Genetically engineered analogs of ascomycin for nerve regeneration.

The polyketides FK506 (tacrolimus) and FK520 (ascomycin) are potent immunosuppressants that function by inhibiting calcineurin phosphatase through formation of an FKBP12-FK506/520-calcineurin ternary complex. They also have calcineurin-independent neuroregenerative properties in cell culture and animal models of nervous system disorders. Based on the crystal structure of the FKBP12-FK506-calcineurin complex, we deduced that the 13- and 15-methoxy groups of FK506 or FK520 are important for inhibition of calcineurin phosphatase but not for binding to FKBP12. By genetic modification of the FK520 gene cluster, we generated 13- and 15-desmethoxy analogs of FK520 that contain hydrogen, methyl, or ethyl instead of methoxy at one or both of these positions. These analogs bind FKBP12 tightly, have decreased calcineurin phosphatase inhibition and immunosuppressive properties, and enhance neurite outgrowth in cell cultures. A representative compound was also shown to accelerate nerve regeneration and functional recovery in the rat sciatic nerve crush model.

Bifurcated drum occluder endograft for treatment of abdominal aortic aneurysm: an experimental study in dogs.

PURPOSE: To evaluate a new, low profile, home-made, bifurcated drum occluder endograft (BDOEG), designed for percutaneous, transcatheter treatment of abdominal aortic aneurysm (AAA). MATERIALS AND METHODS: AAA was created in 10 dogs with over-dilated Palmaz stents. To prevent back filling, the lumbar arteries, inferior mesenteric artery, and common internal iliac arteries were embolized. The BDOEG was constructed of a drum occluder device and two PTFE endografts. The drum device consisted of a modified Z stent with Dacron stretched across and held within the ends of the stent, each with two 8 x 6-mm slits through which PTFE endografts were delivered. The PTFE endografts were 8 mm in diameter and 9.5 cm in length. Preloaded, the BDOEG was delivered through a 10-F sheath from both femoral arteries in a three-step procedure. All 10 animals were treated with BDOEG. Aortography was performed immediately, 6 weeks, and 12 weeks after stent-graft placement. Five animals were killed at 6 weeks and five were killed at 3 months. Gross and histologic evaluation was performed. RESULTS: The infrarenal aortic diameters and both external iliac arteries ranged from 8.0 mm to 10.3 mm (mean, 9.4 mm +/- 0.6) and from 5.2 mm to 6.8 mm (mean, 5.8 mm +/- 0.5), respectively. Creation of the AAA was successful in all 10 dogs. AAA diameters ranged from 13.7 mm to 15.9 mm (mean, 14.9 mm +/- 0.7). Complete exclusion of the AAA was achieved immediately after BDOEG placement and aneurysms remained excluded without perigraft leak to the time of killing in all 10 animals. There was a high incidence of aortoiliac limb occlusion. Occlusion of 12 aortoiliac limbs (60%) caused by intimal hyperplasia at the distal end of the endografts in iliac arteries developed in nine animals (90%). In six animals (60%), one limb occluded and, in three animals (30%), there was occlusion of both limbs. CONCLUSION: This study suggests a new approach for treatment of AAA. BDOEG use reduces sheath size for endograft delivery and may eliminate the need for a surgical cut down on femoral arteries. Tapering of the iliac ends of endografts to the size of the artery will be needed to prevent distal intimal hyperplasia.

Long-tip guiding catheter: successful and safe for left coronary artery angioplasty.

A long-tip guiding catheter was designed for angioplasty of the left coronary artery. Principal factors of guiding catheter function were identified, and the catheter's shape was designed to utilize them efficiently. Emphasis was placed on an overbent secondary curve (150-180 degrees) for more precise catheter control. The distal tip of the catheter is 2 cm long in the 4.0 size and the primary bend is shallow, approximately 20%. A 1.5 cm long segment between the secondary and tertiary curves enhances stability and support. Catheter performance was studied during procedures on 90 patients; 89 patients underwent coronary artery angioplasty and one patient underwent diagnostic angiography. The success rate for angioplasty was 95% with no major complications. Mild pressure damping occurred in 18 patients, and mild catheter displacement from the left main coronary artery occurred in 24 patients. Catheter support was judged as excellent to very good in 82 patients. Judkins or Amplatz catheters were not required during this study. The observed disadvantages of the long-tip catheter were the risk of catheter buckling up during advancement into the left main coronary artery and, perhaps, a higher risk of pressure damping. Superselective engagement of the catheter in the left anterior descending or circumflex arteries may be a problem when the left main coronary artery is very short. This study showed the long-tip catheter to be safe and highly successful for angioplasty of the left coronary artery.

Coronary artery dissection caused by angioplasty balloon rupture.

Three cases of coronary angioplasty balloon rupture complicated by coronary artery dissection are described. Factors that may predispose to this previously undescribed and potentially devastating complication are discussed.

Experience with endomyocardial biopsy in 23 patients with heart transplants.

In the 33-month period April 1985 to December 1987, endomyocardial biopsy was performed 314 times in 23 patients with orthotopic (21) or heterotopic (2) heart transplants at Baptist Medical Center. The technique is described. Adequate tissue was obtained in 99% of cases and there was only one complication from the procedure. Mild to severe acute rejection was seen in 105 specimens (33%). The histopathological interpretation has proved invaluable in the care of patients with heart transplants.

Angled tip of the steerable guidewire and its usefulness in percutaneous transluminal coronary angioplasty.

Theoretical analysis and clinical evaluation of single and multi-angled guidewires as an alternative to widely used J-wires suggested that the major determinants of the wire function are the shortest distance between the tip and a long axis of the wire-reaching distance (RD), angulation of the tip, and the length of the angled arm. Their relationship can be characterized by a formula; reaching distance = sin beta X length of the arm. The two clinically most useful multiple angulations--double and triple angles--were evaluated in 54 patients in whom commercial J-wire failed to pass the lesion in 120 s. This value was compared with an average time of 57.90 +/- 3.9 s needed to pass an angled, individually shaped guidewire from the tip of the guiding catheter through the lesion. (P much less than 0.001 or highly significant.) All patients had tortuous vessels, sharply angled branches, and the largest diameter of the stenosed vessel less than 50% of the largest diameter of the left main coronary artery. Thirty-seven lesions were in the obtuse marginal arteries and 17 in the diagonal arteries. The study suggested that angled guidewires shaped according to described guidelines have superior success to commercial, unshaped J-wires in instrumentation of the tortuous vessels with angled branches and markedly varying diameter.

"Isolength" postextrasystolic potentiation as a predictor of functional restoration following surgical revascularization for myocardial ischemia.

A previously developed method of programmed postextrasystolic potentiation (PESP) was assessed in eight patients with medically refractory unstable angina, as a predictor of functional restoration resulting from surgical revascularization. Prior to coronary arteriography, left ventricular segmental wall motion was determined during ventricular pacing and the first postextrasystolic beat following an extrasystole. The postextrasystole was induced at an interval calculated to occur at a time where ventricular preload was identical to the regular paced beat (isolength interval). The left ventricular wall was divided into six segments, each subscribing one area of the ventriculogram, and correction for rotation during systole was made. Of 48 segments, 21 were considered "jeopardized," due to greater than 70% reduction in cross-sectional lumen of the serving coronary arteries. Fifteen of these 21 responded to PESP, increasing their segmental area ejection fraction from 44 +/- 5 (paced "normal" beat) to 56 +/- 6 (postextrasystolic beat) (p less than 0.05). Following surgical revascularization, these segments showed an improvement in their baseline area ejection fraction from 44 +/- 6 to 58 +/- 5 (p less than 0.05). Six jeopardized segments that failed to respond to PESP prior to revascularization showed functional deterioration after revascularization. The 27 non-jeopardized segments (which were not revascularized) also showed functional improvement, suggesting improved collateral flow. This study demonstrates that isolength postextrasystolic potentiation obtained with a standardized pacing protocol may be used to predict the potential for improvement in cardiac function following surgical revascularization. Our results also show that lack of PESP predicts loss of left ventricular myocardial function following revascularization.

User-friendly communication board for nonverbal, severely physically disabled individuals.

The inability to communicate personal needs, feelings, and ideas is a frustrating barrier for nonverbal patients with severe physical disabilities. It hampers the physician-patient relationship and medical services. This problem has been diminished with the use of a new communication board for patients with brain stem involvement. The communication board display is comprised of 36 squares in a 6 X 6 matrix. The alphabet is arranged in this matrix according to the normal sequence, and each row begins with a vowel. Selection of a desired alphabet letter is done by naming the vowels vertically until the appropriate row is reached, then the individual consonants horizontally until the proper one is indicated by the patient. With this new arrangement, the patient, attendant, or staff can memorize and functionally use the new communication board in a few minutes.

Mechanism of abnormal motion of the posterior leaflet in mitral stenosis.

Echocardiographic visualization of diastolic anterior motion of the posterior leaflet has proven to be diagnostic of mitral stenosis. In order to elucidate the mechanisms which underlie this finding and to explain why it is absent in some proven instances of mitral stenosis, we analyzed leaflet motion as a function of torque and derived a theoretic expression which permitted us to predict the direction of leaflet motion in mitral stenosis in terms of degree of commissural fusion and leaflet dimensions. The analysis was tested in an experimental model consisting of an isolated, perfused pig heart. Dimensions and degree of fusion of mitral valve leaflets were varied surgically in 5 specimens. Corresponding values proportional to torque were computed for each leaflet and the associated modifications of valve motion recorded cinematographically through a fiberscope inserted into the left ventricular cavity. The theoretical considerations indicated that, when leaflet commissures are fused, diastolic movement of the posterior leaflet is determined by the torques on both leaflets and that the relative length (base to free edge) of the leaflets is the major determinant of the direction of the resultant displacing force. The posterior leaflet may move posteriorly early in diastole until this motion is restricted by the fusion, but anterior motion of both leaflets results when the anteriorly directing force becomes dominant. Anterior motion of the posterior leaflet therefore occurs when leaflet fusion is extensive and the anterior leaflet remains longer than the posterior. Posterior motion of the posterior leaflet tends to occur with leaflet fusion, even in severe or moderate mitral stenosis, when the ratio of anterior to posterior leaflet length approximates unity. Direct observations of leaflet motion in the perfused porcine hearts confirmed these relationships.