The NC1/endostatin domain of Caenorhabditis elegans type XVIII collagen affects cell migration and axon guidance.

Type XVIII collagen is a homotrimeric basement membrane molecule of unknown function, whose COOH-terminal NC1 domain contains endostatin (ES), a potent antiangiogenic agent. The Caenorhabditis elegans collagen XVIII homologue, cle-1, encodes three developmentally regulated protein isoforms expressed predominantly in neurons. The CLE-1 protein is found in low amounts in all basement membranes but accumulates at high levels in the nervous system. Deletion of the cle-1 NC1 domain results in viable fertile animals that display multiple cell migration and axon guidance defects. Particular defects can be rescued by ectopic expression of the NC1 domain, which is shown to be capable of forming trimers. In contrast, expression of monomeric ES does not rescue but dominantly causes cell and axon migration defects that phenocopy the NC1 deletion, suggesting that ES inhibits the promigratory activity of the NC1 domain. These results indicate that the cle-1 NC1/ES domain regulates cell and axon migrations in C. elegans.

Transmyocardial laser revascularization in the patient with unmanageable unstable angina.

BACKGROUND: Transmyocardial laser revascularization (TMR) provides relief for patients with chronic angina, nonamenable to direct coronary revascularization. Unmanageable, unstable angina (UUA) defines a subset of patients with refractory angina who are at high risk for myocardial infarction and death. Patients were classified in the UUA group when they had been admitted to the critical care unit with unstable angina for 7 days with three failed attempts at weaning them off intravenous antianginal medications. METHODS: Seventy-six treated patients were analyzed to determine if TMR is a viable option for patients with unmanageable unstable angina. These patients were compared with 91 routine protocol patients (protocol group [PG]) undergoing TMR for chronic angina not amenable to standard revascularization. The procedure was performed through a left thoracotomy without cardiopulmonary bypass. These patients were followed for 12 months after the TMR procedure. Both unmanageable and chronic angina patients had a high incidence of at least one prior surgical revascularization (87% and 91%, respectively). RESULTS: Perioperative mortality (< or = 30 days post-TMR) was higher in the UUAG versus PG (16% vs 3%, p = 0.005). Late mortality, up to 1 year of follow-up, was similar (13% vs 11%, UUAG vs PG; p = 0.83). A majority of the adverse events in the UUAG occurred within the first 3 months post-TMR, and patients surviving this interval did well, with reduced angina of at least two classes occurring in 69%, 82%, and 82% of patients at 3, 6, and 12 months, respectively. The percent improvement in angina class from baseline was statistically significant at 3, 6, and 12 months. A comparable improvement in angina was found in the protocol group of patients. CONCLUSIONS: TMR carried a significantly higher risk in unmanageable, unstable angina than in patients with chronic angina. In the later follow-up intervals, however, both groups demonstrated similar and persistent improvement in their angina up to 12 months after the procedure. TMR may be considered in the therapy of patients with unmanageable, unstable angina who otherwise have no recourse to effective therapy in the control of their disabling angina.

Cuticle chirality and body handedness in Caenorhabditis elegans.

Caenorhabditis elegans adult animals exhibit an inherent chirality of fiber orientation in the basal layer of the cuticle, as well as a naturally invariant but experimentally reversible handedness in the left-right (L-R) asymmetry of the body plan. We have examined the relationship between cuticle chirality and body handedness in normal and L-R reversed animals, using Roller (Rol) mutants and transmission electron microscopy to monitor cuticle properties. Rol phenotypes, several of which have been shown to result from mutations in cuticle collagen genes, are characterized by an invariant, allele-specific handedness in their direction of rolling. We show for several alleles that this direction is not affected by L-R reversal of the body plan. We further show, by electron microscopy, that the chiral orientation of cuticle fibers in animals with normal cuticle is not reversed by L-R body-plan reversal. We conclude that cuticle chirality must be established independently of body-plan handedness. The cues that establish cuticle chirality are still unknown, as are the causes for different rolling directions in different Roller mutants. We discuss the question of how cuticle chirality maintains its independence, and how the orientations of the fiber layers may be determined.

Transmyocardial laser revascularization: results of a multicenter trial with transmyocardial laser revascularization used as sole therapy for end-stage coronary artery disease.

BACKGROUND: Transmyocardial laser revascularization was used as the sole therapy for patients with ischemic heart disease not amenable to percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. This technique uses a carbon dioxide laser to create transmyocardial channels for direct perfusion of the ischemic heart. METHODS: Since 1992, 200 patients, at eight hospitals in the United States, have undergone transmyocardial laser revascularization. The patients have a combined 1560 months of follow-up for an average of 10 +/- 3 months per patient. Their age was 63 +/- 10 years and their ejection fraction was 47% +/- 12%. Eighty-two percent had at least one previous bypass graft operation and 38% had a prior angioplasty. Preoperatively, the patients underwent nuclear single photon emission computed tomography perfusion scans to identify the extent and severity of their ischemia. These scans were repeated at 3, 6, and 12 months. Angina class, admissions for angina, and medications were recorded. RESULTS: The perioperative mortality was 9%. Angina class decreased significantly from before treatment to 3, 6, and 12 months (p < 0.001). Likewise, there was a significant decrease in the number of perfusion defects in the treated left ventricular free wall. Concomitantly, there was a significant decrease in the number of admissions for angina in the year after the procedure when compared with the year before treatment (2.5 vs 0.5 admissions per patient-year). CONCLUSION: These combined results indicate that transmyocardial laser revascularization provides angina relief, decreases hospital admissions, and improves perfusion in patients with severe coronary artery disease.

Developing compound eye in lozenge mutants of Drosophila: lozenge expression in the R7 equivalence group.

The lozenge locus is genetically complex, containing two functionally distinct units, cistrons A and B, that influence the structure of the compound eye. Extreme mutations of either cistron produce adult phenotypes that share similarities and that have striking differences. We have analyzed the expression of several developmentally important eye genes including boss, scabrous, rhomboid, seven-up, and Bar in lozenge mutant backgrounds representing both cistrons. This analysis follows the progressive recruitment of photoreceptor neurons during eye development and has confirmed that the initial development of photoreceptors is normal up to the five cell precluster stage (R8, R2/5 and R3/4). However, when lozenge is mutant, further eye development is perturbed. As cells R1, R6 and R7 are recruited, patterns of gene expression for seven-up and Bar become abnormal. We have also characterized the expression of two different enhancer trap alleles of lozenge. The lozenge product(s) appear to be first expressed in the eye disc in undifferentiated cells shortly after the five cell precluster forms. Then, as distinct cells are recruited to a fate, lozenge expression persists and is refined in those cells. Our data suggests that lozenge functions in cone cells and pigment cells as well as in specific glia. With respect to photoreceptor neurons, lozenge biases the developmental potential of cells R1, R6 and R7, by directly influencing the expression of genes important for establishing cell fate.

Genetic analysis of the lozenge gene complex in Drosophila melanogaster: adult visual system phenotypes.

Mutations at the lozenge (lz) locus are pleiotropic, primarily affecting the sense organs for sight, smell and taste. To better understand the role that lz plays in the visual system, we investigated its complex genetics and the effect mutations have on the structure of the compound eye. Complementation analysis within the lz locus reveals two functional units necessary for a normal eye, cistrons A and B. Previous recombination studies identified four subloci spanning 0.14 m.u. Cistron A mutations map to the distal-most spectacle sub-locus, which has been identified as an insertion point for P-elements. Southern blotting and chromosomal in situ hybridization show that P-allele lzmu2 contains a single P-element; a cosmid clone derived from lzmu2 confirms that the P-element is defective. Mutants of both cistrons perturb lens structure and eye pigmentation. However, the extent of the defects differs between the most severe mutations of the two cistrons. Within the eye, failure to form the fenestrated membrane permits photoreceptor neurons to "fall" into the brain disrupting neural structure. Our analysis shows that lz exerts control over the identity of cone cells, pigment cells and photoreceptor neurons.

Wound Healing: An endpoint for complex peripheral angioplasty.

PURPOSE: The standard endpoint for lower limb revascularization is long-term patency; however, in high-risk patients with end-stage ischemia, healing of chronic ulcerations has been proposed as an acceptable endpoint. To evaluate if today's minimally invasive interventions, in combination with comprehensive wound healing procedures, can resolve nonhealing wounds, we performed a retrospective review of chronic ulceration patients treated at the San Francisco Wound Care Center. METHODS: Eight-five patients with 96 limbs at risk due to nonhealing ulcers were treated with a variety of endovascular procedures: 7 patients (group I) received Palmaz stents for unilateral iliac occlusions; 42 limbs (group II) in 39 patients were treated with balloon angioplasty for superficial femoral and popliteal lesions; and 47 extremities in 39 patients (group III) underwent rotational atherectomy for tibioperoneal lesions. Comprehensive wound management techniques, including the application of growth factors, were used. RESULTS: All group I wounds healed, although 6 of 7 patients required additional procedures to address outflow lesions. In groups II and III, primary patencies were similar (64% and 70%, respectively), and nine treated sites reoccluded in each group. Restenotic lesions were retreated in both groups (three in group II and four in group III) secondary patencies were 71% and 78%, respectively. There were more amputations in group III patients (five) compared to group II (one). In both groups after 5 months, 90% of wounds had healed in group II and 72% in group III. CONCLUSION: The use of endovascular procedures appears to play an important role in the healing of chronic lower extremity ulcerations in high-risk patients with end-stage ischemia.

Clinical trial of percutaneous peripheral ultrasound angioplasty.

OBJECTIVES: The purpose of this study was to present follow-up data as well as short-term results on a larger clinical series of patients undergoing ultrasound angioplasty. BACKGROUND: Previous pilot studies have demonstrated the feasibility of peripheral arterial ultrasound angioplasty. METHODS: We performed percutaneous ultrasound angioplasty on 50 arterial lesions in 45 patients. Our ultrasound ablation system had a frequency of 19.5 kHz. A fixed-wire probe with 2- or 3-mm ball tips and a 3-mm over-the-wire probe were used to treat 40 femoral, 7 popliteal and 3 tibioperoneal lesions. Seventeen (34%) of the lesions were calcific. Thirty (86%) of 35 occluded segments, 0.5 to 28 cm long (mean 6.2 +/- 5.7), were recanalized. RESULTS: In the 45 patent arteries, the stenosis decreased from 94 +/- 10% to 55 +/- 23% after ultrasound angioplasty and to 12 +/- 8% after balloon angioplasty. Mechanical arterial dissections (n = 4) and perforations (n = 4) without clinical consequence occurred only with the fixed non-over-the-wire probes. No evidence of embolism or vasospasm was detected; in fact, vasodilation occurred. There were no clinical manifestations of acute reocclusion. At 24 h, ankle-brachial indexes increased by 0.23 +/- 0.21 (range -0.27 to 0.72). Six- to 12-month clinical and ankle-brachial index follow-up data for 35 patients treated with ultrasound and adjunctive balloon angioplasty were indicative of restenosis in 7 patients (20%). CONCLUSIONS: Our findings indicate that percutaneous peripheral ultrasound angioplasty 1) is useful for recanalization of fibrous, calcific and thrombotic arterial occlusions; 2) reduces arterial stenoses; and 3) has clinical and ankle-brachial index data indicative of a restenosis rate of 20% at 6 to 12 months in a small cohort of patients. A larger randomized series of patients will need to be studied to assess the impact of ultrasound ablation on restenosis.

Ultrasound recanalization of diseased arteries. From experimental studies to clinical application.

At present, percutaneous peripheral ultrasound angioplasty should be considered in those patients with symptoms of claudication or resting limb ischemia. With the development of an over-the-wire system, we treat patients with suprageniculate or infrageniculate lesions. It is expected that the over-the-wire probe will allow application of ultrasound angioplasty not only to lesions below the knee but to contralateral vascular occlusions as well. An intraoperative device for plaque ablation and arterial recanalization is in development for use in less accessible sites such as the coronary arteries. Experimental studies have shown that catheter-delivered therapeutic ultrasound recanalizes complete occlusions, reduces stenoses, dissolves thrombus, vasodilates, and enhances arterial distensibility. The potential clinical applications of therapeutic ultrasound include recanalizing total arterial occlusions, dissolving thrombi, facilitating balloon angioplasty by increasing arterial compliance, and as a stand-alone angioplasty device.

Thermal laser-assisted balloon angioplasty of the superficial femoral artery: a multicenter review of 602 cases.

A multicenter review of 602 procedures was performed to evaluate the effects of thermal laser-assisted balloon angioplasty on the superficial femoral artery. Four hundred thirty-nine (73%) patients underwent laser-assisted balloon angioplasty for claudication, and 163 (27%) underwent the procedure for limb salvage. Two hundred ninety-two laser-assisted balloon angioplasty procedures were performed for multifocal stenotic disease (greater than 80%) diameter reduction), 258 for total occlusion, and 52 procedures for both superficial femoral artery stenosis and occlusion. The initial recanalization rate was 89% (538/602) depending on the length of the lesion. Success of laser-assisted balloon angioplasty was verified by angioscopy or arteriography, and all patients underwent segmental Doppler studies before discharge and during midterm follow-up extending to 30 months (mean, 11.3 months). Complications occurred in 62 (10%) patients, but only one limb amputation occurred because of a complication related to a laser-assisted balloon angioplasty. Overall, 60% of initially successful procedures have remained patent, but long segment (greater than 7 cm) occlusions have fared poorly (25% patency at 30 months). This minimally invasive technology affords the opportunity to treat short segment (less than 7 cm) symptomatic superficial femoral artery occlusive disease with minimal risk. Initial success and midterm patency rates for appropriate lesions appear to make laser-assisted balloon angioplasty a viable adjunct in the treatment of superficial femoral artery occlusive disease.

Peripheral arterial occlusions: initial results from percutaneous angioplasty with a hybrid laser probe.

Percutaneous laser-assisted angioplasty performed with a laser-heated metal-capped fiber has been shown to be safe and effective. A hybrid probe was developed that allows a small percentage of laser light to emerge, converting the rest to heat. The probe was used to recanalize 37 peripheral arterial occlusions (10 in the iliac segment, 2-7 cm long, and 27 in the femoropopliteal segment, 1-35 cm long) in 37 patients. Primary success was defined as successful recanalization and continued patency during the first 24 hours, as assessed at physical examination. Primary success in the iliac segments was 70% and in the femoropopliteal segments was 85% (overall, 81%). The only complication was an arterial wall perforation, which had no sequelae. The probe is safe for use in peripheral arterial occlusions. There was no increase in the rate of perforation compared with the rate with the "hot-tip" laser probe, and the technique may have advantages over use of the original "hot-tip" laser probe.

Ruptured abdominal aortic aneurysms: experience with 70 cases.

During the period 1965-1983, 270 patients underwent resection of abdominal aortic aneurysm. In 70 patients (26%) the aneurysm was ruptured. Overall hospital mortality of patients with ruptures was 34%. Five patients died before the graft could be completed. Common denominators associated with mortality were hypotension, renal failure, cardiac arrest, and postoperative hemorrhage. The average age over the first 10 years was 68, but subsequently, has risen gradually, with a corresponding increase in mortality despite improved surgical technique and postoperative care. Only with more widespread elective resections and earlier diagnosis of rupture followed by prompt operative management, can the outlook for patients with abdominal aortic aneurysm be improved.

Carotid surgery without angiography.

We propose that circumstances exist in which angiography is not necessary or is unwarranted for the diagnosis and treatment of carotid arterial disease. High quality real-time B-mode ultrasonographic imaging, combined with both pulsed gated, and continuous wave Doppler analysis, shows a remarkably close correlation with the pathologic abnormality identified at operation. Scanning in the vascular laboratory not only provides quick, noninvasive, accurate assessment of the atherosclerotic disease, it can also provide plaque and blood flow detail not previously attainable. Carotid surgery can be effectively and safely performed in selected patients with the aid of ultrasonography and Doppler analysis without the need for invasive angiographic imaging.

Sequential internal mammary-coronary artery bypass.

Since April, 1977, a total of eight patients have undergone sequential bypass grafting of the internal mammary artery (IMA) to the coronary arteries at our institution. The indication for this newly described procedure was either insufficient supply of adequate veins (four patients) or the presence of a diseased aortic wall (two patients). Operative procedures included left IMA bypass to the left anterior descending (LAD) artery and its major diagonal branch in six patients; to the obtuse marginal branch and distal circumflex artery in one patient; and to two consecutive sites on the LAD in one patient. All patients became angina-free after operation for a follow-up period lasting up to 6 years. Recatheterization studies were performed in four patients, in all of whom the IMA sequential grafts were found patent. We believe that IMA sequential grafting is an important option available to the cardiac surgeon in managing some patients with coronary artery disease.

Internal mammary coronary artery bypass surgery: experience with 1000 cases.

A study of 813 men and 187 women who underwent internal mammary artery (IMA) bypass from 1976 to the present time is presented. In approximately 10% of patients, only the IMA was used for coronary artery bypass, and in approximately 90%, one to four saphenous vein grafts were used additionally. Hospital mortality in the series was 1.8%. The IMA, when properly selected and carefully harvested, is considered an excellent conduit for myocardial revascularization. Disadvantages include its limited application to the proximal portions of one (or two) coronary vessels, a relatively delicate and difficult anastomosis, and an allegedly high incidence of postoperative chest wall discomfort with pulmonary complications. However, this experience with IMA coronary artery bypass supports the view that it is an ideal conduit for the anterior wall when conditions permit its use.

Coronary artery revascularization: reoperations performed on 124 consecutive patients.

The results of 124 coronary reoperations performed during a 9-year period are reviewed, with the causes of failure of the initial operations and technical considerations in the reoperation procedures. The reoperative experience provided considerable insight as to why an initial revascularization might be unsuccessful. The three basic mechanisms which appeared to lead to recurrence of symptoms or late infarction following coronary bypass were (1) inadequate initial revascularization, (2) graft failure (occlusion or stenosis), and (3) progression of disease in the native circulation. Means of prevention and surgical techniques are reviewed in detail.