bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluctuations in Terrestrial–Marine Environments in the Western Equatorial Pacific during the Late Pleistocene
Authors: Kawahata Hodaka , Maeda Rena , Ohshima Hideaki
Published: September 2002

Large heat storage capacity in the western equatorial Pacific has played an important role in modulating global climate. The fluctuation in pollen and spore abundances, together with organic matter (OM) and lithogenics sedimentation, was investigated to reconstruct terrestrial and marine environmental change around New Guinea during the Late Pleistocene. Although appreciable contribution from Indonesian Maritime Continent was expected, the majority of the pollen and spore grains found in core C4402 was transported from New Guinea. Fern spores accounted for 70% (46–90%) of the total pollens and spores. Positive correlation between lithogenic content and the relative abundance of fern spores suggests that lithogenics could be derived from coastal lowland.

The mass accumulation rate (MAR) of pollen and spores varied from 44 to 7,031×10−3 grains cm−2 yr−1 with maxima in oxygen isotope stages (OIS) 2, 3, 4, and around the OIS 4/5 boundary. Less rainfall during glacial times generally enhanced transport of pollen by wind to Site C4402. Their scavenging from the water column was promoted by high activity of the biological pump. Pollen record from core C4402 suggests that lower montane group vegetation was dominant relative to lowland vegetation and upper and mid-montane group during glacial times. Although appreciable contribution by terrestrial OM is expected from high correlation of MAR between organic carbon (OC) and pollen and spores, fairly low COrganic/N ratios and δ13C values (around −20‰) of OM demonstrate that OM in core C4402 is mainly of marine origin.
Late Pleistocene Glaciations in the Northwestern Sierra Nevada, California
Authors: James L. Allan , Harbor Jon , Fabel Derek , Dahms Dennis , Elmore David
Published: September 2002

Pleistocene fluvial landforms and riparian ecosystems in central California responded to climate changes in the Sierra Nevada, yet the glacial history of the western Sierra remains largely unknown. Three glacial stages in the northwestern Sierra Nevada are documented by field mapping and cosmogenic radionuclide surface-exposure (CRSE) ages. Two CRSE ages of erratic boulders on an isolated till above Bear Valley provide a limiting minimum age of 76,400±3800 10Be yr. Another boulder age provides a limiting minimum age of 48,800±3200 10Be yr for a broad-crested moraine ridge within Bear Valley. Three CRSE ages producing an average age of 18,600±1180 yr were drawn from two boulders near a sharp-crested bouldery lateral moraine that represents an extensive Tioga glaciation in Bear Valley. Nine CRSE ages from striated bedrock along a steep valley transect average 14,100±1500 yr and suggest rapid late-glacial ice retreat from lower Fordyce Canyon with no subsequent extensive glaciations. These ages are generally consistent with glacial and pluvial records in east-central California and Nevada.
Endothelin‐1‐induced venous contraction is maintained in DOCA‐salt hypertension; studies with receptor agonists
Authors: Watts Stephanie W , Fink Gregory D , Northcott Carrie A , Galligan James J
Published: September 2002

Deoxycorticosterone acetate (DOCA) salt hypertension is associated with an endothelin‐1 (ET‐1)‐dependent increase in arterial resistance and mean circulatory filling pressure. Contraction of endothelium‐intact arteries and veins from sham and DOCA‐salt hypertensive rats to agonists of the ETA (ET‐1(1–31)) and ETB receptor (sarafotoxin 6c; S6c) was investigated in tissue baths as was expression of mRNA for ET‐1 and mRNA and protein for the ETA and ETB receptor.

ET‐1(1–31) contracted aorta and vena cava from sham rats with a 30 fold lower potency than ET‐1. Contraction was not altered by the ETB receptor antagonist BQ788 (100 nM) but was abolished by the ETA receptor antagonist ABT‐627 (30 nM).

In DOCA‐salt thoracic aorta, maximum contraction to ET‐1 and ET‐1(1–31) was reduced (36.6±6.3 and 13.3±4.4% of sham response, respectively); aorta did not contract to S6c.

In vena cava from DOCA‐salt rats, contraction to ET‐1 and ET‐1(1–31) was not reduced compared to sham contraction; vena cava from sham and DOCA‐salt rats contracted to S6c with a similar potency.

Real time RT–PCR revealed that prepro ET‐1 mRNA was increased 6.6±3.3 fold and 8.7±3.9 fold greater in DOCA‐salt aorta and vena cava, respectively, compared to sham. Vena cava expressed a higher content of ETA and ETB receptor mRNA than aorta (P<0.05), but no differences were observed between sham and DOCA‐salt tissues. ETA and ETB receptor protein was identified in all tissues. Immunoreactive ETA receptor, observed as a 65, 30 and 28 kDa bands, was expressed 400% greater in DOCA‐salt aorta compared to sham, but was not altered in vena cava. Immunoreactive ETB receptor, observed as 120, 45 and 30 kDa bands, tended to be higher in vena cava compared to aorta, but was not different in sham and DOCA‐salt vena cava.

These results suggest that ETA receptor function is impaired in aorta but not vena cava of DOCA‐salt rats. The ETB receptor was present in the aorta but, unlike in veins, does not mediate contraction directly. A sustained response to ET‐1 in the venous circulation may contribute to the elevated blood pressure in the DOCA‐salt model.

British Journal of Pharmacology (2002) 137, 69–79. doi:10.1038/sj.bjp.0704831
Pamidronate induces bone formation in patients with smouldering or indolent myeloma, with no significant anti‐tumour effect
Authors: Martín Alejandro , García‐Sanz Ramón , Hernández José , Bladé Joan , Suquía Begoña , Fernández‐Calvo Javier , González Marcos , Mateo Gema , Orfao Alberto , San Miguel Jesus F.
Published: September 2002

Summary. Twelve patients with smouldering or indolent multiple myeloma (MM) received 12 courses of intravenous pamidronate as a single agent to evaluate both the antitumour and bone metabolism effects. One patient achieved minor response, eight had stable disease, and three – all indolent MM – showed disease progression. Serum interleukin 6 (IL‐6), IL‐1β and Oncostatin‐M remained stable throughout the study, while tumour necrosis factor‐α increased. Bone density significantly increased after four and 12 courses compared with baseline. Markers for bone resorption and bone formation decreased with treatment. These results suggest that pamidronate treatment reduces bone turnover in smouldering or indolent MM, but has no significant antitumour effect.
Characterization of granulocyte colony‐stimulating factor receptor expressed on human lymphocytes
Authors: Morikawa Keiko , Morikawa Shigeru , Nakamura Masahiko , Miyawaki Toshio
Published: September 2002

Summary. We have studied the characterization of granulocyte colony‐stimulating factor receptor (G‐CSFR) in human lymphocytes. About one‐third to one‐quarter of the B lymphocytes from peripheral B‐cell sources displayed G‐CSF binding on the two‐colour immunofluorescence study. The rate of G‐CSFR‐expressing (G‐CSFR+) B cells was higher in bone marrow and cord blood than in peripheral blood, spleen and tonsil. G‐CSFR expression was greater in the surface immunoglobulin D (IgD)‐positive (sIgD+) B‐cell population, but scarce in the sIgD– B‐cell population. In tonsil, G‐CSFR+ B cells were present among the cells with naive B and germinal‐centre B phenotypes, but those with memory B phenotype were rarely found on triple‐colour immunofluorescence analysis. Mitogen‐activated, but not resting, T lymphocytes also showed G‐CSF binding. Several continuous T‐ and B‐cell lines expressed functional G‐CSFR, because the addition of G‐CSF enhanced the proliferative response of these cell lines. A sequence analysis of G‐CSFR mRNA isoforms obtained from the T and B cells revealed that G‐CSFR was derived from class I and class IV mRNA. Our results indicated that G‐CSFR was constitutively expressed on the B‐cell surface and was inducible in T cells.
Reduced function of the multidrug resistance P‐glycoprotein in CD34+ cells of patients with aplastic anaemia
Authors: Calado Rodrigo T. , Garcia Aglair B. , Gallo Denise A. P. , Falcão Roberto P.
Published: September 2002

Summary. Drug exposure is implicated in the aetiology of some cases of acquired aplastic anaemia (AA), but the reason for this susceptibility remains unclear. We previously demonstrated that P‐glycoprotein (P‐gp) function, a drug efflux pump, is decreased in AA lymphocytes. To further evaluate whether P‐gp activity is also abnormal in AA stem cells, we examined bone marrow (BM) CD34+ cells from newly diagnosed AA patients (AA‐d, n = 25), after immunosuppression (AA‐IST, n = 13) and after BM transplantation (AA‐BMT, n = 8). Of the AA patients with autologous haematopoiesis (AA‐d + AA‐IST), 15 had drug‐induced AA. Thirty‐two BM donors were studied as controls. P‐glycoprotein function was assessed by the rhodamine 123‐efflux assay. P‐glycoprotein function in CD34+ cells was reduced in AA‐d patients (17·8%, 0–67·7) compared with controls (42·5%, 13·4–57·4; P < 0·001), as well as in AA‐IST (20·3%, 1·2–32·0; P < 0·001), but not in AA‐BMT (40·9%, 19·0–55·9). P‐gp function was reduced more in drug‐induced AA (14·5%, 0–27·4) than in the other cases (26·1%, 0–67·7; P = 0·04), but it did not correlate with disease severity. These results indicate that P‐gp function is defective in AA CD34+ cells, pointing to a role of P‐gp in increased cell susceptibility to xenobiotics in AA.
In vitro effects of NIPRISAN (Nix‐0699): a naturally occurring, potent antisickling agent
Authors: Iyamu Efemwonkiekie W. , Turner Ernest A. , Asakura Toshio
Published: September 2002

Summary. Among the various potential antisickling agents tested, hydroxyurea (HU) has been the most effective compound used for the treatment of patients with sickle cell disease (SCD). Although HU is effective in many patients, not all patients respond to this drug. In addition, some patients reveal adverse effects, including myelosuppression. In an attempt to find other effective agents with less adverse effects, we investigated the antisickling effect of NIPRISAN (Nix‐0699). We found that Nix‐0699, an ethanol/water extract from indigenous plants, has a strong antisickling effect. The concentration of Nix‐0699 required to inhibit 50% of erythrocyte sickling was about 0·05 mg/ml. As for the kinetics of polymerization, addition of 0·05 μg/ml Nix‐0699 caused a sixfold prolongation of the delay time prior to deoxy‐Hb S polymerization when compared with that of untreated Hb S samples. The solubility of deoxy‐Hb S significantly increased upon treatment with Nix‐0699. Analysis of the effect of Nix‐0699 on the Hb S oxygen affinity indicated that the drug slightly shifted the oxygen‐dissociation curve of Hb S toward the left without any apparent change in the Hill coefficient. These results suggest that the antisickling properties of Nix‐0699 may involve direct interaction with Hb molecules. Incubation of red blood cell (RBC) suspensions with various concentrations of Nix‐0699 did not dehydrate RBCs, cause haemolysis, increase the amount of denatured Hb, nor form met‐Hb. In view of the outcome of this study, Nix‐0699 may be a promising option for the treatment of patients with SCD.
Audit in transfusion practice
Authors: Joshi Girish P. , Landers Dennis F.
Published: September 2002

Given the growing concern for the safety, cost and adequacy of blood supply, there is an increasing need for appropriate blood product utilization. Despite a number of consensus guidelines for the transfusion of allogeneic blood products, inappropriate blood transfusion continues. We discuss the quality assurance process for improvement in transfusion therapy including audit of blood transfusion. Audits identify areas of problems in transfusion practice which can be corrected by education of doctors, formulation of practice guidelines and algorithms. To improve the effectiveness of the audit programmes, the frequency of audits has to be maintained and there should be continual reinforcement of policies.
Size patterns among competitors: ecological character displacement and character release in mammals, with special reference to island populations
Authors: Dayan Tamar , Simberloff Daniel
Published: September 2002

Morphological relationship among sympatric animal species have often been seen as indirect evidence for competition. Many early ecomorphological studies revealed patterns that were taken as indicating character displacement and character release, driven by competition or lack thereof. These patterns may result from a coevolutionary morphological response or from species sorting according to size. Thus, the relationship between morphology and competition may be crucial for understanding both the morphological evolution of animals and the role of competition in structuring communities. Some earlier research perceived as indicating morphological relationships conditioned by interaction of species was conducted on mammals, particularly carnivores. Subsequent criticism in the ecological literature demonstrated that many of the perceived patterns could not be statistically confirmed, thus calling into question this line of evidence for competition. More recent ecological literature relies on strong statistical analyses and careful consideration both of guild composition and of which morphological traits should be examined. This literature, resting largely on mammals, includes several cases that suggest a coevolutionary morphological response to interspecific competition. These studies have focused on the thropic apparatus directly related to food procurement by mammals — the teeth. Island mammals often show striking morphological patterns, some of which have been interpreted as resulting from release from competition with mainland species that have not reached islands. However, few of these patterns were critically evaluated to demonstrate their support for the hypothesis of character release. Despite several decades of interest and research, many questions regarding competitively induced morphological patterns remain unresolved and require further research. Mammals are especially promising subjects for such researh.
International standards in medical education: assessment and accreditation of medical schools' – educational programmes. A WFME position paper
Authors:   The Executive Council
Published: September 2002

WFME has recently decided to extend its `International Collaborative Programme for the Reorientation of Medical Education', aiming at the implementation of its educational policy at the institutional level. The first objective is to stimulate educational institutions to formulate their own plans for change and for quality improvement to align with international standards. The second objective is to establish a system to assure minimum quality standards for medical school programmes. Both objectives can be accomplished by publishing a World Register of Medical Schools, which will constitute an instrument of quality assurance in medical education. The Register should specify designation of a World Register Accreditation of medical schools, which fulfil internationally accepted and approved standards of medical education programmes. The accreditation could be differentiated in various categories.
Risk factors for pre‐eclampsia among Zimbabwean women: maternal arm circumference and other anthropometric measures of obesity
Authors: Mahomed Kassam , Williams Michelle A. , Woelk Godfrey B. , Jenkins‐Woelk Laura , Mudzamiri Sarah , Longstaff Laura , Sorensen Tanya K.
Published: September 2002

Maternal pre‐pregnancy obesity is a risk factor for pre‐eclampsia (proteinuric hypertension in pregnancy) among North American and European women. We studied the relationship between maternal obesity and risk of pre‐eclampsia among Zimbabwean women. A case‐control study was conducted at Harare Maternity Hospital, Harare, Zimbabwe, between June 1995 and April 1996. Study participants were 144 women with pre‐eclampsia and 194 normotensive women serving as controls. Maternal weight, height and mid‐arm circumference were measured and recorded during study participants’ postpartum hospital admission. Maternal mid‐arm circumference, considered to be relatively stable during pregnancy among women of developing countries, was used as the primary indicator of maternal pre‐pregnancy obesity. Logistic regression procedures were used to estimate odds ratios and 95% confidence intervals. There were linear trends in risk of pre‐eclampsia with increasing mid‐arm circumference, increasing weight and increasing body mass index. After adjusting for potential confounding factors, women in the highest quintile for mid‐arm circumference (28–39 cm) were 4.4 times more likely to have had their pregnancy complicated by pre‐eclampsia than women in the lowest quintile (21–23 cm). Odds ratios of similar magnitude were observed for the other anthropometric measures. To our knowledge, this is the first study to demonstrate a positive association between maternal obesity and pre‐eclampsia risk in a black African population. Biological mechanisms thought to explain this relatively consistent epidemiological finding include endothelial cell injury, possibly resulting from hyperlipidaemia.
Increased Levels of Soluble Tumour Necrosis Factor Receptor‐I (P55) and Decreased IgG1 Reactivities in HIV‐1 Patients with Cytomegalovirus Disease
Authors: Jakobsen  , Dodt  , Meyer  , Katzenstein  , Gerstoft  , Skinhøj
Published: September 2002

The purpose of the study was to investigate potential associations between tumour necrosis factor (TNF), soluble TNF receptors (sTNF‐Rs), immunoglobulin (Ig)G subclasses and development of cytomegalovirus (CMV) disease amongst human immunodeficiency virus (HIV)‐1 patients. We enrolled HIV‐1 patients with CD4 counts less than 100/μl in a prospective study and followed them over 1 year for development of CMV disease. Concentrations of TNF, sTNF‐RI, sTNF‐RII and IgG subclass reactivities were measured by ELISA; levels of CMV pp65 antigenaemia were determined as numbers of pp65 expressing cells/100 000 cells and were measured by staining of leucocytes; and HIV‐1 RNA loads were measured by polymerase chain reaction (PCR). Eighteen patients studied with CMV disease had higher levels of sTNF‐RI than 18 similar patients without CMV disease. Concentrations of sTNF‐RI correlated with levels of CMV antigenaemia in blood samples collected before the development of CMV disease. Patients with CMV disease had lower levels of IgG1 reactivities to CMV than patients without CMV disease. We conclude that increased levels of sTNF‐RI and decreased IgG1 reactivities are associated with an increased risk of development of CMV disease among HIV‐1 patients.
Infiltration Patterns of Short‐ and Long‐Term Cultured A‐NK and T‐LAK Cells Following Adoptive Immunotherapy
Authors: Kjærgaard  , Hokland  , Nannmark  , Hokland  , Basse
Published: September 2002

Direct contact between lymphokine‐activated killer (LAK) cells and tumour cells is believed to be imperative for initiating tumour cell lysis in vitro as well as in vivo. In order to optimize adoptive immunotherapy (AIT) it is therefore desirable to identify the LAK cell subtype, which ensures maximal infiltration of tumours as well as a substantial cytotoxic reactivity. In this report we have compared short‐ and long‐term cultured murine adherent natural killer (A‐NK) cells and mitogen‐stimulated, lymphokine‐activated T‐killer (T‐LAK) cells with respect to their proliferative potential, cytotoxicity, requirement for interleukin‐2 (IL‐2) and ability to infiltrate B16 pulmonary metastases following adoptive transfer. We found that short‐term (5 days) cultured A‐NK and T‐LAK cells both showed a substantial accumulation of tumour tissues. However, A‐NK cells gradually lost this ability during in vitro culture whereas T‐LAK cells cultured for as long as 20 days retained their ability to infiltrate metastases as efficiently as their short‐term cultured counterparts. Moreover, the low requirement of IL‐2 by T‐LAK cells to achieve maximal infiltration of tumours sharply contrasted with the excessive doses necessary to ensure maximal infiltration by A‐NK cells. In conclusion, these data demonstrate that short‐term cultured LAK cells of both NK‐ and T‐cell origin are able to infiltrate B16 pulmonary metastases effectively. Importantly, the T cells retain this ability for a considerably longer time and require much less IL‐2 support than do A‐NK cells, making T‐LAK cells attractive for AIT.
Protective Effect of β‐Glucan Against Mycobacterium bovis, BCG Infection in BALB/c Mice
Authors: Hetland  , Løvik  , Wiker
Published: September 2002

β‐1,3‐Glucan is a potent stimulator of macrophage functions and has a protective effect against a range of infections in rodent models. We examined whether the agent could also protect against the intracellular Mycobacterium bovis, bacillus Calmette–Guérin (BCG) infection in mice. BCG‐susceptible BALB/c mice were injected intravenously (i.v.) with β‐glucan or vehicle 3 days before, or with β‐glucan 7 days after i.v. challenge with live BCG bacilli. The animals were killed 4 or 8 weeks later, their organs were homogenized and applied to object slides and stained with auramin for counting of bacilli, or seeded onto agar in Petri dishes. Mice treated with β‐glucan both pre‐ and postchallenge had significantly lower numbers of BCG bacilli and BCG colony‐forming units in spleen homogenates compared with controls 4 weeks after challenge. A similar, but not statistically significant, tendency was observed in spleen homogenates from mice killed 8 weeks after challenge. In homogenates of liver and lungs there were similar findings, but less pronounced. There was a dose‐dependent effect of β‐glucan injected before BCG challenge on the number of BCG bacilli found in spleen and liver homogenates. In addition, antibody cross‐reactivity was demonstrated between M. tuberculosis cell wall and β‐glucan. The results suggest that β‐glucan has a protective effect against M. bovis, BCG infection in susceptible mice.
Expression of Interferon‐γ, Interleukin‐4 and Interleukin‐5 mRNA in the Nasal Mucosal Membrane of Rats with Allergic Rhinitis
Authors: El‐Naggar  , Ukai  , Takeuchi  , Sakakura
Published: September 2002

The production of immunoglobulin E (IgE) antibody is largely dependent on the ratio between interleukin‐4 (IL‐4) (a T helper 2 (Th2)‐type cytokine) and interferon‐γ (IFN‐γ) (a T helper 1 (Th1)‐type cytokine). Interleukin‐5 (IL‐5) (also a Th2‐type cytokine) is an important eosinophil differentiation factor and also co‐stimulates B‐cell growth and differentiation. The present study was designed to evaluate and compare the expression of IFN‐γ, IL‐4 and IL‐5 mRNA in the nasal mucosal membrane of sensitized Brown–Norway (BN) rats. Fourteen BN rats were divided into two groups: non‐sensitized (control) and sensitized. The sensitized group was injected with ovalbumin (OA) intraperitoneally on three consecutive days. Twenty‐one days later, rats were exposed to 1% OA aerosol. Twenty‐four hours after exposure to aerosol, nasal mucosa was extracted from both groups and reverse transcriptase–polymerase chain reaction (RT–PCR) was performed. The densities of the bands of IL‐4, IL‐5 and IFN‐γ mRNA were expressed as percentages against β‐actin mRNA. Our results showed that the mean values for IL‐4 and IL‐5 mRNA were increased significantly in sensitized rats compared with control rats. In contrast, the mean value for IFN‐γ mRNA was significantly lower in sensitized rats compared with those of the control group. Our data therefore suggest that sensitization of rat nasal mucous membranes results in the predominant expression of Th2‐type cytokines.
Suppression of in vitro proliferative scar fibroblast contraction by interferon alfa‐2b
Authors: Sahara Keiichiro , Kucukcelebi Ahmet , Ko Francis , Phillips Linda , Robson Martin
Published: September 2002

Increased fibroblast activity and collagen production have been observed frequently in proliferative scars. Previous studies have demonstrated that interferons suppress collagen production by means of normal, keloid, and hypertrophic scar‐derived fibroblasts. The fibroblast‐populated collagen lattice is an in vitro model used to study fibroblast function. We used fibroblast‐populated collagen lattices to evaluate the effect of interferon on fibroblasts harvested from normal human skin, human keloid, and hypertrophic scar tissues. Human recombinant interferon alfa‐2b (1000 IU/ml) was added to the culture media. The collagen gel, prepared from rat tail tendon bundles, was overlaid with 5 × 104 fibroblast cells. Keloid fibroblast‐populated collagen lattices showed the highest contraction. Contraction in all the groups appeared suppressed by interferon alfa‐2b during the first 72 hours of study (p < 0.05). The reduction in fibroblast‐populated collagen lattice contraction by interferon alfa‐2b was similar among the groups. The contractile properties of fibroblasts taken from normal human skin, keloids, and hypertrophic scars in this in vitro study were suppressed by interferon alfa‐2b. This suggested that interferon alfa‐2b may be beneficial for the treatment of proliferative scars.
Role of transforming growth factor‐β1 and epidermal growth factor in the wound‐healing process: an in vivo biomechanical evaluation
Authors: Perry Larry C. , Connors Amy W. , Matrisian Lynn M. , Nanney Lillian B. , Charles P. David , Reyes David P. , Kerr Lawrence D. , Fisher Jack
Published: September 2002

The purpose of this study was to assess and evaluate the role of transforming growth factor‐β1, epidermal growth factor, and their respective carriers (collagen and liposomes) in the early phases of the wound‐healing process in linear incision wounds; we used an in vivo biomechanical testing system. One hundred twenty specific pathogen—free male Sprague‐Dawley rats were divided into five experimental groups (n = 24), including one group receiving no treatment at all. Each animal received one abdominal midline incision. At 3 and 5 days after wounding, 12 animals per group were randomly selected for in vivo biomechanical evaluation. Specimens were also randomly obtained from nondisrupted tissues for histologic analysis. Statistical analysis comparing groups revealed that transforming growth factor‐β1 significantly increased wound strength at day 5, and liposomes decreased wound strength at day 3. There were no other significant differences among groups for each of the time intervals studied. Our results suggest that in vivo biomechanical evaluation of tissue response to injury and treatments will add new dimension to future studies of skin and wound healing.
Analysis of therapy‐resistant venous leg ulcers
Authors: Bjellerup Mats , Lindholm Christina , Christensen Ole B. , Zederfeldt Bengt
Published: September 2002

Chronic leg ulcers represent a major health‐care problem with considerable socioeconomic impact. Patients with seemingly therapy‐resistant leg ulcers are common to all clinics. The purpose of the present study was to (1) examine a group of patients with nonhealing venous leg ulcers treated with a double‐layer bandage and (2) evaluate whether the addition of an interactive hydrocolloid wound dressing could initiate healing in these patients. Twenty‐two patients with ulcers caused by venous insufficiency were included. The patients had a mean ulcer duration of 27.6 years. Duration of the present ulcer was at least 1 year (mean ≥ 4.1 years). Twenty of the 22 patients showed massive lipodermatosclerosis. Before inclusion, all patients had used double‐layer bandage consisting of a zinc‐impregnated bandage or stocking and a self‐adhesive compression bandage for 1 year or longer without improvement. The new regimen was a triple‐layer treatment with the hydrocolloid water applied over the ulcer and the traditional double‐layer bandage unchanged. Three patients were dropped from the study. Nineteen patients were followed until healing or for 10 months. Nine of the 19 patients who completed the study healed. Ulcer area was reduced by 70% or greater in 7 patients and by 30% to 40% in two patients. One ulcer did not respond to the treatment and worsened slightly. The results of this study were encouraging and indicate that the triple‐layer treatment with the hydrocolloid dressing applied to the ulcer should be evaluated in a randomized, controlled study in patients with less pessimistic prognoses.
Exogenous transforming growth factor‐β2 enhances connective tissue formation in transforming growth factor‐β1—deficient, healing‐impaired dermal wounds in mice
Authors: Ksander George A. , Gerhardt Carolyn O. , Olsen David R.
Published: September 2002

Connective tissue formation is markedly reduced in full‐thickness mouse dermal wounds that are covered with synthetic, adherent, moisture vapor—permeable membrane when compared with formation in similar but nonoccluded wounds. The transforming growth factors‐β (TGF‐β) are a family of multifunctional peptides thought to have a critical role in the regulation of development and tissue repair. Treatment with exogenous TGF‐β1 stimulated connective tissue formation in wounds covered with synthetic, adherent, moisture vapor—permeable membrane but had no effect on air‐exposed wounds, suggesting that the quantity of endogenous TGF‐β1 in wounds covered with synthetic, adherent, moisture vapor—permeable membrane was less than that in air‐exposed wounds. Immunolocalization studies with an anti‐TGF‐β1 antibody confirmed that wounds covered with synthetic, adherent, moisture vapor—permeable membrane demonstrated markedly reduced levels of endogenous extracellular, matrix‐associated TGF‐β1 as early as 24 hours after wounding. Immunoreactive TGF‐β2 was not detected. These findings suggest that endogenous TGF‐β1, but not TGF‐β2, is required for normal connective tissue formation in this model and that impaired healing is associated with low levels of TGF‐β1. Histologic analysis confirmed previous demonstrations that exogenous TGF‐β2 stimulates enhanced cellularity and connective tissue formation. Immunolocalization showed that exogenous TGF‐β2 stimulates increased expression of endogenous TGF‐β1. Northern blot analysis revealed that TGF‐β2 increased the expression of genes encoding the α1‐chain of types I and III collagens and tissue inhibitor of metalloproteinase‐1. These observations show that TGF‐β2 acts through a variety of mechanisms to stimulate repair in healing‐impaired wounds that are also deficient in endogenous TGF‐β1, but they do not distinguish between direct effects and indirect effects mediated by induced TGF‐β1.
Safety and effect of topical recombinant human interleukin‐1β in the management of pressure sores
Authors: Robson M. C. , Abdullah A. , Burns B. F. , Phillips L. G. , Garrison L. , Cowan W. , Hill D. , Vandeberg J. , Robson L. E. , Scheeler S.
Published: September 2002

Interleukin‐1β is produced by numerous cell types including monocytes and fibroblasts. It has been shown to stimulate multiple cell types including fibroblasts, keratinocytes, endothelial cells, neutrophils, macrophages, and lymphocytes. Previously, interleukin‐1β was shown to accelerate healing in partial‐thickness and full‐thickness wounds in animals and was also shown to be safe when applied topically in Phase I human trials. Therefore a prospectively randomized, blind, placebo‐controlled trial was performed with patients with chronic pressure ulcers. Doses of interleukin‐1β of .01 µg, .10 µg, and 1.0 µg per square centimeter did not show acceleration of healing of the pressure ulcers. Therefore use of recombinant human interleukin‐1β in this study was safe but, at the dose levels tested, did not result in improvement in the healing ratio.
Anti‐inflammatory prednisolone derivatives inhibit collagen synthesis and pro‐α1 (I) collagen promoter activity in rat skin fibroblasts
Authors: Cutroneo Kenneth R. , Meisler Natalie , Counts David F.
Published: September 2002

Inhibition of wound healing by anti‐inflammatory steroids is associated with decreased collagen synthesis. Methyl‐20‐dihydroprednisolonate has been previously reported to be anti‐inflammatory without inhibiting collagen synthesis in skin when given either subcutaneously or intraperitoneally. The data we now report show that this prednisolone derivative, as well as two 9α fluorinated derivatives inhibit both collagen synthesis and pro‐α1 (I) collagen gene promoter activity in rat skin fibroblasts. Our data suggest that metabolism, absorption, or distribution of these corticosteroids results in their inability to inhibit collagen synthesis in vivo. In addition our data indicate that fluorination in the 9α position of the adrenal steroid nucleus is not required for the inhibition of collagen synthesis by methyl‐20‐dihydroprednisolonate.
Scarless human fetal skin repair is intrinsic to the fetal fibroblast and occurs in the absence of an inflammatory response
Authors: Lin Richard Y. , Sullivan Kerry M. , Argenta Peter A. , Peter Lorenz H. , Scott Adzick N.
Published: September 2002

The fetus heals skin wounds without scar formation. Human fetal skin that is transplanted to a subcutaneous location on an adult athymic mouse and subsequently wounded heals without scar formation, whereas the same skin heals with scar formation when transplanted to a cutaneous location. In situ hybridization with species‐specific DNA probes and immunohistochemistry were performed to characterize the healing process of human fetal skin in these two locations. Species‐specific human and mouse DNA probes were constructed and used to probe graft wounds under high stringency in situ hybridization conditions. Immunostaining for species‐specific fibroblasts, macrophages, and neutrophils was also performed. We found that the cutaneous human fetal grafts healed with scar and showed an influx of mouse fibroblasts and macrophages. In contrast, subcutaneous human fetal grafts showed exclusively human fetal fibroblasts in the wound environment, an absence of inflammatory cells, and scar‐free repair. We conclude that the highly organized collagen deposition in scarless human fetal wound repair appears to be intrinsic to the human fetal fibroblasts and occurs in the absence of an adult‐like inflammatory response.
Examination of expanded polytetrafluoroethylene wound healing models
Authors: Wicke Corinna , Halliday Betty J. , Scheuenstuhl Heinz , Foree Elizabeth F. , Hunt Thomas K.
Published: September 2002

The object of this animal study was to examine and further develop the expanded polytetrafluoroethylene wound healing model. The goal was to increase its potential for assessing wound healing by increasing yield, reducing variability, establishing the elements of a standard technique, and further testing its ability to detect variations of healing which have clinical significance. Expanded polytetrafluoroethylene implants of various dimensions and fabrications and several implantation and sterilization techniques were compared in rats. Hydroxyproline, DNA, and protein deposition into the expanded polytetrafluoroethylene implants as parameters for wound healing were assessed. Additionally, a 4 cm skin incision for tensile strength assessment was created. Wound healing was assessed under normal and corticosteroid‐impaired healing conditions. The highest yield of collagen was found in the stiffer fabrication of expanded polytetrafluoroethylene with the larger pore size and after the more traumatic implantation technique of incisional placement. Variability was unaffected by fabrication, implantation technique, indexing by various geometric dimensions of the implant, sterilization, or sampling techniques. Variability was the same in the individual animals as in groups of animals. The expanded polytetrafluoroethylene method also detects the influence of antiinflammatory corticosteroids and reflects the tensile strength of incisional wounds made in other sites in the same animal.
Low‐energy helium‐neon laser irradiation and the tensile strength of incisional wounds in the rat
Authors: Broadley Caroline , Broadley Kenneth N. , Disimone Gerald , Reinisch Lou , Davidson Jeffrey M.
Published: September 2002

Low‐level laser energy has been reported to modulate the wound healing process in some but not all studies. To examine this hypothesis, we investigated incisional wounds made on the dorsal pelt of rats for changes in the healing produced by low‐level irradiation with a helium‐neon laser. The incisions were made with a scalpel and closed with sutures. The rats were irradiated daily for 12 days with four levels of laser light (0.0, 0.47, 0.93, and 1.73 J/cm2). Analysis of wound tensile strength indicated a possible strengthening of fresh wounds at the highest levels of irradiation (1.73 J/cm2). No change was observed in the tensile strength of formalin‐fixed wounds. The distribution of measured tensile strengths did not follow normal statistics; instead they showed a platykurtic distribution. Using resampling statistics, where no assumption is made as to the nature of the distribution, we found that the results were contrary to other studies: no biostimulatory effect was seen.
Expression of bone morphogenetic protein‐4 mRNA during the process of bone formation in embryogenesis and fracture repair
Authors: Nakase Takanobu , Takaoka Kunio , Sugimoto Mizuo , Hirota Seiichi , Sato Motohiko , Yoshikawa Hideki , Nomura Shintaro
Published: September 2002

Bone morphogenetic protein‐4 is a potent inducer of ectopic bone and cartilage formation in vivo. Expression of the bone morphogenetic protein‐4 gene has been detected in bone cells during fracture repair but not in normal adult bone cells. To examine whether the gene is expressed by bone cells during embryonic development, in situ hybridization and reverse transcription polymerase chain reaction methods were used to detect murine bone morphogenetic protein‐4 specific complementary DNA in murine developmental bone tissues. Bone morphogenetic protein‐4 messenger RNA was detected in the cells of various developing bone tissues, but it was not detected in these tissues after birth. Combined with previous reports, our findings indicate that the bone morphogenetic protein‐4 gene is expressed during embryogenesis and bone repair and suggest that its product may be a potent bone‐forming factor in bone development and fracture repair.
Local induction of an insulin‐like growth factor binding protein‐3 degrading protease activity in the course of wound healing
Authors: Fournier Karl , Tavera Catherine , Brazeau Paul , Abribat Thierry
Published: September 2002

Proteases that reduce insulin‐like growth factor binding protein‐3 affinity for insulin‐like growth factor‐I have been found in various biological fluids from human beings and rats. The aim of this study was to assess the local and systemic role of insulin‐like growth factor binding protein‐3 proteases in the course of wound healing. Six rats had polyvinyl alcohol sponges implanted subcutaneously. Wound fluid and serum were collected 3 days after wounding. Gel filtration experiments showed that insulin‐like growth factor‐I was present as a 150 kDa complex in both serum and wound fluid. However, insulin‐like growth factor binding protein‐3 measured by Western ligand blotting was virtually absent in wound fluid. Co‐incubation of serum and wound fluid resulted in an ethylenediamine tetraacetic acid‐inhibitable degradation of serum insulin‐like growth factor binding protein‐3, suggesting the presence of an insulin‐like growth factor binding protein‐3 degrading activity in wound fluid. Incubation of (125I)‐labeled insulin‐like growth factor binding protein‐3 in wound fluid and serum showed a rapid and time‐dependent proteolysis of insulin‐like growth factor binding protein‐3 in wound fluid with metabolites similar to those generated by human term pregnant serum. No sign of insulin‐like growth factor binding protein‐3 degrading activity was observed in rat‐serum. In conclusion, there is an insulin‐like growth factor binding protein‐3 proteolytic activity in wound fluid, and it is hypothesized that this activity results in a localized increase in insulin‐like growth factor‐I bioactivity.
Transforming growth factor type e is a novel mediator of wound repair
Authors: Carter Bobbie J. , Halper Jaroslava
Published: September 2002

Transforming growth factor type e is a potent mitogen for epithelial and fibroblastic cells in vitro. It is primarily produced by epithelial tissues and cells, including normal skin keratinocytes. In this study we examined the effects of transforming growth factor type e in vivo and in vitro. On application of transforming growth factor type e to the chorioallantoic membrane of 8‐day‐old chick embryos, we noted a prominent thickening of the membrane caused primarily by fibroblastic and epithelial proliferation. In a subsequent study, transforming growth factor type e suspended in Matrigel was injected subcutaneously into the abdominal wall of Swiss National Institutes of Health mice. Significant influx of first neutrophils and then macrophages into the gel of transforming growth factor type e‐treated mice, but not of control mice, was observed. Transforming growth factor type e also exhibited a potent chemoattractive effect on the J774 macrophage cell line in vitro. In transcutaneous mouse wounds, topical administration of transforming growth factor type e led first to an influx of neutrophils and macrophages, followed by an increased formation of granulation tissue in the transforming growth factor type e‐treated wounds. These results suggest that transforming growth factor type e plays an important role in wound healing as a chemoattractant for neutrophils and macrophages and as a mitogen for epithelial and fibroblastic cells.
Skin changes with aging and disease
Authors: Jacobson Randye G. , Flowers Franklin P.
Published: September 2002

Skin undergoes numerous macroscopic changes during the aging process. These alterations in the skin result from both intrinsic changes to the cells and connective tissue of the skin that are inherent with the chronologic aging of the individual and changes as a result of environmental insults to the organ, particularly ultraviolet irradiation. The combination of these factors produces a tissue which possesses quite different attributes compared with the skin of a young individual and which may result in characteristic lesions, both malignant and benign. Understanding these changes and the underlying mechanisms for them will help to treat older individuals in whom specific lesions develop as well as help to prevent the occurrence of these pathologic conditions.
Back to the future for wound care?
Authors: Kirkpatrick James J. R. , Curtis Bert , Naylor Ian L.
Published: September 2002

The European Renaissance was a time of enormous change and rapid progress in the arts, sciences, and medicine. A glimpse of wound care in the last phase of the European Renaissance is provided by the analysis of work by Wilhelm Fabry, the “father of German surgery,” as provided in his book De Combustionibus (“Burns”) which details his range of treatments for the burn wound, as well as his approach to the later problems of scarring and contracture. We describe some of the historic events which may have stimulated Fabry's writings, in particular, the influences passed down from the medical school of Padua which thereby advanced the cause of wound care and surgery. Finally, we briefly explore the potential of such an approach to the works of our medical forefathers.
Interobserver agreement, sensitivity, and specificity of a “healed” chronic wound
Authors: Margolis David J. , Berlin Jesse A. , Strom Brian L.
Published: September 2002

The primary end point of most wound healing studies is the clinically subjective evaluation of whether a wound is healed. Recently the Wound Healing Society proposed a definition of an acceptably healed wound. With the use of color transparencies of wounds with known clinical outcomes, the investigation presented here evaluated the reliability and validity of this definition as interpreted by 16 untrained observers. Interobserver reliability (Kappa statistic) was 0.68 (95% confidence interval: 0.66, 0.70), sensitivity 0.84 (confidence interval: 0.81, 0.90), specificity 0.92 (confidence interval: 0.88, 0.97), and positive predictive value 0.93 (confidence interval: 0.89, 0.97). We conclude that reliability and validity of judgments of wound healing are good using this definition of a healed wound, permitting its use in clinical investigations and routine clinical care.
Enhancement of wound repair with a topically applied nitric oxide‐releasing polymer
Authors: Shabani Mohammad , Pulfer Sharon K. , Bulgrin Jeffrey P. , Smith Daniel J.
Published: September 2002

Nitric oxide is an important cytotoxic agent for host defense which also regulates gene expression, signal transduction, and vasodilation. In normal wounds, nitric oxide synthesis and metabolism are significantly increased during inflammation and tissue remodeling. However, nitric oxide production is suppressed in wounds where healing is impaired by diabetes or steroid‐treatment. Topical delivery of nitric oxide in therapeutic amounts may alleviate this deficiency and thereby enhance wound repair. Consequently, we developed polyethyleneimine cellulose NONOate polymer, a nonsoluble, nontoxic, polymer‐based NONOate—one of a new class of compounds that spontaneously release nitric oxide in a controlled fashion in aqueous media. Polyethyleneimine cellulose NONOate polymer was synthesized from polyethyleneimine cellulose to provide extended nitric oxide release with a half‐life of 16 hours. Polyethyleneimine cellulose NONOate polymer or a control polymer was applied topically on full‐thickness dermal wounds of rats at the time of wounding and days 3, 7, 10, 14, 17, and 21. Nitric oxide delivery was determined indirectly by measuring urinary nitrate. The first two polyethyleneimine cellulose NONOate polymer applications increased urinary nitrate output twofold to fourfold, whereas urinary nitrate output of control rats did not significantly increase. Nitrate output in polyethyleneimine cellulose NONOate polymer‐treated rats was elevated compared with controls after each application, although this was attenuated in later applications. Rate of wound closure was measured with computer‐based video imaging. Polyethyleneimine cellulose NONOate polymer‐treated wounds were significantly smaller (p < 0.05) on days 7, 10, and 17 relative to controls, based on percentage of wound open relative to initial wound area. In a second experiment, telemetry‐implanted rats were wounded to detect potential hypotensive effects as a result of polyethyleneimine cellulose NONOate polymer application. Topical polyethyleneimine cellulose NONOate polymer application to wounds showed no prolonged hypotensive effects, in contrast to a soluble NONOate which suppressed systolic blood pressure for over 6 hours. These results show that a nonsoluble, polymeric NONOate can provide topical nitric oxide delivery to wounds in a controlled manner, which may enhance wound healing. Further studies are in progress with other promising NONOate candidates to establish dose‐response effects and therapeutic limits of exogenous nitric oxide release in impaired wound models.