Expression of calcitonin receptors during osteoclast differentiation in mouse metatarsals.

Metatarsal bones of 15-day-old mouse embryos contain proliferative tartrate-resistant acid phosphatase (TRAP) negative (-) osteoclast progenitors that progressively differentiate into multinucleated TRAP positive (+) osteoclasts. Using histochemical and autoradiographic techniques, we have examined the expression of calcitonin receptors during osteoclast differentiation in mouse metatarsals. Fresh mouse metatarsals from embryos aged 14-17 days and metatarsals from 15-day-old embryos cultured for 1, 2, 3, and 6 days were stained for TRAP. Calcitonin binding to osteoclasts and their precursors was studied by incubating metatarsals with [125I]salmon calcitonin (sCT) and quantitating grain counts from autoradiographs of tissue sections. Calcitonin receptors first appear on nonproliferating osteoclast precursors, most often just after or simultaneously with the development of TRAP activity. The effect of sCT on the development of TRAP+ mononuclear preosteoclasts was examined by culturing 15-day-old metatarsals in the continuous presence of 5 mU sCT for periods of up to 3 days and quantitating the number of TRAP+ mononuclear preosteoclasts that develop. Calcitonin did not affect the differentiation of osteoclasts up to the stage of the TRAP+ mononuclear preosteoclast.

Osteoclast differentiation in cocultures of a clonal chondrogenic cell line and mouse bone marrow cells.

Previous reports have demonstrated that hemopoietic progenitor cells derived from mouse bone marrow can form osteoclast-like cells when cultured in the presence of stromal cells and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. We show here that in cocultures of mouse bone marrow cells and a clonal chondrogenic cell line (C5.18), a stimulation of the number of tartrate-resistant acid phosphatase-positive (TRAP+) colonies is seen with or without the addition of 1,25-(OH)2D3 to the cultures. A large proportion of the TRAP+ cells had calcitonin receptors. In addition resorption lacunae were observed on bone slices on which cocultures were maintained, thus these cells had the characteristics of osteoclasts. The number of osteoclast-containing colonies that formed in cocultures varied with the plating density of the C5.18 cells and the length of time the C5.18 cells were cultured before adding mouse bone marrow. These results suggested that osteoclast differentiation decreased with increasing cartilage differentiation. C5.18 cells treated with 1,25-(OH)2D3 before coculture stimulated TRAP+ osteoclast colony formation to a greater extent than untreated C5.18 cells, whereas C5.18 cells cultured in the presence of dexamethasone before coculture inhibited TRAP+ osteoclast colony formation relative to untreated C5.18 cells. Since 1,25-(OH)2D3 inhibits and dexamethasone stimulates cartilage differentiation in C5.18 cells, these results agree with the view that chondroprogenitor cells stimulate osteoclast colony formation, whereas cultures containing predominantly mature chondrocytes do not. Osteoclast-containing colonies were frequently associated with colonies of alkaline phosphatase-positive (AP+) cells. This raised the possibility that C5.18 cells stimulated osteoclast differentiation indirectly by increasing the numbers of AP+ stromal cells from the marrow population, which in turn could stimulate osteoclast differentiation from marrow hemopoietic progenitors. In cocultures in which the C5.18 cells were physically separated from the marrow cells, we also observed increased numbers of TRAP+ colonies growing in association with large colonies of AP+ cells, suggesting that C5.18 cells release a soluble factor that mediates these effects.

Identification of a new human lens UV filter compound.

A new UV filter compound, 4-(2-amino-3-hydroxyphenyl)-4-oxobutanoic acid O-diglucoside, has been identified in human lenses. The structure suggests that it is a further metabolic product of the second most abundant UV filter compound, 4-(2-amino-3-hydroxyphenyl)-4-oxobutanoic acid O-glucoside. Quantification studies on the new compound show that it decreases towards zero in both the nucleus and cortex as a function of age. The discovery of this novel disaccharide completes the identification of the major UV filter compounds present in the human lens.

Shape constancy and theory of mind: is there a link?

In three experiments, children aged between 4 and 7 years viewed a circular disc oriented at a slant. The disc was made of luminous material and situated in a darkened chamber. Children of all ages exaggerated the circularity of the disc when they knew that the object was really a circle (the circle task), and the effect was greatest in the younger members of the sample. Crucially, however, a group of children in Experiment 3 who viewed an identical shape that they knew emanated from an actual ellipse did not exaggerate circularity. In the second experiment, children tackled three standard theory of mind tasks in addition to the circle task mentioned above. A significant correlation emerged (even with age partialed) between the extent of exaggeration made by those who knew that the shape was a circle and ability to pass the theory of mind tests. It seems knowledge of reality contaminates judgements of appearance in the circle task. This might be the same bias that features in realist errors in theory of mind tasks.

Homocysteinemia as a risk factor for atherosclerosis: a review.

Elevation in plasma homocysteine has been widely studied as an independent risk factor for atherosclerosis. Animal laboratory models have demonstrated rapid onset vascular lesions with homocysteine infusion. A large body of data indicates a consistent relationship between plasma homocysteine and symptomatic atherosclerotic disease involving the coronary, peripheral, and cerebral circulations. Elevated plasma homocysteine can be predictably normalized with oral folate in most patients. Despite the wealth of published clinical data on this topic, it is unknown if normalization of plasma homocysteine in patients with symptomatic atherosclerosis will prevent or arrest the disease process.

Congenital venous valvular aplasia of the lower extremities.

A 10-year-old girl had bilateral, symmetrical swelling of the lower extremities, which had been present since the age of 1 year. Noninvasive vascular laboratory measurements of the ambulatory venous pressure, venous recovery time, and maximum venous outflow revealed profound bilateral lower extremity venous valvular incompetence. Duplex imaging of the veins of the lower extremities demonstrated no evidence of thrombosis, and no venous valves could be imaged. On phlebography, the patient was found to have no venous valves in the superficial and deep systems of the leg. We conclude that congenital absence of the venous valves of the lower extremities is almost certainly underdiagnosed and that the vascular laboratory can accurately and easily differentiate between lymphedema and venous valvular imcompetence. Such differentiation may have therapeutic implications.

Fifteen-year results of ambulatory compression therapy for chronic venous ulcers.

A nonoperative approach to venous stasis ulceration of the lower extremity, consisting of initial bedrest, ulcer cleansing, dressing changes, and ambulatory elastic compression stocking therapy, has been maintained for over 15 years. All patients had class III, severe chronic venous insufficiency. One hundred five of 113 patients (93%) experienced complete ulcer healing in a mean of 5.3 months. One hundred two patients were compliant with elastic compression stockings, and 11 patients were noncompliant. Complete ulcer healing occurred in 99 of 102 patients (97%) who were compliant versus six of 11 patients (55%) who were noncompliant (p less than 0.0001). The influence of noncompliance, previous venous ulceration, previous venous surgery, previous known deep venous thrombosis, peripheral arterial insufficiency (ankle brachial systolic blood pressure index less than or equal to 0.60), pretreatment ulcer duration, ulcer size, age, sex, diabetes, smoking, and photoplethysmography venous refill time on ulcer healing was determined by logistic regression analysis. Only noncompliance with elastic compression stockings (p less than 0.0001) and a pretreatment ulcer duration of more than 9 months (p = 0.02) significantly decreased initial ulcer healing. Posthealing follow-up was available in 73 patients for a mean of 30 months. Fifty-eight patients (79%) continued to be compliant with stockings; 15 patients were noncompliant. Total ulcer recurrence in patients who were compliant was 16%. Five-year lifetable recurrence was 29%. All patients who were noncompliant had recurrent ulceration by 36 months. Previous ulceration, previous venous surgery, and peripheral arterial insufficiency had no effect on ulcer recurrence (p greater than 0.05).

Supraceliac aortofemoral bypass.

Increasing numbers of patients with aortoiliac disease are seen with contraindications to standard infrarenal aortofemoral reconstruction. Although axillofemoral bypass is possible in these patients, the decreased patency rate associated with this operation makes alternate procedures desirable. This report details our experience with prosthetic bypass from the supraceliac aorta to the femoral arteries in seven patients with limb-threatening ischemia of the lower extremity, all of whom had undergone multiple previous aortic operations. The operations were performed through thoracoabdominal or flank incision, and the preferred graft configuration consisted of a single Dacron tube from the aorta to the left groin with a standard subcutaneous femorofemoral graft to the right groin. No surgical deaths occurred. At 3 1/2 years' mean follow-up, there has been one graft limb occlusion that resulted in amputation for an overall life table patency and limb salvage rate of 93%. We conclude that supraceliac to femoral artery bypass is a useful procedure for the treatment of patients who have had multiple previous aortic reconstructions fail.

Limb salvage vs amputation for critical ischemia. The role of vascular surgery.

Since 1980, 498 patients with 627 critically ischemic legs (rest pain, gangrene, ischemic ulcer, and ankle-brachial pressure index less than 0.40) were treated with revascularization regardless of operative risk or anticipated operative difficulty. Primary amputation was performed only when no graftable distal vessels were present (14 primary amputations [2.8%]) or in neurologically impaired, hopelessly nonambulatory patients. The mortality for revascularization was 2.3%, and the median hospital stay was 11 days. During follow-up, 41 limbs (7%) required amputation, 31 after failure of revascularization and 10 despite patent revascularizations. Renal failure had an adverse influence on limb salvage (67%) because of a significantly increased requirement for amputation despite patent revascularizations. We conclude aggressive limb revascularization in patients with critical lower-extremity ischemia results in low operative morbidity and mortality and excellent long-term limb salvage. Patients with critical leg ischemia and renal failure are at higher risk for limb loss than patients without renal failure.

Lower-extremity amputations for ischemia.

During the past eight years, we performed 312 lower-extremity amputations for ischemia. Amputation requiring no prosthesis was achieved in 31% of patients, knee joint preservation in 72%, and overall primary amputation healing in 75%. Amputation mortality was 6%. The use of prior arterial reconstruction, careful wound care, and willingness to accept nonhealing of trial amputations were important factors in obtaining the most distal possible healed amputation. An accurate evaluation of the impact of new methods of selecting amputation level and evaluating amputation results can only be achieved by a report of the total institutional amputation experience, not by reports of a single type of amputation.

Limb salvage in end-stage renal disease (ESRD). Comparison of modern results in patients with and without ESRD.

We reviewed our experience with femoral-popliteal-tibial reversed vein bypasses performed for limb salvage in 226 patients without and 19 patients with end-stage renal disease (ESRD). While 18-month primary patency rates were comparable (85% and 89%), limb salvage was significantly lower (76% vs 95%) in patients with ESRD. Five amputations in the ESRD group were required for nonhealing, large foot ulcers in diabetic patients despite patent arterial bypass while only five of 13 amputations in patients without ESRD were required in the presence of patent grafts. The need for major amputation despite patent bypass in diabetic patients with ESRD who have extensive foot gangrene or ischemic ulceration occurs sufficiently often that we recommend primary amputation be considered in these patients without regard to possible vascular reconstruction.

Precise diagnosis of aortic anastomotic aneurysm by computed tomographic scan.

False aneurysms that involve aortoprosthetic anastomoses may be difficult to diagnose prior to fatal rupture. We report a case in which a false aneurysm that developed six year after aortofemoral-graft insertion was accurately diagnosed by a computed tomographic (CT) scan after both ultrasonography and angiography had failed to make the diagnosis. The ability of CT scanning to demonstrate anastomotic aneurysms and accurately determine the presence of periaortic hemorrhage is discussed.

Prevalence of asymptomatic carotid stenosis in patients undergoing infrainguinal bypass surgery.

BACKGROUND: The prevalence of asymptomatic carotid stenosis in patients with lower-extremity ischemia is unknown. This report represents the largest carotid screening program to date of patients undergoing leg bypass. DESIGN: Patients undergoing infrainguinal bypass from 1987 through 1993 on the vascular surgery service at Oregon Health Sciences University, Portland, underwent routine carotid duplex examinations to detect the presence of asymptomatic carotid stenosis. PATIENTS: During the study period, 352 patients underwent infrainguinal revascularization for ischemia, of whom 225 (64%) had no prior carotid surgery, carotid arteriography, or cerebrovascular symptoms. There were 117 men and 108 women, with a mean age of 67 years. The indication for surgery was limb salvage in 67% and claudication in 33% of patients. RESULTS: Sixty-four patients (28.4%) who required lower-extremity revascularization had hemodynamically significant asymptomatic carotid artery stenosis or occlusion; 12.4% had stenosis of 60% or greater, the qualifying level for randomization in the Asymptomatic Carotid Atherosclerosis Study. Based on these findings, eight patients with carotid stenosis of 80% or greater underwent elective carotid endarterectomy. There were no postoperative neurologic events in the 225 leg bypass patients. By multivariate logistic regression analysis, the presence of carotid bruit (P < .001) and the presence of rest pain (P = .006) were associated with carotid stenosis of 50% or greater. Limiting screening to patients with carotid bruit, limb salvage indications for surgery, and/or advanced age excluded significant numbers of patients with stenosis; thus, these were not effective screening strategies. CONCLUSION: Screening carotid duplex scanning is indicated in patients who require lower-extremity revascularization.

Upper extremity ischemia from subclavian artery aneurysm caused by bony abnormalities of the thoracic outlet.

OBJECTIVE: To describe our experience with surgical therapy for upper extremity ischemia incident to emboli from aneurysms of the subclavian artery. DESIGN: Retrospective review case series. SETTING: Vascular surgery practice at a university hospital-based tertiary referral center. PATIENTS: All patients treated for upper extremity ischemia caused by embolism from a subclavian artery aneurysm from January 1, 1990, to July 31, 1996. INTERVENTION: All patients underwent detailed history and physical examination, screening for immunologic and hypercoaguable disorders, noninvasive vascular laboratory evaluation, and arteriography of the aortic arch in both arms and hands. Surgical treatment consisted of rib excision or fracture plating, aneurysm excision, and interposition vein grafting, with additional saphenous vein bypasses to brachial or forearm arteries as needed to provide uninterrupted circulation to the wrist. RESULTS: Twelve patients (6 males; mean age, 37 years) were treated. All had episodic upper extremity ischemia with an initial misdiagnosis of primary vasospastic disorder. Rest pain and/or ischemic ulceration developed in 3. Duration of symptoms before correct diagnosis averaged 7 months (range, 1-36 months). All patients had bony abnormalities of the thoracic outlet (8 cervical ribs, 3 abnormal first ribs, and 1 unstable clavicular fracture). All aneurysms contained intraluminal thrombus, and all patients had multiple ipsilateral distal arm, forearm, and/or hand arterial occlusions indicating chronic and repeated embolization. All patients underwent aneurysm excision and interposition vein grafting, with additional vein bypass to the brachial (3 patients) and/or forearm arteries (5 patients). Mean follow-up was 18 months (range, 2 weeks to 63 months). Eleven patients had complete symptomatic relief, and 1 patient improved. All subclavian interposition grafts remained patient. Two distal bypass grafts occluded in patients with preoperative arteriograms demonstrating no patient forearm arteries. There has been no limb loss. CONCLUSIONS: Hand ischemia caused by embolization from a subclavian artery aneurysm occurs in young patients without atherosclerosis and is frequently misdiagnosed as vasospasm. Despite advanced disease and multiple chronic distal arterial occlusions, surgical treatment by resection of bony abnormalities, aneurysm excision and grafting, and distal bypass grafting produces excellent results.

Ability of ankle-brachial index to detect lower-extremity atherosclerotic disease progression.

BACKGROUND: Accurate determination of progression of lower-extremity arterial occlusive disease (LEAOD) is required for natural history studies and evaluation of therapies for atherosclerosis. OBJECTIVE: To determine if changes in the ankle-brachial index (ABI) correlated with progression of LEAOD as determined by arteriography or duplex scanning. DESIGN: In patients with prior suprainguinal or infrainguinal lower-extremity revascularization, progression of LEAOD in native arteries was determined by comparing a preoperative (baseline) arteriogram with late follow-up arteriography or duplex scanning. Superficial femoral and popliteal arteries were graded as having less than 50% stenosis, 50% to 99% stenosis, or as being occluded. Tibial arteries were graded as continuously patent or occluded. Operated and nonoperated extremities were included in the study. The baseline ABI was performed postoperatively and repeated at follow-up arteriography or duplex scanning. Progression of LEAOD by the ABI was defined as a decrease in the ABI of 0.15 or greater. Progression of LEAOD by imaging studies was defined as an increase in 1 category of stenosis. Extremities with suprasystolic pressures were excluded. SETTING: Tertiary vascular surgical service. EXTREMITIES AND PATIENTS: One hundred ninety-three extremities were studied in 114 patients during a mean follow-up of 3.3 years. RESULTS: Seventy-two lower extremities (37.3%) showed progression of atherosclerosis by late follow-up arteriography or duplex scanning. Using the imaging studies as the criterion standard, the ABI had 102 true negatives, 29 true positives, 42 false negatives, and 20 false positives (sensitivity, 41%; specificity, 84%; positive predictive value, 59%; negative predictive value, 71%; and accuracy, 68%) for determining the progression of LEAOD. CONCLUSIONS: The ABI is relatively insensitive in identifying the progression of LEAOD as demonstrated by the use of imaging studies. In studies of natural history or therapy for atherosclerosis, imaging studies should be used in preference to the ABI to evaluate the progression of LEAOD accurately.

Reducing perioperative myocardial infarction following vascular surgery. The potential role of beta-blockade.

OBJECTIVE: To determine which perioperative variables may influence the occurrence of perioperative myocardial infarction (PMI) following vascular surgery. DESIGN: Case-control study. SETTING: Combined Veterans Affairs Medical Center-university hospital vascular service. PATIENTS: During a 4-year period, all major vascular surgical operations (N = 2088) were evaluated with serial postoperative electrocardiography and cardiac enzyme measurements. Patients with PMI following nonemergent vascular surgery (N = 53) were matched with randomly selected control patients without PMI (N = 106) for age, gender, type of operation, hypertension, and symptoms of coronary artery disease. MAIN OUTCOME MEASURES: The two groups were compared for operative blood loss, blood pressure, and heart rate as well as length of operation, type of anesthetic, and use of perioperative beta-blockers, nitroglycerine, calcium channel blockers, vasopressors, and angiotensin-converting enzyme inhibitors. RESULTS: beta-Blockers were used less frequently in patients with PMI than in control patients without PMI (30% vs 50%; P = .01). Overall beta-blockade was associated with a 50% reduction in PMI (P = .03). Perioperative myocardial infarction was not associated with length of operation, type of anesthetic, blood pressure, or use of other medications. CONCLUSIONS: beta-Blockade is associated with a decreased incidence of PMI in patients undergoing vascular surgery. Prophylactic perioperative use of beta-blockers may decrease PMI in patients requiring major vascular surgery. A prospective randomized trial of beta-blockers in these patients appears to be warranted.

Isolated bypass to the superior mesenteric artery for intestinal ischemia.

OBJECTIVE: A number of reports indicate revascularization for intestinal ischemia should include the superior mesenteric artery (SMA) and the celiac artery. However, no controlled or randomized studies have proven this approach superior to SMA bypass alone. We report our results using bypass to only the SMA for intestinal ischemia. DESIGN: Retrospective review with mean follow-up of 40 months (range, 2 to 110 months). SETTING: University medical center and Veterans Affairs hospital. PATIENTS/METHODS: The records of patients who underwent intestinal revascularization of the SMA alone from 1982 through 1993 were reviewed. Patients were assessed for indication for operation, operative technique, perioperative mortality, and long-term outcome. The SMA grafts were examined for patency within the last 6 months using duplex scanning or arteriography. Patient survival and graft patency rates were calculated using life-table methods. RESULTS: Twenty-nine bypasses to only the SMA were performed in 26 patients (16 female and 10 male; mean age, 59 years; age range, 13 to 81 years). Indication for operation was symptomatic chronic mesenteric ischemia in 23 cases and acute intestinal ischemia in five cases. One bypass was performed for asymptomatic SMA occlusion. There were three perioperative deaths (10% mortality rate), all in patients with acute intestinal ischemia and previous mesenteric arterial surgery. Life-table 4-year primary graft patency and patient survival rates were 89% and 82%, respectively. Symptomatic improvement was maintained in all patients available for follow-up. CONCLUSION: Revascularization of only the SMA for intestinal ischemia provides excellent graft patency with acceptable perioperative mortality and long-term patient survival. The SMA bypass alone for intestinal ischemia appears as successful as bypasses to multiple visceral vessels.

Axillofemoral grafting with externally supported polytetrafluoroethylene.

OBJECTIVE: To evaluate the results of axillofemoral bypass grafting using externally supported polytetrafluoroethylene. DESIGN: Consecutive patients who were operated on by us from 1983 to the present were prospectively followed up in a vascular registry. The results of surgery with respect to morbidity and mortality, patency, limb salvage, and patient survival were determined by life-table methods. PATIENTS: A standardized operative technique was used to perform 184 axillofemoral bypass procedures in 164 consecutive patients (age range, 14 to 90 years; mean age, 67 years; female, 33%). Follow-up ranged from 0 to 95 months (mean, 23 months). RESULTS: Ischemia was the indication for 83% of the procedures, and aortic sepsis was the indication for 16%. There were nine operative deaths (5%) and 17 major complications. Life-table primary patency, limb salvage, and survival rates at 5 years were 71%, 92%, and 52%, respectively. Indication for surgery, patency of the superficial femoral artery, and the performance of multilevel procedures did not significantly influence patency. CONCLUSIONS: The results of axillofemoral grafting using polytetrafluoroethylene are equivalent to those achieved with other accepted methods of treatment for lower extremity ischemia, including balloon angioplasty, aortofemoral bypass, and infrainguinal bypass. Axillofemoral bypass is an appropriate technique that is deserving of more widespread use.

Extrathoracic arterial grafts performed for carotid artery occlusive disease not amenable to endarterectomy.

HYPOTHESIS: Extrathoracic cervical grafts are safe and provide long-lasting stroke prevention in patients with disease not amenable to standard carotid bifurcation endarterectomy. DESIGN: Review of a prospectively maintained vascular surgical registry. SETTING: Combined university and Department of Veterans Affairs vascular surgical service. PARTICIPANTS: Patients requiring surgery for carotid atherosclerotic occlusive disease not amenable to endarterectomy from January 1988 to March 1998. INTERVENTIONS: Carotid interposition grafting, subclavian-carotid bypass, or carotid-carotid bypass. MAIN OUTCOME MEASURES: Perioperative stroke and death, and life-table determination of freedom from stroke, stroke-free survival, and graft patency. RESULTS: Sixty patients (mean age, 65.8 years; range, 36-83) underwent cervically based carotid grafting. All had greater than 70% stenosis or occlusion of the innominate, common carotid, or internal carotid arteries, and 30 (50%) had undergone at least 1 previous ipsilateral carotid endarterectomy. Indication for operation was stroke or transient ischemic attack in 46 (77%) and asymptomatic high-grade stenosis in 14 (23%). Operative procedures included 31 (52%) carotid interposition grafts, 18 (30%) subclavian-carotid grafts, and 11 (18%) carotid-carotid grafts. Mean follow-up was 29 months (range, 1-117 months). Perioperative stroke rate was 5% (3/60) all in symptomatic patients, and there were no perioperative deaths. By life-table analysis, freedom from stroke was 92% at 1 and 5 years. Stroke-free survival was 90% at 1 year and 61% at 5 years. Primary graft patency was 94% at 1 year and 84% at 5 years, with assisted primary patency of 90% at 5 years. CONCLUSION: Cervical carotid artery grafts for complicated or recurrent carotid atherosclerosis not amenable to endarterectomy are durable and provide excellent freedom from stroke with low perioperative morbidity and mortality.