Toe pressure and toe brachial index are predictive of cardiovascular mortality regardless of the most diseased arterial segment in symptomatic lower-extremity artery disease—A retrospective cohort study

Objective Although lower extremity arterial disease (LEAD) is most often multisegmental, the predominant disease location and risk factors differ between patients. Ankle-brachial index (ABI), toe-brachial index (TBI), and toe pressure (TP) are predictive of outcome in LEAD patients. Previously, we reported a classification method defining the most diseased arterial segment (MDAS); crural (CR), femoropopliteal (FP), or aortoiliac (AOI). Current study aimed to analyze the associations between MDAS, peripheral pressure measurements and cardiovascular mortality. Materials and methods We reviewed retrospectively 729 consecutive LEAD patients (Rutherford 2–6) who underwent digital subtraction angiography between January, 2009 to August, 2011 and had standardized peripheral pressure measurements. Results In Cox Regression analyses, cardiovascular mortality was associated with MDAS and noninvasive pressure indices as follows; MDAS AOI, TP 1.30 (HR 6.71, 95% CI 1.89–23.8), and MDAS CR, TP <30 mmHg (HR 4.26, 95% CI 2.19–8.27), TBI <0.25 (HR 7.71, 95% CI 1.86–32.9), and ABI <0.25 (HR 2.59, 95% CI 1.15–5.85). Conclusions Symptomatic LEAD appears to be multisegmental with severe infrapopliteal involvement. Because of this, TP and TBI are strongly predictive of cardiovascular mortality and they should be routinely measured despite the predominant disease location or clinical presentation.Peer reviewe

Chronic limb threatening ischemia and diabetes mellitus: the severity of tibial atherosclerosis and outcome after infrapopliteal revascularization

Background and aims: Diabetes mellitus associates with poor outcomes in chronic limb threatening ischemia but data on different hypoglycemic regimens and outcomes are lacking. We analyzed insulin-treated diabetes mellitus, non-insulin-treated diabetes mellitus, and patients without diabetes mellitus.Materials and methods: All patients with peripheral artery disease and/or diabetes mellitus and infrapopliteal revascularization in the Department of Vascular Surgery, Turku University Hospital during 2007-2015 were included. Tibial atherosclerosis was categorized into crural index classes of I-IV.Results: Of the 497 patients, 180 were insulin-treated diabetes mellitus, 94 non-insulin-treated diabetes mellitus, and 223 patients without diabetes mellitus groups (diabetes mellitus 55.1%). Insulin-treated diabetes mellitus was the most ill, youngest (insulin-treated diabetes mellitus-median: 72.4, interquartile range: 64.0-79.5 versus non-insulin-treated diabetes mellitus-76.0, interquartile range: 67.9-83.6 versus patients without diabetes mellitus-77.3, interquartile range: 68.5-83.7, p p p p = 0.046) and non-insulin-treated diabetes mellitus groups (p = 0.011) compared to surgery, but not for patients without diabetes mellitus (p = 0.15). Patients with crural index IV in insulin-treated diabetes mellitus (p = 0.001) and non-insulin-treated diabetes mellitus (p = 0.013) had higher mortality after revascularization. Crural index IV was a risk factor for limb loss (hazard ratio: 1.37, 95% confidence interval: 1.08-1.74, p = 0.008).Conclusion: Limb salvage after bypass is better for insulin and non-insulin diabetics, compared to the endovascular approach. Extensive tibial atherosclerosis is an independent risk factor for limb loss. It associates with increased mortality in both insulin and non-insulin diabetics.</p

The Structure of an RNAi Polymerase Links RNA Silencing and Transcription

RNA silencing refers to a group of RNA-induced gene-silencing mechanisms that developed early in the eukaryotic lineage, probably for defence against pathogens and regulation of gene expression. In plants, protozoa, fungi, and nematodes, but apparently not insects and vertebrates, it involves a cell-encoded RNA-dependent RNA polymerase (cRdRP) that produces double-stranded RNA triggers from aberrant single-stranded RNA. We report the 2.3-Å resolution crystal structure of QDE-1, a cRdRP from Neurospora crassa, and find that it forms a relatively compact dimeric molecule, each subunit of which comprises several domains with, at its core, a catalytic apparatus and protein fold strikingly similar to the catalytic core of the DNA-dependent RNA polymerases responsible for transcription. This evolutionary link between the two enzyme types suggests that aspects of RNA silencing in some organisms may recapitulate transcription/replication pathways functioning in the ancient RNA-based world

Functional expression of NF1 tumor suppressor protein: association with keratin intermediate filaments during the early development of human epidermis

BACKGROUND: NF1 refers to type 1 neurofibromatosis syndrome, which has been linked with mutations of the large NF1 gene. NF1 tumor suppressor protein, neurofibromin, has been shown to regulate ras: the NF1 protein contains a GTPase activating protein (GAP) related domain which functions as p21rasGAP. Our studies have previously demonstrated that the NF1 protein forms a high affinity association with cytokeratin 14 during the formation of desmosomes and hemidesmosomes in cultured keratinocytes. METHODS: The expression of NF1 protein was studied in developing human epidermis using western transfer analysis, indirect immunofluorescence, confocal laser scanning microscopy, immunoelectron microscopy, and in situ hybridization. RESULTS: The expression of NF1 protein was noted to be highly elevated in the periderm at 8 weeks estimated gestational age (EGA) and in the basal cells at 8–14 weeks EGA. During this period, NF1 protein was associated with cytokeratin filaments terminating to desmosomes and hemidesmosomes. NF1 protein did not display colocalization with α-tubulin or actin of the cytoskeleton, or with adherens junction proteins. CONCLUSIONS: These results depict an early fetal period when the NF1 tumor suppressor is abundantly expressed in epidermis and associated with cytokeratin filaments. This period is characterized by the initiation of differentiation of the basal cells, maturation of the basement membrane zone as well as accentuated formation of selected cellular junctions. NF1 tumor suppressor may function in the regulation of epidermal histogenesis via controlling the organization of the keratin cytoskeleton during the assembly of desmosomes and hemidesmosomes

Waiting times for radiotherapy: variation over time and between cancer networks in southeast England

The aim of this study was to investigate variations in the length of time that patients with cancer wait from diagnosis to treatment with radiotherapy. A total of 57 426 men and 71 018 women diagnosed with cancer between 1992 and 2001 and receiving radiotherapy within 6 months of diagnosis were identified from the Thames Cancer Registry database. In total, 12 sites were identified for which a substantial number or proportion of patients received radiotherapy: head and neck, oesophagus, colon, rectum, lung, nonmelanoma skin cancer, breast, uterus, prostate, bladder, brain and non-Hodgkin's lymphoma. Median waiting times from diagnosis to radiotherapy were calculated, together with the proportion of patients who received radiotherapy within 60 days of diagnosis, and analysed by year of diagnosis, cancer site, deprivation quintile, age at diagnosis, sex and cancer network of either residence or treatment. Logistic regression was used to adjust the proportion receiving treatment within 60 days for the effects of the other factors. There were significant differences in the proportions receiving radiotherapy within 60 days between different networks and different cancer sites, which remained after adjustment. Median waiting times varied from 42 to 65 days across networks of residence, with the adjusted proportion treated within 60 days ranging from 44 to 71%. There was no difference between male and female patients after adjustment for the other factors, particularly site. There was a highly significant trend over time: the median wait increased from 45 days in 1992 to 76 days in 2001, while the adjusted proportion being treated within 60 days declined by almost a half, from 64 to 35%, over the same period

The CXC-Chemokine CXCL4 Interacts with Integrins Implicated in Angiogenesis

The human CXC-chemokine CXCL4 is a potent inhibitor of tumor-induced angiogenesis. Considering that CXCL4 is sequestered in platelet α-granules and released following platelet activation in the vicinity of vessel wall injury, we tested the hypothesis that CXCL4 might function as a ligand for integrins. Integrins are a family of adhesion receptors that play a crucial role in angiogenesis by regulating early angiogenic processes, such as endothelial cell adhesion and migration. Here, we show that CXCL4 interacts with αvβ3 on the surface of αvβ3-CHO. More importantly, human umbilical vein endothelial cells adhere to immobilized CXCL4 through αvβ3 integrin, and also through other integrins, such as αvβ5 and α5β1. We further demonstrate that CXCL4-integrin interaction is of functional significance in vitro, since immobilized CXCL4 supported endothelial cell spreading and migration in an integrin-dependent manner. Soluble CXCL4, in turn, inhibits integrin-dependent endothelial cell adhesion and migration. As a whole, our study identifies integrins as novel receptors for CXCL4 that may contribute to its antiangiogenic effect

The Structure of an RNAi Polymerase Links RNA Silencing and Transcription

RNA silencing refers to a group of RNA-induced gene-silencing mechanisms that developed early in the eukaryotic lineage, probably for defence against pathogens and regulation of gene expression. In plants, protozoa, fungi, and nematodes, but apparently not insects and vertebrates, it involves a cell-encoded RNA-dependent RNA polymerase (cRdRP) that produces double-stranded RNA triggers from aberrant single-stranded RNA. We report the 2.3-Å resolution crystal structure of QDE-1, a cRdRP from Neurospora crassa, and find that it forms a relatively compact dimeric molecule, each subunit of which comprises several domains with, at its core, a catalytic apparatus and protein fold strikingly similar to the catalytic core of the DNA-dependent RNA polymerases responsible for transcription. This evolutionary link between the two enzyme types suggests that aspects of RNA silencing in some organisms may recapitulate transcription/replication pathways functioning in the ancient RNA-based world