IL-10/Fc inhibits macrophage function and prolongs pancreatic islet xenograft survival

BACKGROUND: Xenograft rejection is a complex response in which macrophages and other effector cells are activated by CD4+ T cells. Initiation and regulation of this response is in part mediated by cytokines. In this study we test the hypothesis that xenograft destruction is an interleukin- (IL) 10 responsive, macrophage-mediated event. METHODS: To study the effect of the systemic administration of IL-10 on pancreatic islet xenograft rejection, a fusion protein of IL-10/Fc was used. This immunoligand possesses the bioavailability of IL-10 and the long circulating t1/2 in vivo, characteristic of Ig. Wistar rat islets were transplanted into C57BL6 mice. IL-10/Fc was administered either immediately before transplantation or in the posttransplant period. RESULTS: Both therapeutic protocols prolonged xenograft survival. Macrophage effector function was reduced in IL-10/Fc-treated mice, with a reduced macrophage infiltrate, reduced IL-12 and tumor necrosis factor-alpha gene expression and reduced serum NO2- levels. Although the number of T cells infiltrating islet grafts was not reduced, T cell effector function was inhibited in IL-10/Fc-treated animals with reduced interferon-gamma and IL-4 gene expression, reduced anti-donor cytotoxicity by recipient splenocytes and reduced anti-donor IgG1 antibody production. Ultimate rejection of the xenografts appears to be mediated by a CD4+ T cell dependent mechanism probably as a result of inadequate inhibition of IL-12 production by macrophages. CONCLUSION: IL-10/Fc prolonged rat pancreatic islet xenograft survival by inhibiting macrophage mediated immune responses. The effectiveness of this agent when administered pretransplant suggests it may have a role as an induction agent with potential clinical application.     

Is surgery necessary for incidentally discovered adrenal masses in children?

Background

There are no guidelines that exist to direct the management of incidental adrenal masses (IAM) in children. The aim of this study was to determine if there is a subset of IAMs that could be safely observed.

Methods

A retrospective analysis was conducted of all adrenal masses that were either resected or biopsied between 1990 and 2002 (n = 91) at the Hospital for Sick Children, Toronto. IAM was defined as a solitary adrenal mass discovered by either physical examination (n = 6; 23.1%) or diagnostic imaging for other indications (n = 20; 76.9%), without metastases or biochemical activity.

Results

Twenty-six (28.6%) IAMs were detected (mean age, 4.6 years [range, antenatal to 17 years]; 11 boys, 15 girls). Pathologic diagnoses included neuroblastoma (n = 7), ganglioneuroma (n = 6), adrenocortical adenoma (n = 4), adrenal cyst/pseudocyst (n = 3), adrenal hemorrhage (n = 3), ganglioneuroblastoma (n = 1), nodular cortical hyperplasia (n = 1), and teratoma (n = 1). Eight masses were malignant (30.8%). Two of the 5 masses discovered on antenatal ultrasound scan were neuroblastoma. In comparing the benign with malignant lesions, there was no significant difference in mean size (4.8 cm v 4.3 cm; P = .57), radiologic characteristics, or mode of presentation. Benign lesions occurred more frequently in older children (mean age, 6.5 years v 1.3 years; P = .03).

Conclusions

Clear guidelines cannot be established to predict benign IAM in children. Given the high proportion of malignant lesions, we recommend that all pediatric IAMs should be resected.     

Torsion of the Gallbladder

Introduction  

A 77-year-old woman was seen with progressive abdominal pain.     

Biomechanical study of 4-hole pubic symphyseal plating: locked versus unlocked constructs

To the authors' knowledge, no published studies have examined the use of locking plates on injuries of the anterior pelvic ring. The purpose of this study was to determine whether locked plates provide enhanced stability in the treatment of pubic symphyseal disruptions. Completely unstable pelvic injuries were simulated in pelvic Sawbones (model 1301; Pacific Research Laboratories, Vashon, Washington) and 2 different fixation constructs used for anterior fixation (4-hole, 3.5-mm pubic symphysis plate with all locked or all unlocked screws). Adjunctive sacroiliac screw fixation with a single 7.3-mm screw placed into S1 was used in all specimens. Specimens were analyzed for motion at the pubic symphysis and sacroiliac joints using a Material Testing System (MTS Systems Corporation, Eden Prairie, Minnesota). Each specimen was subjected to compressive loading in a single-limb stance. Side loading was also examined. The main outcome measurement was motion at the pubic symphysis and sacroiliac joints and overall construct stiffness. No significant difference existed in overall construct stiffness between the 2 methods of pubic symphysis fixation. The motions at the pubic symphysis or injured sacroiliac joints were not significantly different. In addition, motion at the pubic symphysis joint with lateral load was not improved with a locking construct.No significant difference existed between 4-hole locked or unlocked constructs used for fixation of the pubic symphysis. No apparent advantage of locking screws exists for disruptions of the pubic symphysis, and recent reports have questioned the possibility of catastrophic failure.     

Anaesthetic management of an adult patient with X-linked adrenoleukodystrophy

Purpose

Adrenoleukodystrophy (ALD) is a rare genetic disorder. Findings include various central nervous system problems in addition to adrenal insufficiency. We present a case of an adult man with X-linked ALD undergoing surgery.

Clinical features

A 40-yr-old man with X-linked ALD presented with an intertrochanteric femoral fracture. Past medical history included recurrent lung atelectasis, urinary incontinence, mental retardation, seizure disorder, and adrenal insufficiency. No sedative pre-medications were ordered, but perioperative steroid coverage with 100 mg hydrocortisone was initiated. In the operating room, the patient would not allow placement of all monitors. Therefore, 1 mg midazolam then 275 mg thiopentone followed immediately by 40 mg rocuronium were used to induce anaesthesia with the application of cricoid pressure and the remaining monitors. Fentanyl 50 μgiv was given soon after induction, and anaesthesia was maintained with nitrous oxide and isoflurane. No further muscle relaxant or opioid was administered and anaesthesia was uneventful. The trachea was extubated with the patient awake and he was taken to the recovery area in stable condition.

Conclusion

Patients with X-linked ALD are rarely seen in a clinical setting because the condition is so uncommon. Adrenal insufficiency, mental retardation, and osteoporosis are major considerations for these patients. In addition, these patients are at risk for reflux, seizures, and major post-operative complications.     

Endovascular treatment of popliteal artery aneurysms: results of a prospective cohort study

OBJECTIVE: Popliteal artery aneurysms can be treated endovascularly with less perioperative morbidity compared with open repair. To evaluate suitability of the endovascular technique and the clinical results of this treatment, we analyzed a prospective cohort of consecutive popliteal aneurysms referred to a tertiary university vascular center. METHODS: All popliteal artery aneurysms between June 1998 and June 2004 that measured >20 mm in diameter were analyzed for endovascular repair. Anatomic suitability was based largely on quality of the proximal and distal landing zone as determined by angiography. Endovascular treatment was performed by using a nitinol-supported expanded polytetrafluoroethylene lined stent graft introduced through the common femoral artery. RESULTS: We analyzed 67 aneurysms in 57 patients. Ten aneurysms (15%) were excluded from endovascular repair, or from any repair at all, for various reasons. The remaining 57 (85%) were treated endovascularly, of which 5 were treated emergently for acute ischemia. During a mean 24-month follow-up, 12 stent grafts (21%) occluded. Primary and secondary patency rates were 80% and 90% at 1 year, and 77% and 87% at 2 years of follow-up. Postoperative treatment with clopidogrel proved to be the only significant predictor for success. CONCLUSIONS: Endovascular repair of a popliteal artery aneurysm is feasible. Changes in the material used and the addition of clopidogrel may improve patency rates.     

Specific uptake of 99mTc-NC100692, an αvβ3-targeted imaging probe,in subcutaneous and orthotopic tumors

IntroductionThe α_vβ₃ integrin, which is expressed by angiogenic epithelium and some tumor cells, is an attractive target for the development of both imaging agents and therapeutics. While optimal implementation of α_vβ₃-targeted therapeutics will require a priori identification of the presence of the target, the clinical evaluation of these compounds has typically not included parallel studies with α_vβ₃-targeted diagnostics. This is at least partly due to the relatively limited availability of PET radiopharmaceuticals in comparison to those labeled with ^99mTc. In an effort to begin to address this limitation, we evaluated the tumor uptake of ^99mTc-NC100692, a cyclic RGD peptide that binds to α_vβ₃ with ~ 1-nM affinity, in an α_vβ₃-positive tumor model as well as its in vivo specificity.MethodsMicroSPECT imaging was used to assess the ability of cilengitide, a therapeutic with high affinity for α_vβ₃, to block and displace ^99mTc-NC100692 in an orthotopic U87 glioma tumor. The specificity of ^99mTc-NC100692 was quantitatively evaluated in mice bearing subcutaneous U87MG tumors, by comparison of the biodistribution of ^99mTc-NC100692 with that of the non-specific structural analogue ^99mTc-AH-111744 and by blocking uptake of ^99mTc-NC100692 with excess unlabeled NC100692.ResultsMicroSPECT imaging studies demonstrated that uptake of ^99mTc-NC100692 in the intracranial tumor model was both blocked and displaced by the α_vβ₃-targeted therapeutic cilengitide. Biodistribution studies provided quantitative confirmation of these imaging results. Tumor uptake of ^99mTc-NC100692 at 1 h post-injection was 2.8 ± 0.7% ID/g compared to 0.38 ± 0.1% ID/g for ^99mTc-AH-111744 (p < 0.001). Blocking ^99mTc-NC100692 uptake by pre-injecting the mice with excess unlabeled NC100692 reduced tumor uptake by approximately five-fold, to 0.68 ± 0.3% ID/g (p = 0.01).ConclusionThese results confirm that ^99mTc-NC100692 does, in fact, target the α_vβ₃ integrin and may, therefore, be useful in identifying patients prior to anti-α_vβ₃ therapy as well as monitoring the response of these patients to therapy.     

Transcatheter closure of residual atrial septal defect after cardiac transplantation.

A 55-year-old male patient experienced 2 acute neurologic events 3 weeks after orthotopic cardiac transplantation. Transesophageal echocardiography demonstrated a patent foramen ovale in the native portion of the interatrial septum with bidirectional shunting by Doppler and microbubble contrast. The defect was closed successfully with a CardioSeal transcatheter septal closure device. This case demonstrates the advantages of the percutaneous approach for closure of residual defects in the post-operative patient.