Biological impact of low dose-rate simulated solar particle event radiation in vivo.

C57Bl6-lacZ animals were exposed to a range of low dose-rate simulated solar particle event (sSPE) radiation at the NASA-sponsored Research Laboratory (NSRL) at Brookhaven National Laboratory (BNL). Peripheral blood was harvested from animals from 1 to 12 days after total body irradiation (TBI) to quantify the level of circulating reticulocytes (RET) and micronucleated reticulocytes (MN-RET) as an early indicator of radiation-induced genotoxicity. Bone marrow lymphocytes and hippocampal tissues from each animal were collected at 12 days and up to two months, to evaluate dose-dependent late effects after sSPE exposure. Early hematopoietic changes show that the % RET was reduced up to 3 days in response to radiation exposure but recovered at 12 days postirradiation. The % MN-RET in peripheral blood was temporally regulated and dependant on the total accumulated dose. Total chromosome aberrations in lymphocytes increased linearly with dose within a week after radiation and remained significantly higher than the control values at 4 weeks after exposure. The level of aberrations in the irradiated animals returned to control levels by 8 weeks postirradiation. Measurements of chromosome 2 and 8 specific aberrations indicate that, consistent with conventional giemsa-staining methods, the level of aberrations is also not significantly higher than in control animals at 8 weeks postirradiation. The hippocampus was surveyed for differential transcriptional regulation of genes known to be associated with neurogenesis. Our results showed differential expression of neurotrophin and their associated receptor genes within 1 week after sSPE exposure. Progressive changes in the profile of expressed genes known to be involved in neurogenic signaling pathways were dependent on the sSPE dose. Our results to date suggest that radiation-induced changes in the hematopoietic system, i.e., chromosome aberrations in lymphocytes, are transient and do not persist past 4 weeks after radiation. On the other hand, alteration in the profile of genes known to be involved in neurotrophic functions in the hippocampal tissue appears to persist for up to 8 weeks after radiation exposure. Such temporal changes confirm that, although cytogenetic changes after a single dose of low-dose and low-dose-rate protons appear to be transient, the impact of this exposure is sufficient to lead to persistent dynamic changes in neuronal tissues long after the initial radiation exposure.

Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial.

BACKGROUND: Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this treatment combination provided greater survival benefit than did chlorambucil or fludarabine. METHODS: 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. FINDINGS: There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38%vs 15%, respectively; overall response rate 94%vs 80%, respectively; p<0.0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0.006 and 0.04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0.00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (V(H)) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. INTERPRETATION: Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.

IgVH genes mutation and usage, ZAP-70 and CD38 expression provide new insights on B-cell prolymphocytic leukemia (B-PLL).

B-prolymphocytic leukemia (B-PLL) is a rare disease with poor prognosis. To further characterize the biological features of this disease, we analyzed immunoglobulin heavy chain (IgVH) mutations, ZAP-70 and CD38 in 19 cases with de novo B-PLL. Immunoglobulin heavy chain genes analysis showed an unmutated pattern (>98% homology to germ line) in 9/17 cases (53%), with 100% homology in eight. In the remaining, it ranged from 90 to 97.4%, with three cases slightly mutated (98-95%) and five heavily mutated (<95%). All B-PLL utilized members of VH3 (11/17) and VH4 (6/17) families, with V3-23, V4-59 and V4-34 gene accounting for more than half of them, regardless of mutational status. ZAP-70, assessed by flow cytometry, ranged from 1 to 91% cells, being > or =20% in 57% of cases. CD38 ranged from 1 to 99% (median 21%). There was no correlation between IgVH status and ZAP-70 or CD38 expression, but male gender and del(17p) were more common in the unmutated group. Neither IgVH mutations, CD38 expression nor del(17p) influenced patients' outcome. Unexpectedly, ZAP-70+ B-PLL patients survived longer (40 months) than ZAP-70- B-PLL (8 months). B-PLL appears biologically heterogeneous regarding IgVH mutations, ZAP-70 and CD38 expression, showing a pattern distinct from that of other lymphoproliferative disorders.

ZAP-70 by flow cytometry: a comparison of different antibodies, anticoagulants, and methods of analysis.

BACKGROUND: The clinical course of chronic lymphocytic leukaemia (CLL) is variable. ZAP-70 expression is believed to provide prognostic information. The flow cytometric detection of ZAP-70 is difficult because it is an intracellular antigen with weak expression in CLL. Consensus has not been reached as to the best method for measurement. METHODS: We analyzed 72 CLL patient samples for ZAP-70 expression and IgVH mutational status. Sensitivity and specificity of ZAP-70 expression against IgVH mutational status were assessed for two clones (2F3.2 and 1E7.2) and for four methods of analysis: percentage positivity (PP), comparing test to isotype control, ratio of geometric means of test and isotype control, and percentage and ratiometric methods comparing test and T/NK cell populations. The effects of anticoagulant, collection times, and time to analysis were also evaluated. RESULTS: Sensitivity and specificity were 85 and 88%, respectively, for Upstate PP; 70 and 88% for Caltag PP; 89 and 91% for Upstate ratio; 89 and 88% for Caltag ratio. Intraobserver variability was smaller when ZAP-70 expression was assessed using a ratiometric approach rather than the percentage method. By 48 h, we observed an average decrease of 13% in the Caltag ratio in the heparin preserved samples compared to an increase of 3% in those collected in EDTA. Within the first 24-h period, a greater percent variability was observed in those samples collected into EDTA compared with heparin. CONCLUSION: Our data support a rapid method for ZAP-70 measurement using commercially available fixation/permeabilization reagents, a conjugated antibody, and a ratiometric method of analysis that minimizes subjective interpretation of the results. This is a method of ZAP-70 assessment that could be included in a routine diagnostic CLL panel; however, the choice of anticoagulant and time of analysis after collection are critical factors in accurate assessment of ZAP-70 expression.

CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT.

We have recently described a specialized subset of human natural killer (NK) cells with a CD56(dim)CD57(+)NKG2C(+) phenotype that expand specifically in response to cytomegalovirus (CMV) reactivation in hematopoietic cell transplant (HCT) recipients and exhibit properties characteristic of adaptive immunity. We hypothesize that these cells mediate relapse protection and improve post-HCT outcomes. In 674 allogeneic HCT recipients, we found that those who reactivated CMV had lower leukemia relapse (26% (17-35%), P=0.05) and superior disease-free survival (DFS) (55% (45-65%) P=0.04) 1 year after reduced intensity conditioning (RIC) compared with CMV seronegative recipients who experienced higher relapse rates (35% (27-43%)) and lower DFS (46% (38-54%)). This protective effect was independent of age and graft-vs-host disease and was not observed in recipients who received myeloablative regimens. Analysis of the reconstituting NK cells demonstrated that CMV reactivation is associated with both higher frequencies and greater absolute numbers of CD56(dim)CD57(+)NKG2C(+) NK cells, particularly after RIC HCT. Furthermore, expansion of these cells at 6 months posttransplant independently trended toward a lower 2-year relapse risk. Together, our data suggest that the protective effect of CMV reactivation on posttransplant relapse is in part driven by adaptive NK cell responses.

Longitudinal copy number, whole exome and targeted deep sequencing of 'good risk' IGHV-mutated CLL patients with progressive disease.

The biological features of IGHV-M chronic lymphocytic leukemia responsible for disease progression are still poorly understood. We undertook a longitudinal study close to diagnosis, pre-treatment and post relapse in 13 patients presenting with cMBL or Stage A disease and good-risk biomarkers (IGHV-M genes, no del(17p) or del(11q) and low CD38 expression) who nevertheless developed progressive disease, of whom 10 have required therapy. Using cytogenetics, fluorescence in situ hybridisation, genome-wide DNA methylation and copy number analysis together with whole exome, targeted deep- and Sanger sequencing at diagnosis, we identified mutations in established chronic lymphocytic leukemia driver genes in nine patients (69%), non-coding mutations (PAX5 enhancer region) in three patients and genomic complexity in two patients. Branching evolutionary trajectories predominated (n=9/13), revealing intra-tumoural epi- and genetic heterogeneity and sub-clonal competition before therapy. Of the patients subsequently requiring treatment, two had sub-clonal TP53 mutations that would not be detected by standard methodologies, three qualified for the very-low-risk category defined by integrated mutational and cytogenetic analysis and yet had established or putative driver mutations and one patient developed progressive, therapy-refractory disease associated with the emergence of an IGHV-U clone. These data suggest that extended genomic and immunogenetic screening may have clinical utility in patients with apparent good-risk disease.

Paenibacillus larvae Phage Tripp Genome Has 378-Base-Pair Terminal Repeats.

Paenibacillus larvae bacteriophage Tripp was isolated from an American foulbrood diseased honey bee hive in North Carolina, USA. The 54,439-bp genome is 48.3% G+C, encodes 92 proteins, no tRNAs, and has 378-bp direct terminal repeats. It is currently unique in Genbank.

Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia.

Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next-generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2 deletions or mutations were often observed as a clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy had reduced progression-free and overall survival compared with cases wild type for all three genes. Consistent with its postulated role as a tumour suppressor, our data highlight SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease.

Assessment and quantification of sources of variability in breast apparent diffusion coefficient (ADC) measurements at diffusion weighted imaging.

PURPOSE: Apparent Diffusion Coefficient (ADC) measurements are increasingly used for assessing breast cancer response to neoadjuvant chemotherapy although little data exists on ADC measurement reproducibility. The purpose of this work was to investigate and characterise the magnitude of errors in ADC measures that may be encountered in such follow-up studies- namely scanner stability, scan-scan reproducibility, inter- and intra- observer measures and the most reproducible measurement of ADC. METHODS: Institutional Review Board approval was obtained for the prospective study of healthy volunteers and written consent acquired for the retrospective study of patient images. All scanning was performed on a 3.0-T MRI scanner. Scanner stability was assessed using an ice-water phantom weekly for 12 weeks. Inter-scan repeatability was assessed across two scans of 10 healthy volunteers (26-61 years; mean: 44.7 years). Inter- and intra-reader analysis repeatability was measured in 52 carcinomas from clinical patients (29-70 years; mean: 50.0 years) by measuring the whole tumor ADC value on a single slice with maximum tumor diameter (ADCS) and the ADC value of a small region of interest (ROI) on the same slice (ADCmin). Repeatability was assessed using intraclass correlation coefficients (ICC) and coefficients of repeatability (CoR). RESULTS: Scanner stability contributed 6% error to phantom ADC measurements (0.071×10(-3)mm(2)/s; mean ADC=1.089×10(-3)mm(2)/s). The measured scan-scan CoR in the volunteers was 0.122×10(-3)mm(2)/s, contributing an error of 8% to the mean measured values (ADCscan1=1.529×10(-3)mm(2)/s; ADCscan2=1.507×10(-3)mm(2)/s). Technical and clinical observers demonstrated excellent intra-observer repeatability (ICC>0.9). Clinical observer CoR values were marginally better than technical observer measures (ADCS=0.035×10(-3)mm(2)/s vs. 0.097×10(-3)mm(2)/s; ADCmin=0.09×10(-3)mm(2)/s vs. 0.114×10(-3)mm(2)/s). Inter-reader ICC values were good 0.864 (ADCS) and fair 0.677 (ADCmin). Corresponding CoR values were 0.202×10(-3)mm(2)/s and 0.264×10(-3)mm(2)/s, respectively. CONCLUSIONS: Both scanner stability and scan-scan variation have minimal influence on breast ADC measurements, contributing less than 10% error of average measured ADC values. Measurement of ADC values from a small ROI contributes a greater variability in measurements compared with measurement of ADC across the whole visible tumor on one slice. The greatest source of error in follow-up studies is likely to be associated with measures made by multiple observers, and this should be considered where multiple measures are required to assess response to treatment.

Recurrent mutations refine prognosis in chronic lymphocytic leukemia.

Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.

The Marfan syndrome and cardiac surgery.

Of 31 patients with Marfan's syndrome and cardiovascular complications, 25 had ascending aortic aneurysms, five with aortic dissection; 26 had aortic regurgitation, two with aortic stenosis; and eight had mitral regurgitation, five with aortic regurgitation. Surgery included prosthetic aortic valve replacement in 24 patients and aortic valvular bicuspidization in two; 19 had resection of aneurysm with Dacron tube replacement, three had lateral aneurysmorrhaphy, and two had circumferential strip excision with end-to-end anastomosis. Four patients underwent mitral valve replacement. Operative complications occurred in 10 patients. There were nine (29 percent) hospital deaths, but only one death occurred in 12 patients operated upon since 1970. Late complications included prosthetic leak in six patients (23 percent) with reoperation in five; all survived. Five late deaths occurred (16 percent); one was unrelated and one was of unknown cause. Although risk of cardiac surgery remains high, our recent results support an aggressive surgical approach, particularly in patients with advanced or deteriorating cardiovascular complications.

Infection following coronary artery surgery. Comparison of two antibiotic prophylaxis regimens.

A prospective randomized study was conducted in 200 patients undergoing coronary artery bypass surgery. All patients received intravenous (IV) cephalothin prophylaxis for 48 hours beginning with anesthetic induction. Group A (99 eligible patients) received cephalexin 500 mg po, qid for three extra days. Group B (94 eligible patients) received no oral therapy. The overall infection rate was 9.3 percent (18 patients). Six patients had multiple sites of involvement. There was no difference between group A (9.0 percent, nine patients) vs B (9.5 percent, nine patients) (p greater than 0.5). The median sternotomy infection rate, superficial or deep, was 2.6% (five patients). The surgical wound infection rate was 4.7 percent (nine patients). The overall infection rate compares favorably with that of high risk groups for clean surgical procedures defined in SENIC study. There was no advantage to prolonged oral cephalexin prophylaxis following coronary artery bypass (CAB) surgery.

Reduction of coronary flow in the native circulation after bypass. Observations in a hydraulic model of the cardiovascular system.

The effects of aorta-coronary bypass upon flow in the native coronary artery were investigated in a hydraulic model of the cardiovascular system. An aorta-coronary bypass with a diameter identical to the coronary artery was used, since a graft diameter-to-coronary diameter ratio of one has been described as optimal. Stenoses of increasing severity were created in the simulated coronary artery. Aorta-coronary bypass eliminated the pressure gradients across the stenotic coronary segments. This caused a 50% reduction of flow in the normal or mildly stenotic native coronary artery. A higher percentage reduction of flow occurred in the bypassed artery when it was severely stenotic. Such a reduction of flow in patients may accelerate the atherosclerotic-thrombotic process and contribute to the high prevalence of occlusion of natural vessels following bypass. This disadvantageous hydraulic circumstance should be considered, particularly when bypass of mildly stenotic vessels is contemplated.

Endoscopic vein harvest for coronary artery bypass grafting: technique and outcomes.

BACKGROUND: The greater saphenous vein is a common conduit for coronary revascularizations. Traditional vein harvesting uses long incision(s) that can lead to significant morbidities. A minimally invasive technique has been developed that allows the harvest of much of the saphenous vein with one incision and fewer morbidities. METHODS: Our technique and outcomes on 110 patients with minimally invasive harvest (endoscopic vein harvesting) is presented. Comparisons are made with an equivalent retrospective group within the same hospital and to a smaller (n = 28) prospective group at other hospitals. RESULTS: Endoscopic vein harvesting has evolved to one above-knee incision of 3 cm length that allows for the harvest of 35 cm of vein. Harvest times were longer for endoscopic vein harvesting, showed a learning curve, and appeared to reach a baseline of 35 minutes. Incision closure times were less for the endoscopic vein harvesting group. Total skin to skin operating times for the entire cardiovascular procedure did not differ between the groups. In relatively homogeneous populations, leg infection rates did not differ, but other leg morbidities were less for the patients who underwent endoscopic vein harvesting. Hospital readmissions for leg wound care were low in both groups although the number of office visits required for leg care was higher for patients undergoing traditional vein harvesting. Pain perception by the patients was much less for the endoscopic vein harvesting and remained lower for up to 4 weeks. CONCLUSIONS: Although endoscopic vein harvesting is a relatively new procedure, it is safe, effective, and less painful for the patient and carries fewer morbidities.

Coronary artery bypass grafting within thirty days of acute myocardial infarction. Early and late results in 406 patients.

Between 1981 and 1987, 1726 coronary artery bypass operations were performed by a single group of surgeons at a community hospital. Overall hospital mortality in this group was 2.4% (41/1726). Of these patients 406 were operated on within 30 days of an acute myocardial infarction. The hospital mortality rate in this group was 6.7% (27/406) versus 1.1% (14/1320) in patients operated on without evidence of recent acute myocardial infarction (p less than 0.0001). In these 406 patients, sex, location of acute myocardial infarction, type of infarction, coronary anatomy, presence of postinfarction angina, technique of myocardial preservation, and the time from infarction to operation were not associated with hospital mortality. Univariate and multivariate analyses showed that three factors were significantly associated with increased hospital death: poor ejection fraction, less than 30% (p less than 0.0001), preoperative shock (p = 0.0005), and age greater than 70 years (p = 0.004). Follow-up was 90% complete (365/406 patients) at a mean time of 35 +/- 21 months. Of these patients 80% (292/365) were in New York Heart Association functional class I, and 10% (36/365) were in functional class II. Of all patients 88% were alive at 3 years, and 84% were alive at 5 years after operation. Multivariate comparison of survival curves showed that ejection fraction less than 30% was associated with decreased survival (p = 0.0002), followed by age (p = 0.0009). Patients younger than 70 years with an ejection fraction greater than 30% and not in cardiogenic shock can be operated on at any time after acute myocardial infarction without increased risk. Long-term survival and freedom from symptoms can be expected in these patients.

Infection in remnant of left ventricular assist device after successful separation from assisted circulation.

There have been two long-term and two short-term survivors among 10 patients in our hospital in whom the left ventricular assist device (LVAD) was implanted for cardiogenic shock after cardiac operations. Two of these four patients developed graft infection in the LVAD remnants left attached to the ascending aorta and left ventricle; one died of sepsis and the other required repeat operations for a chronic draining sinus and hemorrhage from a left ventricular--cutaneous fistula. This experience with infection and demonstration of the feasibility of total removal of both limbs of the LVAD without cardiopulmonary bypass lead us to recommend complete removal of the LVAD conduits in patients weaned from assisted circulation.

Ebstein's malformation. Surgical experience at the Mayo Clinic.

At the Mayo Clinic, 13 patients with Ebstein's malformation have undergone surgical repair since 1963. Their ages ranged from 18 months to 51 years (median 13 years). Ten patients were in Functional Class III or IV. Marked cardiomegaly, cyanosis, paradoxic emboli, and dysrhythmias secondary to Wolff-Parkinson-White syndrome were indications for operation in the remaining 3 patients. A wide range of anatomic variations was encountered. All 5 patients who underwent tricuspid annuloplasty with plication of the atrialized segment of the right ventricle survived operation. Of 5 patients who underwent prosthetic valve replacement, only one survived. Other procedures included atrial septal defect closure alone in one patient, atrial septal defect closure and relief of pulmonary stenosis in one patient, and tricuspid annuloplasty alone in one patient. One patient had concomitant mapping and division of anomalous conduction pathways. Functional classification improved in 8 of 10 operative survivors. There were two late sudden deaths; both patients had had preoperative dysrhythmias. The data suggest that results are improved when the atrialized segment of the right ventricle is dealt with during repair of the tricuspid valve. A combined ventricular plication and tricuspid annuloplasty yielded better early and late results than did valve replacement.

Surgical management of double-outlet right ventricle associated with atrioventricular discordance.

Twenty corrective operations for this unusual syndrome have been performed since 1965. All but two patients also had pulmonary stenosis; one of the exceptions had had pulmonary arterial banding. Two patients had situs inversus of the atria and viscera. In only three of the 20 patients (15 percent) was the apex of the heart positioned normally. Six patients had an entirely intracardiac repair; two early and two late deaths occurred in this group. The other technique, performed in 14 patients, involved insertion of an extracadiac conduit between a ventriculotomy in the morphologically left ventricle and the distal end of the proximally oversewn pulmonary artery; one operative and two late deaths occurred in this group. Heart block occurred in six patients, including two among the eight who had technically satisfactory intraoperative mapping of the His bundle. The intraventricular course of the bundle was not consistently positioned, being anterior to the septal defect in four and posterior in four. No hospital deaths have occurred in the last 13 operations; all except one of the survivors are in New York Heart Association Class I or II. Thus correction currently provides a good early results but leaves the ventricles in an inverted relationship both functionally and anatomically.

Surgical therapy for Prinzmetal's variant angina.

Fifty-two patients underwent coronary artery bypass grafting between 1973 and 1979 for variant angina, defined as pain, usually at rest, associated with S-T segment elevation. Only patients with fixed occlusive coronary artery disease, defined as greater than 70% narrowing in diameter, were included. When fixed coronary artery stenosis is present, variant angina--whether presenting as stable, unstable, or postinfarction angina, and regardless of the number of vessels diseased--is effectively treated by myocardial revascularization. Preoperative intraaortic balloon pumping is a useful therapeutic adjunct in the unstable subset refractory to medical therapy. The results of revascularization in patients with Prinzmetal's variant angina and fixed coronary disease were no different from those in patients with classic angina pectoris of comparable clinical categories.

AFM lithography of aluminum for fabrication of nanomechanical systems.

Nanolithography by local anodic oxidation of surfaces using atomic force microscopy (AFM) has proven to be more reproducible when using dynamic, non-contact mode. Hereby, the tip/sample interaction forces are reduced dramatically compared to contact mode, and thus tip wear is greatly reduced. Anodic oxidation of Al can be used for fabricating nanomechanical systems, by using the Al oxide as a highly selective dry etching mask. In our experiments, areas as large as 2 micro m x 3 micro m have been oxidized repeatedly without any sign of tip-wear. Furthermore, line widths down to 10nm have been routinely obtained, by optimization of AFM parameters, such as tip/sample distance, voltage and scan speed. Finally, AFM oxidation experiments have been performed on CMOS processed chips, demonstrating the first steps of fabricating fully functional nanomechanical devices.