CD4+CD45RBHi T cell transfer induced colitis in mice is accompanied by osteopenia which is treatable with recombinant human osteoprotegerin.

BACKGROUND AND AIMS: Transfer of CD4+CD45RBHi T cells into semi syngeneic immunodeficient mice represents a model of inflammatory bowel disease (IBD). As patients with IBD often suffer from osteopenia, we studied if this T cell transfer in mice results in osteopenia in addition to colitis, and if treatment with osteoprotegerin (OPG) has effects on the bone mineral density of T cell transferred mice. We also investigated whether osteopenia was due to malabsorption as a result of a dysregulated digestive tract or as a consequence of the inflammatory process. METHODS: CD4+CD45RBHi or CD4+CD45RBLo T cells (4 x 10(5)) were sorted from CB6F1 and transferred into C.B.17 scid/scid mice. Recipient mice were treated with human IgG1 Fc (control) or Fc-OPG three times per week in a prophylactic regimen as well as a therapeutic regimen (after 10% body weight loss) and were evaluated for osteopenia and colitis. RESULTS: Mice that received CD4+CD45RBHi T cells developed osteopenia (as indicated by decreased bone density accompanied by decreased osteoblasts and increased osteoclasts) and colitis (as indicated by histological changes in the large intestine). Mice that received CD4+CD45RBLo T cells developed neither osteopenia nor colitis. All animals consumed, on average, the same amount of food and water over the course of the study. Prophylactic treatment with Fc-OPG increased bone density in mice that received either CD4+CD45RBHi or CD4+CD45RBLo T cells but had no effects on the gastrointestinal tract. Fc-OPG treatment of osteopenic mice with established IBD caused the normalisation of bone density. Osteopenia in CD4+CD45RBHi T cell recipients was accompanied by hypoparathyroidism that was partially normalised by treatment with Fc-OPG. CD4+CD45RBHi T cell recipients also had a bone marrow inflammatory cell infiltrate expressing tumour necrosis factor alpha which was unaffected by treatment with Fc-OPG. CONCLUSIONS: CD4+CD45RBHi T cell transfer results in osteopenia in addition to colitis. Evidence suggests that this osteopenia was induced by inflammatory cell infiltration and not by malabsorption of calcium. Recombinant human osteoprotegerin effectively treated the osteopenia. OPG may be a useful therapeutic option for treating osteopenia in patients with IBD.

Cost factors in limb-threatening ischaemia due to infrainguinal arteriosclerosis.

Cost factors are an increasingly important aspect of medical care. In the United States, more than 150,000 patients per year have limb-threatening ischaemia due to infrainguinal atherosclerosis. We studied the economic impact of this disease process and its treatment in 313 consecutive patients seen at our hospital between 1979 and 1981. Minimum follow-up was 3 years. Seventy-nine percent of our patients undergoing revascularisation attempts had limb salvage with full function at 1 year and 60% had full function at 3 years. Of the patients who died, 85% died with their limbs intact. The mean patient cost for all 289 arterial reconstructions was $26,194 +/- $876 S.E. ($23,026 +/- $1117 for 166 femoropopliteal bypasses; $30,380 +/- $1349 for 123 distal bypasses). The mean length of stay (LOS) for the reconstruction group was 50 days. In this patient population, the following adverse risk factors were present: Gangrene or necrosis in the foot (72%), age more than 70 (56%), and previous vascular surgery (21%). A significantly higher cost was associated with each of these factors (gangrene, $32,653 +/- $1534; age greater than 70, $28,089 +/- $1235; previous bypass, $29,666 +/- $1962). During the same time period, initial patient costs for 24 patients undergoing primary below-knee amputation and rehabilitation were $27,225 +/- $2896 S.E. Twenty-nine percent of the patients with below-knee amputations never walked again. The nonambulatory patients had a significant continuing expenditure for institutionalisation ($100/day) or home care ($270/week). These facts document the high cost of limb-threatening arteriosclerosis and its treatment by vascular reconstruction or primary below-knee amputation.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraoperative outflow resistance as a predictor of late patency of femoropopliteal and infrapopliteal arterial bypasses.

To evaluate the efficacy of intraoperative outflow resistance (OR) measurements in predicting late graft patency rates (PR) for femoropopliteal (FP) and femoroinfrapopliteal (FD) bypasses, we have reviewed 134 such cases performed during the past 3 years at our institution. Of these, 64 bypasses were FP (13 autogenous saphenous vein [ASV] and 51 polytetrafluoroethylene [PTFE]) and 70 were FD (43 ASV and 27 PTFE). Total and distal OR measurements (measured in millimeters of mercury per milliliter per minute) were divided into four groups each for all infrainguinal bypasses combined and for FP and FD bypasses separately. The relationship of PR to total and distal OR measurements were analyzed according to the product limit method. Overall 1- and 2-year PRs were 64% and 56%, respectively. For FP bypasses the same PRs were 78% and 67% whereas for FD bypasses, they were 52% and 45%, respectively. The 1-year PRs for FP and FD bypasses within each respective OR group were analyzed. For FP bypasses in the lowest to the highest total OR groups, the 1-year PRs were 86%, 75%, 78%, and 62% (NS), and for FD bypasses they were 72%, 89%, 23%, and 22% (p less than 0.001). Similar trends were observed when distal OR measurements were analyzed. For infrainguinal PTFE bypasses, both total and distal OR measurements were significant predictors of patency, whereas for those with ASV only distal OR measurements were predictive. These data reaffirm our early experience with OR measurements. Although a trend for predicting graft patency was noted for FP bypasses, OR measurements were highly predictive only for FD bypasses.

Infrapopliteal bypasses to heavily calcified rock-like arteries. Management and results.

Of the 355 consecutive infrapopliteal bypasses for limb salvage performed over a 5 year period at our institution, 116 (Group I) were to noncalcified vessels, 203 (Group II) were to vessels of varying degrees of calcification (mild to moderate), and 36 (Group III) were to heavily and circumferentially calcified arteries. A new intraoperative fracture technique was used to overcome the rigidity of the arterial wall in the latter group. Three year cumulative patency rates for Groups I, II, and III were 45 percent, 58 percent, and 47 percent, respectively. Comparable limb salvage rates for Groups I, II, and III were 66 percent, 73 percent, and 75 percent. No significant difference in patency or limb salvage results could be elicited between the three groups by the log-rank test. These findings suggest that arterial calcification is an invalid predictor of failure in small vessel bypasses. Even circumferentially calcified arteries, which are generally thought to be surgically unapproachable, should not be a deterrent to limb salvage attempts.

Six year experience with expanded polytetrafluoroethylene arterial grafts for limb salvage.

We have used 822 polytetrafluoroethylene (PTFE) grafts in arterial reconstructions for limb salvage over the last 6 years at Montefiore Medical Center-Albert Einstein College of Medicine, Four hundred and twenty-seven femoropopliteal reconstructions with PTFE had a 6 year cumulative life table patency rate of 55% with follow-up of 76 grafts for more than 3 years and 28 grafts for more than 4 years. Seventy-nine bypasses to the isolated popliteal segment had a 6 year cumulative patency rate of 72%. There were 207 bypasses performed to the tibial, peroneal or dorsalis pedis arteries. Life table patency rates were 55% at 1 year, 40% at 2 years and 37% at 4 years. Ninety-two PTFE femorofemoral and 62 axillofemoral bypasses had 5 1/2 year cumulative life table patency rates of 83% and 75%, respectively. Axillopopliteal PTFE bypasses can salvage otherwise doomed limbs. Thirty-four such grafts had 74% 1 year and 45% 5 year patency rates. The overall infection rate in all 822 PTFE grafts was only 0.5%. Thus, PTFE is a promising vascular prosthetic material which facilitates otherwise difficult or impossible limb salvage procedures.

Five year experience with axillopopliteal bypasses for limb salvage.

Over the last 5 years, we have performed 34 axillopopliteal bypasses to salvage threatened limbs of patients in whom standard anatomic or extra-anatomic bypasses had either failed or were not feasible. The indications for these axillopopliteal bypasses, all of which were performed with 6 mm polytetrafluoroethylene grafts, were: (1) severe atherosclerotic disease of the common, superficial and deep femoral arteries which precluded use of these vessels for inflow or outflow for a standard vascular procedure (15 cases); (2) failed aortofemoral bypass with sufficient fibrosis or disease progression in the profunda femoris artery to prevent its use in a reoperation (7 cases); (3) insufficient hemodynamic improvement and failure to heal a foot lesion after an axillofemoral bypass (9 cases); and (4) sepsis in the groin from a previously infected bypass (3 cases). Graft patency was determined by objective measures. Cumulative life table graft patency rates were 77% at 1 year, 51% at 3 years, and 45% at 5 years. Although these rates are not as good as those for our axillofemoral bypasses (75% at 5 years), 22 limbs revascularized by axillopopliteal bypasses were salvaged with function for 1 year and 9 were salvaged with function for 2 years or longer in situations in which no option other than amputation was available. This justifies the continuing use of axillopopliteal bypass in an effort to salvage those limbs imminently threatened with amputation and in which no standard reconstruction is feasible because of disease or infection.

Monosomy 13q32.3----qter: report of two cases.

Two unrelated patients with monosomy 13q32.3----qter are reported. Comparison with six similar cases previously published indicates that the craniofacial dysmorphism of the 13qter monosomy syndrome is related to band 13q34, the thumb hypoplasia to band 13q32, and an apparently different phenotype to band 13q33. Coagulation deficiency appears to be non-specific in monosomy 13qter.

Gangliosidosis GM2 tipo 2: enfermedad de Sandhoff / Gangliosidosis GM2 type 2: Sandhoff's disease

Se estudió a un niño de 19 meses de edad con un cuadro clínico sugestivo de gangliosidosis GM2: facies peculiar, retardo psicomotor severo, espasticidad generalizada, crisis convulsivas tónicas, macrocefalia, pérdida de la función visual y auditiva, reflejos osteotendinosos exaltados y primer dedo de ambos pies en flexión sostenida; manchas rojo cereza en fondo de ojo y atrofia cerebral demostrada por EEG y TAC. Mediante cromatografía de capa fina se identificaron oligosacáridos en diferentes muestras de orina con un patrón cromatográfico característico. La actividad de las hexosaminidasas A y B en el paciente y sus padre fueron compatibles con homocigocidad y heterocigocidad respectivamente, para la deficiencia de ambas enzimas. Estos resultados permitieron precisar el diagnóstico de gangliosidosis GM2 tipo 2 (Enfermedad de Sandhoff). Se señala la importancia de la identificación de la oligosacariduria

Comparison of axillounifemoral and axillobifemoral bypass operations.

Routine use of axillobifemoral (ABF) bypass has been advocated because this operation is thought to achieve better patency than the axillounifemoral (AUF) procedure. In 5 years we performed 34 AUF and 22 ABF bypass operations for limb salvage in high-risk patients using 6 mm polytetrafluoroethylene grafts. Five-year cumulative life table patency rates for AUF bypasses were 71% with reoperation (secondary patency) and 44% without reoperation (primary patency). These values were not significantly different (p greater than 0.5) from those for ABF bypasses (77% and 50%, respectively). Five-year limb salvage results (AUF 73%; ABF 89%) were also not significantly different (p greater than 0.1). Correlation of arterial outflow characteristics with graft patency revealed that 78% of the patients who never had graft occlusion had occluded superficial femoral arteries (SFA) demonstrated at the first operation, while 79% of the patients who experienced graft closure had comparable SFA occlusions. Our aggressive approach to graft thrombosis included angiographic study of the inflow arterial system. This revealed that 16% of the failed grafts were associated with hemodynamically significant stenosis of the donor subclavian artery. Our results indicate that AUF bypass is the procedure of choice for unilateral limb ischemia in high-risk patients who require an axillary source and that patency of the SFA does not affect outcome. These results also emphasize the need to obtain angiographic evaluation of the inflow system.

Components of outflow resistance and their correlation with graft patency in lower extremity arterial reconstructions.

We have used a simple reproducible method to measure total outflow resistance (OR) and its proximal and distal components in 101 bypasses (46 femoropopliteal [FP] and 55 femorodistal [FD]). All bypasses with a distal OR greater than 1.2 mm Hg/ml/min failed within 3 months and all with distal OR less than 1.2 mm Hg/ml/min remained patent for at least 3 months. To evaluate the contribution of vasospasm to OR and its role in graft failure, 60 bypasses (29 FP, 31 FD) had OR measurements before and after local infusion of papaverine hydrochloride (60 mg). Within 3 months, nine grafts (all FD) occluded and 51 remained patent. All nine failures had distal OR greater than 1.2 mm Hg/ml/min before papaverine infusion. After infusion, the mean percentage decrease in both total and distal OR for all grafts was 30% and 31%, respectively. However, there was no significant difference between these papaverine-induced decreases in OR and 3-month graft failure or success. Moreover, in three bypasses, even though papaverine lowered the distal OR from greater than 1.2 to less than 1.2 mm Hg/ml/min, early occlusion occurred. In six grafts (1 FP, 5 FD) when total and distal OR before and after papaverine was greater than 1.2 mm Hg/ml/min, the graft was extended to a second distal artery as a sequential bypass. These six grafts have remained patent over 3 months. Thus measurement of OR and particularly distal OR is a most accurate predictor of early graft success or failure. Pharmacologic manipulation does not enhance the predictive value of the OR measurement. OR measurements also help to select those FD bypass cases in which extension to a second distal artery as a sequential bypass improves patency.

Diagnosis and management of failing lower extremity arterial reconstructions prior to graft occlusion.

In 191 instances, infrainguinal graft occlusion was presumed because of a rethreatened foot, diminished pulses and/or decreased ankle pressure. Routine urgent arteriography revealed 38 instances where the graft was patent (22 vein, 16 PTFE). Ten of these grafts were to the femoral artery, 18 to the popliteal artery and 10 were to infrapopliteal arteries. The deterioration despite a patent graft was due to development of inflow stenosis (15), vein graft lesions (13) or distal disease progression (10). All were treated successfully by percutaneous transluminal angioplasty (30) or simple local operative revisions (8). Cumulative life table patency rates 2 years after reintervention were 89% for failing reconstructions to the femoral artery, 94% for those to the popliteal artery and 89% for infrapopliteal procedures. Comparable rates for limb salvage were 90%, 100% and 100%, respectively. These findings underscore the importance of urgent angiography in suspected lower extremity graft failure. Defects may be detected before real graft occlusion occurs and appropriate interventional treatment can provide important additional periods of limb salvage.

System for widespread application of microcomputers to vascular surgery.

The application of microcomputers to vascular surgery has been limited because of the lack of software that allows collection and effective evaluation of a large amount of patient-related data. We have developed a microcomputer-based data handling system for evaluating vascular patients that is inexpensive ($6000 to $8000), easy to use, and flexible. Its simplicity for nonprogrammers is achieved through a natural interface with menu-driven operations and descriptive English language messages. With this system eight data entry forms were designed, and data on more than 1000 patients treated for peripheral vascular disease over the last 7 years were entered into the computer by clerical personnel with minimal training. A query language report generator allowed us to obtain reports of results in simple English on any set of selection criteria with all relevant statistical functions, including cumulative life-table patency rates. This system has the following advantages: rapid evaluation of data from several retrospective and prospective studies, such as comparison of graft material, effect of local and systemic risk factors, cost of limb-salvage surgery, and correlation of noninvasive laboratory tests with other parameters; more accurate patient follow-up, with elimination of many of the pitfalls involved in observing large groups of patients frequently; and quantitation of individual surgeon or service results for quality control and self-review, which guide the vascular surgeon to modify treatment protocols, patient selection, and/or surgical techniques. Wider use of this system for data collection and evaluation will help to standardize data reporting and thus allow accurate comparison of data from different centers.

Quantitative assessment of outflow resistance in lower extremity arterial reconstructions.

Graft patency is thought to correlate with resistance in the runoff bed or outflow resistance. However, accurate measurement of this parameter has been difficult. A simple and reproducible method for direct measurement of outflow resistance following completion of the distal anastomosis of a bypass graft has been developed. This method employs injection of a fixed amount of normal saline through the proximal end of the graft and measurement of the resulting integrated pressure increment by an analog computer. Division of this pressure integral by the volume injected is a measure of the outflow resistance expressed in resistance units (mm Hg/ml/min). The median outflow resistance in 31 femoropopliteal bypasses was 0.29 units with a range of 0.08-1.38 units. The median outflow resistance in 33 femorodistal bypasses was 0.7 units with a range of 0.18-2.34 units. All bypasses with an outflow resistance of 1.1 units or less remained patent for 3 months. There were 51 grafts in this group (30 femoropopliteal; 21 femorodistal) and their outflow resistance ranged from 0.08 to 1.1 units. All bypasses with an outflow resistance of 1.2 units or higher thrombosed within the first postoperative month. There were 13 grafts in this group (1 femoropopliteal; 12 femorodistal) and their outflow resistance ranged from 1.2 to 2.38 units. Eight of the 13 grafts that failed originally were subjected to thrombectomy, which was uniformly unsuccessful. Although this method does not yet allow bypass surgery to be denied to any patient, it does define a group of patients in whom thrombectomy will not be effective and should not be attempted.(ABSTRACT TRUNCATED AT 250 WORDS)