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Background: Drug-coated balloons (DCBs) have shown promise in improving the outcomes for patients with peripheral artery disease. We compared a paclitaxel-coated balloon with percutaneous transluminal angioplasty (PTA) for the treatment of symptomatic superficial femoral and popliteal artery disease., Methods and Results: The IN.PACT SFA Trial is a prospective, multicenter, single-blinded, randomized trial in which 331 patients with intermittent claudication or ischemic rest pain attributable to superficial femoral and popliteal peripheral artery disease were randomly assigned in a 2:1 ratio to treatment with DCB or PTA. The primary efficacy end point was primary patency, defined as freedom from restenosis or clinically driven target lesion revascularization at 12 months. Baseline characteristics were similar between the 2 groups. Mean lesion length and the percentage of total occlusions for the DCB and PTA arms were 8.94 ± 4.89 and 8.81 ± 5.12 cm (P=0.82) and 25.8% and 19.5% (P=0.22), respectively. DCB resulted in higher primary patency versus PTA (82.2% versus 52.4%; P<0.001). The rate of clinically driven target lesion revascularization was 2.4% in the DCB arm in comparison with 20.6% in the PTA arm (P<0.001). There was a low rate of vessel thrombosis in both arms (1.4% after DCB and 3.7% after PTA [P=0.10]). There were no device- or procedure-related deaths and no major amputations., Conclusions: In this prospective, multicenter, randomized trial, DCB was superior to PTA and had a favorable safety profile for the treatment of patients with symptomatic femoropopliteal peripheral artery disease., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique Identifiers: NCT01175850 and NCT01566461., (© 2014 The Authors.)

We have examined the participation of NK1 receptors in neuropathic pain by comparing behavioural responses after partial sciatic nerve ligation in wild-type (WT) and NK1 receptor knockout (KO) mice. Mechanical responses were tested with von Frey hairs, and cooling responses with acetone. WT and KO mice showed similar reactions before surgery. Nerve-ligated WT and KO mice showed equivalent spontaneous pain-related behaviour. Mechanical (mean threshold 20 +/- vs 9 +/- 1 mN) and cold allodynia (61 +/- vs 14 +/- 2 behaviours evoked by acetone) were significantly greater than in sham animals, but similar in WT and KO mice. We conclude that NK1 receptors are not essential for mechanical and cold allodynia evoked by partial nerve ligation.

To clarify the mechanisms of allodynia we have examined whether 'wind-up' of nociceptive withdrawal reflexes (NWR), a phenomenon characteristic of nociceptive C fiber spinal processing, can be mimicked by stimulation of tactile A beta fibers in monoarthritic decerebrate spinal rats. Knee joint monoarthritis was induced by carrageenan/kaolin under halothane anaesthesia 5 h before recordings. In arthritic, but not in control rats, wind-up of NWR of the semitendinosus muscle could be evoked by repeated stimulation of A beta fibres. By contrast, peroneus longus reflexes did not exhibit marked wind-up. Bicuculline (0.03-0.3 mg/kg, i.v.) dose-dependently inhibited this wind-up. Hence, reflex wind-up can be elicited by tactile A beta fibers in arthritis rats through a GABAA dependent mechanism.

Background: Previous reports have suggested higher procedural and long-term complications among patients treated with multiple stents for diffuse lesions and/or long dissections., Methods and Results: To evaluate procedural success, major complications, and clinical outcomes (> or = 1 year) in a consecutive series of patients treated with multiple (> or = 3) contiguous stents in single lesions, we evaluated in-hospital and long-term (1-year) clinical outcomes in 117 consecutive patients treated with > or = 3 coronary stents compared with a concurrent series of patients treated with 1 or 2 stents (n=1673) between January 1, 1994, and December 31, 1995. Multiple stents were implanted more often in larger vessels, in the right coronary artery or saphenous vein grafts, and for unfavorable lesion characteristics, including long (>20 mm), calcified, ulcerated, thrombotic, and/or flow-obstructing lesions. Overall procedural success was obtained in 97.4% of patients and was similar whether 1 or 2 versus > or = 3 stents were used. Non-Q-wave MI (CK-MB > or = 5 times normal) was more frequent after > or = 3 stents (22.8% versus 13.4%, P=.005). Target lesion revascularization (TLR) was 14.6% for 1 or 2 stents and 13.3% for > or = 3 stents (P=.70). There was no difference in death (2.2% versus 0.9%, P=.34) or Q-wave MI (1.4% versus 0.9%, P=.64) between the two groups (1 or 2 stents versus > or = 3 stents, respectively), and overall cardiac event-free survival was similar during follow-up (P=.70)., Conclusions: Patients treated with multiple (> or = 3) contiguous stents compared with 1 or 2 stents have (1) similar in-hospital procedural success and major complications despite having more unfavorable lesion characteristics, (2) a higher rate of procedural non-Q-wave MI, and (3) similar TLR and overall major cardiac event rates during 1 year of follow-up.

Non-steroidal anti-inflammatory drugs inhibit constitutive (COX-1) and induced cyclooxygenase (COX-2), blocking prostaglandin production. We have compared the effects on nociceptive reflexes of meloxicam, which is COX-2 selective, with indomethacin, which is non-selective, using an in vitro spinal cord preparation. Cords were taken from naive rats, and from rats with carrageenan-induced hyperalgesia of one hindpaw. Reflex thresholds were lower in carrageenan preparations. Superfusion with meloxicam (10-100 microM) dose-dependently inhibited baseline reflexes and wind-up in normal and carrageenan preparations, whereas indomethacin (100-300 microM) had no effect. Thus meloxicam inhibits spinal reflexes, whereas indomethacin does not, despite its high affinity for both COX isoforms. We conclude that meloxicam has spinal antinociceptive actions which cannot be explained by the current concept of COX inhibition.

We examined the separate and combined effects of hypohydration level and exercise intensity on aldosterone (ALD) and arginine vasopressin (AVP) responses during exercise-heat stress. Nine heat acclimated men performed 50 min of treadmill exercise in a warm room (30 degrees C dry bulb (DB), 50% relative humidity (RH) at 25%, 45% and 65% VO2max when euhydrated and when hypohydrated by 3% and 5% of body weight. Blood samples were drawn at rest and at 20 min of exercise. ALD and AVP increased (P < 0.05) in a graded manner with hypohydration level, and this effect persisted during exercise-heat stress. High intensity exercise produced greater ALD and AVP increases than low intensity exercise. ALD responses during exercise were independent of hypohydration level. AVP responses were closely related to osmolality (N = 6 of 7 subjects; r = 0.51 to r = 0.98; average r = 0.84) despite varying hydration, exercise intensity, or core temperature. We conclude that: 1) ALD and AVP increase in a graded manner with hypohydration, and this effect persists during exercise-heat stress; 2) ALD and AVP increases elicited by exercise are greater during high intensity than low intensity exercise; 3) Hypohydration and exercise intensity have additive effects on ALD: and 4) AVP responses are closely coupled to osmolality.

Background: Neointimal formation causes restenosis after intracoronary stent placement. Endovascular radiation delivered via a stent has been shown to reduce neointimal formation after placement in porcine and rabbit iliac arteries. The objective of this study was to evaluate the dose-related effects of a beta-particle-emitting radioactive stent in a porcine coronary restenosis model., Methods and Results: Thirty-seven swine underwent placement of 35 nonradioactive and 39 beta-particle-emitting stents with activity levels of 23.0, 14.0, 6.0, 3.0, 1.0, 0.5, and 0.15 microCi of 32P. Treatment effect was assessed by histological analysis 28 days after stent placement. Neointimal and medial smooth muscle cell density were inversely related to increasing stent activity. The neointima of the high-activity (3.0- to 23.0-microCi) stents consisted of fibrin, erythrocytes, occasional inflammatory cells, and smooth muscle cells with partial endothelialization of the luminal surface. In the 1.0-microCi stents, the neointima was expanded and consisted of smooth muscle cells and a proteoglycan-rich matrix. The neointima of the low-activity (0.15- and 0.5-microCi) stents was composed of smooth muscle cells and matrix with complete endothelialization of the luminal surface. At low and high stent activities, there was a reduction in neointimal area (low, 1.63 +/- 0.67 mm2 and high, 1.73 +/- 0.97 mm2 versus control, 2.40 +/- 0.87 mm2) and percent area stenosis (low, 26 +/- 7% and high, 26 +/- 12%) compared with control stents (37 +/- 12%, P < or = .01). The 1.0-microCi stents, however, had greater neointimal formation (4.67 +/- 1.50 mm2) and more luminal narrowing (64 +/- 16%) than the control stents (P < .0001)., Conclusions: The differential response to the doses of continuous beta-particle irradiation used in this experimental model suggests a complex biological interaction of endovascular radiation and vascular repair after stent placement. Further study is required to determine the clinical potential for this therapy to prevent stent restenosis.

Background: Restenosis after successful percutaneous transluminal coronary angioplasty is the major factor limiting the long-term effectiveness of this procedure. Neointimal proliferation in response to arterial injury is an important contributor to restenosis. The use of radiation for the treatment of malignant and benign proliferative conditions has been well established. External beam irradiation and endovascular irradiation by use of an after-loading technique have been shown to inhibit neointimal proliferation in experimental models of restenosis. The objective of this study was to investigate whether low-dose irradiation from a beta-particle-emitting stent would inhibit neointimal proliferation after placement in porcine iliac arteries., Methods and Results: Fourteen titanium-mesh stents were implanted in the iliac arteries of nine NIH miniature swine. There were seven beta-particle-emitting radioisotope stents (32P, activity level 0.14 microCi) and seven control stents (31P, nonradioactive). Treatment effect was assessed by angiography and histomorphological examination of the stented iliac segments 28 days after implantation. There was a significant reduction in neointimal area (1.76 +/- 0.37 mm2 versus 2.81 +/- 1.22 mm2, P = .05) and percent area stenosis (24.6 +/- 2.9% versus 36.0 +/- 10.7%, P = .02) within the beta-particle-emitting stents compared with the control stents. Neointimal thickness, which was assessed at each wire site, was also significantly less within the treatment stents (0.26 +/- 0.04 mm versus 0.38 +/- 0.10 mm, P = .012). Scanning electron microscopy was performed on sections from four stents. This demonstrated endothelialization of both the treatment and control stents. There was no excess inflammatory reaction or fibrosis in the media, adventitia, or perivascular space of vessels treated with the beta-particle-emitting stent compared with control vessels. At 28 days, there was no difference in smooth muscle cell proliferation as measured by the proliferating cell nuclear antigen index., Conclusions: A local, continuous source of low-dose endovascular irradiation via a beta-particle-emitting stent inhibits neointimal formation in porcine arteries. This low dose of local irradiation did not prevent endothelialization of the stents. This novel technique offers promise for the prevention of restenosis and warrants further investigation.

We examined whether stimulation of sensitive mechanoreceptors from an area of allodynia evokes nociceptor activity expressed as axon reflexes. Experiments were conducted on human volunteers. Cutaneous blood flow was measured with a laser Doppler flowmeter. Allodynia was induced with mustard oil (25-100%) or by intradermal injections of capsaicin (25-50 micrograms) in the skin of the forearm or the hand. Tactile stimulation of normal skin or outside zones of allodynia did not evoke axon reflexes. The same stimulation in areas of allodynia evoked pain as well as axon reflexes. Cooling the area of primary hyperalgesia or blocking the A fibres in the nerve that innervated the allodynia area abolished the allodynia and the axon reflex. These results demonstrate central interactions between sensitive mechanoreceptors and nociceptors concomitant with the development of allodynia.

Given the substantial reserve of normal myocardium, its inability to sustain life in the presence of 30-50% necrosis of the left ventricle (LV) seems a paradox. It is known that dyskinesia of the infarcted area probably plays a dominant role in initiating failure after an infarction. To study this problem, a well defined experimental infarction was produced by cryogenic means in 58 rabbits, and the animals were allowed to recover. Groups of rabbits were killed 4 hours and 1,2,5, or 10 days following infarction. As quickly as possible (within 4 minutes) a sample specimen from the infarcted area was removed from the LV and subjected to a force-elongation test while being bathed in Ringer solution at 37 degrees C equilibrated with 95% O2-5% CO2. The data were interpreted assuming an exponential stress-strain law with constants K and C. Mean values of K of 10.6 +/- 0.94 (SEM) were found for the noninfarcted control group, whereas, rather surprisingly, no significant trend in K over 10 days was found in the infarcted group. Mean values of K +/- SEM for the postinfarction groups were as follows: 4 hours, 9.51 +/- 0.63; 1 day 10.54 +/- 1.13; 2 days, 13.15 +/- 2.28; 5 days, 11.59 +/- 1.36; and over 10 days, 12.93 +/-1.02. The functional implications were estimated with a simple model of the shortening required of the viable muscle during the isovolumic phase. It was found that contractile reserve fell rapidly with increasing infarct size, reaching zero for a 60% infarct when K = 10. With K greater than 100, there was no appreciable reduction in reserve. With a constant infarct size, variation in reserve with the afterload-preload ration was found to be logarithmic.

The goal of this study was to develop, on a rational basis, an index of the intrinsic diastolic elastic properties of the left ventricle. A relatively simple analytic model employing a thin-walled spherical geometry coupled with an approximate formulation of a two-dimensional constitutive relation, was used to examine the primary determinants of the pressure-volume relationship of the intact heart. The results permit comparison with other indices of compliance or wall stiffness. The slope of the dP/dV vs P curve was found to be sensitive to the non-linear elastic constant K, but is also sensitive to variations in cardiac muscle volume. VdP/dV was found to be sensitive to pressure. m = d(log P)/d(log V) = (V/P)(dP/dV) is proposed as an index sensitive to K and relatively insensitive to both pressure and initial cardiac geometry. The index is compared with published studies. Using the data of Fester and Samet, mean values of the asymptotic log-log P-V slope, m, evaluated at end-diastole for normal, idiopathic hypertrophy, mild, moderate and severe coronary artery disease were 3.95 +/- 0.60 (SEM), 5.05 +/- 1.60, 5.24 +/- 0.96, 8.35 +/- 2.06, and 15.13 +/- 3.0, respectively. At values of LVEDP less than 7 mm Hg the concept of simple distension is questioned. The advantages and limitations of this approximate index are discussed. This index seems to afford a practical measure of the elastic properties of the wall over a rather wide range of pressure, volume, wall mass and wall thickness.