Roadmap for the expression of canonical and extended endocannabinoid system receptors and metabolic enzymes in peripheral organs of preclinical animal models.

The endocannabinoid system is widely expressed throughout the body and is comprised of receptors, ligands, and enzymes that maintain metabolic, immune, and reproductive homeostasis. Increasing interest in the endocannabinoid system has arisen due to these physiologic roles, policy changes leading to more widespread recreational use, and the therapeutic potential of Cannabis and phytocannabinoids. Rodents have been the primary preclinical model of focus due to their relative low cost, short gestational period, genetic manipulation strategies, and gold-standard behavioral tests. However, the potential for lack of clinical translation to non-human primates and humans is high as cross-species comparisons of the endocannabinoid system have not been evaluated. To bridge this gap in knowledge, we evaluate the relative gene expression of 14 canonical and extended endocannabinoid receptors in seven peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and non-human primate rhesus macaques. Notably, we identify species- and organ-specific heterogeneity in endocannabinoid receptor distribution where there is surprisingly limited overlap among the preclinical models. Importantly, we determined there were no receptors with identical expression patterns among mice (three males and two females), rats (six females), and rhesus macaques (four males). Our findings demonstrate a critical, yet previously unappreciated, contributor to challenges of rigor and reproducibility in the cannabinoid field, which has implications in hampering progress in understanding the complexity of the endocannabinoid system and development of cannabinoid-based therapies.

Roadmap For The Expression Of Canonical and Extended Endocannabinoid System Receptors and Proteins in Peripheral Organs of Preclinical Animal Models.

The endocannabinoid system is widely expressed throughout the body and is comprised of receptors, ligands, and enzymes that maintain metabolic, immune, and reproductive homeostasis. Increasing interest in the endocannabinoid system has arisen due to these physiologic roles, policy changes leading to more widespread recreational use, and the therapeutic potential of Cannabis and phytocannabinoids. Rodents have been the primary preclinical model of focus due to their relative low cost, short gestational period, genetic manipulation strategies, and gold-standard behavioral tests. However, the potential for lack of clinical translation to non-human primates and humans is high as cross-species comparisons of the endocannabinoid system has not been evaluated. To bridge this gap in knowledge, we evaluate the relative gene expression of 14 canonical and extended endocannabinoid receptors in seven peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and non-human primate rhesus macaques. Notably, we identify species- and organ-specific heterogeneity in endocannabinoid receptor distribution where there is surprisingly limited overlap among the preclinical models. Importantly, we determined there were only five receptors (CB2, GPR18, GPR55, TRPV2, and FAAH) that had identical expression patterns in mice, rats, and rhesus macaques. Our findings demonstrate a critical, yet previously unappreciated, contributor to challenges of rigor and reproducibility in the cannabinoid field, which has profound implications in hampering progress in understanding the complexity of the endocannabinoid system and development of cannabinoid-based therapies.

Sustained in vivo release from imprinted therapeutic contact lenses.

In this paper, we demonstrate the successful in vivo extended release of a small molecular weight therapeutic, ketotifen fumarate (MW=425), from molecularly imprinted, therapeutic contact lenses. This is the first time that a steady, effective concentration of drug is maintained in the tear film from a contact lens for an extended period of time for the entire duration of lens wear. Poly(HEMA-co-AA-co-AM-co-NVP-co-PEG200DMA) soft contact lenses were prepared (100±5 µm thickness, diameter 11.8 mm, power zero), and a constant tear film concentration of 170±30 µg/mL was measured for up to 26 hrs in a New Zealand white rabbit model. The results showed a dramatic increase in ketotifen mean residence time (MRT) and bioavailability compared to topical drop therapy and drug soaked lenses. The MRT for imprinted lenses was 12.47±3.99 hrs, ~4 and 50 fold greater than non-imprinted lenses and 0.035% eye drops (Zaditor®), respectively. Furthermore, AUC(0-26 hrs) was 9 and 94 fold greater for imprinted lenses than non-imprinted lenses and eye drops, respectively. The results indicate that molecular imprinting provides an exciting rational engineering strategy for sustained release. It is clear that imprinted lenses are very promising combination devices and are much more effective and efficient delivery devices than eye drops.

Classification and differentiation of the genus Peganum indigenous to China based on chloroplast trnL-F and psbA-trnH sequences and seed coat morphology.

The genus Peganum (Zygophyllaceae) consists of six species and one subspecies; three of which are distributed in China, P. harmala Linn, P. nigellastrum Bunge and P. multisectum (Maxim.) Bobr. A probable new or intermediate species, Peganum sp., has been suggested in the wild in northwest China. Traditional classification in genus Peganum has focused on hairs on the plant surface. In this study, seed coat characteristics of Peganum species were investigated using light and scanning electron microscopy, demonstrating clear differences in morphology between species. In addition, DNA sequence data from two sequences (chloroplast: trnL-F, psbA-trnH) were used to differentiate Peganum sp. and study polygenetic relationships. Diversity in DNA sequences among Peganum species was found, with inter-specific sequence divergence ranging from 0.6% to 5.6% in psbA-trnH, and 0.0% to 1.8% in trnL-F. The variations within species were low: from 0.0% to 0.4% in psbA-trnH and 0.0% to 0.4% in trnL-F. Therefore, Peganum species can now be easily identified as separate entities based on variations in DNA sequences. Phylogenetic trees were constructed from the combined data set for the two gene fragments, and the results indicate that Peganum sp. is monophyletic and sister to P. harmala and P. nigellastrum, while P. multisectum is also monophyletic. DNA data further confirmed that P. multisectum is an independent species and that a new species, Peganum sp., exists within the genus Peganum growing wild in China.

Tips and tricks in renal artery angioplasty and stenting: angiography, stent placement, embolic protection, complications, and contrast induced nephropathy.

Patient selection and a thorough understanding of the technical aspects of percutaneous transluminal renal artery stent placement (PTRS) are paramount to obtaining optimal outcomes. The purpose of this paper is to review renal artery angiography and stent placement techniques. Tips and tricks for successful procedural outcome are described. The potential role of embolic protection devices is discussed and practices for avoiding complications including contrast induced nephropathy are reviewed.

A self-sustaining ultrahigh-frequency nanoelectromechanical oscillator.

Sensors based on nanoelectromechanical systems vibrating at high and ultrahigh frequencies are capable of levels of performance that surpass those of larger sensors. Nanoelectromechanical devices have achieved unprecedented sensitivity in the detection of displacement, mass, force and charge. To date, these milestones have been achieved with passive devices that require external periodic or impulsive stimuli to excite them into resonance. Here, we demonstrate an autonomous and self-sustaining nanoelectromechanical oscillator that generates continuous ultrahigh-frequency signals when powered by a steady d.c. source. The frequency-determining element in the oscillator is a 428 MHz nanoelectromechanical resonator that is embedded within a tunable electrical feedback network to generate active and stable self-oscillation. Our prototype nanoelectromechanical oscillator exhibits excellent frequency stability, linewidth narrowing and low phase noise performance. Such ultrahigh-frequency oscillators provide a comparatively simple means for implementing a wide variety of practical sensing applications. They also offer intriguing opportunities for nanomechanical frequency control, timing and synchronization.

Infrapopliteal drug-eluting stents for chronic limb ischemia.

OBJECTIVE: We report our experience with the elective placement of below-knee, drug-eluting stents in patients with chronic limb ischemia. BACKGROUND: Infrapopliteal percutaneous transluminal angioplasty has been associated with a lower rate of procedural success and high rate of restenosis because of the small size of the tibial vessels and the prevalence of calcified and diffuse atherosclerotic disease. Prior published data reports 3-year patency rates below 25%. Bare metal stents have been reported in bailout situations. Drug-eluting stents have markedly reduced restenosis compared to bare metal stents in the coronary vasculature, but there is little data supporting the use of these devices below the knee. METHODS: Elective placement of drug-eluting stents in infrapopliteal lesions was performed on 10 patients with severe (> or =Fontaine Stage IIb) claudication (n = 1) or limb-threatening ischemia (n = 9) (rest pain, nonhealing ulcers and gangrene). RESULTS: A total of 17 drug-eluting stents were electively placed in 12 below-knee arteries in 10 patients, resulting in an average of 1.7 +/- 0.7 stents per patient. The mean lesion length was 24.8 +/- 10.9 mm, the mean total stent length was 38.3 +/- 19.1 mm, and the mean nominal stent diameter was 2.8 +/- 0.3 mm. One patient required target vessel revascularization (TVR) at 3 weeks because of stent thrombosis. TVR was 10% at 12.4 +/- 6.5 months of follow-up. Clinically driven angiography in three different patients was performed at 4, 15, and 16 months and confirmed drug-eluting stent patency in each case. CONCLUSIONS: The use of below-knee drug-eluting stents is feasible and appears to be safe in our small series of complex infrapopliteal lesions causing chronic limb ischemia. The occurrence of a single case of stent thrombosis warrants continued observation in this cohort. Prospective clinical trials will be necessary to confirm the benefits and justify the costs of this strategy for treating patients with infrapopliteal culprit lesions and chronic limb ischemia.

Carotid artery intervention.

Atherosclerotic carotid artery disease is a major contributor to the incidence of stroke, particularly in the elderly. Atherosclerosis is a systemic illness and patients often present with multisystem involvement of several vascular beds including coronary, cerebral, and peripheral vascular territories. The majority of strokes related to carotid artery disease are embolic in nature, not occlusive. Non-invasive screening tests including ultrasound, CT angiography and MR angiography are helpful in identifying pathology. However, the gold standard, for diagnosis and treatment allocation remains invasive angiography. Medical therapy to reduce the risk of stroke includes antiplatelet agents, primarily aspirin in doses of 81 mg to 325 mg per day. Control of blood pressure and the use of statin therapy is effective in reducing the incidence of stroke. Carotid endarterectomy is more effective for preventing stroke in symptomatic (transient ischemic attack or stroke) patients with = or >50% diameter stenosis and asymptomatic patients with = or >60% diameter stenosis, than aspirin therapy. In patients at increased risk for surgical complications during stroke prevention surgery (carotid endarterectomy), carotid stents have been shown to be as good or better than surgery at improving outcomes.

Astragaloside IV and polysaccharide production by hairy roots of Astragalus membranaceus in bioreactors.

Hairy roots of Astragalus membranaceus were grown in bioreactors up to 30 l for 20 d. Cultures from a 30 l airlift bioreactor gave 11.5 g l dry wt with 1.4 mg g(-1) astragaloside IV, similar to cultures from 250 ml and 1 l flasks, but greater than yields from a 10 l bioreactor (dry wt 9.4 g l(-1), astragaloside IV 0.9 mg g(-1)). Polysaccharide yields were similar amongst the different bioreactors (range 25-32 mg g(-1)). The active constituent content of the cells approached that of plant extracts, indicating that large scale hairy root cultures of A. membranaceus has the potential to provide an alternative to plant crops without compromising yield or pharmacological potential.

Penetrating atherosclerotic ulcer of the aorta.

PURPOSE: To describe a case of penetrating atherosclerotic ulcer of the aorta with a review of its natural history, diagnosis and management. CASE REPORT: An elderly patient with a history of hypertension presented to the emergency room with the sudden onset of severe chest pain radiating to the back. The electrocardiogram showed left ventricular hypertrophy; the chest radiograph revealed mediastinal widening. Computed tomography was suspicious for a mediastinal hematoma without aortic dissection. Transesophageal echocardiography was also negative for dissection. An aortogram revealed a penetrating atherosclerotic ulcer of the descending thoracic aorta. The patient underwent successful resection and repair of the lesion. CONCLUSIONS: Penetrating atherosclerotic ulcer of the aorta is a potentially lethal lesion that must be promptly diagnosed and treated.

Vertebral artery stenting.

The safety and efficacy of endoluminal stenting in treating atherosclerotic vertebral artery disease was evaluated in 38 vessels in 32 patients. Indications for revascularization included diplopia (n = 4), blurred vision (n = 4), dizziness (n = 23), transient ischemic attacks (n = 4), drop attack (n = 1), gait disturbance (n = 1), headache (n = 2), and asymptomatic critical stenosis (n = 1). Success (< 20% residual diameter stenosis, without stroke or death) was achieved in all 32 patients (100%). One patient experienced a transient ischemic attack (TIA) 1 hr after the procedure. At follow-up (mean, 10.6 months), all patients (100%) were alive and 31/32 (97%) were asymptomatic. One patient (3%) had in-stent restenosis at 3.5 months and underwent successful balloon angioplasty. Endoluminal stenting of vertebral artery lesions is safe, effective, and durable as evidenced by the low recurrence rate. Primary stent placement is an attractive option for atherosclerotic vertebral artery stenotic lesions. Cathet Cardiovasc Intervent 2001;54:1-5.

Treatment of femoral artery pseudoaneurysm with percutaneous thrombin injection.

Pseudoaneurysm formation of the femoral artery is a well-known complication following catheter-based vascular procedures. Ultrasound-guided compression or surgical correction are commonly used for its repair. We describe a new method of treatment for femoral pseudoaneurysm. The pseudoaneurysm is visualized by contralateral angiography and thrombosed with a percutaneous thrombin injection while the distal vessel is isolated with a brief balloon inflation. Fluoroscopically guided percutaneous thrombin injection is a promising, minimally invasive technique for the treatment of iatrogenic pseudoaneurysm, especially in patients with compromised distal circulation.

Provisional stenting for symptomatic intracranial stenosis using a multidisciplinary approach: acute results, unexpected benefit, and one-year outcome.

Percutaneous techniques have dramatically changed our approach to coronary and peripheral revascularization. Intracranial atherosclerosis is a highly morbid disease; however, techniques for revascularization are still in evolution. The authors comprise a multidisciplinary team of neurologists, neuroradiologists, and interventional cardiologists who have collaborated in treating fifteen patients with symptomatic intracranial stenosis who have failed medical therapy. The acute success rate (100%) and one-year freedom from death and stroke (93.4%) using balloon angioplasty and provisional stenting are encouraging. A surprising observation in this patient cohort was that 53% of patients had improvement or resolution of a deficit that was chronic and presumed to be permanent and irreversible. This type of chronic but reversible deficit is termed "brain angina". The background, rationale for a multidisciplinary team, techniques, and preliminary results of intracranial angioplasty with provisional stenting are presented.

Dynamic phase transition, universality, and finite-size scaling in the two-dimensional kinetic Ising model in an oscillating field.

We study the two-dimensional kinetic Ising model below its equilibrium critical temperature, subject to a square-wave oscillating external field. We focus on the multidroplet regime, where the metastable phase decays through nucleation and growth of many droplets of the stable phase. At a critical frequency, the system undergoes a genuine nonequilibrium phase transition, in which the symmetry-broken phase corresponds to an asymmetric stationary limit cycle for the time-dependent magnetization. We investigate the universal aspects of this dynamic phase transition at various temperatures and field amplitudes via large-scale Monte Carlo simulations, employing finite-size scaling techniques adopted from equilibrium critical phenomena. The critical exponents, the fixed-point value of the fourth-order cumulant, and the critical order-parameter distribution all are consistent with the universality class of the two-dimensional equilibrium Ising model. We also study the cross-over from the multidroplet regime to the strong-field regime, where the transition disappears.

Percutaneous profundaplasty in the treatment of lower extremity ischemia: results of long-term surveillance.

PURPOSE: To assess the procedural and long-term clinical outcomes of balloon angioplasty of the profunda femoris artery in patients with severe limb ischemia. METHODS: Thirty-one consecutive patients were evaluated for severe ischemia in 32 limbs: 13 (41%) were categorized Fontaine class 2B, and 19 (59%) were class 3 or 4. The superficial femoral artery was occluded in 20 (62%) limbs; an additional vessel was treated in 22 (69%) limbs. RESULTS: Procedural success was achieved in 91% (31/32) of limbs. The ankle-brachial index increased from 0.5 +/- 0.2 at baseline to 0.7 +/- 0.2 after intervention (p < 0.01). In-hospital limb salvage was 94% (30/32), and in-hospital event-free survival was 90% (28/31). At a mean follow-up of 34 +/- 20 months, no additional amputations were necessary; 3 patients required repeat revascularization, and 5 patients died. Freedom from revascularization was 88% in the 25 survivors. At follow-up, 88% of the patients had Fontaine class 1 or 2A symptoms, and only 12% had Fontaine class 2B or higher (p < 0.001 compared with baseline). CONCLUSIONS: These data suggest that percutaneous profundaplasty is safe, effective, and may be considered as an alternative to surgical therapy in patients with anatomically suitable lesions.

Reduction in QT dispersion with rheolytic thrombectomy in acute myocardial infarction: evidence of electrial stability with reperfusion therapy.

An increase in QT dispersion (QTd) is associated with myocardial ischemia and may serve as a marker of ischemia and ventricular arrhythmia. We studied the effect of early reperfusion with rheolytic thrombectomy using an angiojet catheter (Possis, Minneapolis, MN) on QTd in 12 patients who presented with acute myocardial infarction. QTd and QT dispersion, rate-corrected for RR interval, were significantly reduced from 57 +/- 16 and 68 +/- 13 msec before reperfusion to 34 +/- 16 and 44 +/- 19 msec after reperfusion respectively (mean +/- SD; P < 0.002 and P < 0.0008, respectively). Successful reperfusion with rheolytic thrombectomy reduces QTd and may confer electrical stability to vulnerable myocardium. Reduction in indexes of repolarization inhomogeneity with reperfusion may serve as a noninvasive marker of coronary patency.

Non-surgical treatment of patients with peripheral vascular disease.

Dotter first described percutaneous revascularization of peripheral vascular disease (PVD) in 1964. In 1974, Gruentzig developed a balloon catheter for dilation of vascular lesions. Currently, percutaneous transluminal angioplasty (PTA) employs a variety of devices ranging from implantable stents to endovascular radiation devices for re-stenosis and is recognized as a safe and effective alternative to surgery for selected patients. In addition to the general efficacy of peripheral angioplasty, which is comparable to that of bypass surgery for selected lesions, angioplasty offers several distinct advantages over surgery. It is performed under local anaesthesia, making it feasible to treat patients who are at high risk for general anaesthesia. When compared to surgical revascularization, the morbidity from angioplasty is low, generally related to problems at the vascular access site, and mortality is extremely rare. Unlike vascular surgery, there is no recovery period after angioplasty, and most patients can return to normal activity within 24-48 h of an uncomplicated procedure. Finally, angioplasty can be repeated if necessary usually without increased difficulty or increased patient risk compared to the first procedure, and does not preclude surgery as adjunctive or definitive therapy.

Global revascularization.

Percutaneous endovascular intervention has revolutionized the treatment of peripheral vascular disease by allowing successful treatment of patients who are not good surgical candidates. Cardiologists with peripheral vascular training are more readily able to identify patients with concomitant peripheral arterial disease. It has been our experience that the technical skills necessary to perform coronary angioplasty are transferable to the peripheral vasculature. However, an understanding of the natural history of peripheral disease and of patient and lesion selection criteria, and the knowledge of other treatment alternatives are essential elements required to perform these procedures safely and effectively. There are inherent advantages for patients when the interventionalist performing the procedure is also the clinician responsible for the pre- and post-procedure care, analogous to the vascular surgeon who cares for patients before and after surgical procedures. In view of the increased incidence of coronary artery disease in patients with atherosclerotic peripheral vascular disease, the participation of a cardiologist in their care seems appropriate.

Carotid stent placement for extracranial carotid artery disease: current state of the art.

Percutaneous revascularization techniques have dramatically altered traditional approaches to the management of both coronary and peripheral vascular disease. Their major advantage is that they are less invasive than conventional surgical procedures, offering revascularization without the risk of general anesthesia and with lesser procedural morbidity and mortality, shorter hospital stay, and lower cost. In patients with comorbidities that increase their risk of surgical complications, percutaneous revascularization techniques are the procedures of choice. The Achilles heel of balloon angioplasty, the higher risk of lesion recurrence, restenosis, has been markedly reduced with the use of endovascular stents. Over the past 20 years, percutaneous angioplasty and stenting have become accepted alternatives to surgical revascularization of aortoiliac, renal, femoropopliteal, subclavian, brachiocephalic, and dialysis access lesions. The most recent application of percutaneous intervention has been to explore its clinical utility and safety for stroke prevention in stenotic extracranial carotid arteries. Cathet. Cardiovasc. Intervent. 51:339-346, 2000.