No drain, autologous transfusion drain or suction drain? A randomised prospective study in total hip replacement surgery of 168 patients

We performed a prospective, randomised controlled trial to assess the differences in the use of a conventional suction drain, an Autologous Blood Transfusion (ABT) drain and no drain, in 168 patients. There was no significant difference between the drainage from ABT drains ( mean : 345 ml) and the suction drain (314 ml). Forty percent of patients receiving a suction drain had a haemoglobin level less than 10 g/dL at 24 hours, compared to 35% with no drain and 28% with an ABT drain. Patients that had no drains had wounds that were dry significantly sooner, mean 3.0 days compared to a mean of 3.9 days with an ABT drain and a mean of 4 days with a suction drain. Patients that did not have a drain inserted stayed in hospital a significantly shorter period of time, compared with drains. We feel the benefits of quicker drying wounds, shorter hospital stays and the economic savings justify the conclusion that no drain is required after hip replacement

FABM-PCLake – linking aquatic ecology with hydrodynamics

This study presents FABM-PCLake, a redesigned structure of the PCLake aquatic ecosystem model, which we implemented in the Framework for Aquatic Biogeochemical Models (FABM). In contrast to the original model, which was designed for temperate, fully mixed freshwater lakes, the new FABM-PCLake represents an integrated aquatic ecosystem model that can be linked with different hydrodynamic models and allows simulations of hydrodynamic and biogeochemical processes for zero-dimensional, one-dimensional as well as three-dimensional environments. FABM-PCLake describes interactions between multiple trophic levels, including piscivorous, zooplanktivorous and benthivorous fish, zooplankton, zoobenthos, three groups of phytoplankton and rooted macrophytes. The model also accounts for oxygen dynamics and nutrient cycling for nitrogen, phosphorus and silicon, both within the pelagic and benthic domains. FABM-PCLake includes a two-way communication between the biogeochemical processes and the physics, where some biogeochemical state variables (e.g., phytoplankton) influence light attenuation and thereby the spatial and temporal distributions of light and heat. At the same time, the physical environment, including water currents, light and temperature influence a wide range of biogeochemical processes. The model enables studies on ecosystem dynamics in physically heterogeneous environments (e.g., stratifying water bodies, and water bodies with horizontal gradients in physical and biogeochemical properties), and through FABM also enables data assimilation and multi-model ensemble simulations. Examples of potential new model applications include climate change impact studies and environmental impact assessment scenarios for temperate, sub-tropical and tropical lakes and reservoirs

The Angio-Fibrotic Switch of VEGF and CTGF in Proliferative Diabetic Retinopathy

BACKGROUND: In proliferative diabetic retinopathy (PDR), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) cause blindness by neovascularization and subsequent fibrosis, but their relative contribution to both processes is unknown. We hypothesize that the balance between levels of pro-angiogenic VEGF and pro-fibrotic CTGF regulates angiogenesis, the angio-fibrotic switch, and the resulting fibrosis and scarring. METHODS/PRINCIPAL FINDINGS: VEGF and CTGF were measured by ELISA in 68 vitreous samples of patients with proliferative DR (PDR, N = 32), macular hole (N = 13) or macular pucker (N = 23) and were related to clinical data, including degree of intra-ocular neovascularization and fibrosis. In addition, clinical cases of PDR (n = 4) were studied before and after pan-retinal photocoagulation and intra-vitreal injections with bevacizumab, an antibody against VEGF. Neovascularization and fibrosis in various degrees occurred almost exclusively in PDR patients. In PDR patients, vitreous CTGF levels were significantly associated with degree of fibrosis and with VEGF levels, but not with neovascularization, whereas VEGF levels were associated only with neovascularization. The ratio of CTGF and VEGF was the strongest predictor of degree of fibrosis. As predicted by these findings, patients with PDR demonstrated a temporary increase in intra-ocular fibrosis after anti-VEGF treatment or laser treatment. CONCLUSIONS/SIGNIFICANCE: CTGF is primarily a pro-fibrotic factor in the eye, and a shift in the balance between CTGF and VEGF is associated with the switch from angiogenesis to fibrosis in proliferative retinopathy

The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution

Recurrent submicroscopic deletions in genes affecting key cellular pathways are a hallmark of pediatric acute lymphoblastic leukemia (ALL). To gain more insight into the mechanism underlying these deletions, we have studied the occurrence and nature of abnormalities in one of these genes, the B-cell translocation gene 1 (BTG1), in a large cohort of pediatric ALL cases. BTG1 was found to be exclusively affected by genomic deletions, which were detected in 65 out of 722 B-cell precursor ALL (BCP-ALL) patient samples (9%), but not in 109 T-ALL cases. Eight different deletion sizes were identified, which all clustered at the telomeric site in a hotspot region within the second (and last) exon of the BTG1 gene, resulting in the expression of truncated BTG1 read-through transcripts. The presence of V(D)J recombination signal sequences at both sites of virtually all deletions strongly suggests illegitimate RAG1/RAG2-mediated recombination as the responsible mechanism. Moreover, high levels of histone H3 lysine 4 trimethylation (H3K4me3), which is known to tether the RAG enzyme complex to DNA, were found within the BTG1 gene body in BCP-ALL cells, but not T-ALL cells. BTG1 deletions were rarely found in hyperdiploid BCP-ALLs, but were predominant in other cytogenetic subgroups, including the ETV6-RUNX1 and BCR-ABL1 positive BCP-ALL subgroups. Through sensitive PCR-based screening, we identified multiple additional BTG1 deletions at the subclonal level in BCP-ALL, with equal cytogenetic distribution which, in some cases, grew out into the major clone at relapse. Taken together, our results indicate that BTG1 deletions may act as “drivers” of leukemogenesis in specific BCP-ALL subgroups, in which they can arise independently in multiple subclones at sites that are prone to aberrant RAG1/RAG2-mediated recombination events. These findings provide further evidence for a complex and multiclonal evolution of ALL

17β-Estradiol Prevents Early-Stage Atherosclerosis in Estrogen Receptor-Alpha Deficient Female Mice

Estrogen is atheroprotective and a high-affinity ligand for both known estrogen receptors, ERα and ERβ. However, the role of the ERα in early-stage atherosclerosis has not been directly investigated and is incompletely understood. ERα-deficient (ERα−/−) and wild-type (ERα+/+) female mice consuming an atherogenic diet were studied concurrent with estrogen replacement to distinguish the actions of 17β-estradiol (E2) from those of ERα on the development of early atherosclerotic lesions. Mice were ovariectomized and implanted with subcutaneous slow-release pellets designed to deliver 6 or 8 μg/day of exogenous 17β-estradiol (E2) for a period of up to 4 months. Ovariectomized mice (OVX) with placebo pellets (E2-deficient controls) were compared to mice with endogenous E2 (intact ovaries) and exogenous E2. Aortas were analyzed for lesion area, number, and distribution. Lipid and hormone levels were also determined. Compared to OVX, early lesion development was significantly (p < 0.001) attenuated by E2 with 55–64% reduction in lesion area by endogenous E2 and >90% reduction by exogenous E2. Compared to OVX, a decline in lesion number (2- to 4-fold) and lesser predilection (~4-fold) of lesion formation in the proximal aorta also occurred with E2. Lesion size, development, number, and distribution inversely correlated with circulating plasma E2 levels. However, atheroprotection was independent of ERα status, and E2 athero-protection in both genotypes was not explained by changes in plasma lipid levels (total cholesterol, triglyceride, and high-density lipoprotein cholesterol). The ERα is not essential for endogenous/exogenous E2-mediated protection against early-stage atherosclerosis. These observations have potentially significant implications for understanding the molecular and cellular mechanisms and timing of estrogen action in different estrogen receptor (ER) deletion murine models of atherosclerosis, as well as implications to human studies of ER polymorphisms and lipid metabolism. Our findings may contribute to future improved clinical decision-making concerning the use of hormone therapy

The link between volcanism and plutonism in epizonal magma systems; high-precision U–Pb zircon geochronology from the Organ Mountains caldera and batholith, New Mexico

The Organ Mountains caldera and batholith expose the volcanic and epizonal plutonic record of an Eocene caldera complex. The caldera and batholith are well exposed, and extensive previous mapping and geochemical analyses have suggested a clear link between the volcanic and plutonic sections, making this an ideal location to study magmatic processes associated with caldera volcanism. Here we present high-precision thermal ionization mass spectrometry U–Pb zircon dates from throughout the caldera and batholith, and use these dates to test and improve existing petrogenetic models. The new dates indicate that Eocene volcanic and plutonic rocks in the Organ Mountains formed from ~44 to 34 Ma. The three largest caldera-related tuff units yielded weighted mean [superscript 206]Pb/[superscript 238]U dates of 36.441 ± 0.020 Ma (Cueva Tuff), 36.259 ± 0.016 Ma (Achenback Park tuff), and 36.215 ± 0.016 Ma (Squaw Mountain tuff). An alkali feldspar granite, which is chemically similar to the erupted tuffs, yielded a synchronous weighted mean [superscript 206]Pb/[superscript 238]U date of 36.259 ± 0.021 Ma. Weighted mean [superscript 206]Pb/[superscript 238]U dates from the larger volume syenitic phase of the underlying Organ Needle pluton range from 36.130 ± 0.031 to 36.071 ± 0.012 Ma, and the youngest sample is 144 ± 20 to 188 ± 20 ka younger than the Squaw Mountain and Achenback Park tuffs, respectively. Younger plutonism in the batholith continued through at least 34.051 ± 0.029 Ma. We propose that the Achenback Park tuff, Squaw Mountain tuff, alkali feldspar granite and Organ Needle pluton formed from a single, long-lived magma chamber/mush zone. Early silicic magmas generated by partial melting of the lower crust rose to form an epizonal magma chamber. Underplating of the resulting mush zone led to partial melting and generation of a high-silica alkali feldspar granite cap, which erupted to form the tuffs. The deeper parts of the chamber underwent continued recharge and crystallization for 144 ± 20 ka after the final eruption. Calculated magmatic fluxes for the Organ Needle pluton range from 0.0006 to 0.0030 km3/year, in agreement with estimates from other well-studied plutons. The petrogenetic evolution proposed here may be common to many small-volume silicic volcanic systems

Advanced glycation end products cause increased CCN family and extracellular matrix gene expression in the diabetic rodent retina

Aims/hypothesis Referred to as CCN, the family of growth factors consisting of cystein-rich protein 61 (CYR61, also known as CCN1), connective tissue growth factor (CTGF, also known as CCN2), nephroblastoma overexpressed gene (NOV, also known as CCN3) and WNT1-inducible signalling pathway proteins 1, 2 and 3 (WISP1, -2 and -3; also known as CCN4, -5 and -6) affects cellular growth, differentiation, adhesion and locomotion in wound repair, fibrotic disorders, inflammation and angiogenesis. AGEs formed in the diabetic milieu affect the same processes, leading to diabetic complications including diabetic retinopathy. We hypothesised that pathological effects of AGEs in the diabetic retina are a consequence of AGE-induced alterations in CCN family expression. Materials and methods CCN gene expression levels were studied at the mRNA and protein level in retinas of control and diabetic rats using real-time quantitative PCR, western blotting and immunohistochemistry at 6 and 12 weeks of streptozotocin-induced diabetes in the presence or absence of aminoguanidine, an AGE inhibitor. In addition, C57BL/6 mice were repeatedly injected with exogenously formed AGE to establish whether AGE modulate retinal CCN growth factors in vivo. Results After 6 weeks of diabetes, Cyr61 expression levels were increased more than threefold. At 12 weeks of diabetes, Ctgf expression levels were increased twofold. Treatment with aminoguanidine inhibited Cyr61 and Ctgf expression in diabetic rats, with reductions of 31 and 36%, respectively, compared with untreated animals. Western blotting showed a twofold increase in CTGF production, which was prevented by aminoguanidine treatment. In mice infused with exogenous AGE, Cyr61 expression increased fourfold and Ctgf expression increased twofold in the retina. Conclusion/interpretation CTGF and CYR61 are downstream effectors of AGE in the diabetic retina, implicating them as possible targets for future intervention strategies against the development of diabetic retinopath

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

High-resolution DNA copy number and gene expression analyses distinguish chromophobe renal cell carcinomas and renal oncocytomas

Contains fulltext : 80487.pdf (publisher's version ) (Open Access)BACKGROUND: The diagnosis of benign renal oncocytomas (RO) and chromophobe renal cell carcinomas (RCC) based on their morphology remains uncertain in several cases. METHODS: We have applied Affymetrix GeneChip Mapping 250 K NspI high-density oligoarrays to identify small genomic alterations, which may occur beyond the specific losses of entire chromosomes, and also Affymetrix GeneChip HG-U133 Plus2.0 oligoarrays for gene expression profiling. RESULTS: By analysing of DNA extracted from 30 chRCCs and 42 ROs, we have confirmed the high specificity of monosomies of chromosomes 1, 2, 6, 10, 13, 17 and 21 in 70-93% of the chRCCs, while ROs displayed loss of chromosome 1 and 14 in 24% and 5% of the cases, respectively. We demonstrated that chromosomal gene expression biases might correlate with chromosomal abnormalities found in chromophobe RCCs and ROs. The vast majority genes downregulated in chromophobe RCC were mapped to chromosomes 2, 6, 10, 13 and 17. However, most of the genes overexpressed in chromophobe RCCs were located to chromosomes without any copy number changes indicating a transcriptional regulation as a main event. CONCLUSION: The SNP-array analysis failed to detect recurrent small deletions, which may mark loci of genes involved in the tumor development. However, we have identified loss of chromosome 2, 10, 13, 17 and 21 as discriminating alteration between chromophobe RCCs and ROs. Therefore, detection of these chromosomal changes can be used for the accurate diagnosis in routine histology

Rare Copy Number Variants Observed in Hereditary Breast Cancer Cases Disrupt Genes in Estrogen Signaling and TP53 Tumor Suppression Network

Breast cancer is the most common cancer in women in developed countries, and the contribution of genetic susceptibility to breast cancer development has been well-recognized. However, a great proportion of these hereditary predisposing factors still remain unidentified. To examine the contribution of rare copy number variants (CNVs) in breast cancer predisposition, high-resolution genome-wide scans were performed on genomic DNA of 103 BRCA1, BRCA2, and PALB2 mutation negative familial breast cancer cases and 128 geographically matched healthy female controls; for replication an independent cohort of 75 similarly mutation negative young breast cancer patients was used. All observed rare variants were confirmed by independent methods. The studied breast cancer cases showed a consistent increase in the frequency of rare CNVs when compared to controls. Furthermore, the biological networks of the disrupted genes differed between the two groups. In familial cases the observed mutations disrupted genes, which were significantly overrepresented in cellular functions related to maintenance of genomic integrity, including DNA double-strand break repair (P = 0.0211). Biological network analysis in the two independent breast cancer cohorts showed that the disrupted genes were closely related to estrogen signaling and TP53 centered tumor suppressor network. These results suggest that rare CNVs represent an alternative source of genetic variation influencing hereditary risk for breast cancer