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Wrist endoprosthesis is still an exceptional indication compared to the prosthesis of large joints, especially when a rescue surgery procedure of the wrist is no longer possible and the complete wrist arthrodesis is to be considered the ultima ratio. However, a suspended function in the wrist is accompanied by a significant restriction in the patient's daily life. Using the fourth-generation endoprosthesis, the situation regarding long-term results for the hand has already improved. This means that a durability of more than 6 years is no longer a rarity. Defect situations in joints, in particular those which occur after tumor, still pose a greater challenge. If autologous reconstructions cannot be performed, custom-made prostheses can be considered as very rare indications for joint reconstruction. While these have been used for years on large joints such as shoulder, elbow, knee and hip, they have only been described on the hand in particular cases. We report the 10-year follow-up of implantation of a custom-made wrist prothesis (UNI-2™, KMI, Germany) in a 36-year-old patient with tumorous destruction of the distal radius by a giant cell tumor. [ABSTRACT FROM AUTHOR]

Background: Non-autonomous VNTR (Variable Number of Tandem Repeats) composite retrotransposons – SVA (SINE-R-VNTR-Alu) and LAVA (L1-Alu-VNTR-Alu) – are specific to hominoid primates. SVA expanded in great apes, LAVA in gibbon. Both SVA and LAVA have been shown to be mobilized by the autonomous LINE-1 (L1)-encoded protein machinery in a cell-based assay in trans. The efficiency of human SVA retrotransposition in vitro has, however, been considerably lower than would be expected based on recent pedigree-based in vivo estimates. The VNTR composite elements across hominoids – gibbon LAVA, orangutan SVA_A descendants and hominine SVA_D descendants – display characteristic structures of the 5′ Alu-like domain and the VNTR. Different partner L1 subfamilies are currently active in each of the lineages. The possibility that the lineage-specific types of VNTR composites evolved in response to evolutionary changes in their autonomous partners, particularly in the nucleic acid binding L1 ORF1-encoded protein, has not been addressed. Results: Here I report the identification and functional characterization of a highly active human SVA element using an improved mneo retrotransposition reporter cassette. The modified cassette (mneoM) minimizes splicing between the VNTR of human SVAs and the neomycin phosphotransferase stop codon. SVA deletion analysis provides evidence that key elements determining its mobilization efficiency reside in the VNTR and 5′ hexameric repeats. Simultaneous removal of the 5′ hexameric repeats and part of the VNTR has an additive negative effect on mobilization rates. Taking advantage of the modified reporter cassette that facilitates robust cross-species comparison of SVA/LAVA retrotransposition, I show that the ORF1-encoded proteins of the L1 subfamilies currently active in gibbon, orangutan and human do not display substrate preference for gibbon LAVA versus orangutan SVA versus human SVA. Finally, I demonstrate that an orangutan-derived ORF1p supports only limited retrotransposition of SVA/LAVA in trans, despite being fully functional in L1 mobilization in cis. Conclusions: Overall, the analysis confirms SVA as a highly active human retrotransposon and preferred substrate of the L1-encoded protein machinery. Based on the results obtained in human cells coevolution of L1 ORF1p and VNTR composites does not appear very likely. The changes in orangutan L1 ORF1p that markedly reduce its mobilization capacity in trans might explain the different SVA insertion rates in the orangutan and hominine lineages, respectively. [ABSTRACT FROM AUTHOR]

So far, research has insufficiently addressed the long-term effectiveness of business responses to climate change in delivering actual outcomes. The aim of this article is therefore to analyze the determinants of such strategies and their influence on firms' financial and carbon performance over time. It is argued that corporate carbon strategies have three main objectives: carbon governance, carbon reduction and carbon competitiveness. To assess the complex interactions between these strategic objectives, their determinants and outcomes, an integrative structural equation model is developed and empirically tested. Data are sourced from a global sample of 45 leading enterprises from the steel, cement and automotive sector, including some of the largest GHG emitters in the world. In order to account for the long-term impacts of strategies, the firm-level change in financial and carbon performance is calculated by comparing two different points in time, namely 2008 and 2013. The results provide empirical evidence for the positive effect of institutional and stakeholder pressure on emission reduction activities. Proof for a positive impact of carbon pressure on organizational capabilities and corporate competitiveness in the context of climate change cannot be established. Surprisingly, the results also indicate no relationship between carbon reduction activities and long-term improvements in carbon performance. However, such measures are linked to long-term financial gains. Advancements in carbon performance, in turn, are not found to be associated with economic benefits. [ABSTRACT FROM AUTHOR]

Composite retrotransposons are widely distributed in the plant and animal kingdoms. Some of the most complex of these are found in hominoid primates. SVA, LAVA, PVA and FVA combine simple repeats,Alufragments, a VNTR (Variable Number of Tandem Repeats) and variable 3′ domains, which are, except for PVA, derived from other retrotransposons. Although a likely precursor of SVA–a “tailed VNTR” named SVA2–had been identified in the Rhesus genome, the exact sequence and mechanism of the assembly of this type of composite retrotransposon had been elusive. The discovery of LAVA, PVA and FVA in gibbons provided the opportunity to delineate the order of assembly of the components of VNTR-containing retrotransposons. Our recent analysis suggests that an extinct “Alu-SVA2” acquired variant 3′ ends by splicing. In this commentary I will discuss the mode of assembly of VNTR composites in the context of their capacity to engage in alternative splicing to co-mobilize host RNA sequences and to become exonized. The second part will focus on structural determinants of VNTR composite retrotransposon mobilization in the context of lineage-specific expansion of particular families/subfamilies of these elements. [ABSTRACT FROM AUTHOR]

The corticotropin releasing factor (CRF) system plays a critical role in responses to stressful stimuli, and is expressed in many areas of the brain involved in processing fear, anxiety, and social behaviors. To better understand the mechanisms by which the CRF system modulates responses to stressful events and social stimuli, we employed a mouse model that selectively disrupts NMDA receptor function via NMDA receptor subunit NR1 ( Grin 1) knockout specifically in Cre-expressing CRF neurons. These animals (Cre+/ fGrin 1+ ) were compared with littermates lacking Cre expression (Cre−/ fGrin 1+ ). Following cue discrimination fear conditioning, male Cre+/ fGrin 1+ mice showed increased fear expression to the tone paired with a foot shock (CS+) while still discriminating the CS+ from a tone never paired with a foot shock (CS−). In contrast to males, female mice learned and discriminated fear cues equivalently across the genotypes. Similarly, no genotype differences in sociability or social novelty were observed in female mice, but Cre+/ fGrin 1+ males displayed greater naive sociability and preference for social novelty than Cre−/ fGrin 1+ littermates. Furthermore, the level of social withdrawal exhibited by male Cre+/ fGrin 1+ mice susceptible to social defeat stress relative to same genotype controls was significantly more pronounced than that displayed by susceptible Cre−/ fGrin 1+ mice compared to control Cre−/ fGrin 1+ mice. Together, these results demonstrate increased fear, social, and stress responsiveness specifically in male Cre+/ fGrin 1+ mice. Our findings indicate that NMDA-mediated glutamatergic regulation of CRF neurons is important for appropriately regulating fear and social responses, likely functioning to promote survival under aversive circumstances. [ABSTRACT FROM AUTHOR]

Introduction: Treatment for giant cell tumors of the distal radius is challenging when motion is to be preserved. As standard wrist prostheses typically do not achieve favorable results, we treated a 36-year-old man with giant cell tumor of the distal radius with a new, custom-made implant. Methods: A custom-made wrist prosthesis with a long shaft was designed according to the patient's X-ray findings. After complete tumor resection, the prosthesis was subsequently implanted into the distal radius without complications. Results: Two months after surgery, range of motion was 30°-0-25° for extension/flexion, 10°-0-5° for ulnar/radial abduction, 80°-0-0 for pronation/supination, complete range of motion for the fingers, and a grip strength of 6 kg. Two years after surgery, implant position was still correct and range of motion was 45°-0-10° for extension/flexion, 10°-0-20° for ulnar/radial abduction, and 80°-0-10° for pronation/supination. Grip strength was 16 kg, and DASH score was 25 compared to 39 before surgery. The patient returned to work as a craftsman. Conclusion: Custom-made wrist prostheses could become a practical option in patients with large defects of the distal radius who desire to preserve wrist motion. [ABSTRACT FROM AUTHOR]

A 43-year-old healthy man presented with bilateral hypertrophy of the first dorsal interosseus muscles of both hands. Neurophysiologic and laboratory examinations revealed no pathologic findings. Doubled muscle width was found by ultrasound. Myopathic changes were present in muscle biopsy with varying fiber sizes but without inflammatory features. The clinical impression of massive bilateral symmetric enlargement of the first dorsal interosseus muscles was characterized by subtle, non-specific muscular pathology. [ABSTRACT FROM AUTHOR]

Zusammenfassung  Die Bursitis olecrani ist eine häufige Erkrankung, welche jedoch in den überwiegenden Fällen konservativ behandelt werden kann. In akut infektiösen, offenen oder chronischen Fällen ist eine chirurgische Therapie angezeigt. Trotz ausreichender Beachtung chirurgischer Grundprinzipien bei der Erstoperation einer Bursitis olecrani kann die Entstehung von Defekten nach Infektionen nicht immer vermieden werden. Für komplizierte Verläufe mit verbliebenen Weichteildefekten stehen standardisierte Verfahren zur Weichteildeckung zur Verfügung. Ziel ist der definitive Defektverschluss zur Erhaltung der Funktion des Ellenbogengelenkes und die Vermeidung eines monate- oder jahrelang dauernden Behandlungsverfahrens. Hierzu dienen folgende Maßnahmen: VAC-Therapie, lokale Lappenplastiken, Insellappen, Fernlappen oder freie Lappenplastiken. Im Zeitraum von 1996–2007 wurden in unserer Klinik 12 Patienten wegen einer komplizierten Bursitis olecrani behandelt, 11 davon operativ. Bei 2 der Patienten waren mehrere Operationen notwendig. In allen Fällen konnte eine stabile Weichteildeckung herbeigeführt werden. Bei komplizierten Verläufen der Bursitis olecrani mit Weichteildefekten, rezidivierenden Wundheilungsstörungen oder Fistelungen stehen verschiedene Verfahren der plastischen Deckung des Ellenbogens zur Verfügung. [ABSTRACT FROM AUTHOR]

SVA (SINE-R-VNTR-Alu) elements are non-autonomous non-LTR (Long Terminal Repeat) retrotransposons. They are found in all hominoid primates but did not amplify to appreciable numbers in gibbons. Recently, phylogenetic networks of hominid (orangutan, gorilla, chimpanzee, human) SVA elements based on comparison of overall sequence identity have been reported. Here I present a detailed phylogeny of SVA_D elements in gorilla, chimpanzee and humans based on sorting of co-segregating substitutions. Complementary comparative genomics analysis revealed that the majority (1763 out of 1826–97%) of SVA_D elements in gorilla represent species-specific insertions – indicating very low activity of the subfamily before the gorilla/chimpanzee-human split. The origin of the human-specific subfamily SVA_F could be traced back to a source element in the hominine common ancestor. The major expanding lineage-specific subfamilies were found to differ between chimpanzee and humans. Precursors of the dominant chimpanzee SVA_D subfamily are present in humans; however, they did not expand to appreciable levels. The analysis also uncovered that one of the chimpanzee-specific subfamilies was formed by splicing of the STK40 first exon to the SVA Alu-like region. Many of the 94 subfamily members contain additional 5′ transductions – among them exons of 8 different other genes. Striking similarities to the MAST2-containing human SVA_F1 suggest parallel evolution of non-canonical SVAs in chimpanzees and humans. [ABSTRACT FROM AUTHOR]

During development, hematopoiesis initiates in the yolk sac through a process that depends on VEGF/Flk1 signaling and on the function of the SCL/Tall transcription factor. Here we show that VEGF modifies the developmental potential of primitive erythroid progenitors and prolongs their life span. Furthermore, the survival of yolk sac erythrocytes in vivo depends on the dose of VEGF. Interestingly, in Vegflo/lo embryos carrying a hypomorph allele, Flkl-positive cells reach the yolk sac at E8.5, but are severely compromised in their ability to generate primitive erythroid precursors. These observations indicate that during embryonic development, different thresholds of VEGF are required for the migration and clonal expansion of hematopoietic precursors. The near absence of primitive erythroid precursors in Vegflo/lo embryos correlates with low levels of Scl in the yolk sac. Strikingly, gain-of-function of SCL partially complements the hematopoietic defect caused by the hypomorph Veglo allele, and re-establishes the survival of erythroid cells and the expression of erythroid genes (Gata1 and βH1). This indicates that SCL functions downstream of VEGF to ensure an expansion of the hematopoietic compartment. [ABSTRACT FROM AUTHOR]

SINEs (Short INterspersed Elements) are widely distributed among eukaryotes. Some SINE families are organized in superfamilies characterized by a shared central domain. These central domains are conserved across species, classes, and even phyla. Here we report the identification of two novel such superfamilies in the genomes of gastropod and bivalve mollusks. The central conserved domain of the first superfamily is present in SINEs in Caenogastropoda and Vetigastropoda as well as in all four subclasses of Bivalvia. We designated the domain MESC (Romanian for MElc--snail and SCoica--mussel) because it appears to be restricted to snails and mussels. The second superfamily is restricted to Caenogastropoda. Its central conserved domain--Snail--is related to the Nin-DC domain. Furthermore, we provide evidence that a 40-bp subdomain of the SINE V-domain is conserved in SINEs in mollusks and arthropods. It is predicted to form a stable stem-loop structure that is preserved in the context of the overall SINE RNA secondary structure in invertebrates. Our analysis also recovered short retrotransposons with a Long INterspersed Element (LINE)-derived 50 end. These share the body and/or the tail with transfer RNA (tRNA)-derived SINEs within and across species. Finally, we identified CORE SINEs in gastropods and bivalves--extending the distribution range of this superfamily. [ABSTRACT FROM AUTHOR]

Dupuytren's disease ( DD) is a progressive fibromatosis that causes the formation of nodules and cords in the palmar aponeurosis leading to flexion contracture of affected fingers. The etiopathogenesis is multifactorial with a strong genetic predisposition. It is the most frequent genetic disorder of connective tissues. We have collected clinical data from 736 unrelated individuals with DD who underwent surgical treatment from Germany and Switzerland. We evaluated a standardised questionnaire, assessed the importance of different risk factors and compared subgroups with and without positive family history. We found that family history clearly had the strongest influence on the age at first surgery compared to environmental factors, followed by male sex. Participants with a positive family history were on average 55.9 years of age at the first surgical intervention, 5.2 years younger than probands without known family history (p = 6.7 × 10−8). The percentage of familial cases decreased with age of onset from 55% in the 40-49 years old to 17% at age 80 years or older. Further risk factors analysed were cigarettes, alcohol, diabetes, hypertension, and epilepsy. Our data pinpoint the importance of genetic susceptibility for DD, which has long been underestimated. [ABSTRACT FROM AUTHOR]

Background: VNTR (Variable Number of Tandem Repeats) composite retrotransposons - SVA (SINE-R-VNTR-Alu), LAVA (LINE-1-Alu-VNTR-Alu), PVA (PTGR2-VNTR-Alu) and FVA (FRAM-VNTR-Alu) - are specific to hominoid primates. Their assembly, the evolution of their 5' and 3' domains, and the functional significance of the shared 5' Alu-like region are well understood. The central VNTR domain, by contrast, has long been assumed to represent a more or less random collection of 30-50 bp GC-rich repeats. It is only recently that it attracted attention in the context of regulation of SVA expression. Results: Here we provide evidence that the organization of the VNTR is non-random, with conserved repeat unit (RU) arrays at both the 5' and 3' ends of the VNTRs of human, chimpanzee and orangutan SVA and gibbon LAVA. The younger SVA subfamilies harbour highly organized internal RU arrays. The composition of these arrays is specific to the human/chimpanzee and orangutan lineages, respectively. Tracing the development of the VNTR through evolution we show for the first time how tandem repeats evolve within the constraints set by a functional, non-autonomous non-LTR retrotransposon in two different families - LAVA and SVA - in different hominoid lineages. Our analysis revealed that a microhomology-driven mechanism mediates expansion/contraction of the VNTR domain at the DNA level. Elements of all four VNTR composite families have been shown to be mobilized by the autonomous LINE1 retrotransposon in trans. In case of SVA, key determinants of mobilization are found in the 5' hexameric repeat/ Alu-like region. We now demonstrate that in LAVA, by contrast, the VNTR domain determines mobilization efficiency in the context of domain swaps between active and inactive elements. Conclusions: The central domain of VNTR composites evolves in a lineage-specific manner which gives rise to distinct structures in gibbon LAVA, orangutan SVA, and human/chimpanzee SVA. The differences observed between the families and lineages are likely to have an influence on the expression and mobilization of the elements. [ABSTRACT FROM AUTHOR]

The genetics responsible for the inter-individually variable G-CSF responsiveness remain elusive. A single nucleotide polymorphism (SNP) in the 3’UTR of CXCL12, rs1801157, was implicated in X4-tropic HiV susceptibility and later, in two small studies, in G-CSR responsiveness in patients and donors. The position of the SNP in the 3’UTR together with in-silico predictions suggested differential binding of micro-RNA941 as an underlying mechanism. In a cohort of 515 healthy stem cell donors we attempted to reproduce the correlation of the CXCL12 3’UTR SNP and mobilization responses and tested the role of miR941 in this context. The SNP was distributed with the expected frequency. Mobilization efficiency for CD34+ cells in WT, heterozygous and homozygous SNP individuals was indistinguishable, even after controlling for gender. miR941 expression in non-hematopoietic bone marrow cells was undetectable and miR941 did not interact with the 3’ UTR of CXCL12. Proposed effects of the SNP rs1801157 on G-CSF responsiveness cannot be confirmed in a larger cohort. [ABSTRACT FROM AUTHOR]

Most common methods for inferring transposable element (TE) evolutionary relationships are based on dividing TEs into subfamilies using shared diagnostic nucleotides. Although originally justified based on the “master gene” model of TE evolution, computational and experimental work indicates that many of the subfamilies generated by these methods contain multiple source elements. This implies that subfamily-based methods give an incomplete picture of TE relationships. Studies on selection, functional exaptation, and predictions of horizontal transfer may all be affected. Here, we develop a Bayesian method for inferring TE ancestry that gives the probability that each sequence was replicative, its frequency of replication, and the probability that each extant TE sequence came from each possible ancestral sequence. Applying our method to 986 members of the newly-discovered LAVA family of TEs, we show that there were far more source elements in the history of LAVA expansion than subfamilies identified using the CoSeg subfamily-classification program. We also identify multiple replicative elements in the AluSc subfamily in humans. Our results strongly indicate that a reassessment of subfamily structures is necessary to obtain accurate estimates of mutation processes, phylogenetic relationships and historical times of activity. [ABSTRACT FROM AUTHOR]

Objective:We introduce our surgical technique in two male genital reconstruction cases out of 15 post-bariatric patients. Methods: At our Department for Plastic Surgery at the University Hospital Magdeburg, 15 patients, 6 male and 9 female, underwent a surgical abdominoplasty after weight loss in 2009. Results: The average weight of the 15 patients was preoperatively 197.2 kg and the average hospital stay was of 14 days. In 2 cases, a second procedure for male genital reconstruction was necessary. After primary dietary measures and weight loss, we performed genital reconstruction in a second step with a sleeve-, Z-, VY-plasty and a "bilobed flap" to restore function and appearance of the male genitalia. In these patients, the average weight was 207.5 kg and hospital stay lasted 32 days. Conclusion: The increase of patients with obesity-related genital deformities will be expected in the future. Therefore, more controlled long-term studies should be published to develop guidelines for genital reconstruction techniques in plastic surgery. [ABSTRACT FROM AUTHOR]

The approach of combining different mechanisms of antibacterial action by designing hybrid nanomaterials provides a new paradigm in the fight against resistant bacteria. Here, we present a new method for the synthesis of silver nanoparticles enveloped in the biopolymer chitosan. The method aims at the production of bionanocomposites with enhanced antibacterial properties. We find that chitosan and silver nanoparticles act synergistically against two strains of Gram-positive Staphylococcus aureus (S. aureus). As a result the bionanocomposites exhibit higher antibacterial activity than any component acting alone. The minimum inhibitory (MIC) and minimum bactericidal (MBC) concentrations of the chitosan-silver nanoparticles synthesized at 0 degC were found to be lower than those reported for other types of silver nanoparticles. Atomic force microscopy (AFM) revealed dramatic changes in morphology of S. aureus cells due to disruption of bacterial cell wall integrity after incubation with chitosan-silver nanoparticles. Finally, we demonstrate that silver nanoparticles can be used not only as antibacterial agents but also as excellent plasmonic substrates to identify bacteria and monitor the induced biochemical changes in the bacterial cell wall via surface enhanced Raman scattering (SERS) spectroscopy. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to evaluate the feasibility, quality, and possible future implications of magnetic resonance imaging (MRI) of the human hand and wrist at 7 T.Materials and Methods: Images of the left hand of a healthy volunteer were acquired with a 7- and a 1.5-T whole body system and comparatively analyzed. Axial and coronal two-dimensional gradient echo (GRE) images with inflow saturation, coronal 3D GRE images, and time-of-flight angiographies were obtained without averaging. Image details were related to the complex hand anatomy.Results: With the 7-T protocols established in this study, high-quality and high-resolution images of the hand and wrist were obtained. In the 2D GRE images at 7 T, small anatomical structures of the hand were depicted in vivo with superior detail and resolution, compared to 1.5 T and published studies at lower field strength. Signal-to-noise ratios (SNRs) were approximately five times higher at 7 T compared to 1.5 T. Additionally, thin 3D GRE images with good quality of the whole hand were obtained in a short acquisition time. Moreover, time-of-flight angiographies of the small hand arteries have been acquired without the application of contrast agents.Conclusion: Seven-tesla imaging of the hand can be used in vivo with ultra-high resolution and sufficient SNR. It allows for exact delineation of most anatomical structures including nerves, muscles, tendons, ligaments, cartilage, and blood vessels. [ABSTRACT FROM AUTHOR]

Abstract Objective  The purpose of this study was to evaluate the feasibility, quality, and possible future implications of magnetic resonance imaging (MRI) of the human hand and wrist at 7 T. Materials and methods  Images of the left hand of a healthy volunteer were acquired with a 7- and a 1.5-T whole body system and comparatively analyzed. Axial and coronal two-dimensional gradient echo (GRE) images with inflow saturation, coronal 3D GRE images, and time-of-flight angiographies were obtained without averaging. Image details were related to the complex hand anatomy. Results  With the 7-T protocols established in this study, high-quality and high-resolution images of the hand and wrist were obtained. In the 2D GRE images at 7 T, small anatomical structures of the hand were depicted in vivo with superior detail and resolution, compared to 1.5 T and published studies at lower field strength. Signal-to-noise ratios (SNRs) were approximately five times higher at 7 T compared to 1.5 T. Additionally, thin 3D GRE images with good quality of the whole hand were obtained in a short acquisition time. Moreover, time-of-flight angiographies of the small hand arteries have been acquired without the application of contrast agents. Conclusion  Seven-tesla imaging of the hand can be used in vivo with ultra-high resolution and sufficient SNR. It allows for exact delineation of most anatomical structures including nerves, muscles, tendons, ligaments, cartilage, and blood vessels. [ABSTRACT FROM AUTHOR]

To determine the function of VEGF-A in nervous system development, we have utilized the Nestin promoter-driven Cre recombinase transgene, in conjunction with a conditional and hypomorphic VEGF-A allele, to lower VEGF-A activity in neural progenitor cells. Mice with intermediate levels of VEGF-A activity showed decreased blood vessel branching and density in the cortex and retina, resulting in a thinner retina and aberrant structural organization of the cortex. Severe reductions in VEGF-A led to decreases in vascularity and subsequent hypoxia, resulting in the specific degeneration of the cerebral cortex and neonatal lethality. Decreased neuronal proliferation and hypoxia was evident at E11.5, leading to increased neuronal apoptosis in the cortex by E15.5. In order to address whether the observed changes in the structural organization of the nervous system were due to a direct and autocrine role of VEGF-A on the neural population, we conditionally inactivated the main VEGF-A receptor, Flk1, specifically in neuronal lineages, by using the Nestin Cre transgene. The normality of these mice ruled out the possibility that VEGF-A/Flk1 signaling has a significant autocrine role in CNS development. VEGF-A dosage is therefore a critical parameter regulating the density of the vascular plexus in the developing CNS that is in turn a key determinant in the development and architectural organization of the nervous system. [Copyright &y& Elsevier]

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is a mitogen and chemotactic factor for endothelial cells in vitro and an angiogenesis and vascular permeability factor in vivo. Due to its properties, VEGF is a candidate for both angiogenesis and vascular permeability/oedema induction which typically occur in glioblastomas. In this study we test the hypothesis that the antioedema effect of dexamethasone is mediated by downregulation of VEGF or VEGF receptor expression. VEGF mRNA and protein levels of two rat glioma cells lines, C6 and GS-9L, were determined after incubation with dexamethasone under normoxic and hypoxic conditions. In normoxic C6 and GS9L cells, we observed 50–60% downregulation of VEGF mRNA by dexamethasone (P=0.015 and P=0.01, respectively). This effect was dependent on glucocorticoid-receptor (GR) function. The inhibitory effect of dexamethasone on VEGF gene expression by tumour cells was markedly reduced by hypoxia which suggests that the upregulation of VEGF driven by hypoxia overcomes the effect of the dexamethasone. Dexamethasone did not alter VEGFR-2 mRNA levels in human umbilical endothelial cells. In a subcutaneous glioma tumour model, we observed only a 15% decrease in VEGF mRNA expression in dexamethasone treated animals (n=12) compared with controls animals (P=0.24). We conclude that dexamethasone may decrease brain tumour-associated oedema by reduction of VEGF expression in tumour cells. However, the highly reduced activity on hypoxic tumour cells suggests that dexamethasone efficacy may be limited by hypoxia in rapidly growing tumours. [ABSTRACT FROM AUTHOR]