Heart xenograft survival with chimeric pig donors and modest immune suppression

OBJECTIVE: To assess the use of donor pigs with cellular chimerism for prevention of acute rejection with modest immune suppression. The clinical use of pig organ xenografts is currently precluded by severe acute rejection, which resists standard immune suppression. SUMMARY BACKGROUND DATA: For long-term survival of pig organ xenografts, immune suppression significantly greater than used with allografts would currently be necessary, leaving the recipient immune deficient and at increased risk for infections. Induction of immune tolerance and tissue accommodation could enhance xenograft survival but would lead to complications and frequent graft failure. Induction of cellular chimerism within the donor pigs, however, could accomplish these goals before transplantation, significantly reducing the risk. METHODS: Marrow cells from sheep were infused into fetal pigs. Heart xenografts from chimeric or nonchimeric pigs were transplanted heterotopically into recipient sheep, simultaneous with infusion of splenocytes. Posttransplant suppression consisted of cyclosporine and tapered corticosteroids, comparable with allotransplants. RESULTS: All of the control grafts (n = 12) were rejected by acute vascular rejection in 4 to 8 days. In contrast, only one episode of vascular rejection was observed in the experimental group (n = 13). Four experimental recipients had an episode of moderate diffuse cellular rejection (grade 3) and one had moderate focal cellular rejection (grade 2). Each episode responded to pulse steroids. Seven grafts showed no significant rejection. There was little evidence of immune deficiency, infection, or toxicity. CONCLUSIONS: Acute vascular rejection was prevented in a large animal model without the need for severe immune suppression.     

A national and single institutional experience in the contemporary treatment of acute lower extremity ischemia

OBJECTIVE: To determine the contemporary clinical relevance of acute lower extremity ischemia and the factors associated with amputation and in-hospital mortality. SUMMARY BACKGROUND DATA: Acute lower extremity ischemia is considered limb- and life-threatening and usually requires therapy within 24 hours. The equivalency of thrombolytic therapy and surgery for the treatment of subacute limb ischemia up to 14 days duration is accepted fact. However, little information exists with regards to the long-term clinical course and therapeutic outcomes in these patients. METHODS: Two databases formed the basis for this study. The first was the National Inpatient Sample (NIS) from 1992 to 2000 of all patients (N = 23,268) with a primary discharge diagnosis of acute embolism and thrombosis of the lower extremities. The second was a retrospective University of Michigan experience from 1995 to 2002 of matched ICD-9-CM coded patients (N = 105). Demographic factors, atherosclerotic risk factors, the need for amputation, and in-hospital mortality were assessed by univariate and multivariate logistic regression analysis. RESULTS: In the NIS, the mean patient age was 71 years, and 54% were female. The average length of stay (LOS) was 9.4 days, and inflation-adjusted cost per admission was $25,916. The amputation rate was 12.7%, and mortality was 9%. Decreased amputation rates accompanied: female sex (0.90, 0.81-0.99), age less than 63 years (0.47, 0.41-0.54), angioplasty (0.46, 0.38-0.55), and embolectomy (0.39, 0.35-0.44). Decreased mortality accompanied: angioplasty (0.79, 0.64-0.96), heparin administration (0.50, 0.29-0.86), and age less than 63 years(0.27, 0.23-0.33).The University of Michigan patients' mean age was 62 years, and 57% were men. The LOS was 11 days, with a 14% amputation rate and a mortality of 12%. Prior vascular bypasses existed in 23% of patients, and heparin use was documented in 16%. Embolectomy was associated with decreased amputation rates (0.054, 0.01-0.27) and mortality (0.07, 0.01-0.57). CONCLUSIONS: In patients with acute limb ischemia, the more widespread use of heparin anticoagulation and, in select patients, performance of embolectomy rather than pursuing thrombolysis may improve patient outcomes.     

Intracranial stent placement for the treatment of a carotid-cavernous fistula associated with intracranial angioplasty. Case report

The authors report a case of an iatrogenic carotid-cavernous fistula (CCF) associated with intracranial angioplasty. Angioplasty was performed using a 3 x 10-mm Open Sail coronary balloon in a patient with high-grade stenosis of the left cavernous internal carotid artery (ICA). After angioplasty, a perforation developed in the cavernous ICA, resulting in a CCF. A 3.5 x 9-mm S670 coronary stent was used to treat the fistula. To the authors' knowledge, this is the first reported case in which a CCF developed after angioplasty was performed using a coronary balloon. Long-term angiographic and clinical evaluation is needed to test the suitability and durability of intracranial angioplasty and stent placement in the treatment of symptomatic intracranial stenosis.     

Modulation of mitochondrial adenosine triphosphate-sensitive potassium channels and sodium-hydrogen exchange provide additive protection from severe ischemia-reperfusion injury

BACKGROUND: Preconditioning and inhibition of sodium-proton exchange attenuate myocardial ischemia-reperfusion injury by means of independent mechanisms that might act additively when used together. The hypothesis of this study is that treatment with a sodium-proton exchange inhibitor and a mitochondrial adenosine triphosphate-sensitive potassium channel opener produces superior functional recovery and a greater decrease in left ventricular infarct size compared with treatment with either drug alone in a model of severe global ischemia. METHODS: Isolated crystalloid-perfused rat hearts (n = 8 hearts per group) were administered vehicle (control, 0.04% dimethyl sulfoxide), diazoxide (100 micromol/L in 0.04% dimethyl sulfoxide), cariporide (10 micromol /L in 0.04% dimethyl sulfoxide), or diazoxide and cariporide before 40 minutes of ischemia at 35.5 degrees C to 36.5 degrees C and 30 minutes of reperfusion. RESULTS: The combination group had superior postischemic systolic function compared with that seen in the cariporide, diazoxide, and control groups (recovery of developed pressure: 91% +/- 7% vs 26% +/- 5%, 35% +/- 6%, and 16% +/- 3%, respectively; P <.05). Postischemic diastolic function in the combination group was superior compared with that seen in the other groups (change(pre-post) diastolic pressure of 67 +/- 4 mm Hg with control, 49 +/- 11 mm Hg with diazoxide, 59 +/- 10 mm Hg with cariporide, and 3 +/- 3 mm Hg with diazoxide and cariporide combination; P <.05). The left ventricular infarct area was less in the combination group compared with that in the cariporide, diazoxide, and control groups (6% +/- 2% vs 35% +/- 7%, 25% +/- 3%, and 37% +/- 9%, respectively; P <.05). CONCLUSIONS: Combining a selective mitochondrial adenosine triphosphate-sensitive potassium channel opener with a selective reversible inhibitor of sarcolemmal sodium-proton exchange improves recovery of contractile function from severe global ischemia in the isolated buffer-perfused rat heart. The putative mechanism for this benefit is superior protection of mitochondrial function.     

The natural history of an untreated isolated scapholunate interosseus ligament injury

The natural history of an untreated isolated scapholunate interosseus ligament injury remains unclear, although it is commonly assumed that patients continue to suffer with pain, stiffness and weakness of the wrist and ultimately develop secondary osteoarthritis (SLAC wrist). In this study, we evaluated the clinical condition of 11 patients with an arthroscopically proven interosseus scapholunate ligament injury, but without any radiological signs of either DISI deformity or scapholunate gapping, who had declined further treatment at an average follow-up of 7 years. Whilst there was on going pain and functional limitation in all cases, there was no rapid progression to degenerative change (SLAC wrist).     

Evaluating chronic venous disease with a new venous severity scoring system

BACKGROUND: The Venous Clinical Severity Score (VCSS) has been proposed by the American Venous Forum as an objective means to clinically assess venous disease more completely than with the clinical CEAP classification. However, validation of the VCSS against an objective test is lacking. The purpose of this study was to test the VCSS against abnormalities found on venous ultrasound (US) scans. METHODS: As part of a screening project in a large kindred population with protein C deficiency, VCSS and venous US scanning were performed in 210 patients (420 limbs). A single examiner scored the VCSS (0-3) clinically for pain, varicose veins, edema, skin pigmentation, inflammation, induration, ulcer duration and size, and compressive therapy. Another experienced examiner, blinded to the subject's medical history, performed a US examination of the deep and superficial venous system, with a hand-carried US system. The relationship between US and VCSS scores was analyzed by calculating an odds ratio (OR) and its 95% confidence interval (CI). RESULTS: Of the 420 limbs screened, VCSS was 0 in 283 limbs, and VCSS was 1 or greater in the following categories: pain, 63 limbs; varicose veins, 70 limbs; edema, 51 limbs; skin pigmentation, 17 limbs; inflammation, 2 limbs; induration, 8 limbs; and compressive therapy, 9 limbs. The highest total score in any limb was 8. A clear association was seen with the VCSS and abnormalities found on US scans. When the score was dichotomized (0 = normal, 1 = any abnormality), it was a strong predictor of US scan abnormalities; limbs with VCSS greater than 0 had a 26-fold greater chance of US scan abnormalities than did limbs with VCSS = 0 (OR, 26.5; 95% CI, 11-64). With ultrasonography as the standard, sensitivity of VCSS compared with US scans was 89.3%, and specificity was 76.1%. Negative predictive value of VCSS = 0 was 97.9%, and positive predictive value for any positive score was 36.5% CONCLUSIONS: The results of this study are based on a large kindred population with a higher risk for venous disease than found in the general population. Though the VCSS was devised to quantify the severity of chronic venous disease, this study found it a useful screening tool. The VCSS showed good association with abnormalities on US scans, and when VCSS = 0 there is a high likelihood that the patient does not have venous disease. This simple test may prove valuable in clinical practice.     

A new in vitro model of venous hypertension: the effect of pressure on dermal fibroblasts

PURPOSE: Venous hypertension leads to venous stasis ulcers. White cell activation, protein leakage from pressurized capillaries, and cytokine imbalances have all been implicated as indirect effects of venous hypertension that contribute to dermal changes seen in chronic venous insufficiency. The direct effect of increased tissue pressures on dermal elements has not been investigated. Prior studies have shown that fibroblasts isolated from venous ulcers have altered growth rates, morphologies, and protein production similar to senescent or aged fibroblasts. We hypothesize that neonatal fibroblasts (NNFs) cultured in conditions of increased atmospheric pressure will demonstrate altered cell function when compared with those grown at normal atmospheric pressure (ATM). METHODS: A pressure incubator was used to culture populations of NNFs at ATM, 60 mm Hg over ATM (ATM + 60 mm Hg), and 120 mm Hg over ATM (ATM + 120 mm Hg). NNF population growth rates were determined by periodic flow cytometry analysis over a 2-week period. Light microscopy and digital imaging were used to evaluate cell morphology. Senescence-associated B-galactosidase (SA-beta-Gal) activity was determined using the X-Gal stain. Fibronectin production was assessed by exposing cells sequentially to anti-fibronectin antibodies and Oregon Green-conjugated goat anti-mouse secondary antibodies. Flow cytometry then was used to determine relative proportions of cells staining positively for fibronectin. Statistical analysis was accomplished with analysis of variance. RESULTS: Populations of cells grown under increased pressures (both ATM + 60 and ATM + 120) showed reduced growth rates (P <.001). Similarly, morphologies of cells grown under pressure had increased cytoplasm to nuclear ratios with abnormal nuclear shapes. Populations of cells grown under pressure had higher percentages of cells staining positive for fibronectin (ATM = 45%, ATM + 60 = 59%, ATM + 120 = 79%). After 14 days of growth under pressure, fibroblast populations did not demonstrate augmented productions of the senescence marker SA-beta-Gal (ATM =.5%, ATM + 60 =.25%, ATM + 120 =.75%). CONCLUSIONS: This study demonstrated that NNFs grown in culture under increased pressures undergo a transformation not seen in cells grown at atmospheric pressure. Cells grown under pressure demonstrated reduced growth rates, increased fibronectin production, and abnormal morphologies similar to fibroblasts isolated from venous ulcers. This study suggests that pressure elevations (like venous hypertension) can directly result in altered cell function and morphology that may contribute to the delayed wound healing seen in patients with venous ulcers. This model uses a pressurized incubator that may prove to be a valuable adjunct in studying the effects of venous hypertension.     

Endovascular treatment of aortic aneurysms in patients with renal transplants

Endovascular treatment of an abdominal aortic aneurysm was undertaken in two orthotopic renal transplant recipients with US Food and Drug Administration-approved aortic stents without specific measures taken to protect the transplanted kidney. Renal function remained unchanged in both patients. Follow-up imaging studies showed successful aneurysm exclusion. Endovascular abdominal aortic aneurysm treatment in renal transplant recipients does not appear to place the transplanted kidney at undue ischemic risk and may be the preferred approach in select patients.     

Surgeon specialty and provider volumes are related to outcome of intact abdominal aortic aneurysm repair in the United States

OBJECTIVE: This study was undertaken to determine the relative importance of surgeon specialty, hospital volume, and surgeon volume on outcome after abdominal aortic aneurysm (AAA) repair. METHODS: Data were reviewed for 3912 patients undergoing AAA repair in the Nationwide Inpatient Sample during 1997. In-hospital mortality was compared between high-volume hospitals and low-volume hospitals and between high-volume surgeons and low-volume surgeons. High-volume hospitals performed more than 35 AAA repairs per year, and high-volume surgeons performed more than 10 AAA repairs per year. Vascular, cardiac, and general surgery specialization was identified by analysis of other procedures performed by each surgeon. RESULTS: Overall, AAA repair mortality was 4.2%, and was lower at high-volume hospitals (3.0%) than at low-volume hospitals (5.5%) (P <.001). Lowest mortality was associated with operations performed by vascular surgeons (2.2%) compared with cardiac surgeons (4.0%) and general surgeons (5.5%) (P <.001). Mortality rates were also lower for high-volume hospitals (2.5%) compared with low-volume hospitals (5.6%) (P <.001). In a risk-adjusted analysis, high-volume hospital, vascular surgery specialty, and high-volume surgeon were all independently associated with lower risk of in-hospital mortality. In this analysis, risk reduction was 30% for high-volume hospitals (95% confidence interval [CI], 2%-51%; P <.05) and 40% for surgery by a high-volume surgeon (95% CI, 12%-60%; P =.01). AAA repair by general surgeons compared with vascular surgeons was associated with 76% greater risk for death (95% CI, 10%-190%; P =.02). No significant difference in mortality was found between cardiac and vascular surgeons. CONCLUSIONS: High surgeon volume and hospital volume of AAA repair were both associated with lower mortality compared with low-volume providers. Increased specialization in vascular surgery was associated with markedly decreased mortality independent of AAA repair volume. Health policy in support of selective referral for AAA repair should consider surgical specialization in addition to provider volume thresholds.