake highstands previously inferred from beach ridge studies. Intervening periods of lower lake levels and relative sand starvation apparently permitted forestation and soil development at the sites we studied. While late Holocene lake-level change led to development and preservation of prominent foredunes along the southern and southwestern shores of Lake Michigan, the modern dune landscape of the eastern shore is dominated by perched dunes formed during ∼150-yr lake highstands over the past 1500 yr.
A 12,000-Year Pollen Record from Lake Maliq, Albania
Authors: Denèfle Michelle , Lézine Anne-Marie , Fouache Eric , Dufaure Jean-Jacques
Published: September 2002

Pollen data from Lake Maliq, the first from Albania, contribute new information to the discussion of the vegetational, hydrological, and climatological history of the Balkans since 12,000 yr B.P. During late-glacial time, a perennial lake expanded at Maliq. It was surrounded by a complex vegetation association composed of steppe and mixed forest elements. The highly diverse forest flora suggest that late-glacial forest refugia were more developed here at middle altitude, rather than at higher altitude as previously suggested. The forest developed after 9800 yr B.P., while the water level remained high in the Korçë basin until 5000 yr B.P. Different environmental conditions, characterized by lower available moisture and warmer winters, progressively took place after this date. Human activity in the Korçë basin ca. 4500 yr B.P. was coeval with conditions characterized by an increase in winter temperatures and a decrease in summer moisture.
Late-Glacial and Early Holocene Vegetation and Climate Change near Owens Lake, Eastern California
Authors: Mensing Scott A.
Published: September 2002

Pollen and algae from Owens Lake in eastern California provide evidence for a series of climatic oscillations late in the last glaciation. Juniper woodland, which dominated the Owens Valley from 16,200 to 15,500 cal yr B.P., suggests much wetter conditions than today. Although still wetter and cooler than today, the area then became fairly warm and dry, with woodland being replaced by shrubs (mainly sagebrush) from 15,500 to 13,100 cal yr B.P. Next, Chenopodiaceae (shadscale) increased, woody species declined, and lake levels fell—all evidence for a brief (ca. 100–200 yr) drought about 13,000 cal yr B.P. The climate continued to oscillate between wet and dry from 13,000 to 11,000 cal yr B.P. After 11,000 cal yr B.P., low lake levels and the increased dominance of desert shrubs indicate the beginning of warm, dry Holocene conditions. The region's climate was unstable during the Younger Dryas but uncertainities in dating prevent identification of the Younger Dryas interval in the Owens Lake record. Comparison of the Owens Lake record with studies in the Sierra Nevada and Great Basin suggest that the climate was generally wetter between 13,000 and 11,000 cal yr B.P., with warmer summers, although no consistent pattern of climate change emerges.
Pacific Sea Surface Temperature Forcing Dominates Orbital Forcing of the Early Holocene Monsoon
Authors: Bush Andrew Basil George
Published: September 2002

Orbital forcing is known to play a primary role in regulating the strength of the south Asian monsoon circulation. In this study, a comparison is made between orbital forcing and Pacific sea surface temperature (SST) forcing of the monsoon through a sequence of atmospheric general circulation model experiments configured for 6,000 and 9,000 yr B.P. Early–mid Holocene orbital parameters are shown to increase continental seasonality as well as the meridional mean, the zonal mean, and the summer monsoon circulations. Winds in the southeast Asian monsoon are weakened by warm Pacific SST to such an extent that the increase in strength caused by early Holocene orbital parameters is offset. These results imply that SSTs are potentially as important as orbital parameters in governing the monsoon and that more data—particularly from the equatorial Pacific—are crucial to deciphering Holocene climate.
Multiproxy Record of Late Pleistocene–Holocene Climate and Vegetation Changes from a Peat Bog in Patagonia
Authors: Pendall Elise , Markgraf Vera , White James W. C. , Dreier Mark , Kenny Ray
Published: September 2002

Pollen assemblage changes and stable hydrogen isotope analysis of mosses (Sphagnum magellanicum and Drepanocladus s.l.) from a bog in Tierra del Fuego, Argentina, provided independent proxies for reconstructing changes in effective moisture and temperature over the past 16,000 cal yr B.P. A deterministic model was used to reconstruct the stable hydrogen isotope composition of meteoric water from the D/H ratios of bog mosses over the last 16,000 years. Abrupt changes in temperature, as recorded in D/H ratios of moss cellulose, were accompanied by synchronous changes in vegetation composition during the late Pleistocene and early and middle Holocene, when moisture levels were lower than today. In contrast, temperature variability during the late Holocene was not accompanied by comparable vegetation changes. In particular, grass pollen (Poaceae) increased during periodic cold spells between 15,000 and 11,000 cal yr B.P., but a cold spell of similar magnitude ca. 2000 cal yr B.P. did not appear to affect vegetation. During the late Pleistocene, the isotopic record from the peat core shows variations similar to the D/H ratios in the Antarctic Taylor Dome ice core. However, the timing of the changes in the Harberton record is more in line with the timing of other Southern Hemisphere records.
Rates of Sediment Supply to Arroyos from Upland Erosion Determined Usingin SituProduced Cosmogenic10Be and26Al
Authors: Clapp Erik M. , Bierman Paul R. , Nichols Kyle K. , Pavich Milan , Caffee Marc
Published: September 2002

Using10Be and26Al measured in sediment and bedrock, we quantify rates of upland erosion and sediment supply to a small basin in northwestern New Mexico. This and many other similar basins in the southwestern United States have been affected by cycles of arroyo incision and backfilling several times in the past few millennia. The sediment generation (275 ± 65 g m−2yr−1) and bedrock equivalent lowering rates (102 ± 24 m myr−1) we determine are sufficient to support at least three arroyo cycles in the past 3,000 years, consistent with rates calculated from a physical sediment budget within the basin and regional rates determined using other techniques. Nuclide concentrations measured in different sediment sources and reservoirs suggest that the arroyo is a good spatial and temporal integrator of sediment and associated nuclide concentrations from throughout the basin, that the basin is in steady-state, and that nuclide concentration is independent of sediment grain size. Differences between nuclide concentrations measured in sediment sources and reservoirs reflect sediment residence times and indicate that subcolluvial bedrock weathering on hillslopes supplies more sediment to the basin than erosion of exposed bedrock.
Late Quaternary Paleoclimate in Semiarid Northeastern Brazil from U-Series Dating of Travertine and Water-Table Speleothems
Authors: Auler Augusto S. , Smart Peter L.
Published: September 2002

Fossil travertine and subaqueous speleothems in presently dry caves suggest periods of enhanced ground-water recharge during the Quaternary Period in semiarid northeastern Brazil. Travertine deposits and water-table speleothems were dated by the 230Th/234U technique, yielding new evidence for the timing of past periods of increased rainfall. The travertine was deposited in two distinct phases, extensive in situ deposits during marine isotope stage 2 and fragmentary, indurated deposits dating to ca. 400,000 yr B.P. (possibly marine isotope stage 10 or 12). Dating of water-table speleothems showed that the regional water table was 13±1 m above the present level at the last glacial maximum. A second site yielded ages suggesting a still higher water table during marine isotope stage 6. These new data demonstrate that northeastern Brazil did not follow the general pattern of a dry last glacial maximum, as suggested by other continental records in Amazonia and southeastern Brazil, and as depicted in recent General Circulation Model (GCM) simulations. Our results thus indicate that significant variability in regional rainfall patterns occurred in the area during glaciations and caution against overgeneralization of paleoclimate patterns.
Extensive Early and Middle Wisconsin Glaciation on the Western Olympic Peninsula, Washington, and the Variability of Pacific Moisture Delivery to the Northwestern United States
Authors: Thackray Glenn D.
Published: September 2002

Large glaciers descended western valleys of the Olympic Mountains six times during the last (Wisconsin) glaciation, terminating in the Pacific coastal lowlands. The glaciers constructed extensive landforms and thick stratigraphic sequences, which commonly contain wood and other organic detritus. The organic material, coupled with stratigraphic data, provides a detailed radiocarbon chronology of late Pleistocene ice-margin fluctuations. The early Wisconsin Lyman Rapids advance, which terminated prior to ca. 54,000 14C yr B.P., represented the most extensive ice cover. Subsequent glacier expansions included the Hoh Oxbow 1 advance, which commenced between ca. 42,000 and 35,000 14C yr B.P.; the Hoh Oxbow 2 advance, ca. 30,800 to 26,300 14C yr B.P.; the Hoh Oxbow 3 advance, ca. 22,000–19,300 14C yr B.P.; the Twin Creeks 1 advance, 19,100–18,300 14C yr B.P.; and the subsequent, undated Twin Creeks 2 advance. The Hoh Oxbow 2 advance represents the greatest ice extent of the last 50,000 yr, with the glacier extending 22 km further downvalley than during the Twin Creeks 1 advance, which is correlative with the global last glacial maximum. Local pollen data indicate intensified summer cooling during successive stadial events. Because ice extent was diminished during colder stadial events, precipitation—not summer temperature—influenced the magnitude of glaciation most strongly. Regional aridity, independently documented by extensive pollen evidence, limited ice extent during the last glacial maximum. The timing of glacier advances suggests causal links with North Atlantic Bond cycles and Heinrich events.
A High-Resolution Sea-Surface Temperature Record from the Tropical South China Sea (16,500–3000 yr B.P.)
Authors: Steinke Stephan , Kienast Markus , Pflaumann Uwe , Weinelt Mara , Stattegger Karl
Published: September 2002

The timing and magnitude of sea-surface temperature (SST) changes in the tropical southern South China Sea (SCS) during the last 16,500 years have been reconstructed on a high-resolution,14C-dated sediment core using three different foraminiferal transfer functions (SIMMAX28, RAM, FP-12E) and geochemical (Uk′37) SST estimates. In agreement with CLIMAP reconstructions, both the FP-12E and the Uk′37SST estimates show an average late glacial–interglacial SST difference of 2.0°C, whereas the RAM and SIMMAX28 foraminiferal transfer functions show only a minor (0.6°C) or no consistent late glacial–interglacial SST change, respectively. Both the Uk′37and the FP-12E SST estimates, as well as the planktonic foraminiferal δ18O values, indicate an abrupt warming (ca. 1°C in <200 yr) at the end of the last glaciation, synchronous (within dating uncertainties) with the Bølling transition as recorded in the Greenland Ice Sheet Project 2 (GISP2) ice core, whereas the RAM-derived deglacial SST increase appears to lag during this event by ca. 500 yr. The similarity in abruptness and timing of the warming associated with the Bølling transition in Greenland and the southern SCS suggest a true synchrony of the Northern Hemisphere warming at the end of the last glaciation. In contrast to the foraminiferal transfer function estimates that do not indicate any consistent cooling associated with the Younger Dryas (YD) climate event in the tropical SCS, the Uk′37SST estimates show a cooling of ca. 0.2–0.6°C compared to the Bølling–Allerød period. These Uk′37SST estimates from the southern SCS argue in favor of a Northern Hemisphere-wide, synchronous cooling during the YD period.
Late Quaternary Sea-Level Change in South Africa
Authors: Ramsay Peter J. , Cooper J. Andrew G.
Published: September 2002

A Late Quaternary sea-level curve for South Africa is presented on the basis of new and published data from a range of sea level indicators and a variety of locations. Available evidence suggests that sea level in South Africa broadly follows that described from the Caribbean but that deviations occur during sea-level highstands. During the last interglaciation (oxygen isotope stage 5) and the late Holocene, coastal emergence produced higher sea levels in South Africa than those identified in the Caribbean during the same time intervals. This is tentatively ascribed to predicted lithospheric deformation in continental margin settings.
Inhibition of LPS‐stimulated pathways in macrophages by the flavonoid luteolin
Authors: Xagorari Angeliki , Roussos Charis , Papapetropoulos Andreas
Published: September 2002

We have previously shown that the flavonoid luteolin inhibits the expression of pro‐inflammatory molecules induced by LPS. In the present study we tested the ability of luteolin to block signalling pathways implicated in LPS‐induced inflammatory gene expression in macrophages.

Exposure of the murine macrophage cell line RAW 264.7 to LPS increased phosphorylation of the mitogen‐activated protein kinase family members ERK1/2, p38 and JNK1/2 in a time‐dependent manner. Pretreatment of RAW 264.7 with luteolin inhibited the LPS‐induced ERK1/2 and p38, but not JNK1/2, phosphorylation, and blocked the LPS‐induced TNF‐α release.

To investigate which of these pathways contribute to the inhibitory effects of luteolin on TNF‐α release, cells were pretreated with pharmacological inhibitors of these pathways; PD98059 and SB203580 when used alone failed to inhibit TNF‐α release, whereas pretreatment with both agents attenuated TNF‐α release.

We have previously shown that luteolin blocks Akt phosphorylation in response to LPS in RAW 264.7 macrophages. To determine the role of Akt in TNF‐α release, cells were transiently transfected with a dominant negative form of Akt (K179M). Overexpression of K179M Akt did not alter LPS‐induced TNF‐α release, suggesting that inhibition of this kinase does not mediate the inhibitory action of luteolin.

In addition, DRB (a pharmacological inhibitor of CK2) blocked TNF‐α release in a concentration‐dependent manner, whereas co‐treatment of cells with luteolin and DRB did not have an additive effect.

We conclude that luteolin interferes with LPS signalling by reducing the activation of several MAPK family members and that its inhibitory action on TNF‐α release correlates with inhibition of ERK, p38 and CK2 activation.

British Journal of Pharmacology (2002) 136, 1058–1064. doi:10.1038/sj.bjp.0704803
A desensitization‐selective potentiator of AMPA‐type glutamate receptors
Authors: Sekiguchi Masayuki , Nishikawa Kaori , Aoki Shunsuke , Wada Keiji
Published: September 2002

We examined the effects of PEPA, an allosteric potentiator of AMPA receptors, on AMPA receptor kinetics.

PEPA did not affect the deactivation of glutamate responses but potently attenuated the extent of receptor desensitization without slowing the onset of desensitization in most of the recombinant AMPA receptors (GluR1‐flip, GluR1‐flop, GluR3‐flip, GluR3‐flip + GluR2‐flip, and GluR3‐flop + GluR2‐flop) expressed in Xenopus oocytes. For the GluR3‐flop subunit, PEPA attenuated the extent of desensitization and only weakly prolonged deactivation (1.3 fold).

PEPA did not significantly affect recovery from desensitization in oocytes expressing GluR3‐flip, GluR1‐flop, and GluR1‐flop, but weakly accelerated (2.6 fold) recovery from desensitization in oocytes expressing GluR3‐flop.

PEPA's effect on desensitization of GluR3‐flop‐containing receptors is unique in that onset is very slow.

Simulation studies using simplified kinetic models for AMPA receptors are utilized to explore the differential effects of PEPA on GluR3‐flip and ‐flop. It is possible to simulate the action on GluR3‐flip by modulating two rate constants in a 12‐state kinetic model. For simulation of the action on GluR3‐flop, the 12‐state kinetic model is not enough, and it is necessary to invoke a 13th state, a PEPA‐bound receptor to which glutamate cannot bind.

These results suggest that attenuation of extent of desensitization represents the principal mechanism underlying the potentiation of AMPA receptors by PEPA, and that PEPA exhibits different mechanisms with respect to GluR3‐flip and GluR3‐flop.

British Journal of Pharmacology (2002) 136, 1033–1041. doi:10.1038/sj.bjp.0704804
Cyclo‐oxygenase‐2 inhibition increases blood pressure in rats
Authors: Höcherl Klaus , Endemann Dierk , Kammerl Martin C , Grobecker Horst F , Kurtz Armin
Published: September 2002

It is known that nonselective cyclo‐oxygenase (COX) inhibitors have small but significant effects on blood pressure (BP), most notably in hypertensive patients on antihypertensive medication. Whether selective COX‐2 inhibitors also interfere with BP regulation is not well understood. Therefore, we aimed to examine the effect of chronic treatment with a selective COX‐2 inhibitor (rofecoxib) on systolic blood pressure (sBP) in normotensive Wistar‐Kyoto rats (WKY) and on the developmental changes of sBP in young spontaneously hypertensive rats (SHR). In addition, we investigated a possible influence of salt intake on the effects of COX‐2 inhibition on BP in these two rat strains.

Rofecoxib dose dependently increased sBP and decreased plasma levels of 6‐keto prostaglandin (PG)F1α in WKY rats fed a normal salt diet (0.6% NaCl, wt wt−1), without affecting serum thromboxane (TX)B2 levels.

Rofecoxib significantly elevated sBP in both rat strains fed normal salt or high salt diet (8% NaCl, wt wt−1), but not in rats on low salt intake (0.02% NaCl, wt wt−1).

Rofecoxib significantly decreased plasma levels of 6‐keto PGF1α in both rat strains fed normal or high salt diet, but not in rats during low salt intake.

Rofecoxib exerted no influence on the changes of body weight nor on water intake. Plasma renin activity (PRA) and renocortical renin mRNA abundance were not changed by rofecoxib, but plasma aldosterone concentration (PAC) was significantly reduced.

These results suggest that chronic inhibition of COX‐2 causes an increase of blood pressure that depends on prostacyclin synthesis. Furthermore, this increase is independent on genetic predisposition and can be prevented by salt deprivation. Since water intake and body weight gain were not changed by rofecoxib, fluid retention appears not to be a major reason for the development of hypertension. Similarly, an activation of the renin‐angiotensin‐aldosterone axis appears to be an unlikely candidate mechanism.

British Journal of Pharmacology (2002) 136, 1117–1126. doi:10.1038/sj.bjp.0704821
Characterization of GABAA receptor ligands in the rat cortical wedge preparation: evidence for action at extrasynaptic receptors?
Authors: Ebert B , I Storustovu S , Mortensen M , Frølund B
Published: September 2002

GABAA receptor agonists have previously been characterized at human GABAA receptors expressed in Xenopus oocytes. The correlation between these data and functional in vivo data of 4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol (THIP) has shown that THIP is 100 fold more potent in clinical studies than in oocytes.

THIP and a series of agonists (GABA, Isoguvacine), partial agonists (Imidazole acetic acid; P4S, 4‐PIOL, thio‐4‐PIOL) and one antagonist (SR95531) were characterized in the rat cortical wedge preparation using inhibition of spontaneous activity in Mg++ free medium as the measurable parameter.

Agonists were in general 40 times more potent in the wedge preparation than at α1β3γ2s containing receptors expressed in Xenopus oocytes, whereas the antagonist was equipotent under these two conditions.

Partial agonists with responses above 6% at α1β3γ2s containing receptors were full agonists in the rat cortical wedge preparation, whereas partial agonists with maximum responses below 6% behaved as partial agonists in the rat cortical wedge preparation.

These data suggest that only a small fraction of the GABAA receptors in the rat cortical wedge needs to be activated by GABAA agonists in order to obtain a maximum response. Results therefore indicate a significant contribution of extrasynaptic receptors to pharmacological activity of exogenous applied GABAA agonists in this system.

British Journal of Pharmacology (2002) 137, 1–8. doi:10.1038/sj.bjp.0704846
Expression of the BCRP gene (ABCG2/MXR/ABCP) in childhood acute lymphoblastic leukaemia
Authors: Sauerbrey Axel , Sell Wieland , Steinbach Daniel , Voigt Astrid , Zintl Felix
Published: September 2002

Summary.  The breast cancer resistance protein (BCRP), also known as mitoxantrone resistance protein (MXR) or placenta ABC protein (ABC‐P), is the second member of the ABCG subfamily of ABC transport proteins (gene symbol ABCG2). BCRP has been detected in acute myeloid leukaemia and in breast, colon and gastric cancer but there has been no reports regarding BCRP expression in acute lymphoblastic leukaemia (ALL). We report the first results of BCRP expression in childhood ALL. Sixty‐seven children (47 initial stage, 20 relapses) with ALL were analysed for BCRP gene expression by TaqMan real‐time polymerase chain reaction. The expression of BCRP in mononuclear cells obtained from the bone marrow (BM) and peripheral blood (PB) of healthy donors was also investigated. There was no relationship between BCRP expression and age, sex, initial blast cell count, prednisolone response or BM response on d 15 and 33. Patients with T‐lineage ALL showed a lower expression of BCRP (P = 0·044). Kaplan–Meier analysis of the relapse‐free interval showed no prognostic significance of BCRP expression when different levels of BCRP expression were used as cut‐off points. No significant difference in expression of BCRP mRNA was measured between initial‐stage and relapsed‐stage ALL or between normal MNC obtained from BM and ALL patients. The results indicate a low expression of BCRP in childhood ALL. Relationships between BCRP and clinical, molecular or in vivo resistance characteristics of the patients were not observed.
Differences in p53 and cadherin–catenin complex expression between histological subtypes in diffusely infiltrating gastric carcinoma
Authors: Kozuki T , Yao T , Nakamura S , Matsumoto T , Tsuneyoshi M
Published: September 2002

Aims:  The aim of this study was to elucidate possible clinicopathological differences between diffusely infiltrating gastric carcinoma of ‘pure type’ (poorly differentiated carcinoma without any glandular component) and ‘mixed type’ (coexistence of poorly differentiated carcinoma and intramucosal glandular component).

Methods and results:  The clinicopathological features and immunohistochemical expression of p53 and intercellular adhesion molecules (E‐cadherin and α‐, β‐ and γ‐catenins) were compared between the patients with pure (n=59) and mixed (n=56) types of diffusely infiltrating gastric carcinoma. Intestinal metaplasia (P < 0.01), prominent lymphatic permeation (P < 0.001) and lymph node metastasis (P < 0.05) were more frequently observed in mixed type than in pure type, while survival probability did not differ between the two groups. The frequency of p53 over‐expression was higher in mixed type (56%) than in pure‐type (19%) (P < 0.001). In mixed type, p53 expression was not different between glandular and poorly differentiated components. By contrast, the expression of adhesion molecules was more frequently preserved in glandular components than in poorly differentiated components.

Conclusions:  These two subtypes seem to be different in nature and biological behaviour. The preservation of adhesion molecules in mixed type may be associated with higher incidence of lymphatic permeation and lymph node metastasis.
Cellular distribution of epidermal growth factor, transforming growth factor‐α, and epidermal growth factor receptor in fascia and peritoneum during healing in the rat: an autoradiographic and immunohistochemical study
Authors: Chegini Nasser , Rossi Michael J. , Schultz Gregory S. , Dunn William A. , Masterson Byron J.
Published: September 2002

The presence and cellular distribution of epidermal growth factor (EGF), TGF‐α, and EGF‐R were determined in the rat fascial and peritoneal tissue during healing of an incisional injury by means of immunohistochemistry and autoradiographic techniques. The immunostaining intensity for EGF in the regenerating wound area was substantially higher during the first 14 days, then decreased to near prewound levels during 14 to 35 days after surgery. Within the wound area, the most intense immunostaining occurred with inflammatory cells, followed by fascial striated muscle and arterioles, whereas fibroblasts in the regenerating area contained very low immunostaining intensity. The immunostaining pattern for TGF‐α with the use of three separate polyclonal antibodies that were directed against the amino and carboxy termini of TGF‐α precursor and a fragment of the mature 50‐amino‐acid form of TGF‐α was similar to that seen with EGF and persisted until 28 days after injury. However, fibroblasts in the regenerating area immunostained intensely for TGF‐α but not for EGF. Quantitative autoradiography of iodine 125—labeled EGF binding and immunohistochemical studies of the EGF‐R with monoclonal antibodies that were directed against the extracellular binding domain of EGF‐R demonstrated the presence of specific EGF‐R in regenerating fascial and peritoneal tissue. Net grain density (100 µm2), representing specific binding of 125I‐EGF, was calculated for different cell types in the wound. The grain density over fascial striated muscle, migratory fibroblasts and peritoneal fibroblasts increased by two and one half, three, and four times, respectively, at 7 days and decreased to the values in adjacent unwounded tissue by 21 days after injury (p < 0.05). Immunostaining for the EGF‐R generated similar patterns, which persisted for 14 days after injury. The grain density and immunostaining for EGF‐R over the arterioles in the wound did not change during the course of healing and was similar to that of the uninjured regions. In summary, these observations indicate that the local levels of EGF, TGF‐α, and EGF‐R increase during the early phases of healing in fascial and peritoneal injury, which suggests a role for these growth factors in the normal mechanism of fascial/peritoneal wound healing and fibrous adhesion formation.
Role of platelet‐derived growth factor in osteoblast function and bone synthesis
Authors: Goodkin David A. , Pierce Glenn F.
Published: September 2002

In vitro studies have shown that platelet‐derived growth factor binds to specific receptors on osteoblasts and induces proliferation. Some reports also indicate that platelet‐derived growth factor may inhibit differentiation of bone cells. Such findings are difficult to interpret, however, because many of these studies used impure platelet‐derived growth factor extracted from platelets (rather than pure, recombinant platelet‐derived growth factor), used mixed cell populations, and added serum to the culture media (likely introducing additional growth factors). In vivo studies also have yielded conflicting results regarding the effects of platelet‐derived growth factor on bone formation. Platelet‐derived growth factor may act in concert with insulin‐like growth factor I to induce bone formation in a canine periodontal system. Other investigators, however, have shown that platelet‐derived growth factor inhibits the effects of osteoinductive proteins such as osteogenin. No evidence of bone formation has been detected in patients receiving platelet‐derived growth factor treatment of soft tissue wounds overlying bony prominences in clinical trials. Thus, despite the observations that osteoblasts can specifically bind and proliferate in response to platelet‐derived growth factor in tissue culture, platelet‐derived growth factor alone has not yet been proved to be osteoinductive in vivo. These observations suggest that in the presence of the many cytokines and multiple cell types found in wounds and fractures, the direct effects of platelet‐derived growth factor on osteoblasts are eclipsed.
Correlation of transforming growth factor‐α and epidermal growth factor receptor with proliferating cell nuclear antigen in human burn wounds
Authors: Wenczak Barbara , Nanney Lillian B.
Published: September 2002

The purpose of this study was to localize transforming growth factor‐α, a mitogenic peptide, and its receptor, epidermal growth factor receptor, to correlate these findings with epithelial cell proliferation in human burn wounds. Proliferating cell nuclear antigen, a marker of cellular proliferative activity, was used in conjunction with the immunolocalization of transforming growth factor‐α and epidermal growth factor receptor in a series of partial‐ and full‐thickness burn wounds 2 to 22 days after injury. Identification of the proliferating population by proliferating cell nuclear antigen nuclear labelling indicated that both ligand and its receptor are concurrently present in proliferating epidermis. The simultaneous, intense localization of transforming growth factor‐α and epidermal growth factor receptor during the early, intermediate, and late postburn period lends further support to an epidermal growth factor/transforming growth factor‐α/epidermal growth factor receptor—mediated growth repair mechanism. Furthermore, the distribution of transforming growth factor‐α and epidermal growth factor receptor in nonproliferating populations within healing burn wounds suggests additional multifunctional roles for this growth factor pathway during human cutaneous wound repair.
Microanalyses of enzymes and metabolites in ischemia/reperfusion‐induced partial‐thickness skin wounds
Authors: Im Michael J. , Angel Michael F. , Vander Kolk Craig A. , Manson Paul N.
Published: September 2002

A transition zone between well‐perfused proximal tissue and inadequately perfused distal tissue was evaluated histologically and biochemically in skin flaps. Cranially based pedicle flaps, 3 × 7.5 cm, were made on the backs of female Sprague‐Dawley rats. Flap survival was 22% of the original flap area at 7 days and 40% at 14 days after flap elevation (p < 0.001). The transition zone consisted of full‐thickness skin survival proximally and partial‐thickness wound distally. It is evident that skin wounds induced by ischemia or reperfusion repair continuously between 7 and 14 days after flap elevation. Tissue glucose, lactate, and hypoxanthine levels were measured to assess capillary perfusion in the transition zone on postoperative day 3. The proximal full‐thickness skin 5 mm from the wound margin demonstrated no significant changes in glucose and lactate levels compared with normal skin. The partial‐thickness wounds exhibited no change in glucose (a 33% decrease was not statistically significant) but a significant increase (319% of normal) in lactate level (p < 0.05). Hypoxanthine levels increased to 453% of normal in full‐thickness skin (p < 0.01) and to 787% in partial‐thickness wounds (p < 0.001). Metabolic response was evaluated by enzyme assays in the transition zone. Hexokinase activity increased by 251% of normal (p < 0.05), glucose 6‐phosphate dehydrogenase by 245% (p < 0.01), and glutathione reductase by 184% (p < 0.05) in the proximal full‐thickness skin. Hexokinase activity further increased by 482% of normal (p < 0.01), glucose 6‐phosphate dehydrogenase by 379% (p < 0.05), and glutathione reductase by 346% (p < 0.01) in partial‐thickness wounds. The results suggest that partial‐thickness wounds have less capillary circulation but greater antioxidant enzyme activities than does the survival area with full‐thickness skin.
Dermal regeneration in native non‐cross‐linked collagen sponges with different extracellular matrix molecules
Authors: De Vries Henry J. C. , Middelkoop Esther , Mekkes Jan R. , Dutrieux Richard P. , Wildevuur Charles H. R. , Westerhof Wiete
Published: September 2002

Collagenous dermal templates can prevent scarring and wound contraction in the healing of full‐thickness defects. In a porcine wound model, full‐thickness wounds were substituted by reconstituted and native collagen sponges in combination with autologous split‐skin mesh grafts and covered with a semipermeable wound membrane. Native collagen sponges were also linked with either hyaluronic acid, elastin, or fibronectin. Reconstituted collagen matrixes, composed of cross‐linked small collagen fibrils, disintegrated within a week and did not contribute to dermal regeneration, whereas native collagen matrixes, composed of intact collagen fibers, disintegrated within 2 weeks and did contribute to dermal regeneration. Addition of extracellular matrix proteins retarded the disintegration to 4 weeks. However, fibronectin‐treated matrixes caused aberrant epithelization. When hyaluronic acid was added, matrixes were invaded by more fibroblasts and myofibroblasts. This process correlated with fibrosis and wound contraction. In contrast, the native collagen/elastin matrix reduced the amount of fibroblasts and myofibroblasts. This latter matrix resulted in optimal dermal regeneration and little wound contraction.
Wound healing in the fetus
Authors: Longaker Michael T. , Bouhana Karyn S. , Harrison Michael R. , Danielpour David , Roberts Anita B. , Banda Michael J.
Published: September 2002

Macrophages are believed to play a crucial role in wound healing by synthesizing and secreting numerous cytokines. Some of these cytokines, such as transforming growth factor‐β and tumor necrosis factor‐α, promote fibrosis and repair. We have shown that macrophages are recruited to sterile fetal wounds and have the potential to regulate repair by synthesizing transforming growth factor‐β1, transforming growth factor‐β2, and tumor necrosis factor‐α. Transforming growth factor‐β was present in fetal lamb wounds in higher amounts than in adult sheep wounds. Furthermore, the concentrations and ratios of the transforming growth factor‐β isoforms in wounds that healed without scarring were different from those in wounds that scarred; transforming growth factor‐β2 was highest in fetal wounds that did not scar and lowest in adult wounds. These data suggest that concentrations of transforming growth factor‐β isoforms rather than total transforming growth factor‐β concentration may be important in the regulation of fibrosis in prenatal and postnatal wound healing.
Definitions and guidelines for assessment of wounds and evaluation of healing
Authors: Lazarus Gerald S. , Cooper Diane M. , Knighton David R. , Margolis David J. , Percoraro Roger E. , Rodeheaver George , Robson Martin C.
Published: September 2002

Chronic wounds represent a worldwide problem. For laboratory and clinical research to adequately address this problem, a common language needs to exist. This language should include a system of wound classification, a lexicon of wound descriptors, and a description of the processes that are likely to affect wound healing and would healing end points. The report that follows defines wound, acute wound, chronic wound, healing and forms of healing, wound assessment, wound extent, wound burden, and wound severity. The utility of these definitions is demonstrated as they relate to the healing of a skin wound, but these definitions are broadly applicable to all wounds.
Enhanced healing of ulcers in patients with diabetes by topical treatment with glycyl‐l‐histidyl‐l‐lysine copper
Authors: Mulder Gerit D. , Patt Leonard M. , Sanders Lee , Rosenstock Julio , Altman Morton I. , Hanley Marie E. , Duncan Gordon W.
Published: September 2002

A multicenter, randomized, evaluator‐blinded, placebo‐controlled clinical study was conducted to evaluate the safety and effectiveness of glycyl‐l‐histidyl‐l‐lysine: copper complex (lamin Gel) in the treatment of diabetic neuropathic ulcers. All patients were enrolled in an aggressive standardized wound care protocol consisting of sharp debridement at study entry, daily application of a metered dose of drug, standardized pressure‐relieving footwear, and patient education relating to diabetes control and activity modifications. Treatment with lamin Gel significantly increased the percentage of closure of plantar ulcers (98.5% median area percentage closure compared with 60.8% for vehicle; p < 0.05) and the proportion of patients healing 98% or better. The rate of closure was three times faster with lamin Gel treatment compared with standard care and vehicle. The enhancement of wound closure was more pronounced (median of 89.2% compared with −10.3% for vehicle; p < 0.01) in larger (greater than 100 mm2 initial area at study entry) plantar ulcers caused by the failure of this size of ulcer to respond adequately to standardized wound care treatments in the absence of lamin Gel. Treatment must commence immediately after the initial wound debridement to obtain optimal enhancement of the ulcer closure. The incidence of ulcer infections was significantly lower (7% incidence compared with 34% for vehicle, p < 0.05) in the plantar ulcers treated immediately after debridement with the lamin Gel.