Detection of peripheral vascular stenosis by assessing skeletal muscle flow reserve

ObjectivesWe sought to determine whether the severity of peripheral arterial disease (PAD) can be assessed by measuring blood flow reserve in limb skeletal muscle with contrast-enhanced ultrasound (CEU).BackgroundNoninvasive imaging of distal limb perfusion could improve management of patients with PAD by evaluating the impact of large and small vessel disease, and collateral flow.MethodsIn 12 dogs, blood flow in the quadriceps femoris was measured by CEU at rest and during either electrostimulated contractile exercise or adenosine infusion. Femoral artery blood flow was measured by Doppler ultrasound. Studies were performed in the absence and presence of either moderate or severe stenosis (pressure gradient of 10 to 20 mm Hg and >20 mm Hg, respectively).ResultsResting femoral artery blood flow progressively decreased with stenosis severity, while resting skeletal muscle flow was reduced only with severe stenosis (52 ± 21% of baseline, p < 0.05), indicating the presence of collateral flow. Skeletal muscle flow reserve during contractile exercise or adenosine decreased incrementally with increasing stenosis severity (p < 0.01). The stenotic pressure gradient correlated with skeletal muscle flow reserve for exercise and adenosine (r = 0.70 for both, p < 0.01).ConclusionsContrast-enhanced ultrasound of limb skeletal muscle can be used to assess the severity of PAD by measuring muscle flow reserve during either contractile exercise or pharmacologic vasodilation. Unlike currently used methods, this technique may provide a measure of the physiologic effects of large- and small-vessel PAD, and the influence of collateral perfusion

The Drosophila Perlecan gene trol regulates multiple signaling pathways in different developmental contexts

<p>Abstract</p> <p>Background</p> <p>Heparan sulfate proteoglycans modulate signaling by a variety of growth factors. The mammalian proteoglycan Perlecan binds and regulates signaling by Sonic Hedgehog, Fibroblast Growth Factors (FGFs), Vascular Endothelial Growth Factor (VEGF) and Platelet Derived Growth Factor (PDGF), among others, in contexts ranging from angiogenesis and cardiovascular development to cancer progression. The <it>Drosophila </it>Perlecan homolog <it>trol </it>has been shown to regulate the activity of Hedgehog and Branchless (an FGF homolog) to control the onset of stem cell proliferation in the developing brain during first instar. Here we extend analysis of <it>trol </it>mutant phenotypes to show that <it>trol </it>is required for a variety of developmental events and modulates signaling by multiple growth factors in different situations.</p> <p>Results</p> <p>Different mutations in <it>trol </it>allow developmental progression to varying extents, suggesting that <it>trol </it>is involved in multiple cell-fate and patterning decisions. Analysis of the initiation of neuroblast proliferation at second instar demonstrated that <it>trol </it>regulates this event by modulating signaling by Hedgehog and Branchless, as it does during first instar. Trol protein is distributed over the surface of the larval brain, near the regulated neuroblasts that reside on the cortical surface. Mutations in <it>trol </it>also decrease the number of circulating plasmatocytes. This is likely to be due to decreased expression of <it>pointed</it>, the response gene for VEGF/PDGF signaling that is required for plasmatocyte proliferation. Trol is found on plasmatocytes, where it could regulate VEGF/PDGF signaling. Finally, we show that in second instar brains but not third instar brain lobes and eye discs, mutations in <it>trol </it>affect signaling by Decapentaplegic (a Transforming Growth Factor family member), Wingless (a Wnt growth factor) and Hedgehog.</p> <p>Conclusion</p> <p>These studies extend the known functions of the <it>Drosophila </it>Perlecan homolog <it>trol </it>in both developmental and signaling contexts. These studies also highlight the fact that Trol function is not dedicated to a single molecular mechanism, but is capable of regulating different growth factor pathways depending on the cell-type and event underway.</p

Cam morphology but neither acetabular dysplasia nor pincer morphology is associated with osteophytosis throughout the hip: findings from a cross-sectional study in UK Biobank

Objectives: to examine whether acetabular dysplasia (AD), cam and/or pincer morphology are associated with radiographic hip osteoarthritis (rHOA) and hip pain in UK Biobank (UKB) and, if so, what distribution of osteophytes is observed.Design: participants from UKB with a left hip dual-energy X-ray absorptiometry (DXA) scan had alpha angle (AA), lateral centre-edge angle (LCEA) and joint space narrowing (JSN) derived automatically. Cam and pincer morphology, and AD were defined using AA and LCEA. Osteophytes were measured manually and rHOA grades were calculated from JSN and osteophyte measures. Logistic regression was used to examine the relationships between these hip morphologies and rHOA, osteophytes, JSN, and hip pain.Results: 6,807 individuals were selected (mean age: 62.7; 3382/3425 males/females). Cam morphology was more prevalent in males than females (15.4% and 1.8% respectively). In males, cam morphology was associated with rHOA [OR 3.20 (95% CI 2.41–4.25)], JSN [1.53 (1.24–1.88)], and acetabular [1.87 (1.48–2.36)], superior [1.94 (1.45–2.57)] and inferior [4.75 (3.44–6.57)] femoral osteophytes, and hip pain [1.48 (1.05–2.09)]. Broadly similar associations were seen in females, but with weaker statistical evidence. Neither pincer morphology nor AD showed any associations with rHOA or hip pain.Conclusions: cam morphology was predominantly seen in males in whom it was associated with rHOA and hip pain. In males and females, cam morphology was associated with inferior femoral head osteophytes more strongly than those at the superior femoral head and acetabulum. Further studies are justified to characterise the biomechanical disturbances associated with cam morphology, underlying the observed osteophyte distribution

Intravenous xenogeneic transplantation of human adipose-derived stem cells improves left ventricular function and microvascular integrity in swine myocardial infarction model

OBJECTIVES: The potential for beneficial effects of adipose-derived stem cells (ASCs) on myocardial perfusion and left ventricular dysfunction in myocardial ischemia (MI) has not been tested following intravenous delivery. METHODS: Surviving pigs following induction of MI were randomly assigned to 1 of 3 different groups: the placebo group (n = 7), the single bolus group (SB) (n = 7, 15 × 10(7) ASCs), or the divided dose group (DD) (n = 7, 5 × 10(7) ASCs/day for three consecutive days). Myocardial perfusion defect area and coronary flow reserve (CFR) were compared during the 28-day follow-up. Also, serial changes in the absolute number of circulating CD4(+) T and CD8(+) T cells were measured. RESULTS: The increases in ejection fraction were significantly greater in both the SB and the DD groups compared to the placebo group (5.4 ± 0.9%, 3.7 ± 0.7%, and -0.4 ± 0.6%, respectively), and the decrease in the perfusion defect area was significantly greater in the SB group than the placebo group (-36.3 ± 1.8 and -11.5 ± 2.8). CFR increased to a greater degree in the SB and the DD groups than in the placebo group (0.9 ± 0.2, 0.8 ± 0.1, and 0.2 ± 0.2, respectively). The circulating number of CD8(+) T cells was significantly greater in the SB and DD groups than the placebo group at day 7 (3,687 ± 317/µL, 3,454 ± 787/µL, and 1,928 ± 457/µL, respectively). The numbers of small vessels were significantly greater in the SB and the DD groups than the placebo group in the peri-infarct area. CONCLUSIONS: Both intravenous SB and DD delivery of ASCs are effective modalities for the treatment of MI in swine. Intravenous delivery of ASCs, with its immunomodulatory and angiogenic effects, is an attractive noninvasive approach for myocardial rescue

SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance

Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into an epithelial-mesenchymal gradient of RMC cells associated with loss of renal epithelial transcription factors TFCP2L1, HOXB9 and MITF and gain of MYC and NFE2L2-associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells

Short Term Synaptic Depression Imposes a Frequency Dependent Filter on Synaptic Information Transfer

Depletion of synaptic neurotransmitter vesicles induces a form of short term depression in synapses throughout the nervous system. This plasticity affects how synapses filter presynaptic spike trains. The filtering properties of short term depression are often studied using a deterministic synapse model that predicts the mean synaptic response to a presynaptic spike train, but ignores variability introduced by the probabilistic nature of vesicle release and stochasticity in synaptic recovery time. We show that this additional variability has important consequences for the synaptic filtering of presynaptic information. In particular, a synapse model with stochastic vesicle dynamics suppresses information encoded at lower frequencies more than information encoded at higher frequencies, while a model that ignores this stochasticity transfers information encoded at any frequency equally well. This distinction between the two models persists even when large numbers of synaptic contacts are considered. Our study provides strong evidence that the stochastic nature neurotransmitter vesicle dynamics must be considered when analyzing the information flow across a synapse