The Human Embryo Research Panel: lessons for public ethics.
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Advisory Committees↗
Biomedical subjects
R M Green
Publications and source records attributed to R M Green.
Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin.
We assessed factors which affect cisplatin concentrations in human surgical tumour specimens. Cisplatin 10 mg m-2 was given i.v. to 45 consenting patients undergoing surgical resection of neoplasms, and platinum was assayed in resected tumour and in deproteinated plasma by flameless atomic absorption spectrophotometry. By multiple stepwise regression analysis of normalised data, patient characteristics that emerged as being most closely associated (P < 0.05) with tumour platinum concentrations (after correcting for associations with other variables) were tumour 'source' [primary brain lymphomas, medulloblastomas and meningiomas ('type LMM') > 'others' > lung cancer > head/neck cancer > gliomas) or tumour 'type' (LMM > brain metastases > extracerebral tumours > gliomas), serum calcium and chloride (positive correlations) and bilirubin (negative). Tumour location (intracranial vs extracranial) did not correlate with platinum concentrations. If values for a single outlier were omitted, high-grade gliomas had significantly higher platinum concentrations (P < 0.003) than low-grade gliomas. For intracranial tumours, the computerised tomographic scan feature that correlated most closely with platinum concentrations in multivariate analysis was the darkness of peritumoral oedema. Tumour source or type is a much more important correlate of human tumour cisplatin concentrations than is intracranial vs extracranial location. Serum calcium, chloride and bilirubin levels may affect tumour cisplatin uptake or retention. CT scan characteristics may help predict cisplatin concentrations in intracranial tumours.
Blood-Brain Barrier↗
Hepatocellular cholestasis: pathobiology and histological outcome.
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Cholestasis, Intrahepatic↗
Atherosclerosis of the lower extremity and free-tissue reconstruction for limb salvage.
Atherosclerosis of the lower extremity frequently leads to limb-threatening ischemic soft-tissue wounds. Over the past 44 months, 30 selected patients with arterial disease documented by angiography were treated with combined vascular reconstruction and free-tissue transfer for limb salvage. Soft-tissue defects occurred on the plantar and dorsal surfaces of the foot and distal tibia with significant bone, tendon, or joint exposure. Thirteen patients had osteomyelitis. Eighteen patients underwent simultaneous soft-tissue and vascular reconstruction, while 12 patients underwent delayed soft-tissue reconstruction. The free-flap tissues included the rectus abdominis flap in 13, the latissimus dorsi flap in 7, the radial forearm flap in 5, the scapular flap in 3, and the omentum flap in 2. Autogenous venous bypass was performed to the popliteal segment in 6 patients and the infrapopliteal arteries in 18. Five patients had inadequate outflow for complete vascular reconstruction and were treated with proximal vein grafts directed into the free flap. Twenty-two patients (73 percent) had successful free-tissue transfer and bypass graft patency and were independent ambulators over the mean follow-up period of 22 months. Of the 8 unsuccessful reconstructions, 3 patients had early free-flap and graft failure. Five patients developed new areas of ischemic disease despite graft and flap patency. All 8 patients were treated with amputation; 7 never regained ambulation. The combined application of vascular and free-flap soft-tissue reconstruction for the threatened ischemic lower extremity has produced excellent functional results in the majority of our patients.
Adult↗
Infrarenal aortic aneurysm structure: implications for transfemoral repair.
PURPOSE: The structure of infrarenal aortic aneurysm was studied as a basis for design of a transfemoral system of aneurysm repair. This information was particularly important because endovascular techniques, unlike conventional techniques, afford little opportunity for intraoperative adjustments. METHODS: Three-dimensional computer reconstructions of the distal aorta, the renal arteries, the aneurysm and the iliac arteries were generated from computed tomography scanning data in 22 patients with aortic aneurysms. RESULTS: The proximal neck of the aneurysm was longer than 20 mm in 14 patients, and the mean length (of all 22) was 26.7 +/- 4.1 mm. In contrast, only one patient had a distal cuff longer than 20 mm and 14 of the others had no measurable distal cuff. The mean distal cuff length (of all 22) was 4.2 +/- 1.6 mm. There was no significant difference between mean aneurysm diameter in the anteroposterior direction (58.0 +/- 3.2 mm) and the transverse direction (56.4 +/- 3.3 mm), although corresponding values in individual patients were often different. Aneurysm diameter correlated with aneurysm length (r = 0.79, p < 0.001). The proximal right common iliac artery deviated from the axis of the distal aorta by 40.0 +/- 5.8 degrees, whereas the left deviated by 47.8 +/- 5.4 degrees. One of the iliac arteries deviated by more than 45 degrees in 12 cases. Eleven common iliac arteries in seven patients were aneurysmal. Fifteen patients had no aneurysm of the common iliac arteries, and another three had segments of nondilated common iliac artery distal to iliac aneurysms on both sides. CONCLUSIONS: Computerized three-dimensional reconstruction facilitated interpretation of anatomic information from computed tomography scans, particularly the length of the aneurysm neck and shape of the iliac arteries. On the basis of this information, we expect that few patients will have too short an aneurysm neck for endovascular aneurysm repair, but many will require a bifurcated graft for secure, hemostatic implantation distally.
Aortic Aneurysm, Abdominal↗
A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia.
PURPOSE: Despite the widespread use of intraarterial thrombolytic therapy for peripheral arterial occlusive disease, a randomized study comparing its efficacy with that of operative intervention has never been performed. This study evaluates the potential of intraarterial urokinase infusion to provide clinical benefits in patients with acute peripheral arterial occlusion. METHODS: Patients with limb-threatening ischemia of less than 7 days' duration were randomly assigned to intraarterial catheter-directed urokinase therapy or operative intervention. Anatomic lesions unmasked by thrombolysis were treated with balloon dilation or operation. The primary end points of the study were limb salvage and survival. RESULTS: A total of 57 patients were randomized to the thrombolytic therapy group, and 57 patients were randomized to the operative therapy group. Thrombolytic therapy resulted in dissolution of the occluding thrombus in 40 (70%) patients. Although the cumulative limb salvage rate was similar in the two treatment groups (82% at 12 months), the cumulative survival rate was significantly improved in patients randomized to the thrombolysis group (84% vs 58% at 12 months, p = 0.01). The mortality differences seemed to be primarily attributable to an increased frequency of in-hospital cardiopulmonary complications in the operative treatment group (49% vs 16%, p = 0.001). The benefits of thrombolysis were achieved without significant differences in the duration of hospitalization (median 11 days) and with only modest increases in hospital cost in the thrombolytic treatment arm (median $15,672 vs $12,253, p = 0.02). CONCLUSIONS: Intraarterial thrombolytic therapy was associated with a reduction in the incidence of in-hospital cardiopulmonary complications and a corresponding increase in patient survival rates. These benefits were achieved without an appreciable increase in the duration of hospitalization and with only modest increases in hospital cost, suggesting that thrombolytic therapy may offer a safe and effective alternative to operation in the initial treatment of patients diagnosed with acute limb-threatening peripheral arterial occlusion.
Acute Disease↗
Interleukin-6 inhibits hepatocyte taurocholate uptake and sodium-potassium-adenosinetriphosphatase activity.
The potential effects of cytokines on hepatocellular transport functions remain undefined. Interleukin-6 (IL-6) is a cytokine that is produced in sepsis, hepatitis, and other inflammatory conditions often associated with cholestasis. Using cultured rat hepatocytes, we have investigated the effects of IL-6 on hepatocellular bile salt uptake. Because hepatocyte Na(+)-K(+)-adenosinetriphosphatase (ATPase) produces the electrochemical gradient that drives sodium-dependent bile salt contransport, we also examined the effects of IL-6 on Na(+)-K(+)-ATPase activity. Hepatocytes cultured for 20 h in media containing IL-6 exhibited a dose-dependent noncompetitive inhibition of [3H]taurocholate uptake, which was maximal at an IL-6 dose of 100 U/ml. IL-6 treatment had no effect on hepatocyte sodium-independent taurocholate uptake. Northern blotting of RNA from cultured hepatocytes revealed that IL-6 had no effect on steady-state RNA levels of the Na(+)-taurocholate transporter (Ntcp). Hepatocytes incubated with IL-6 for 20 h, however, exhibited a 55% decrease in hepatocyte Na(+)-K(+)-ATPase activity. This effect also was dose dependent, with maximal inhibition occurring at an IL-6 dose of 100 U/ml. Similar treatment with IL-6 did not influence hepatocyte Mg(2+)-ATPase activity. The inhibition of Na(+)-K(+)-ATPase activity induced by IL-6 provides a putative mechanism for the observed inhibition of sodium-dependent taurocholate uptake. Since modulation of bile salt transport and Na(+)-K(+)-ATPase activity occurred at IL-6 concentrations comparable to the serum levels observed in patients with severe inflammatory states, these findings have potential pathophysiological relevance for the cholestasis of sepsis and other inflammatory disorders.
Animals↗
1994 William J. Stickel Silver Award. Closing base wedge versus Austin bunionectomies for metatarsus primus adductus.
Hallux abducto valgus with concomitant metatarsus primus adductus was treated by either an isolated Austin bunionectomy or by a combination of a modified McBride bunionectomy, along with a closing base wedge osteotomy, on a total of 73 patients (88 feet) from 1983 to 1993. Both subjective and objective similarities and differences were compared between these two groups of patients. Long-term elevation or depression of the first ray was analyzed by using a technique termed sagittal plane displacement. The prevalent preoperative symptoms were significantly reduced postoperatively in both groups of patients. Initial postoperative elevation of the first ray occurred in approximately one third of the cases in both groups. Long-term elevation of the first ray was greater with the base wedge osteotomy and did not change appreciably with the Austin procedure. The sagittal plane displacement method is a helpful tool in analyzing changes in the position of the first ray perioperatively.
Adult↗
Predictive value of dobutamine echocardiography just before noncardiac vascular surgery.
This study prospectively evaluated 75 consecutive patients (mean age 69 +/- 9 years) undergoing major vascular surgery to test the hypothesis that dobutamine stress echocardiography can be used to predict perioperative cardiac events. A positive test was defined as a new or worsening wall motion abnormality in at least 2 of 18 wall segments. Up to 40 micrograms/kg/min of dobutamine was administered. All readings were done by physicians unaware of the patients' symptoms and electrocardiographic response. In addition, physicians caring for the patients were unaware of the test result. End points of the study were unstable angina with documented electrocardiographic changes, nonfatal myocardial infarction or cardiac death. The perioperative ischemic event rate was 7% (5 of 75 patients). Three patients developed unstable angina and 2 sustained nonfatal myocardial infarctions. All of these patients had positive results on dobutamine stress echocardiography (sensitivity 100%). However, 22 patients who also had positive results on dobutamine stress echocardiography did not have perioperative events (specificity 69%). The corresponding positive predictive value was 19%. None of the 48 patients who had negative results on dobutamine stress echocardiography had events (negative predictive value 100%). In conclusion, dobutamine stress echocardiography can be used to predict perioperative events with great sensitivity, but its positive predictive value in this patient population in low, likely due to the low incidence of perioperative events in patients with known coronary artery disease and the imperfect specificity of dobutamine stress echocardiography in identifying significant coronary stenosis. Dobutamine stress echocardiography is most useful in this setting when negative, because it predicts safety from complications with confidence.
Aged↗
Human autopsy tissue distribution of the epipodophyllotoxins etoposide and teniposide.
Autopsy tissues were collected from ten patients who had received etoposide, 150-3480 mg, from 1 to 412 days antemortem and from five patients who had received teniposide, 234-1577 mg, from 3 to 52 days antemortem. Tissues were assayed for etoposide and teniposide using high-pressure liquid chromatography with electrochemical detection. Etoposide was detectable in tissues of three of four patients dying < 5 days after their last etoposide treatments to cumulative doses of 150-432 (median, 280) mg but was detectable in tissues of only one of six patients dying 7-412 (median, 37) days after their last etoposide treatment to a cumulative dose of 607-3600 (median, 1553) mg. The highest tissue concentrations were in the small bowel, prostate, thyroid, bladder, spleen, and testicle. Intermediate concentrations were found in the lymph node, skeletal muscle, adrenal gland, stomach, tumor, liver, lung, pancreas, and kidney, and the lowest concentrations were found in the heart, brain, diaphragm, vagina, and esophagus. Teniposide was detectable in one patient dying 3 days after a cumulative teniposide dose of 576 mg (spleen, prostate, heart > large bowel, liver, pancreas > thyroid, adrenal, stomach, small bowel, bladder, testicle, and skeletal muscle) but was not detectable in any tissue from four patients dying 5-52 (median, 8) days after their last treatment to a cumulative teniposide dose of 234-1577 (median, 520) mg. The very short tissue half-life contrasts with our previous observations for human autopsy tissue concentrations of mitoxantrone, doxorubicin, menogaril metabolites, diaziquone, and amsacrine. The short tissue half-life may help explain the schedule dependency of epipodophyllotoxin efficacy and may also help explain the lack of visceral toxicity of these compounds.
Chromatography, High Pressure Liquid↗
Human autopsy-tissue distribution of menogaril and its metabolites.
Autopsy-tissues were obtained from eight patients who had last received menogaril (total cumulative dose, 175-1080 mg/m2) intravenously (one patient) or orally (seven patients) from 1 to 285 days prior to death. Tissue samples were assayed for menogaril and its metabolities by high-pressure liquid chromatography. Unchanged menogaril was found only in a single lung-tissue sample from a patient who had died < 24 h after receiving his last treatment. N-Demethylmenogaril was found in two lung-tissue samples and in single samples of the thyroid, lymph node, pancreas, cerebellum, and tumor. The major menogaril metabolite found in human autopsy-tissues was 7-deoxynogarol. The highest 7-deoxynogarol concentrations were found in the large bowel (median, 201 ng/g), liver (median, 183 ng/g), and lung (median, 177 ng/g). The heart ranked as the 9th of 18 organs in median 7-deoxynogarol concentration, after the large bowel, liver, lung, tumor, thyroid, skeletal muscle, adrenal gland, and kidney. The lowest concentrations were detected in brain tissue. Our results suggest that the low degree of cardiac toxicity and the possible pulmonary toxicity of menogaril may be related to relative tissue concentrations of menogaril metabolites. Tumor 7-deoxynogarol concentrations were comparable with those in normal tissues, except that concentrations in intracerebral tumors were higher than those in the normal brain. Tissue 7-deoxynogarol concentrations appeared to be directly related to the cumulative dose and inversely related to the time from the last treatment to death; the value obtained by dividing dose by time correlated (P < 0.05) with tissue 7-deoxynogarol concentrations.
Chromatography, High Pressure Liquid↗
Neurologic events following carotid endarterectomy: prediction of outcome.
A total of 1572 carotid endarterectomies were performed at one institution between 1975 and 1987. One hundred five patients had early (< 3 weeks) neurologic events following carotid endarterectomy. Sixty-five patients had cerebral vascular accidents (CVAs) (4.1%), 14 patients had reversible ischemic neurologic deficits (0.9%), and 26 patients had transient ischemic attacks (1.7%). Eight patients died from CVAs (0.5%). The mean follow-up was 31 months (range 1 to 137 months) with a 5-year cumulative survival of 77%. The median time of occurrence of neurologic events was 4 hours. Ages, cerebral protection, patches, carotid occlusion time (mean 29 minutes), gender, and status of the contralateral carotid arteries were not predictors of outcome. Death from neurologic events increased significantly in patients who had preoperative CVAs compared with patients with preoperative transient neurologic deficits (p < 0.05). The time of occurrence of CVA after carotid endarterectomy affected outcome, and an early CVA (< 4 hours) was associated with a higher mortality at 30 days and at 4 months as a consequence of the initial CVA (p = 0.11). Patients who had a neurologic event more than 4 hours after surgery had a significantly better resolution of their symptoms (66%) compared with patients who had an early neurologic event (35%, p < 0.05). The long-term follow-up of the surviving patients demonstrated an improvement in neurologic function in 75% of the CVA group (36/48) and 92% (76/83) of all patients who had neurologic events in long-term follow-up.
Aged↗
Intraoperative autotransfusion in aortic surgery.
PURPOSE: Intraoperative autotransfusion is frequently used in aortic surgery, despite the paucity of data regarding its safety and efficacy. This study was designed to compare whole blood autotransfusion with homologous transfusion for the replacement of blood lost during abdominal aortic procedures. METHODS: Whole blood autotransfusion was evaluated in 200 patients undergoing aortic reconstructive procedures during a 3-year period. Collection and reinfusion of unwashed filtered shed blood was undertaken in 100 patients, and clinical, laboratory, and economic parameters were compared with those in a group of 100 patients undergoing aortic operation with homologous banked blood replacement. RESULTS: The two groups were comparable with respect to demography, the type of procedure, baseline laboratory profile, and the frequency of coexistent medical illnesses. The amount of blood salvaged and reinfused averaged 1729 +/- 68 ml in the autotransfusion group. Patients undergoing autotransfusion received a mean of 0.6 +/- 0.1 units of banked blood during operation, compared with 3.4 +/- 0.1 units in the homologous group (p < 0.001). Operative morbidity and mortality rates were comparable between the groups, as were length of hospital stay and total hospital costs. Coagulopathy, renal insufficiency, abnormalities of oxygen exchange, and electrolyte disorders were infrequent. Autotransfusion offered significant advantages over homologous blood replacement with respect to improved preservation of circulating platelets (201 +/- 9 vs 157 +/- 6 x 10(3)mm3, p < 0.001) and coagulation factors (242 +/- 11 vs 196 +/- 14 mg fibrinogen/dl, p < 0.01) and limitation of exposure to homologous blood (34% vs 92%, p < 0.001). There was a significant cost advantage with the use of autotransfusion, with an average savings of $288 in hospital expenses associated with blood products and infusion equipment. Patients undergoing autotransfusion demonstrated aberrations in fibrin degradation products (33 +/- 4.4 vs 9.6 +/- 3.2 micrograms/ml, p < 0.001) and free plasma hemoglobin (29 +/- 9.1 vs 9.4 +/- 0.5 mg/dl, p < 0.05), but these laboratory abnormalities did not acquire clinical significance. CONCLUSION: These data suggest that autotransfusion of unwashed, filtered blood is a safe and efficacious alternative to homologous blood replacement in patients undergoing major aortic reconstructive procedures.
Aged↗
Transfemoral endovascular aortic graft placement.
PURPOSE: The purpose of this study was to develop an endovascular system for transfemoral placement of straight aortic grafts and bifurcated aortoiliac grafts. METHODS: Both types of graft consist of barbed, self-expanding stents attached to a woven polyester fabric. Survival studies of straight-graft function were performed in six large mongrel dogs. Digital subtraction fluoroscopic equipment was used to guide insertion and record angiograms at 0, 1, and 3 months. Bifurcated grafts were inserted in an additional eight dogs, four with distal stents and four without. Straight grafts were inserted into six cadaveric aortas (five atherosclerotic and one aneurysmal; age 68.7 + 5.7 years) to assess stent attachment. RESULTS: Angiograms obtained immediately after straight-graft insertion showed placement to be within 4.6 + 1.6 mm of the intended level. Follow-up angiograms at 1 and 3 months showed no migration, no leakage, and patency of all six grafts. After bifurcated graft insertion there were no angiographic signs of perigraft leakage, with or without distal stents. The mean force required to displace straight grafts 10 mm from their original position in cadaveric aortas was 1388 + 127 g. CONCLUSION: These preliminary results show that straight and bifurcated endovascular grafts can be positioned accurately and securely in the abdominal aorta.
Aged↗
Extension of limb salvage by combined vascular reconstruction and adjunctive free-tissue transfer.
PURPOSE: Vascular reconstruction alone can be insufficient for extremity salvage in some patients with severe soft-tissue wounds. We present our experience in 20 patients with vascular reconstruction for ischemic disease and free-tissue transfer for limb-threatening soft-tissue wounds. METHODS: Nineteen patients underwent autogenous venous bypasses and one patient underwent an aortobifemoral bypass. Ten soft-tissue reconstruction were performed at the time of the vascular reconstruction and 10 were delayed. Free-tissue transferred included muscle, fasciocutaneous flaps, and omentum. Inflow to the flap was from the bypass graft (n = 12) or the distal tibial artery. RESULTS: One free flap and graft failed immediately in the same patient. One successful flap and graft required a below-knee amputation for ongoing infection in the surrounding soft tissues. Eighteen of 20 patients have had free-flap and graft patency during the mean follow-up period of 17 months (range 6 to 33 months). These 18 patients ambulate independently. CONCLUSIONS: In patients with arterial insufficiency and severe soft-tissue wounds, combined vascular reconstruction and free-tissue transfer permits extended limb salvage with excellent functional results.
Aged↗
The method of public morality versus the method of principlism.
Two years ago in two articles in a thematic issue of this journal the three of us engaged in a critique of principlism. In a subsequent issue, B. Andrew Lustig defended aspects of principlism we had criticized and argued against our own account of morality. Our reply to Lustig's critique is also in two parts, corresponding with his own. Our first part shows how Lustig's criticisms are seriously misdirected. Our second and philosophically more important part picks up on Lustig's challenge to us to show that our account of mortality is more adequate than principlism. In particular we show that recognition of mortality as public and systematic enables us to provide a far better description of morality than does principlism. This explains why we adopt the label "Dartmouth Descriptivism."
Beneficence↗
Peroneal artery bypass: a multifactorial analysis.
Sixty-two bypass grafts to the peroneal artery were performed at the University of Rochester Medical Center between 1984 and 1990. An autogenous conduit was used in 45 patients and a prosthetic conduit in 17 patients. Primary cumulative patency rates were 49% at two years and 30% at four years following operation. Limb salvage was achieved in 68% of patients. The two year cumulative patency rate was significantly better when the peroneal artery was of good quality arteriographically compared with those in which stenoses were present (75% versus 25%, p less than 0.05); in patients without inflow disease compared with patients with inflow disease (56% versus 11%, p less than 0.05); and in saphenous vein grafts compared with prosthetic grafts (55% versus 17%, p less than 0.05). The factors that did not influence patency were the presence of a direct peroneal collateral vessel filling a pedal vessel, age, sex, diabetes, and the size of the peroneal artery. The results of peroneal artery bypass in end-stage patients are dependent on the presence of adequate autogenous vein and a recipient peroneal vessel free of disease. Under these circumstances, the results of the procedure approach that of standard femorotibial reconstruction.
Aged↗
An evaluation of new methods of expressing aortic aneurysm size: relationship to rupture.
The diameter of aortic aneurysms were standardized to measures of patient size and normal aortic size in an effort to define indexes that might be more predictive of aneurysm rupture than raw aneurysm diameter alone. Normal aortic diameters were measured in 100 patients undergoing abdominal CT scans for other reasons, and an average infrarenal aortic diameter of 2.10 +/- 0.05 cm was observed. Normal aortic diameter was dependent on both age and sex, ranging from 1.71 +/- 0.06 cm in women below age 40 years to 2.85 +/- 0.04 cm in men above age 70 years. Overall, 11 (5.1%) of the ruptures occurred in aneurysms less than 5 cm in diameter, and four (1.9%) occurred in aneurysms less than 4.0 cm in diameter. When the CT scans of 100 patients undergoing elective aneurysm resection were compared with those of 36 patients with ruptured aneurysms, no threshold diameter value accurately discriminated between the two groups. However, standardization of the aneurysm diameter to the transverse diameter of the third lumbar vertebral body as an index of patient body size produced an accurate predictor of rupture when a threshold ratio of 1.0 was used. No aneurysm ruptured below this ratio, but 29% of elective aneurysms were smaller than the vertebral body diameter. Receiver operating characteristic curve analysis confirmed the superiority of the aneurysm to vertebral body diameter ratio as a discriminator of ruptured aneurysms. It appears that aneurysm diameter alone is not sufficiently predictive of rupture to be used as the sole indication for elective resection.
Adult↗