How I do it: Pedal access and pedal loop revascularization for patients with chronic limb-threatening ischemia.

An increasing proportion of patients with chronic limb-threatening ischemia are older and have multiple comorbidities, including diabetes and renal failure. For those who are not candidates for a surgical bypass, this set of patients presents a challenge to vascular surgeons and interventionalists owing to the complex below-the-knee and increasingly below-the-ankle disease pattern that can fail traditional approaches for endovascular intervention. Two techniques, the retrograde pedal access and the pedal-plantar loop technique, can be useful in these settings and in skilled hands can be used safely, with a high technical success rate. In patients with chronic limb-threatening ischemia who are not candidates for a single-segment saphenous vein bypass, the retrograde pedal access technique can be used not only in the setting of failed antegrade treatment, but also primarily when faced with a difficult groin or as an adjunct during a planned antegrade-retrograde intervention. The pedal plantar loop technique allows for retrograde access to tibial vessels without retrograde vessel puncture and additionally offers the ability to treat the pedal-plantar arch, which may have added benefit in wound healing. We describe the tips and tricks for these two techniques used in our limb salvage practice.

Lytic Therapy for Retained Traumatic Hemothorax: A Systematic Review and Meta-analysis.

BACKGROUND: Intrapleural lytic therapy has been established as an important modality of treatment for many pleural disorders, including hemothorax and empyema. Retained traumatic hemothorax is a common and understudied subset of pleural disease. The current standard of care for retained traumatic hemothorax is operative management. The use of lytic therapy for avoidance of operative intervention in the trauma population has not been well established. METHODS: Randomized controlled trials (RCTs) and non-RCTs reporting operative intervention following the use of intrapleural lytic treatment for retained traumatic hemothorax were identified in the literature. The primary outcome was avoidance of surgery following treatment with any lytic agent. Meta-analysis was performed to pool the results of those studies. Subgroup analysis by type of lytic therapy and analysis of length of stay were also performed. RESULTS: One RCT and nine non-RCTs including 162 patients were pooled in the analysis. Avoidance of surgery following treatment with any lytic agent was found to be 87% (95% CI, 81%-92%). Tissue plasminogen activator resulted in 83% operative avoidance (95% CI, 71%-94%), and other, non-tissue plasminogen activator lytic agents resulted in 87% operative avoidance (95% CI, 82%-93%). The average length of stay for patients undergoing lytic therapy was 14.88 days (95% CI, 12.88-16.88). CONCLUSIONS: Lytic therapy could reduce the need for operative intervention in trauma patients with retained traumatic hemothorax. RCTs are indicated to definitively evaluate the benefit of this approach.

Comparison of arterial pressure and plasma ANG II responses to three methods of subcutaneous ANG II administration.

Angiotensin II (ANG II)-induced hypertension is a commonly studied model of experimental hypertension, particularly in rodents, and is often generated by subcutaneous delivery of ANG II using Alzet osmotic minipumps chronically implanted under the skin. We have observed that, in a subset of animals subjected to this protocol, mean arterial pressure (MAP) begins to decline gradually starting the second week of ANG II infusion, resulting in a blunting of the slow pressor response and reduced final MAP. We hypothesized that this variability in the slow pressor response to ANG II was mainly due to factors unique to Alzet pumps. To test this, we compared the pressure profile and changes in plasma ANG II levels during subcutaneous ANG II administration (150 ng·kg(-1)·min(-1)) using either Alzet minipumps, iPrecio implantable pumps, or a Harvard external infusion pump. At the end of 14 days of ANG II, MAP was highest in the iPrecio group (156 ± 3 mmHg) followed by Harvard (140 ± 3 mmHg) and Alzet (122 ± 3 mmHg) groups. The rate of the slow pressor response, measured as daily increases in pressure averaged over days 2-14 of ANG II, was similar between iPrecio and Harvard groups (2.7 ± 0.4 and 2.2 ± 0.4 mmHg/day) but was significantly blunted in the Alzet group (0.4 ± 0.4 mmHg/day) due to a gradual decline in MAP in a subset of rats. We also found differences in the temporal profile of plasma ANG II between infusion groups. We conclude that the gradual decline in MAP observed in a subset of rats during ANG II infusion using Alzet pumps is mainly due to pump-dependent factors when applied in this particular context.

Bone marrow stromal and vascular smooth muscle cells have chemosensory capacity via bitter taste receptor expression.

The ability of cells to detect changes in the microenvironment is important in cell signaling and responsiveness to environmental fluctuations. Our interest is in understanding how human bone marrow stromal-derived cells (MSC) and their relatives, vascular smooth muscle cells (VSMC), interact with their environment through novel receptors. We found, through a proteomics screen, that MSC express the bitter taste receptor, TAS2R46, a protein more typically localized to the taste bud. Expression was also confirmed in VSMCs. A prototypical bitter compound that binds to the bitter taste receptor class, denatonium, increased intracellular calcium release and decreased cAMP levels as well as increased the extracellular release of ATP in human MSC. Denatonium also bound and activated rodent VSMC with a change in morphology upon compound exposure. Finally, rodents given denatonium in vivo had a significant drop in blood pressure indicating a vasodilator response. This is the first description of chemosensory detection by MSC and VSMCs via a taste receptor. These data open a new avenue of research into discovering novel compounds that operate through taste receptors expressed by cells in the marrow and vascular microenvironments.

Time-dependent changes in autonomic control of splanchnic vascular resistance and heart rate in ANG II-salt hypertension.

Previous studies suggest that ANG II-induced hypertension in rats fed a high-salt (HS) diet (ANG II-salt hypertension) has a neurogenic component dependent on an enhanced sympathetic tone to the splanchnic veins and independent from changes in sympathetic nerve activity to the kidney or hind limb. The purpose of this study was to extend these findings and test whether altered autonomic control of splanchnic resistance arteries and the heart also contributes to the neurogenic component. Mean arterial pressure (MAP), heart rate (HR), superior mesenteric artery blood flow, and mesenteric vascular resistance (MVR) were measured during 4 control days, 14 days of ANG II delivered subcutaneously (150 ng·kg(-1)·min(-1)), and 4 days of recovery in conscious rats fed a HS (2% NaCl) or low-salt (LS; 0.1% NaCl) diet. Autonomic effects on MAP, HR, and MVR were assessed by acute ganglionic blockade with hexamethonium (20 mg/kg iv) on day 3 of control, days 1, 3, 5, 7, 10, and 13 of ANG II, and day 4 of recovery. MVR increased during ANG II infusion in HS and LS rats but remained elevated only in HS rats. Additionally, the MVR response to hexamethonium was enhanced on days 10 and 13 of ANG II selectively in HS rats. Compared with LS rats, HR in HS rats was higher during the 2nd wk of ANG II, and its response to hexamethonium was greater on days 7, 10, and 13 of ANG II. These results suggest that ANG II-salt hypertension is associated with delayed changes in autonomic control of splanchnic resistance arteries and the heart.

Neural mechanisms of angiotensin II-salt hypertension: implications for therapies targeting neural control of the splanchnic circulation.

Chronically elevated plasma angiotensin II (AngII) causes a salt-sensitive form of hypertension that is associated with a differential pattern of peripheral sympathetic outflow. This "AngII-salt sympathetic signature" is characterized by a transient reduction in sympathetic nervous system activity (SNA) to the kidneys, no change in SNA to skeletal muscle, and a delayed activation of SNA to the splanchnic circulation. Studies suggest that the augmented sympathetic influence on the splanchnic vascular bed increases vascular resistance and decreases vascular capacitance, leading to hypertension via translocation of blood volume from the venous to the arterial circulation. This unique sympathetic signature is hypothesized to be generated by a balance of central excitatory inputs and differential baroreceptor inhibitory inputs to sympathetic premotor neurons in the rostral ventrolateral medulla. The relevance of these findings to human hypertension and the future development of targeted sympatholytic therapies are discussed.

Single-quantum-dot-based DNA nanosensor.

Rapid and highly sensitive detection of DNA is critical in diagnosing genetic diseases. Conventional approaches often rely on cumbersome, semi-quantitative amplification of target DNA to improve detection sensitivity. In addition, most DNA detection systems (microarrays, for example), regardless of their need for target amplification, require separation of unhybridized DNA strands from hybridized stands immobilized on a solid substrate, and are thereby complicated by solution-surface binding kinetics. Here, we report an ultrasensitive nanosensor based on fluorescence resonance energy transfer (FRET) capable of detecting low concentrations of DNA in a separation-free format. This system uses quantum dots (QDs) linked to DNA probes to capture DNA targets. The target strand binds to a dye-labelled reporter strand thus forming a FRET donor-acceptor ensemble. The QD also functions as a concentrator that amplifies the target signal by confining several targets in a nanoscale domain. Unbound nanosensors produce near-zero background fluorescence, but on binding to even a small amount of target DNA (approximately 50 copies or less) they generate a very distinct FRET signal. A nanosensor-based oligonucleotide ligation assay has been demonstrated to successfully detect a point mutation typical of some ovarian tumours in clinical samples.