Temporal Changes in Innate and Adaptive Immunity During Sepsis as Determined by ELISpot.

Background: The inability to evaluate host immunity in a rapid quantitative manner in patients with sepsis has severely hampered development of novel immune therapies. The ELISpot assay is a functional bioassay that measures the number of cytokine-secreting cells and the relative amount of cytokine produced at the single-cell level. A key advantage of ELISpot is its excellent dynamic range enabling a more precise quantifiable assessment of host immunity. Herein, we tested the hypothesis on whether the ELISpot assay can detect dynamic changes in both innate and adaptive immunity as they often occur during sepsis. We also tested whether ELISpot could detect the effect of immune drug therapies to modulate innate and adaptive immunity. Methods: Mice were made septic using sublethal cecal ligation and puncture (CLP). Blood and spleens were harvested serially and ex vivo IFN-γ and TNF-α production were compared by ELISpot and ELISA. The capability of ELISpot to detect changes in innate and adaptive immunity due to in vivo immune therapy with dexamethasone, IL-7, and arginine was also evaluated. Results: ELISpot confirmed a decreased innate and adaptive immunity responsiveness during sepsis progression. More importantly, ELISpot was also able to detect changes in adaptive and innate immunity in response to immune-modulatory reagents, for example dexamethasone, arginine, and IL-7 in a readily quantifiable manner, as predicted by the reagents known mechanisms of action. ELISpot and ELISA results tended to parallel one another although some differences were noted. Conclusion: ELISpot offers a unique capability to assess the functional status of both adaptive and innate immunity over time. The results presented herein demonstrate that ELISpot can also be used to detect and follow the in vivo effects of drugs to ameliorate sepsis-induced immune dysfunction. This capability would be a major advance in guiding new immune therapies in sepsis.

Children with atopic histories exhibit impaired lipopolysaccharide-induced Toll-like receptor-4 signalling in peripheral monocytes.

BACKGROUND: The hygiene hypothesis states that early exposure to bacterial products such as lipopolysaccharide (LPS) may be protective against the development of allergic diseases. Whether atopic disease affects the ability of immune cells to respond to LPS is unclear. Our laboratory has demonstrated previously that children express high levels of Toll-like receptor (TLR)-4 on CD4(+) cells in nasal mucosa. OBJECTIVE: To determine if children with a history of allergic disease have impaired responses to LPS on circulating CD4(+) leucocytes. METHODS: Peripheral blood mononuclear cells from children (aged 2-18) and adults with or without a history of atopic conditions were cultured with/without IL-4 or LPS for up to 24 h. Expression of surface TLR-4, CD14, CD4, CD3, as well as of intracellular phosphorylated (p42/p44) ERK and p38 mitogen-activated protein kinase (MAPK) were assessed by flow cytometry. RESULTS: A history of atopy in children was associated with impaired LPS-induced TLR-4-dependent phosphorylation of (p42/44) ERK and p38 MAPK by CD4(+) monocytes. Decreased LPS signalling was reproduced by pre-incubation of control cells with recombinant IL-4. LPS stimulation also decreased TLR-4 expression on monocytes from children without atopic histories but not from atopic subjects. CD4(+) T lymphocytes showed limited LPS responsiveness, regardless of atopic status. In contrast with non-atopic children, TLR-4 expression on monocytes of children with atopic histories decreased as a function of age. CONCLUSIONS: This study provides evidence for defective LPS recognition on circulating CD4(+) leucocytes of subjects with atopic histories compared with those from non-atopic children. CD4(+) TLR4(+) monocytes from children with atopic histories failed to phosphorylate MAPKs. Our results suggest that a history of atopic disease is associated with impaired TLR-4-mediated innate immune function compared with non-atopic children.

Three-dimensional color Doppler sonography before and after fibroid embolization.

Three-dimensional color Doppler sonography was performed within 1 hour, 1 day, 3 months, and 6 months of fibroid embolization in 20 patients who had a total of 31 fibroids greater than 2 cm in average dimension. The greatest decrease in vascularity occurred 1 day after the procedure, whereas the greatest volume change was found at the 3 month follow-up examination. In about one half of the patients scanned, depiction of fibroid vascularity by color Doppler sonography was found to improve the delineation of the size, location, and extent of myometrial involvement. Hypervascular fibroids (12 of 31) tended to decrease in size after treatment more than isovascular (10 of 31) or hypovascular ones (9 of 31). Additional investigations that are similar to this one will be needed to determine if three-dimensional color Doppler sonography can be used to predict those who will be responders, partial responders, or nonresponders to embolotherapy.

Transcatheter arterial chemoembolization as primary treatment for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) in Western populations has historically been associated with poor survival. METHODS: In this study, we conducted a 7-year retrospective analysis of patients with HCC undergoing transcatheter arterial chemoembolization (TACE) at our institution and examined demographics, outcomes, and complications. RESULTS: During the period of study, 39 patients (25 male [64%], mean age 58 [range 17 to 86]) underwent a total of 78 chemoembolization treatments. During the same time period, an additional 31 patients received supportive care only. The majority of patients had late stage disease (American Joint Committee on Cancer stage III, IVa, or IVb) with no statistical difference noted between the two groups (P = 0.2). However, patients receiving supportive care only had significantly worse hepatic dysfunction by Child's classification (P = 0.005). Twenty-nine patients (74%) had documented cirrhosis, with hepatitis C being the most common cause in 11 of 29 (38%). In patients undergoing TACE, overall actuarial survival was 35%, 20%, and 11% at 1, 2, and 3 years with a median survival of 9.2 months, significantly improved over the group receiving supportive care only (P < 0.0001). Median survival for the group receiving supportive care was less than 3 months. Neither age nor stage had a significant impact on survival. The most common complications of TACE included transient nausea, abdominal pain, vomiting, and fever. CONCLUSIONS: TACE is a safe and effective therapeutic option for selected patients with HCC not amenable to surgical intervention.

Use of a delayed cortical bone graft to treat diaphyseal defects in the forearm.

The technique of delayed autogenous cortical bone grafting was used in 17 patients (6 women, 11 men, with an average age of 22 years) to treat diaphyseal defects resulting mainly from closed or compound fractures complicated by infection and bone tissue loss. Bones affected were the humerus in 1 case, the radius in 7 cases, the ulna in 4 cases, the radius and ulna in 2 cases, the first metacarpal in 1 case, and the femur in 2 cases. The average length of the defect was 5.7 cm and the graft, prepared from the anteromedial aspec of the tibia, was at least 1.5 cm longer than the defect. The graft application was combined with rigid internal fixation using an AO 3.5 mm DCP plate in most cases and this permitted early active movement. Union occurred without the need for any additional grafting procedure in 14 patients and within an average of 23 weeks. In most cases there was an increase in the thickness of the graft probably as a result of osteo-induction, with consequent restoration of the original diameter of the recipient bone diaphysis. The most frequent complication was infection (4 cases), and this was controlled by means of debridement, cleaning and antibiotics. A delayed graft provides mechanical support, incorporates quickly and is therefore a reasonable alternative method for treating diaphyseal defects of long bones, particularly in the upper limb.

Hepatic artery chemoembolization for management of patients with advanced metastatic carcinoid tumors.

BACKGROUND: Patients with advanced metastatic carcinoid tumors who have disease progression despite conventional therapy are left with few therapeutic options. Hepatic artery chemoembolization (HACE) may play a role in palliating these patients' symptoms. METHODS: Fifteen patients with biopsy-proven advanced bilobar hepatic carcinoid metastases who demonstrated progression of symptoms and/or tumor size despite treatment with somatostatin analogues were treated with intra-arterial chemotherapy and HACE to determine efficacy and safety. Five days of intra-arterial 5-fluorouracil (1 g/m2) were followed by HACE with adriamycin (60 mg), cisplatin (100 mg), mitomycin C (30 mg), and polyvinyl alcohol (Ivalon); 200 micron to 710 micron). Patients were continued on octreotide at the same dose (150 to 2000 microg subcutaneous q 8 hours) before, during, and after the procedure. RESULTS: Efficacy of treatment was assessed by comparing pretreatment and 3-month clinical, laboratory, radiographic, and quality of life parameters. Symptoms were improved in 8 of 12 patients who had diarrhea, 7 of 12 who had flushing, 9 of 12 who had abdominal pain, and in 4 of 7 who had malaise. Elevated tumor markers decreased in all patients. Biochemical markers (mean +/- SE) at 3 months decreased by 60% +/- 6% for 5-HIAA, 75% +/- 10% for chromogranin A and 50% +/- 7% for neuron-specific enolase. Tomographic assessment revealed tumor liquefaction in 10 of 13 patients. The Karnofsky performance status improved from a mean of 66 +/- 2 to 84 +/- 2 (P <0.001). Median follow-up was 16 months, with 13 deaths occurring from 1 week to 71 months after treatment. CONCLUSIONS: Hepatic artery chemoembolization improves symptoms of carcinoid syndrome, has a high tumor response rate, and improves short-term quality of life in this group of patients with advanced hepatic carcinoid disease.

Positron emission tomography with F-18-fluorodeoxyglucose to evaluate the results of hepatic chemoembolization.

BACKGROUND: Positron emission tomography (PET) using F-18-flurodeoxyglucose (18FDG) is an imaging modality allowing direct evaluation of cellular glucose metabolism. The purpose of this study was to examine the role of 18FDG-PET in monitoring chemoembolization therapy of patients with liver metastases from adenocarcinoma. METHODS: Thirty-four hepatic lesions in 4 patients were evaluated with 18FDG-PET before and 2-3 months after interventional therapy. All patients underwent transcatheter arterial chemoembolization. A total of nine PET studies were performed. Semiquantitative measurement of the metabolic activity of the lesions was performed using the standard uptake value (SUV) of 18FDG. Comparison was performed between sequential PET scans using Student's t test for paired data analysis. The PET findings were also compared with tumor marker levels measured at the time of the PET scans. RESULTS: Twenty-five of 34 lesions had decreased 18FDG uptake (SUV = 8 +/- 2 vs. 3 +/- 1; P < 0.00001), as expected in successful tumor chemoembolization. These findings were associated with a significant decrease in serum tumor marker levels (86 +/- 4%; P < 0.05) after treatment. However, there were 3 new lesions, and 6 of the 34 lesions demonstrated persistent or increased 18FDG uptake after treatment (SUV = 8 +/- 2 vs. 13 +/- 3; P < 0.05), consistent with the presence of residual viable tumor. These findings led to further interventional therapy in all patients. CONCLUSIONS: 18FDG-PET allows monitoring of response to treatment with hepatic chemoembolization in patients with liver metastases from adenocarcinoma. PET is a useful diagnostic tool and has the potential to be used to guide further interventional therapy.

The use of inferior vena cava filters in pediatric patients for pulmonary embolus prophylaxis.

PURPOSE: To report our experience with inferior vena cava (IVC) filters in pediatric patients. METHODS: Over a 19-month period, eight low-profile percutaneously introducible IVC filters were placed in four male and four female patients aged 6-16 years (mean 11 years). Indications were contraindication to heparin in six patients, anticoagulation failure in one, and idiopathic infrarenal IVC thrombosis in one. Six of the eight devices placed were titanium Greenfield filters. One LGM and one Bird's Nest filter were also placed. Two of the filters were introduced via the right internal jugular vein by cutdown, and the remainder were placed percutaneously via the right internal jugular vein or the right common femoral vein. Patients received follow-up abdominal radiographs from 2 to 13 months after IVC filter placement. RESULTS: All filters were inserted successfully without complication. Three of the patients died during the follow-up period: two due to underlying brain tumors at 2 and 12 months and a third at 6 weeks due to progressive idiopathic renal vein and IVC thrombosis. The remaining five patients were all alive and well at follow-up without evidence of IVC thrombosis, pulmonary emboli, or filter migration. CONCLUSION: IVC filter placement using available devices for percutaneous delivery is technically feasible, safe, and effective in children.

Sonography of transjugular intrahepatic portosystemic shunts.

Transjugular intrahepatic portosystemic shunting (TIPS) is an effective procedure for relieving portal hypertension. Sonography can usefully assist portal vein puncture. Color and duplex sonography after TIPS demonstrates changes in hepatic vascular hemodynamics, detects complications, and confirms shunt patency. A large proportion of shunts will develop progressive stenosis over 12 months. Stenosis occurs because of pseudointimal hyperplasia in the stent or in the hepatic vein. Patent shunts are characterized by velocities in excess of 70 cm/s and hepatofugal flow in the portal circulation distal to the shunt. Although the cause of the stenosis can rarely be seen, velocities of less than 50 cm/s indicate shunt stenosis. Loss of cardiac pulsatility is another useful sign of shunt stenosis. Regular sonographic monitoring reliably detects stenosis, allowing stent revision and preventing recurrence of bleeding.

Incidence of shunt occlusion or stenosis following transjugular intrahepatic portosystemic shunt placement.

BACKGROUND/AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) placement has been used for the treatment of recurrent variceal hemorrhage. The 1-year incidence of shunt stenosis or occlusion after TIPS placement was prospectively assessed, and the accuracy of Doppler ultrasonography to predict TIPS stenosis was evaluated. METHODS: Twenty-two patients with recurrent variceal hemorrhage were selected for TIPS placement between April 1991 and May 1992. Preoperative and postoperative evaluation included clinical assessment, upper gastrointestinal endoscopy, portal angiography with pressure measurements, and Doppler ultrasonography. Follow-up was performed at 3 and 12 months post-TIPS and when patients developed recurrent bleeding. RESULTS: Twenty-one of 22 patients (Child-Pugh class A-1, B-11, C-9) had successful TIPS placement. Seventeen of 21 patients have completed follow-up for at least 12 months. Of these 17 patients, 2 of 17 (12%) developed TIPS occlusion, 7 of 17 (41%) developed shunt stenosis, and 8 of 17 (47%) showed no stenosis on follow-up angiography. Doppler ultrasonographic assessment of the TIPS predicted shunt stenosis or occlusion with 100% sensitivity, 98% specificity, and 90% positive predictive value. CONCLUSIONS: Shunt occlusion or stenosis develops frequently within 12 months after TIPS placement, and Doppler ultrasonography is accurate in the noninvasive assessment of shunt stenosis. TIPS placement without careful follow-up and shunt revision cannot be considered a long-term treatment of variceal hemorrhage.

Transjugular intrahepatic portosystemic shunt: US assessment with maximum flow velocity.

PURPOSE: To evaluate the ability of Doppler ultrasonography (US) to depict the patency of a transjugular intrahepatic portosystemic shunt (TIPS). MATERIALS AND METHODS: Twenty-eight patients were followed up after creation of TIPS with US, angiography, and endoscopy performed at regular intervals. Magnetic resonance (MR) angiography was performed in four patients. US was performed first, and the results were correlated with those at angiography. Measurements of maximum flow velocity (Vmax) were taken from the proximal part of the shunt. RESULTS: In normal shunts, mean Vmax was 95 cm/sec. Shunt obstruction was seen in 12 cases: occlusion in four and stenosis in eight. All cases of occlusion were detected with US and appeared as absent flow within the shunt. There was one false-positive diagnosis of occlusion. All cases of stenosis resulted in reduced Vmax (mean, 32 cm/sec; P < .001). After successful revision in seven patients, Vmax rose to a mean of 122 cm/sec. Artifact from the metal stent prevented flow assessment with MR imaging. CONCLUSION: US can be performed to evaluate shunt status, and Vmax is an accurate noninvasive parameter for assessing shunt patency.

Hydrostatic pulmonary edema in sheep. Effects of bronchial artery embolization on the plain chest radiograph.

RATIONALE AND OBJECTIVES: The bronchial circulation may influence pulmonary edema. This study evaluates possible effects of bronchoesophageal artery embolization on the plain film manifestations of hydrostatic pulmonary edema in sheep. METHODS: Anteroposterior and lateral chest radiographs were obtained during the induction of pulmonary edema both before and after embolization of the bronchoesophageal artery in six adult sheep. Interstitial lines and perivascular, segmental bronchial, proximal bronchial, carinal, tracheal, and parenchymal edema were evaluated. RESULTS: Only parenchymal edema was graded consistently. Though edema increased with left atrial pressure before embolization (P < .001), there was no similar change afterward. The embolized animals tended to be more edematous by the first film. CONCLUSION: Rather than any protective effect, bronchoesophageal artery embolization may increase edema. This model may be inappropriate for further investigation of the bronchial circulation in the development of human pulmonary edema.

Obstruction of the inferior vena cava: a multiple-modality demonstration of causes, manifestations, and collateral pathways.

This article explores the causes and manifestations of obstruction of the inferior vena cava (IVC) with a multiple-modality approach. Caval obstruction may be due to thrombus, extension of a tumor, extrinsic compression, or intrinsic caval disease. Evaluation of the IVC should be tailored to the individual circumstance; no single modality is best in all situations. Although magnetic resonance offers multiplanar imaging, vena cavography or ultrasound are often necessary to exclude intraluminal tumor extension. Computed tomography is sensitive for intracaval thrombus and compression but does not delineate the hepatic IVC well. Nuclear venography demonstrates well the resultant collateral pathways, which can be separated into the deep, intermediate, superficial, and portal systems. Despite the clear visualization of these pathways with this modality, congenital caval anomalies, such as caval interruption with azygos continuation, can be confused with acquired caval disease.

Practical aspects of gated magnetic resonance imaging of the pulmonary artery.

A practical clinical evaluation of the role of gated magnetic resonance imaging (GMRI) for the evaluation of congenital and acquired diseases of the pulmonary artery is presented, comparing GMRI to the already established usefulness of other various noninvasive and invasive imaging modalities.

Gadolinium-DTPA enhanced MR imaging of intravenous extension of adrenocortical carcinoma.

A case of magnetic resonance imaging of adrenocortical carcinoma extending into the inferior vena cava is presented. Magnetic resonance was able to outline the intraluminal extent of tumor thrombus accurately. Signal intensity ratios (mean 0.98 +/- 0.02) of tumor thrombus/primary tumor on T1- and T2-weighted sequences were useful for tissue characterization of tumor thrombus. Time course of the signal intensity of thrombus before and after intravenous administration of 0.1 mmol/kg gadolinium-diethylenetriamine pentaacetic acid was identical to the primary tumor which aided in differentiation from nontumor thrombus.

Detection of caval obstruction by magnetic resonance imaging after intraatrial repair of transposition of the great arteries.

Vena caval obstruction may cause significant morbidity after intraatrial repair of transposition of the great arteries (TGA). Two noninvasive methods of diagnosing vena caval obstruction were compared with cardiac catheterization. Echocardiographically gated magnetic resonance imaging (MRI) and echocardiographic evaluation (2-dimensional saline contrast echocardiography and pulsed Doppler flow measurement) were performed on 15 patients 0.7 to 13.5 years after intraatrial repair of TGA (8 Mustard, 7 Senning). At catheterization, complete superior vena cava or partial caval obstruction (gradient greater than 5 mm Hg from cava to systemic venous atrium) was present in 7 of 15 patients. Superior vena cava obstruction was directly visualized by MRI in both patients with catheterization-proved complete superior vena cava occlusion. A dilated azygous/hemiazygous venous complex (greater than or equal to 5 mm cross-sectional diameter) was seen by MRI in 5 of 7 patients with complex or partial vena caval obstruction and in no patient without vena caval obstruction. MRI showed superior vena caval dilatation (ratio of superior vena caval diameter to aortic diameter greater than 1.45) in 3 of 5 patients with partial vena caval obstruction and in 0 of 8 without vena caval obstruction. Direct visualization of narrowing within the atrium was unreliable for any MRI plane because of the 3-dimensional nature of the intraatrial baffle. Two-dimensional saline contrast echocardiography, successfully performed in 12 of 15 patients, detected complete superior vena caval obstruction only in the 2 patients with catheterization-proved complete superior vena cava occlusion. Contrast echocardiography failed to identify any of the 5 patients with partial vena caval obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)